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Novel immunostimulant combo shows early efficacy
SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.
Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.
“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.
NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.
The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.
In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.
The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.
The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.
The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.
Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.
Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.
Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.
The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.
The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.
The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.
The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.
SOURCE: Diab A et al. ASCO-SITC, Abstract 26.
SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.
Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.
“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.
NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.
The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.
In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.
The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.
The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.
The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.
Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.
Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.
Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.
The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.
The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.
The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.
The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.
SOURCE: Diab A et al. ASCO-SITC, Abstract 26.
SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.
Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.
“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.
NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.
The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.
In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.
The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.
The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.
The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.
Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.
Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.
Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.
The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.
The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.
The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.
The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.
SOURCE: Diab A et al. ASCO-SITC, Abstract 26.
REPORTING FROM ASCO-SITC
Checkpoint inhibitors ‘viable treatment option’ in HIV-infected individuals
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
FROM JAMA ONCOLOGY
Key clinical point: Immune checkpoint inhibitors are a viable treatment option for HIV-infected patients, according to data supporting their safety and efficacy in this patient population.
Major finding: The treatment was well tolerated, with an 8.6% rate of grade 3 or greater immune-related adverse events, and no impact on HIV-related parameters.
Study details: A systematic review of 73 patients with HIV infection who had received treatment with a checkpoint inhibitor.
Disclosures: The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. One study author reported disclosures related to CARIS Life Science and AstraZeneca.
Source: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Cardiac failure due to left atrial angiosarcoma
Sorafenib extends PFS for refractory desmoid tumors
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: There is no accepted standard of systemic therapy for recurrent, refractory, or symptomatic desmoid tumors.
Major finding: Median progression-free survival with sorafenib after a median follow-up of 27.2 months was 81% versus 36% for placebo.
Study details: A double-blind, phase 3 trial with 2:1 randomization of sorafenib to placebo in 87 patients.
Disclosures: The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
Source: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
Cardiac failure due to left atrial angiosarcoma
Abstract
Primary heart sarcomas are rare and represent 20% of all primary cardiac tumors. Symptoms depend on which chambers and cardiac structures are involved. Angiosarcoma is one of the most common and the most aggressive types of primary heart sarcomas. Typically, these tumors are found in the right atrium, however, cardiac angiosarcomas may involve any part of the heart. Most of these tumors are diagnosed in advanced stages and the patient prognosis is poor. Most tumors are diagnosed using echocardiography. Computed tomography (CT) and magnetic resonance imaging (MRI) provide useful information on tumor size and location for planning surgery, which is the only treatment shown to increase survival. We present the case of a 69-year-old woman who presented to the emergency department with hypotension, dyspnea and progressive shortness of breath. After adequate resuscitation, a cardiac mass was identified and surgery was successfully performed. Pathology confirmed a grade 2 primary heart angiosarcoma. Following surgery, the patient was admitted to the intensive care unit and later died secondary to multi-organ system failure.
Introduction
Primary heart angiosarcoma is an aggressive and usually fatal cardiac neoplasm (1). Angiosarcomas can originate at any location in the heart (2, 3), but these tumors typically reside in the right atrium and frequently cause nonspecific symptoms such as dyspnea, cough, heart failure, and arrhythmias. (2) Surgery followed by chemotherapy is the typical approach to these tumors. (4)
We present the case of a 69-year-old woman who presented to the emergency department with hypotension and severe dyspnea.
Case Report
The patient was a 69-year-old woman with a medical history of diabetes. A week before seeking care in the emergency department, she experienced a general feeling of unwellness, dyspnea, and mild respiratory distress. She reported these symptoms had become more and more severe in the last 24 hours and were accompanied by acute chest pain and progressive shortness of breath.
On clinical examination, the patient was hypotensive, had tachypnea and tachycardia, and was hypoxic. Cardiac auscultation detected a systolic murmur in the apex, and auscultation of the lungs revealed crackles and rales, especially at the bases of the lungs. The remainder of her clinical examination was unremarkable. She had sinus tachycardia on an electrocardiogram. A chest X-ray showed a left atrial enlargement along with some patchy opacities in the middle and lower zones of the lungs, along with Kerley B lines suggestive of pulmonary edema.
With these findings, and after adequate resuscitation, a contrast-enhanced computed tomography (CT) scan detected a filling defect in the left atrium suggestive of a large intra-cardiac mass with a thick and hyper-enhanced interatrial septum. Bilateral pleural effusions also were evident, (Figure 1A) hence an echocardiogram was requested and it confirmed the presence of a 30 x 29 x 40 mm lobulated highly mobile mass in the left atrium. 
After a cardiothoracic consultation, cardiac magnetic resonance imaging (MRI) was performed. The findings showed the presence of a 58 x 45 x 6 mm well-circumscribed hyperemic mass on the anterior leaflet of the mitral valve and a second 10 x 10 x 6 mm smaller mass firmly adhered to the posterior leaflet of the mitral valve. 
The patient, who was hypotensive and hypoxic, was admitted to the hospital for surgical treatment.
Following sternotomy and cardiopulmonary bypass, a right atriotomy was performed using a trans-septal approach. The large left atrial mass was firmly adhered to the endocardium at the level of the anterior leaflet of the mitral valve and the interatrial septum. The mass had a grey and whitish appearance with some bluish necrotic patches, (Figure 1B, 2B, 3B). 
The patient had a complicated postoperative course in the Intensive Care Unit (ICU) and needed inotropic support and vasoactive agents. A postop echocardiogram indicated appropriate left ventricle systolic function, nonetheless, the patient persisted in a hypotensive status that caused refractory shock and ultimately provoked severe organ dysfunction that led to the patient’s death.
Discussion
Primary heart sarcomas are extremely rare malignant neoplasms derived from mesenchymal cells, (1) with an incidence ranging from 0.001% to 0.28% at autopsy. 
Cardiac angiosarcomas (CA) account for one-third of all primary heart sarcomas (4) and usually develop as gray-brown masses with hemorrhagic patches in the right atrium of male patients. The tumors are filled with vascular channels and their cells are positive for CD34 and factor VIII. (5) Left-sided cardiac angiosarcoma can cause heart failure early in the disease process, but the tumors tend to be more circumscribed, less infiltrative, and associated with better overall survival. (6, 7) Most patients are asymptomatic early in their disease, (2) making the diagnosis even more difficult and worsening its already poor prognosis. (1) The preference of cardiac angiosarcomas for the right heart often leads to a presentation with right-sided congestive heart failure. (2) At later stages, symptoms depend on the structures compromised and range from mild dyspnea on exertion to cardiogenic shock. (8) Cardiac angiosarcomas tend to have a notable intracavitary element, and in some cases may intermittently compromise a cardiac valve, thereby simulating a stenosis or regurgitation. (2, 7)
Our patient presented with acute cardiac failure, pulmonary edema and severe valve dysfunction due to a mass in the left atrium. The tumor had a vascular supply and showed positivity for CD34.
Most patients with cardiac angiosarcoma have metastases, typically to the lung, at diagnosis. (1) Several decades ago, cardiac angiosarcoma was mainly diagnosed postmortem. (1) Now, it can be suspected when cardiomegaly or pleural effusions are seen on chest x-rays (8). Echocardiography is the most useful diagnostic tool, (2) however, CT and MRI can provide useful information on tumor size, invasion and localization. (2, 9) This imaging combination generally provides an excellent anatomic description for preoperative planning. (1, 9)
In our patient, progressive dyspnea was the main symptom and after a prompt evaluation an intracardiac mass was identified as the cause of severe cardiac dysfunction. Because of this finding and the clinical condition of the patient, surgery was planned.
Complete resection of the tumor is the treatment of choice, and is the only therapy currently seen to influence survival. (8) But because of the highly aggressive behavior and a high incidence of systemic metastases with cardiac angiosarcomas, a complete surgical resection is often hampered. (1) Cardiac angiosarcoma carries a grim prognosis as these tumors are universally fatal with a mean survival time of several months after initial presentation even after successful surgery. (2) Chemotherapy is recommended after surgery, even when clear surgical margins are obtained because of the high probability of missed microscopic disease. (1, 2)
High clinical suspicion together with an appropriate history, a thorough physical examination, and precise complementary tests are vital for timely diagnosis and proper treatment.
Authors and Affiliations
Santiago A. Endara: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Gerardo A. Dávalos: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Patricia M. Pontón: Hospital Metropolitano, Quito, Ecuador. Department of Internal Medicine Division of Pathology, MD
Gabriel A. Molina: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY4 General Surgery Resident, MD
Daniel L. Mogrovejo: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY1 General Surgery Resident, MD
Corresponding Author Info:
Santiago A. Endara, Hospital Metropolitano, Av. Mariana de Jesus Oe 7/47 y Conclina, Edificio Diagnostico 2000 tercer piso 3/3, Quito, Ecuador, + 593 9 98416157
Email: [email protected]
1. Orlandi A, Ferlosio A, Roselli M, Chiariello L, Spagnoli L. Cardiac Sarcomas: An Update. Journal of Thoracic Oncology. 2010;5(9):1483-1489.
2. Brandt R, Arnold R, Bohle R, Dill T, Hamm C. Cardiac angiosarcoma: case report and review of the literature. Zeitschrift für Kardiologie. 2005;94(12):824-828.
3. Kurian K, Weisshaar D, Parekh H, Berry G, Reitz B. Primary cardiac angiosarcoma: case report and review of the literature. Cardiovascular Pathology. 2006;15(2):110-112.
4. Habibi R, Faramarzi N, Altamirano A, Dadkhah S. A Patient Presenting with Cardiac Tamponade and the Challenges of Finding Its Cause: A Cardiac Angiosarcoma. Case Reports in Cardiology. 2018;2018:1-3.
5. Leduc C, Jenkins S, Sukov W, Rustin J, Maleszewski J. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases. Human Pathology. 2017;60:199-207.
6. Ramlawi B, Leja M, Abu Saleh W, Al Jabbari O, Benjamin R, Ravi V et al. Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience. The Annals of Thoracic Surgery. 2016;101(2):698-702.
7.Engelen M. Primary left atrial angiosarcoma mimicking severe mitral valve stenosis. Heart. 2005;91(4):e27-e27.
8. Chenier M, Johnson D, Ohman M, Pavlisko E. Cardiac angiosarcoma presenting as progressive dyspnea on exertion. Journal of Cardiovascular Medicine. 2011;12(12):904-907.
9. Lindsey J, Stacey R. Cardiac magnetic resonance in cardiac angiosarcoma. Echocardiography. 2017;34(7):1077-1081.
Abstract
Primary heart sarcomas are rare and represent 20% of all primary cardiac tumors. Symptoms depend on which chambers and cardiac structures are involved. Angiosarcoma is one of the most common and the most aggressive types of primary heart sarcomas. Typically, these tumors are found in the right atrium, however, cardiac angiosarcomas may involve any part of the heart. Most of these tumors are diagnosed in advanced stages and the patient prognosis is poor. Most tumors are diagnosed using echocardiography. Computed tomography (CT) and magnetic resonance imaging (MRI) provide useful information on tumor size and location for planning surgery, which is the only treatment shown to increase survival. We present the case of a 69-year-old woman who presented to the emergency department with hypotension, dyspnea and progressive shortness of breath. After adequate resuscitation, a cardiac mass was identified and surgery was successfully performed. Pathology confirmed a grade 2 primary heart angiosarcoma. Following surgery, the patient was admitted to the intensive care unit and later died secondary to multi-organ system failure.
Introduction
Primary heart angiosarcoma is an aggressive and usually fatal cardiac neoplasm (1). Angiosarcomas can originate at any location in the heart (2, 3), but these tumors typically reside in the right atrium and frequently cause nonspecific symptoms such as dyspnea, cough, heart failure, and arrhythmias. (2) Surgery followed by chemotherapy is the typical approach to these tumors. (4)
We present the case of a 69-year-old woman who presented to the emergency department with hypotension and severe dyspnea.
Case Report
The patient was a 69-year-old woman with a medical history of diabetes. A week before seeking care in the emergency department, she experienced a general feeling of unwellness, dyspnea, and mild respiratory distress. She reported these symptoms had become more and more severe in the last 24 hours and were accompanied by acute chest pain and progressive shortness of breath.
On clinical examination, the patient was hypotensive, had tachypnea and tachycardia, and was hypoxic. Cardiac auscultation detected a systolic murmur in the apex, and auscultation of the lungs revealed crackles and rales, especially at the bases of the lungs. The remainder of her clinical examination was unremarkable. She had sinus tachycardia on an electrocardiogram. A chest X-ray showed a left atrial enlargement along with some patchy opacities in the middle and lower zones of the lungs, along with Kerley B lines suggestive of pulmonary edema.
With these findings, and after adequate resuscitation, a contrast-enhanced computed tomography (CT) scan detected a filling defect in the left atrium suggestive of a large intra-cardiac mass with a thick and hyper-enhanced interatrial septum. Bilateral pleural effusions also were evident, (Figure 1A) hence an echocardiogram was requested and it confirmed the presence of a 30 x 29 x 40 mm lobulated highly mobile mass in the left atrium.
After a cardiothoracic consultation, cardiac magnetic resonance imaging (MRI) was performed. The findings showed the presence of a 58 x 45 x 6 mm well-circumscribed hyperemic mass on the anterior leaflet of the mitral valve and a second 10 x 10 x 6 mm smaller mass firmly adhered to the posterior leaflet of the mitral valve.
The patient, who was hypotensive and hypoxic, was admitted to the hospital for surgical treatment.
Following sternotomy and cardiopulmonary bypass, a right atriotomy was performed using a trans-septal approach. The large left atrial mass was firmly adhered to the endocardium at the level of the anterior leaflet of the mitral valve and the interatrial septum. The mass had a grey and whitish appearance with some bluish necrotic patches, (Figure 1B, 2B, 3B).
The patient had a complicated postoperative course in the Intensive Care Unit (ICU) and needed inotropic support and vasoactive agents. A postop echocardiogram indicated appropriate left ventricle systolic function, nonetheless, the patient persisted in a hypotensive status that caused refractory shock and ultimately provoked severe organ dysfunction that led to the patient’s death.
Discussion
Primary heart sarcomas are extremely rare malignant neoplasms derived from mesenchymal cells, (1) with an incidence ranging from 0.001% to 0.28% at autopsy.
Cardiac angiosarcomas (CA) account for one-third of all primary heart sarcomas (4) and usually develop as gray-brown masses with hemorrhagic patches in the right atrium of male patients. The tumors are filled with vascular channels and their cells are positive for CD34 and factor VIII. (5) Left-sided cardiac angiosarcoma can cause heart failure early in the disease process, but the tumors tend to be more circumscribed, less infiltrative, and associated with better overall survival. (6, 7) Most patients are asymptomatic early in their disease, (2) making the diagnosis even more difficult and worsening its already poor prognosis. (1) The preference of cardiac angiosarcomas for the right heart often leads to a presentation with right-sided congestive heart failure. (2) At later stages, symptoms depend on the structures compromised and range from mild dyspnea on exertion to cardiogenic shock. (8) Cardiac angiosarcomas tend to have a notable intracavitary element, and in some cases may intermittently compromise a cardiac valve, thereby simulating a stenosis or regurgitation. (2, 7)
Our patient presented with acute cardiac failure, pulmonary edema and severe valve dysfunction due to a mass in the left atrium. The tumor had a vascular supply and showed positivity for CD34.
Most patients with cardiac angiosarcoma have metastases, typically to the lung, at diagnosis. (1) Several decades ago, cardiac angiosarcoma was mainly diagnosed postmortem. (1) Now, it can be suspected when cardiomegaly or pleural effusions are seen on chest x-rays (8). Echocardiography is the most useful diagnostic tool, (2) however, CT and MRI can provide useful information on tumor size, invasion and localization. (2, 9) This imaging combination generally provides an excellent anatomic description for preoperative planning. (1, 9)
In our patient, progressive dyspnea was the main symptom and after a prompt evaluation an intracardiac mass was identified as the cause of severe cardiac dysfunction. Because of this finding and the clinical condition of the patient, surgery was planned.
Complete resection of the tumor is the treatment of choice, and is the only therapy currently seen to influence survival. (8) But because of the highly aggressive behavior and a high incidence of systemic metastases with cardiac angiosarcomas, a complete surgical resection is often hampered. (1) Cardiac angiosarcoma carries a grim prognosis as these tumors are universally fatal with a mean survival time of several months after initial presentation even after successful surgery. (2) Chemotherapy is recommended after surgery, even when clear surgical margins are obtained because of the high probability of missed microscopic disease. (1, 2)
High clinical suspicion together with an appropriate history, a thorough physical examination, and precise complementary tests are vital for timely diagnosis and proper treatment.
Authors and Affiliations
Santiago A. Endara: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Gerardo A. Dávalos: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Patricia M. Pontón: Hospital Metropolitano, Quito, Ecuador. Department of Internal Medicine Division of Pathology, MD
Gabriel A. Molina: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY4 General Surgery Resident, MD
Daniel L. Mogrovejo: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY1 General Surgery Resident, MD
Corresponding Author Info:
Santiago A. Endara, Hospital Metropolitano, Av. Mariana de Jesus Oe 7/47 y Conclina, Edificio Diagnostico 2000 tercer piso 3/3, Quito, Ecuador, + 593 9 98416157
Email: [email protected]
Abstract
Primary heart sarcomas are rare and represent 20% of all primary cardiac tumors. Symptoms depend on which chambers and cardiac structures are involved. Angiosarcoma is one of the most common and the most aggressive types of primary heart sarcomas. Typically, these tumors are found in the right atrium, however, cardiac angiosarcomas may involve any part of the heart. Most of these tumors are diagnosed in advanced stages and the patient prognosis is poor. Most tumors are diagnosed using echocardiography. Computed tomography (CT) and magnetic resonance imaging (MRI) provide useful information on tumor size and location for planning surgery, which is the only treatment shown to increase survival. We present the case of a 69-year-old woman who presented to the emergency department with hypotension, dyspnea and progressive shortness of breath. After adequate resuscitation, a cardiac mass was identified and surgery was successfully performed. Pathology confirmed a grade 2 primary heart angiosarcoma. Following surgery, the patient was admitted to the intensive care unit and later died secondary to multi-organ system failure.
Introduction
Primary heart angiosarcoma is an aggressive and usually fatal cardiac neoplasm (1). Angiosarcomas can originate at any location in the heart (2, 3), but these tumors typically reside in the right atrium and frequently cause nonspecific symptoms such as dyspnea, cough, heart failure, and arrhythmias. (2) Surgery followed by chemotherapy is the typical approach to these tumors. (4)
We present the case of a 69-year-old woman who presented to the emergency department with hypotension and severe dyspnea.
Case Report
The patient was a 69-year-old woman with a medical history of diabetes. A week before seeking care in the emergency department, she experienced a general feeling of unwellness, dyspnea, and mild respiratory distress. She reported these symptoms had become more and more severe in the last 24 hours and were accompanied by acute chest pain and progressive shortness of breath.
On clinical examination, the patient was hypotensive, had tachypnea and tachycardia, and was hypoxic. Cardiac auscultation detected a systolic murmur in the apex, and auscultation of the lungs revealed crackles and rales, especially at the bases of the lungs. The remainder of her clinical examination was unremarkable. She had sinus tachycardia on an electrocardiogram. A chest X-ray showed a left atrial enlargement along with some patchy opacities in the middle and lower zones of the lungs, along with Kerley B lines suggestive of pulmonary edema.
With these findings, and after adequate resuscitation, a contrast-enhanced computed tomography (CT) scan detected a filling defect in the left atrium suggestive of a large intra-cardiac mass with a thick and hyper-enhanced interatrial septum. Bilateral pleural effusions also were evident, (Figure 1A) hence an echocardiogram was requested and it confirmed the presence of a 30 x 29 x 40 mm lobulated highly mobile mass in the left atrium.
After a cardiothoracic consultation, cardiac magnetic resonance imaging (MRI) was performed. The findings showed the presence of a 58 x 45 x 6 mm well-circumscribed hyperemic mass on the anterior leaflet of the mitral valve and a second 10 x 10 x 6 mm smaller mass firmly adhered to the posterior leaflet of the mitral valve.
The patient, who was hypotensive and hypoxic, was admitted to the hospital for surgical treatment.
Following sternotomy and cardiopulmonary bypass, a right atriotomy was performed using a trans-septal approach. The large left atrial mass was firmly adhered to the endocardium at the level of the anterior leaflet of the mitral valve and the interatrial septum. The mass had a grey and whitish appearance with some bluish necrotic patches, (Figure 1B, 2B, 3B).
The patient had a complicated postoperative course in the Intensive Care Unit (ICU) and needed inotropic support and vasoactive agents. A postop echocardiogram indicated appropriate left ventricle systolic function, nonetheless, the patient persisted in a hypotensive status that caused refractory shock and ultimately provoked severe organ dysfunction that led to the patient’s death.
Discussion
Primary heart sarcomas are extremely rare malignant neoplasms derived from mesenchymal cells, (1) with an incidence ranging from 0.001% to 0.28% at autopsy.
Cardiac angiosarcomas (CA) account for one-third of all primary heart sarcomas (4) and usually develop as gray-brown masses with hemorrhagic patches in the right atrium of male patients. The tumors are filled with vascular channels and their cells are positive for CD34 and factor VIII. (5) Left-sided cardiac angiosarcoma can cause heart failure early in the disease process, but the tumors tend to be more circumscribed, less infiltrative, and associated with better overall survival. (6, 7) Most patients are asymptomatic early in their disease, (2) making the diagnosis even more difficult and worsening its already poor prognosis. (1) The preference of cardiac angiosarcomas for the right heart often leads to a presentation with right-sided congestive heart failure. (2) At later stages, symptoms depend on the structures compromised and range from mild dyspnea on exertion to cardiogenic shock. (8) Cardiac angiosarcomas tend to have a notable intracavitary element, and in some cases may intermittently compromise a cardiac valve, thereby simulating a stenosis or regurgitation. (2, 7)
Our patient presented with acute cardiac failure, pulmonary edema and severe valve dysfunction due to a mass in the left atrium. The tumor had a vascular supply and showed positivity for CD34.
Most patients with cardiac angiosarcoma have metastases, typically to the lung, at diagnosis. (1) Several decades ago, cardiac angiosarcoma was mainly diagnosed postmortem. (1) Now, it can be suspected when cardiomegaly or pleural effusions are seen on chest x-rays (8). Echocardiography is the most useful diagnostic tool, (2) however, CT and MRI can provide useful information on tumor size, invasion and localization. (2, 9) This imaging combination generally provides an excellent anatomic description for preoperative planning. (1, 9)
In our patient, progressive dyspnea was the main symptom and after a prompt evaluation an intracardiac mass was identified as the cause of severe cardiac dysfunction. Because of this finding and the clinical condition of the patient, surgery was planned.
Complete resection of the tumor is the treatment of choice, and is the only therapy currently seen to influence survival. (8) But because of the highly aggressive behavior and a high incidence of systemic metastases with cardiac angiosarcomas, a complete surgical resection is often hampered. (1) Cardiac angiosarcoma carries a grim prognosis as these tumors are universally fatal with a mean survival time of several months after initial presentation even after successful surgery. (2) Chemotherapy is recommended after surgery, even when clear surgical margins are obtained because of the high probability of missed microscopic disease. (1, 2)
High clinical suspicion together with an appropriate history, a thorough physical examination, and precise complementary tests are vital for timely diagnosis and proper treatment.
Authors and Affiliations
Santiago A. Endara: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Gerardo A. Dávalos: Department of General Surgery, Division of Cardiothoracic Surgery, Hospital Metropolitano, Quito, Ecuador, MD
Patricia M. Pontón: Hospital Metropolitano, Quito, Ecuador. Department of Internal Medicine Division of Pathology, MD
Gabriel A. Molina: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY4 General Surgery Resident, MD
Daniel L. Mogrovejo: Pontificia Universidad Católica del Ecuador (PUCE), Quito, Ecuador. PGY1 General Surgery Resident, MD
Corresponding Author Info:
Santiago A. Endara, Hospital Metropolitano, Av. Mariana de Jesus Oe 7/47 y Conclina, Edificio Diagnostico 2000 tercer piso 3/3, Quito, Ecuador, + 593 9 98416157
Email: [email protected]
1. Orlandi A, Ferlosio A, Roselli M, Chiariello L, Spagnoli L. Cardiac Sarcomas: An Update. Journal of Thoracic Oncology. 2010;5(9):1483-1489.
2. Brandt R, Arnold R, Bohle R, Dill T, Hamm C. Cardiac angiosarcoma: case report and review of the literature. Zeitschrift für Kardiologie. 2005;94(12):824-828.
3. Kurian K, Weisshaar D, Parekh H, Berry G, Reitz B. Primary cardiac angiosarcoma: case report and review of the literature. Cardiovascular Pathology. 2006;15(2):110-112.
4. Habibi R, Faramarzi N, Altamirano A, Dadkhah S. A Patient Presenting with Cardiac Tamponade and the Challenges of Finding Its Cause: A Cardiac Angiosarcoma. Case Reports in Cardiology. 2018;2018:1-3.
5. Leduc C, Jenkins S, Sukov W, Rustin J, Maleszewski J. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases. Human Pathology. 2017;60:199-207.
6. Ramlawi B, Leja M, Abu Saleh W, Al Jabbari O, Benjamin R, Ravi V et al. Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience. The Annals of Thoracic Surgery. 2016;101(2):698-702.
7.Engelen M. Primary left atrial angiosarcoma mimicking severe mitral valve stenosis. Heart. 2005;91(4):e27-e27.
8. Chenier M, Johnson D, Ohman M, Pavlisko E. Cardiac angiosarcoma presenting as progressive dyspnea on exertion. Journal of Cardiovascular Medicine. 2011;12(12):904-907.
9. Lindsey J, Stacey R. Cardiac magnetic resonance in cardiac angiosarcoma. Echocardiography. 2017;34(7):1077-1081.
1. Orlandi A, Ferlosio A, Roselli M, Chiariello L, Spagnoli L. Cardiac Sarcomas: An Update. Journal of Thoracic Oncology. 2010;5(9):1483-1489.
2. Brandt R, Arnold R, Bohle R, Dill T, Hamm C. Cardiac angiosarcoma: case report and review of the literature. Zeitschrift für Kardiologie. 2005;94(12):824-828.
3. Kurian K, Weisshaar D, Parekh H, Berry G, Reitz B. Primary cardiac angiosarcoma: case report and review of the literature. Cardiovascular Pathology. 2006;15(2):110-112.
4. Habibi R, Faramarzi N, Altamirano A, Dadkhah S. A Patient Presenting with Cardiac Tamponade and the Challenges of Finding Its Cause: A Cardiac Angiosarcoma. Case Reports in Cardiology. 2018;2018:1-3.
5. Leduc C, Jenkins S, Sukov W, Rustin J, Maleszewski J. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases. Human Pathology. 2017;60:199-207.
6. Ramlawi B, Leja M, Abu Saleh W, Al Jabbari O, Benjamin R, Ravi V et al. Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience. The Annals of Thoracic Surgery. 2016;101(2):698-702.
7.Engelen M. Primary left atrial angiosarcoma mimicking severe mitral valve stenosis. Heart. 2005;91(4):e27-e27.
8. Chenier M, Johnson D, Ohman M, Pavlisko E. Cardiac angiosarcoma presenting as progressive dyspnea on exertion. Journal of Cardiovascular Medicine. 2011;12(12):904-907.
9. Lindsey J, Stacey R. Cardiac magnetic resonance in cardiac angiosarcoma. Echocardiography. 2017;34(7):1077-1081.
Soft Tissue Sarcoma Chemotherapy
Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.
Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.
Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.
Reports from the annual meeting of The Connective Tissue Oncology Society held in Rome, November 14-17, 2018 Sarcoma of the Year: Intimal Sarcoma
This year’s annual meeting of The Connective Tissue Oncology Society brought new insights on intimal sarcoma. Four studies in a featured session at the meeting examined both current and novel treatments for this rare and aggressive cancer, and emphasized the need for new therapies.
Anthracycline-based regimens as preferred first-line therapies
Anthracycline-based regimens were the preferred first-line therapies used in 83 adults with intimal sarcomas in a retrospective study of data from the World Sarcoma Network, reported by Anna Maria Frezza, MD, of the, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues. The researchers described the experience with anthracycline-based regimens as well as gemcitabine-based regimens and pazopanib among MDM2-positive patients with intimal sarcomas treated at 16 sarcoma reference centers in Europe, the United States, and Japan. Their findings speak to the need for new active drugs, which they said should target the MDM2 and CDK4 overexpression seen in patients with this rare sarcoma.Of the 83 patients studied, nearly all (76 patients) initially received an anthracycline-based regimen. Gemcitabine-based regimens were used in 29 patients and pazopanib in 10 patients; 20 of the 39 patients received more than one treatment.
Anthracycline-based regimens were associated with a 12-month progression-free survival rate of 38% in 76 patients with intimal sarcomas. All of the 76 patients received anthracycline regimens as their initial systemic therapy; 27 were treated for localized disease with a curative intent and the remaining 49 had advanced disease. The researchers also noted that anthracycline regimens were safely used in 22 patients with cardiac intimal sarcomas, as none of them died of cardiotoxicity.
Based on RECIST 1.1 measures, the overall response rate was 37% in 57 evaluable patients: 3 patients had a complete response, 18 had a partial response, 27 had stable disease, and 9 had progressive disease. For those with localized disease, the median time to progression was 14 months, and overall survival time was 51. For patients with advanced disease, the median time to progression was 8 months and overall survival was 22 months.
Outcomes were less favorable when patients were treated with gemcitabine regimens or pazopanib. In most of these cases, however, patients were either on their second (gemcitabine) or third (pazopanib) lines of therapy.
In the gemcitabine group, 2 patients were treated for localized disease with curative intent and 27 for advanced disease. Of 28 evaluable patients, best response was partial remission in 3, stable disease in 8, and progressive disease in 17. In the 27 patients with advanced disease, the median progression free survival time was 3 months and overall survival was 13 months.
All 10 patients in the pazopanib group had advanced disease and had undergone a median of two prior lines of therapy. One patient had a partial remission, 3 had stable disease, and 6 had progressive disease. The median progression free survival was 4 months and median overall survival was 12 months.
Rarest of the rare: Primary malignant sarcoma of the heart
Luke Smith, of the School of Clinical Medicine, University of Cambridge, U.K., detailed the experience of 28 patients diagnosed with sarcomas of the heart or great vessels at the university’s Royal Papworth Hospital and Addenbrooke’s Hospital between 2000 and 2018.
Based on this retrospective review, surgery offers the best chance for long-term survival for these patients, who would otherwise experience progressive heart failure and die. Adjuvant chemotherapy and radiation therapy might be able to extend their survival and improve symptomatic relief, he said, but these outcomes have not been prospectively studied.
Typically, the patients in this series, 20 with pulmonary artery sarcoma and 8 with cardiac sarcoma, presented with symptoms mimicking heart failure, pulmonary hypertension, or thromboembolic disease. Nearly all, 24 patients reported breathlessness. Eight patients had chest pain or tightness, 6 had cough, 6 had peripheral edema, 6 had constitutional symptoms, 3 had hemoptysis, and 1 had a TIA. Only 1 patient had a seriously impaired left ventricular ejection fraction of less than 30%. LVEF was normal at 55% or more in 16 patients, and moderately impaired at 30% or more in 10 patients.
Median overall survival was 17 months. The 19 patients who underwent surgical resection of their primary tumor survived much longer than the 10 patients who did not--median overall survival of 20 months vs. 9 months--but this finding may simply reflect more advanced disease in patients with inoperable disease. There were 3 perioperative deaths among the 19 patients who underwent surgery: 14 with pulmonary artery sarcomas had pulmonary endarterectomy and 4 with cardiac sarcomas underwent resection or maximal debulking of their tumors.
Based on the retrospective study, adjuvant chemotherapy and radiation were safe and may lead to better outcomes for these patients. Active chemotherapy regimens in the palliative setting included paclitaxel (angiosarcoma) and anthracycline ± ifosfamide.
Nine patients received post-surgical chemotherapy, and after completion five also had radiotherapy. The 3 cardiac sarcoma patients who had surgical resection with curative intent were treated with adjuvant ifosfamide-based chemotherapy (with close monitoring of fluid balance), and showed no evidence of disease on last follow-ups. One patient received post-operative paclitaxel following maximal debulking of a cardiac angiosarcoma.
Post-surgical anthracycline with and without ifosfamide were used in patients with pulmonary artery sarcomas with no clinical cardiotoxicity. Although the median overall survival for patients who received post-operative chemo- and radio-therapy was 28 months and the median overall survival with surgery alone was 9 months, the difference was not statistically significant.
In the palliative setting, partial responses were observed with paclitaxel and anthracycline (including liposomal doxorubicin) in patients with cardiac angiosarcoma. For pulmonary artery intimal sarcomas, partial responses were achieved with anthracycline with and without ifosfamide. Radiotherapy provided good local control.
The longest surviving pulmonary artery sarcoma patient, at 103 months, had pulmonary artery endarterectomy, followed by adjuvant epirubicin and radiotherapy. She developed lung metastases 7 years later and was treated with radiofrequency ablation. The longest surviving cardiac sarcoma patient, at 24 months, remains disease free. He had surgery to resect a high-grade undifferentiated sarcoma with involved margins, followed by adjuvant ifosfamide and radiotherapy to the right atrium.
Therapeutically exploitable genetic aberrations in intimal sarcomas
Imatinib and olaratumab might prove to be therapeutic approaches for some patients with intimal sarcomas, based on a retrospective evaluation of genetic aberrations in 11 patients with intimal sarcomas, Jason Roszik, PhD, MBA, reported at the meeting.
Dr. Roszik and his colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed information on 11 patients with intimal sarcomas in the American Association for Cancer Research (AACR) project, Genomics Evidence Neoplasia Information Exchange (GENIE). Sampling was taken from the primary tumor in 8 patients and from the metastatic site in the other 3.
MDM2 amplifications were seen in 8 of 10 patients with available copy number alterations. Amplifications in the CDK pathway were present in 5, PDGFRA gain was seen in 4, and CDKN2A copy number loss was present in 3. Mutations that could be targeted with drugs included ALK, ATM/ATR, PTCH1 and PDGFRB, he said.
Unique genomic rearrangement events included PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion tumor, and PDGFRB mutations in both fusion-positive cases.
The researchers also drew on the published findings of whole-exome sequencing and array-comparative genomic hybridization from an autopsy case of cardiac intimal sarcoma (Virchows Arch. 2017 Sep;471(3):423-428). That study identified concurrent PDGFRA amplification and PDGFRB mutation.
The researchers additionally examined clinical trial enrollments and could find no patient with intimal sarcoma among 406 sarcoma enrolled patients. Intimal sarcomas were not eligible for any clinical trial given the location of the tumors in major blood vessels.
“The somatic mutations and DNA copy number alterations in the PDGFR pathway relevant to the pathogenesis and potential targeted therapy of cardiac intimal sarcoma may be targeted by imatinib or olaratumab. Inclusion of such rare tumors in targeted therapy basket trials with a waiver for inclusion criteria is warranted,” Dr. Roszik and his colleagues concluded in the abstract of their presentation.
The promise of combination therapy
The “largest experience using multimodality therapy with proton based local therapy” for sarcomas involving the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries was reported by Yen-Lin E. Chen, MD, and her colleagues at Massachusetts General Hospital, Boston.
They examined an institutional sarcoma data repository of 13,950 patients and found 37 patients with sarcomas arising from the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries. These included 9 with unclassified pleomorphic sarcoma/malignant fibrous histiocytoma, 8 with angiosarcoma, 4 with spindle cell sarcoma, 4 with sarcoma not otherwise specified, 3 with leiomyosarcoma, 2 with osteosarcoma, 2 with Ewing sarcoma, and 1 each with chondrosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and intimal sarcoma.
Two-thirds of the patients had induction chemotherapy with or without maintenance therapy. Adriamycin, ifosfamide, and taxol therapies were most common. Two-thirds received proton based radiotherapy. Of the 23 patients who underwent resection, 11 were R2 (macroscopic positive margins), 3 were R1 (microscopic positive margins), and 9 were R0 (clear margins).
The 1-year overall survival rate was 64%, which fell to 37% at 3 years and to 28% at 5 years. Median survival was 28 months, twice that typically seen in the literature, Dr. Chen said.
For patients receiving proton based radiotherapy to a median dose of 64.8 GyRBE (range 63-72 GyRBE, 3 with additional intraoperative electrons), local failure free survivals were 80%, 64%, and 52% at 1, 3, and 5 years, respectively. For patients who did not receive radiotherapy, local failure free survival rates were 13%, 10%, 10%, respectively.
Overall, the 1, 3, and 5 year metastatic free survival rates were 25%, 14%, and 14%.
Survival rate was significantly better for patients with tumors smaller than 5 cm ( P =0.036), those over 40 years old ( P =0.028), those able to have surgery ( P =0.011), and those with non-angiosarcoma histologies ( P = 0.002).
This year’s annual meeting of The Connective Tissue Oncology Society brought new insights on intimal sarcoma. Four studies in a featured session at the meeting examined both current and novel treatments for this rare and aggressive cancer, and emphasized the need for new therapies.
Anthracycline-based regimens as preferred first-line therapies
Anthracycline-based regimens were the preferred first-line therapies used in 83 adults with intimal sarcomas in a retrospective study of data from the World Sarcoma Network, reported by Anna Maria Frezza, MD, of the, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues. The researchers described the experience with anthracycline-based regimens as well as gemcitabine-based regimens and pazopanib among MDM2-positive patients with intimal sarcomas treated at 16 sarcoma reference centers in Europe, the United States, and Japan. Their findings speak to the need for new active drugs, which they said should target the MDM2 and CDK4 overexpression seen in patients with this rare sarcoma.Of the 83 patients studied, nearly all (76 patients) initially received an anthracycline-based regimen. Gemcitabine-based regimens were used in 29 patients and pazopanib in 10 patients; 20 of the 39 patients received more than one treatment.
Anthracycline-based regimens were associated with a 12-month progression-free survival rate of 38% in 76 patients with intimal sarcomas. All of the 76 patients received anthracycline regimens as their initial systemic therapy; 27 were treated for localized disease with a curative intent and the remaining 49 had advanced disease. The researchers also noted that anthracycline regimens were safely used in 22 patients with cardiac intimal sarcomas, as none of them died of cardiotoxicity.
Based on RECIST 1.1 measures, the overall response rate was 37% in 57 evaluable patients: 3 patients had a complete response, 18 had a partial response, 27 had stable disease, and 9 had progressive disease. For those with localized disease, the median time to progression was 14 months, and overall survival time was 51. For patients with advanced disease, the median time to progression was 8 months and overall survival was 22 months.
Outcomes were less favorable when patients were treated with gemcitabine regimens or pazopanib. In most of these cases, however, patients were either on their second (gemcitabine) or third (pazopanib) lines of therapy.
In the gemcitabine group, 2 patients were treated for localized disease with curative intent and 27 for advanced disease. Of 28 evaluable patients, best response was partial remission in 3, stable disease in 8, and progressive disease in 17. In the 27 patients with advanced disease, the median progression free survival time was 3 months and overall survival was 13 months.
All 10 patients in the pazopanib group had advanced disease and had undergone a median of two prior lines of therapy. One patient had a partial remission, 3 had stable disease, and 6 had progressive disease. The median progression free survival was 4 months and median overall survival was 12 months.
Rarest of the rare: Primary malignant sarcoma of the heart
Luke Smith, of the School of Clinical Medicine, University of Cambridge, U.K., detailed the experience of 28 patients diagnosed with sarcomas of the heart or great vessels at the university’s Royal Papworth Hospital and Addenbrooke’s Hospital between 2000 and 2018.
Based on this retrospective review, surgery offers the best chance for long-term survival for these patients, who would otherwise experience progressive heart failure and die. Adjuvant chemotherapy and radiation therapy might be able to extend their survival and improve symptomatic relief, he said, but these outcomes have not been prospectively studied.
Typically, the patients in this series, 20 with pulmonary artery sarcoma and 8 with cardiac sarcoma, presented with symptoms mimicking heart failure, pulmonary hypertension, or thromboembolic disease. Nearly all, 24 patients reported breathlessness. Eight patients had chest pain or tightness, 6 had cough, 6 had peripheral edema, 6 had constitutional symptoms, 3 had hemoptysis, and 1 had a TIA. Only 1 patient had a seriously impaired left ventricular ejection fraction of less than 30%. LVEF was normal at 55% or more in 16 patients, and moderately impaired at 30% or more in 10 patients.
Median overall survival was 17 months. The 19 patients who underwent surgical resection of their primary tumor survived much longer than the 10 patients who did not--median overall survival of 20 months vs. 9 months--but this finding may simply reflect more advanced disease in patients with inoperable disease. There were 3 perioperative deaths among the 19 patients who underwent surgery: 14 with pulmonary artery sarcomas had pulmonary endarterectomy and 4 with cardiac sarcomas underwent resection or maximal debulking of their tumors.
Based on the retrospective study, adjuvant chemotherapy and radiation were safe and may lead to better outcomes for these patients. Active chemotherapy regimens in the palliative setting included paclitaxel (angiosarcoma) and anthracycline ± ifosfamide.
Nine patients received post-surgical chemotherapy, and after completion five also had radiotherapy. The 3 cardiac sarcoma patients who had surgical resection with curative intent were treated with adjuvant ifosfamide-based chemotherapy (with close monitoring of fluid balance), and showed no evidence of disease on last follow-ups. One patient received post-operative paclitaxel following maximal debulking of a cardiac angiosarcoma.
Post-surgical anthracycline with and without ifosfamide were used in patients with pulmonary artery sarcomas with no clinical cardiotoxicity. Although the median overall survival for patients who received post-operative chemo- and radio-therapy was 28 months and the median overall survival with surgery alone was 9 months, the difference was not statistically significant.
In the palliative setting, partial responses were observed with paclitaxel and anthracycline (including liposomal doxorubicin) in patients with cardiac angiosarcoma. For pulmonary artery intimal sarcomas, partial responses were achieved with anthracycline with and without ifosfamide. Radiotherapy provided good local control.
The longest surviving pulmonary artery sarcoma patient, at 103 months, had pulmonary artery endarterectomy, followed by adjuvant epirubicin and radiotherapy. She developed lung metastases 7 years later and was treated with radiofrequency ablation. The longest surviving cardiac sarcoma patient, at 24 months, remains disease free. He had surgery to resect a high-grade undifferentiated sarcoma with involved margins, followed by adjuvant ifosfamide and radiotherapy to the right atrium.
Therapeutically exploitable genetic aberrations in intimal sarcomas
Imatinib and olaratumab might prove to be therapeutic approaches for some patients with intimal sarcomas, based on a retrospective evaluation of genetic aberrations in 11 patients with intimal sarcomas, Jason Roszik, PhD, MBA, reported at the meeting.
Dr. Roszik and his colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed information on 11 patients with intimal sarcomas in the American Association for Cancer Research (AACR) project, Genomics Evidence Neoplasia Information Exchange (GENIE). Sampling was taken from the primary tumor in 8 patients and from the metastatic site in the other 3.
MDM2 amplifications were seen in 8 of 10 patients with available copy number alterations. Amplifications in the CDK pathway were present in 5, PDGFRA gain was seen in 4, and CDKN2A copy number loss was present in 3. Mutations that could be targeted with drugs included ALK, ATM/ATR, PTCH1 and PDGFRB, he said.
Unique genomic rearrangement events included PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion tumor, and PDGFRB mutations in both fusion-positive cases.
The researchers also drew on the published findings of whole-exome sequencing and array-comparative genomic hybridization from an autopsy case of cardiac intimal sarcoma (Virchows Arch. 2017 Sep;471(3):423-428). That study identified concurrent PDGFRA amplification and PDGFRB mutation.
The researchers additionally examined clinical trial enrollments and could find no patient with intimal sarcoma among 406 sarcoma enrolled patients. Intimal sarcomas were not eligible for any clinical trial given the location of the tumors in major blood vessels.
“The somatic mutations and DNA copy number alterations in the PDGFR pathway relevant to the pathogenesis and potential targeted therapy of cardiac intimal sarcoma may be targeted by imatinib or olaratumab. Inclusion of such rare tumors in targeted therapy basket trials with a waiver for inclusion criteria is warranted,” Dr. Roszik and his colleagues concluded in the abstract of their presentation.
The promise of combination therapy
The “largest experience using multimodality therapy with proton based local therapy” for sarcomas involving the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries was reported by Yen-Lin E. Chen, MD, and her colleagues at Massachusetts General Hospital, Boston.
They examined an institutional sarcoma data repository of 13,950 patients and found 37 patients with sarcomas arising from the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries. These included 9 with unclassified pleomorphic sarcoma/malignant fibrous histiocytoma, 8 with angiosarcoma, 4 with spindle cell sarcoma, 4 with sarcoma not otherwise specified, 3 with leiomyosarcoma, 2 with osteosarcoma, 2 with Ewing sarcoma, and 1 each with chondrosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and intimal sarcoma.
Two-thirds of the patients had induction chemotherapy with or without maintenance therapy. Adriamycin, ifosfamide, and taxol therapies were most common. Two-thirds received proton based radiotherapy. Of the 23 patients who underwent resection, 11 were R2 (macroscopic positive margins), 3 were R1 (microscopic positive margins), and 9 were R0 (clear margins).
The 1-year overall survival rate was 64%, which fell to 37% at 3 years and to 28% at 5 years. Median survival was 28 months, twice that typically seen in the literature, Dr. Chen said.
For patients receiving proton based radiotherapy to a median dose of 64.8 GyRBE (range 63-72 GyRBE, 3 with additional intraoperative electrons), local failure free survivals were 80%, 64%, and 52% at 1, 3, and 5 years, respectively. For patients who did not receive radiotherapy, local failure free survival rates were 13%, 10%, 10%, respectively.
Overall, the 1, 3, and 5 year metastatic free survival rates were 25%, 14%, and 14%.
Survival rate was significantly better for patients with tumors smaller than 5 cm ( P =0.036), those over 40 years old ( P =0.028), those able to have surgery ( P =0.011), and those with non-angiosarcoma histologies ( P = 0.002).
This year’s annual meeting of The Connective Tissue Oncology Society brought new insights on intimal sarcoma. Four studies in a featured session at the meeting examined both current and novel treatments for this rare and aggressive cancer, and emphasized the need for new therapies.
Anthracycline-based regimens as preferred first-line therapies
Anthracycline-based regimens were the preferred first-line therapies used in 83 adults with intimal sarcomas in a retrospective study of data from the World Sarcoma Network, reported by Anna Maria Frezza, MD, of the, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues. The researchers described the experience with anthracycline-based regimens as well as gemcitabine-based regimens and pazopanib among MDM2-positive patients with intimal sarcomas treated at 16 sarcoma reference centers in Europe, the United States, and Japan. Their findings speak to the need for new active drugs, which they said should target the MDM2 and CDK4 overexpression seen in patients with this rare sarcoma.Of the 83 patients studied, nearly all (76 patients) initially received an anthracycline-based regimen. Gemcitabine-based regimens were used in 29 patients and pazopanib in 10 patients; 20 of the 39 patients received more than one treatment.
Anthracycline-based regimens were associated with a 12-month progression-free survival rate of 38% in 76 patients with intimal sarcomas. All of the 76 patients received anthracycline regimens as their initial systemic therapy; 27 were treated for localized disease with a curative intent and the remaining 49 had advanced disease. The researchers also noted that anthracycline regimens were safely used in 22 patients with cardiac intimal sarcomas, as none of them died of cardiotoxicity.
Based on RECIST 1.1 measures, the overall response rate was 37% in 57 evaluable patients: 3 patients had a complete response, 18 had a partial response, 27 had stable disease, and 9 had progressive disease. For those with localized disease, the median time to progression was 14 months, and overall survival time was 51. For patients with advanced disease, the median time to progression was 8 months and overall survival was 22 months.
Outcomes were less favorable when patients were treated with gemcitabine regimens or pazopanib. In most of these cases, however, patients were either on their second (gemcitabine) or third (pazopanib) lines of therapy.
In the gemcitabine group, 2 patients were treated for localized disease with curative intent and 27 for advanced disease. Of 28 evaluable patients, best response was partial remission in 3, stable disease in 8, and progressive disease in 17. In the 27 patients with advanced disease, the median progression free survival time was 3 months and overall survival was 13 months.
All 10 patients in the pazopanib group had advanced disease and had undergone a median of two prior lines of therapy. One patient had a partial remission, 3 had stable disease, and 6 had progressive disease. The median progression free survival was 4 months and median overall survival was 12 months.
Rarest of the rare: Primary malignant sarcoma of the heart
Luke Smith, of the School of Clinical Medicine, University of Cambridge, U.K., detailed the experience of 28 patients diagnosed with sarcomas of the heart or great vessels at the university’s Royal Papworth Hospital and Addenbrooke’s Hospital between 2000 and 2018.
Based on this retrospective review, surgery offers the best chance for long-term survival for these patients, who would otherwise experience progressive heart failure and die. Adjuvant chemotherapy and radiation therapy might be able to extend their survival and improve symptomatic relief, he said, but these outcomes have not been prospectively studied.
Typically, the patients in this series, 20 with pulmonary artery sarcoma and 8 with cardiac sarcoma, presented with symptoms mimicking heart failure, pulmonary hypertension, or thromboembolic disease. Nearly all, 24 patients reported breathlessness. Eight patients had chest pain or tightness, 6 had cough, 6 had peripheral edema, 6 had constitutional symptoms, 3 had hemoptysis, and 1 had a TIA. Only 1 patient had a seriously impaired left ventricular ejection fraction of less than 30%. LVEF was normal at 55% or more in 16 patients, and moderately impaired at 30% or more in 10 patients.
Median overall survival was 17 months. The 19 patients who underwent surgical resection of their primary tumor survived much longer than the 10 patients who did not--median overall survival of 20 months vs. 9 months--but this finding may simply reflect more advanced disease in patients with inoperable disease. There were 3 perioperative deaths among the 19 patients who underwent surgery: 14 with pulmonary artery sarcomas had pulmonary endarterectomy and 4 with cardiac sarcomas underwent resection or maximal debulking of their tumors.
Based on the retrospective study, adjuvant chemotherapy and radiation were safe and may lead to better outcomes for these patients. Active chemotherapy regimens in the palliative setting included paclitaxel (angiosarcoma) and anthracycline ± ifosfamide.
Nine patients received post-surgical chemotherapy, and after completion five also had radiotherapy. The 3 cardiac sarcoma patients who had surgical resection with curative intent were treated with adjuvant ifosfamide-based chemotherapy (with close monitoring of fluid balance), and showed no evidence of disease on last follow-ups. One patient received post-operative paclitaxel following maximal debulking of a cardiac angiosarcoma.
Post-surgical anthracycline with and without ifosfamide were used in patients with pulmonary artery sarcomas with no clinical cardiotoxicity. Although the median overall survival for patients who received post-operative chemo- and radio-therapy was 28 months and the median overall survival with surgery alone was 9 months, the difference was not statistically significant.
In the palliative setting, partial responses were observed with paclitaxel and anthracycline (including liposomal doxorubicin) in patients with cardiac angiosarcoma. For pulmonary artery intimal sarcomas, partial responses were achieved with anthracycline with and without ifosfamide. Radiotherapy provided good local control.
The longest surviving pulmonary artery sarcoma patient, at 103 months, had pulmonary artery endarterectomy, followed by adjuvant epirubicin and radiotherapy. She developed lung metastases 7 years later and was treated with radiofrequency ablation. The longest surviving cardiac sarcoma patient, at 24 months, remains disease free. He had surgery to resect a high-grade undifferentiated sarcoma with involved margins, followed by adjuvant ifosfamide and radiotherapy to the right atrium.
Therapeutically exploitable genetic aberrations in intimal sarcomas
Imatinib and olaratumab might prove to be therapeutic approaches for some patients with intimal sarcomas, based on a retrospective evaluation of genetic aberrations in 11 patients with intimal sarcomas, Jason Roszik, PhD, MBA, reported at the meeting.
Dr. Roszik and his colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed information on 11 patients with intimal sarcomas in the American Association for Cancer Research (AACR) project, Genomics Evidence Neoplasia Information Exchange (GENIE). Sampling was taken from the primary tumor in 8 patients and from the metastatic site in the other 3.
MDM2 amplifications were seen in 8 of 10 patients with available copy number alterations. Amplifications in the CDK pathway were present in 5, PDGFRA gain was seen in 4, and CDKN2A copy number loss was present in 3. Mutations that could be targeted with drugs included ALK, ATM/ATR, PTCH1 and PDGFRB, he said.
Unique genomic rearrangement events included PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion tumor, and PDGFRB mutations in both fusion-positive cases.
The researchers also drew on the published findings of whole-exome sequencing and array-comparative genomic hybridization from an autopsy case of cardiac intimal sarcoma (Virchows Arch. 2017 Sep;471(3):423-428). That study identified concurrent PDGFRA amplification and PDGFRB mutation.
The researchers additionally examined clinical trial enrollments and could find no patient with intimal sarcoma among 406 sarcoma enrolled patients. Intimal sarcomas were not eligible for any clinical trial given the location of the tumors in major blood vessels.
“The somatic mutations and DNA copy number alterations in the PDGFR pathway relevant to the pathogenesis and potential targeted therapy of cardiac intimal sarcoma may be targeted by imatinib or olaratumab. Inclusion of such rare tumors in targeted therapy basket trials with a waiver for inclusion criteria is warranted,” Dr. Roszik and his colleagues concluded in the abstract of their presentation.
The promise of combination therapy
The “largest experience using multimodality therapy with proton based local therapy” for sarcomas involving the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries was reported by Yen-Lin E. Chen, MD, and her colleagues at Massachusetts General Hospital, Boston.
They examined an institutional sarcoma data repository of 13,950 patients and found 37 patients with sarcomas arising from the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries. These included 9 with unclassified pleomorphic sarcoma/malignant fibrous histiocytoma, 8 with angiosarcoma, 4 with spindle cell sarcoma, 4 with sarcoma not otherwise specified, 3 with leiomyosarcoma, 2 with osteosarcoma, 2 with Ewing sarcoma, and 1 each with chondrosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and intimal sarcoma.
Two-thirds of the patients had induction chemotherapy with or without maintenance therapy. Adriamycin, ifosfamide, and taxol therapies were most common. Two-thirds received proton based radiotherapy. Of the 23 patients who underwent resection, 11 were R2 (macroscopic positive margins), 3 were R1 (microscopic positive margins), and 9 were R0 (clear margins).
The 1-year overall survival rate was 64%, which fell to 37% at 3 years and to 28% at 5 years. Median survival was 28 months, twice that typically seen in the literature, Dr. Chen said.
For patients receiving proton based radiotherapy to a median dose of 64.8 GyRBE (range 63-72 GyRBE, 3 with additional intraoperative electrons), local failure free survivals were 80%, 64%, and 52% at 1, 3, and 5 years, respectively. For patients who did not receive radiotherapy, local failure free survival rates were 13%, 10%, 10%, respectively.
Overall, the 1, 3, and 5 year metastatic free survival rates were 25%, 14%, and 14%.
Survival rate was significantly better for patients with tumors smaller than 5 cm ( P =0.036), those over 40 years old ( P =0.028), those able to have surgery ( P =0.011), and those with non-angiosarcoma histologies ( P = 0.002).
Patterns of malignancies in patients with HIV-AIDS: a single institution observational study
India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.1 In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).1 There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.2 However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.3 The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.4 In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.
Methods
We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
Results
A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.
The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm3 (50-734 cells/mm3). There were 104 patients with CD4 counts of ≤200 cells/mm3, and 181 patients had CD4 counts of >200 cells/mm3 (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).
The most common malignancies in this population were gynecologic malignancies, followed by hematologic malignancies. Cervical cancer was the most common malignancy among women as well as in the overall study population. Among men, the most common malignancy was NHL. The second and third most common malignancies in men were carcinoma oral cavity and carcinoma oropharynx, respectively, whereas in women, they were NHL and breast cancer. The distribution of various hematologic, head and neck, and gastrointestinal malignancies in this group of patients is shown in Figures 1, 2, and 3.
The ADMs in the study were NHL, including 2 patients diagnosed with primary central nervous system (CNS) lymphomas, and cervical cancer. No case of Kaposi sarcoma, also considered an ADM, was identified in this study. The common NADMs include head and neck malignancies (Figure 2), gastrointestinal malignancies (Figure 3), gynecological and genitourinary malignancies, and breast cancer. The mean CD4 count in the ADM subgroup was 221 cells/mm3, and in the NADM subgroup, it was 250 cells/mm3. There was a significant difference in the distribution of CD4 counts between the ADM and NADM subgroups (P = .03; Mann-Whitney U test). A statistical difference was also noted when the CD4 counts of the patients with NHL were compared with other malignancies (P = .0001; Mann-Whitney U test) There was no statistically significant difference noted when CD4 counts of patients with cervical cancer were compared with NADMs (P = .914).
Discussion
In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).5 The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.5 The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.6 However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.7 The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.8 This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.
Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.10 Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.
Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.10 The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.10 Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,11-13 and similar findings were also reported in a study from northern India.9 The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.10,14
As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.
An increasing incidence of NADMs has been noted in the Western literature.7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.8 This is in concordance with previous publications from India.8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.10 Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.
In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.17 A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.17 In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.14 In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.18 Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.19-21
Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.22 Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.23 As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.24 PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.22
The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.14 The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.25 Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.22 The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.26 Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.27 The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.28
Conclusions
With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.
1. UNAIDS. Prevention gap report. http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_en.pdf. Released 2016. Accessed December 27, 2017.
3. Dubrow R, Silverberg MJ, Park LS, Crothers K, Justice AC. HIV infection, aging, and immune function: implications for cancer risk and prevention. Curr Opin Oncol. 2012;24(5):506-516.
4. Biggar RJ, Chaturvedi AK, Bhatia K, Mbulaiteye SM. Cancer risk in persons with HIV-AIDS in India: a review and future directions for research. Infect Agent Cancer. 2009;4:4.
5. National AIDS Control Organisation & National Institute of Medical Statistics, ICMR, Ministry of Health & Family Welfare, Government of India. India HIV estimations 2015, technical report. http://www.naco.gov.in/sites/default/files/India%20HIV%20Estimations%202015.pdf. Published 2015. Accessed December 27, 2017.
6. Bonnet F, Lewden C, May T, et al. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer. 2004;101(2):317-324.
7. Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23(1):41-50.
8. Sharma S, Soneja M, Ranjan S. Malignancies in human immunodeficiency virus infected patients in India: initial experience in the HAART era. Indian J Med Res. 2015;142(5):563-567.
9. Sachdeva RK, Sharma A, Singh S, Varma S. Spectrum of AIDS defining & non-AIDS defining malignancies in north India. In
10. Dhir AA, Sawant S, Dikshit RP, et al. Spectrum of HIV-AIDS related cancers in India. Cancer Causes Control. 2007;19(2):147-153.
11. Venkatesh KK, Saghayam S, Devaleenal B, et al. Spectrum of malignancies among HIV-infected patients in South India. Indian J Cancer. 2012;49(1):176-180.
12. Shruti P, Narayanan G, Puthuveettil J, Jayasree K, Vijayalakshmi K. Spectrum of HIV/AIDS-associated cancers in south India. J Clin Oncol. 2014;32(suppl):e12534.
13. Paul TR, Uppin MS, Uppin SG, et al. Spectrum of malignancies in human immunodeficiency virus–positive patients at a Tertiary Care Centre in South India. Indian J Cancer. 2014;51(4):459-463.
14. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762.
15. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728-736.
16. Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):187-194.
17. Robbins HA, Shiels MS, Pfeiffer RM, Engels EA. Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS. 2014;28(6):881-890.
18. Tanaka LF, Latorre MDRD, Gutierrez EB, Heumann C, Herbinger KH, Froeschl G. Trends in the incidence of AIDS-defining and non-AIDS-defining cancers in people living with AIDS: a population-based study from São Paulo, Brazil. Int J STD AIDS. 2017;28(12):1190-1198.
19. Mutyaba I, Phipps W, Krantz EM, et al. A population-level evaluation of the effect of antiretroviral therapy on cancer incidence in Kyadondo County, Uganda, 1999–2008. J Acquir Immune Defic Syndr. 2015;69(4):481-486.
20. Dryden-Peterson S, Medhin H, Kebabonye-Pusoentsi M, et al. Cancer incidence following expansion of HIV treatment in Botswana. PLoS ONE. 2015;10(8):e0135602.
21. Shiels MS, Engels EA. Evolving epidemiology of HIV-associated malignancies. Curr Opin HIV AIDS. 2017;12(1):6-11.
22. Yarchoan R, Uldrick TS. HIV-associated cancers and related diseases. N Engl J Med. 2018;378(11):1029-1041.
23. Gao SJ, Kingsley L, Li M, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nat Med. 1996;2(8):925-928.
24. Epstein-Barr virus and AIDS-associated lymphomas. Lancet. 1991;338(8773):979-981.
25. Picard A, Badoual C, Hourseau M, et al. Human papilloma virus prevalence in HIV patients with head and neck squamous cell carcinoma. AIDS. 2016;30(8):1257-1266.
26. Minkoff H, Zhong Y, Burk RD, et al. Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Infect Dis. 2010;201(5):681-690.
27. Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: past, present and future. Gynecol Oncol Rep. 2017;21:101-108.
28. Kojic EM, Rana AI, Cu-Uvin S. Human papillomavirus vaccination in HIV-infected women: need for increased coverage. Expert Rev Vaccines. 2016;15(1):105-117.
India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.1 In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).1 There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.2 However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.3 The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.4 In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.
Methods
We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
Results
A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.
The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm3 (50-734 cells/mm3). There were 104 patients with CD4 counts of ≤200 cells/mm3, and 181 patients had CD4 counts of >200 cells/mm3 (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).
The most common malignancies in this population were gynecologic malignancies, followed by hematologic malignancies. Cervical cancer was the most common malignancy among women as well as in the overall study population. Among men, the most common malignancy was NHL. The second and third most common malignancies in men were carcinoma oral cavity and carcinoma oropharynx, respectively, whereas in women, they were NHL and breast cancer. The distribution of various hematologic, head and neck, and gastrointestinal malignancies in this group of patients is shown in Figures 1, 2, and 3.
The ADMs in the study were NHL, including 2 patients diagnosed with primary central nervous system (CNS) lymphomas, and cervical cancer. No case of Kaposi sarcoma, also considered an ADM, was identified in this study. The common NADMs include head and neck malignancies (Figure 2), gastrointestinal malignancies (Figure 3), gynecological and genitourinary malignancies, and breast cancer. The mean CD4 count in the ADM subgroup was 221 cells/mm3, and in the NADM subgroup, it was 250 cells/mm3. There was a significant difference in the distribution of CD4 counts between the ADM and NADM subgroups (P = .03; Mann-Whitney U test). A statistical difference was also noted when the CD4 counts of the patients with NHL were compared with other malignancies (P = .0001; Mann-Whitney U test) There was no statistically significant difference noted when CD4 counts of patients with cervical cancer were compared with NADMs (P = .914).
Discussion
In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).5 The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.5 The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.6 However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.7 The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.8 This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.
Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.10 Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.
Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.10 The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.10 Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,11-13 and similar findings were also reported in a study from northern India.9 The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.10,14
As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.
An increasing incidence of NADMs has been noted in the Western literature.7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.8 This is in concordance with previous publications from India.8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.10 Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.
In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.17 A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.17 In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.14 In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.18 Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.19-21
Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.22 Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.23 As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.24 PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.22
The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.14 The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.25 Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.22 The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.26 Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.27 The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.28
Conclusions
With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.
India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.1 In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).1 There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.2 However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.3 The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.4 In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.
Methods
We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
Results
A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.
The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm3 (50-734 cells/mm3). There were 104 patients with CD4 counts of ≤200 cells/mm3, and 181 patients had CD4 counts of >200 cells/mm3 (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).
The most common malignancies in this population were gynecologic malignancies, followed by hematologic malignancies. Cervical cancer was the most common malignancy among women as well as in the overall study population. Among men, the most common malignancy was NHL. The second and third most common malignancies in men were carcinoma oral cavity and carcinoma oropharynx, respectively, whereas in women, they were NHL and breast cancer. The distribution of various hematologic, head and neck, and gastrointestinal malignancies in this group of patients is shown in Figures 1, 2, and 3.
The ADMs in the study were NHL, including 2 patients diagnosed with primary central nervous system (CNS) lymphomas, and cervical cancer. No case of Kaposi sarcoma, also considered an ADM, was identified in this study. The common NADMs include head and neck malignancies (Figure 2), gastrointestinal malignancies (Figure 3), gynecological and genitourinary malignancies, and breast cancer. The mean CD4 count in the ADM subgroup was 221 cells/mm3, and in the NADM subgroup, it was 250 cells/mm3. There was a significant difference in the distribution of CD4 counts between the ADM and NADM subgroups (P = .03; Mann-Whitney U test). A statistical difference was also noted when the CD4 counts of the patients with NHL were compared with other malignancies (P = .0001; Mann-Whitney U test) There was no statistically significant difference noted when CD4 counts of patients with cervical cancer were compared with NADMs (P = .914).
Discussion
In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).5 The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.5 The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.6 However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.7 The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.8 This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.
Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.10 Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.
Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.10 The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.10 Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,11-13 and similar findings were also reported in a study from northern India.9 The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.10,14
As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.
An increasing incidence of NADMs has been noted in the Western literature.7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.8 This is in concordance with previous publications from India.8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.10 Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.
In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.17 A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.17 In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.14 In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.18 Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.19-21
Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.22 Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.23 As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.24 PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.22
The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.14 The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.25 Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.22 The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.26 Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.27 The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.28
Conclusions
With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.
1. UNAIDS. Prevention gap report. http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_en.pdf. Released 2016. Accessed December 27, 2017.
3. Dubrow R, Silverberg MJ, Park LS, Crothers K, Justice AC. HIV infection, aging, and immune function: implications for cancer risk and prevention. Curr Opin Oncol. 2012;24(5):506-516.
4. Biggar RJ, Chaturvedi AK, Bhatia K, Mbulaiteye SM. Cancer risk in persons with HIV-AIDS in India: a review and future directions for research. Infect Agent Cancer. 2009;4:4.
5. National AIDS Control Organisation & National Institute of Medical Statistics, ICMR, Ministry of Health & Family Welfare, Government of India. India HIV estimations 2015, technical report. http://www.naco.gov.in/sites/default/files/India%20HIV%20Estimations%202015.pdf. Published 2015. Accessed December 27, 2017.
6. Bonnet F, Lewden C, May T, et al. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer. 2004;101(2):317-324.
7. Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23(1):41-50.
8. Sharma S, Soneja M, Ranjan S. Malignancies in human immunodeficiency virus infected patients in India: initial experience in the HAART era. Indian J Med Res. 2015;142(5):563-567.
9. Sachdeva RK, Sharma A, Singh S, Varma S. Spectrum of AIDS defining & non-AIDS defining malignancies in north India. In
10. Dhir AA, Sawant S, Dikshit RP, et al. Spectrum of HIV-AIDS related cancers in India. Cancer Causes Control. 2007;19(2):147-153.
11. Venkatesh KK, Saghayam S, Devaleenal B, et al. Spectrum of malignancies among HIV-infected patients in South India. Indian J Cancer. 2012;49(1):176-180.
12. Shruti P, Narayanan G, Puthuveettil J, Jayasree K, Vijayalakshmi K. Spectrum of HIV/AIDS-associated cancers in south India. J Clin Oncol. 2014;32(suppl):e12534.
13. Paul TR, Uppin MS, Uppin SG, et al. Spectrum of malignancies in human immunodeficiency virus–positive patients at a Tertiary Care Centre in South India. Indian J Cancer. 2014;51(4):459-463.
14. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762.
15. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728-736.
16. Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):187-194.
17. Robbins HA, Shiels MS, Pfeiffer RM, Engels EA. Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS. 2014;28(6):881-890.
18. Tanaka LF, Latorre MDRD, Gutierrez EB, Heumann C, Herbinger KH, Froeschl G. Trends in the incidence of AIDS-defining and non-AIDS-defining cancers in people living with AIDS: a population-based study from São Paulo, Brazil. Int J STD AIDS. 2017;28(12):1190-1198.
19. Mutyaba I, Phipps W, Krantz EM, et al. A population-level evaluation of the effect of antiretroviral therapy on cancer incidence in Kyadondo County, Uganda, 1999–2008. J Acquir Immune Defic Syndr. 2015;69(4):481-486.
20. Dryden-Peterson S, Medhin H, Kebabonye-Pusoentsi M, et al. Cancer incidence following expansion of HIV treatment in Botswana. PLoS ONE. 2015;10(8):e0135602.
21. Shiels MS, Engels EA. Evolving epidemiology of HIV-associated malignancies. Curr Opin HIV AIDS. 2017;12(1):6-11.
22. Yarchoan R, Uldrick TS. HIV-associated cancers and related diseases. N Engl J Med. 2018;378(11):1029-1041.
23. Gao SJ, Kingsley L, Li M, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nat Med. 1996;2(8):925-928.
24. Epstein-Barr virus and AIDS-associated lymphomas. Lancet. 1991;338(8773):979-981.
25. Picard A, Badoual C, Hourseau M, et al. Human papilloma virus prevalence in HIV patients with head and neck squamous cell carcinoma. AIDS. 2016;30(8):1257-1266.
26. Minkoff H, Zhong Y, Burk RD, et al. Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Infect Dis. 2010;201(5):681-690.
27. Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: past, present and future. Gynecol Oncol Rep. 2017;21:101-108.
28. Kojic EM, Rana AI, Cu-Uvin S. Human papillomavirus vaccination in HIV-infected women: need for increased coverage. Expert Rev Vaccines. 2016;15(1):105-117.
1. UNAIDS. Prevention gap report. http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_en.pdf. Released 2016. Accessed December 27, 2017.
3. Dubrow R, Silverberg MJ, Park LS, Crothers K, Justice AC. HIV infection, aging, and immune function: implications for cancer risk and prevention. Curr Opin Oncol. 2012;24(5):506-516.
4. Biggar RJ, Chaturvedi AK, Bhatia K, Mbulaiteye SM. Cancer risk in persons with HIV-AIDS in India: a review and future directions for research. Infect Agent Cancer. 2009;4:4.
5. National AIDS Control Organisation & National Institute of Medical Statistics, ICMR, Ministry of Health & Family Welfare, Government of India. India HIV estimations 2015, technical report. http://www.naco.gov.in/sites/default/files/India%20HIV%20Estimations%202015.pdf. Published 2015. Accessed December 27, 2017.
6. Bonnet F, Lewden C, May T, et al. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer. 2004;101(2):317-324.
7. Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23(1):41-50.
8. Sharma S, Soneja M, Ranjan S. Malignancies in human immunodeficiency virus infected patients in India: initial experience in the HAART era. Indian J Med Res. 2015;142(5):563-567.
9. Sachdeva RK, Sharma A, Singh S, Varma S. Spectrum of AIDS defining & non-AIDS defining malignancies in north India. In
10. Dhir AA, Sawant S, Dikshit RP, et al. Spectrum of HIV-AIDS related cancers in India. Cancer Causes Control. 2007;19(2):147-153.
11. Venkatesh KK, Saghayam S, Devaleenal B, et al. Spectrum of malignancies among HIV-infected patients in South India. Indian J Cancer. 2012;49(1):176-180.
12. Shruti P, Narayanan G, Puthuveettil J, Jayasree K, Vijayalakshmi K. Spectrum of HIV/AIDS-associated cancers in south India. J Clin Oncol. 2014;32(suppl):e12534.
13. Paul TR, Uppin MS, Uppin SG, et al. Spectrum of malignancies in human immunodeficiency virus–positive patients at a Tertiary Care Centre in South India. Indian J Cancer. 2014;51(4):459-463.
14. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762.
15. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728-736.
16. Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):187-194.
17. Robbins HA, Shiels MS, Pfeiffer RM, Engels EA. Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS. 2014;28(6):881-890.
18. Tanaka LF, Latorre MDRD, Gutierrez EB, Heumann C, Herbinger KH, Froeschl G. Trends in the incidence of AIDS-defining and non-AIDS-defining cancers in people living with AIDS: a population-based study from São Paulo, Brazil. Int J STD AIDS. 2017;28(12):1190-1198.
19. Mutyaba I, Phipps W, Krantz EM, et al. A population-level evaluation of the effect of antiretroviral therapy on cancer incidence in Kyadondo County, Uganda, 1999–2008. J Acquir Immune Defic Syndr. 2015;69(4):481-486.
20. Dryden-Peterson S, Medhin H, Kebabonye-Pusoentsi M, et al. Cancer incidence following expansion of HIV treatment in Botswana. PLoS ONE. 2015;10(8):e0135602.
21. Shiels MS, Engels EA. Evolving epidemiology of HIV-associated malignancies. Curr Opin HIV AIDS. 2017;12(1):6-11.
22. Yarchoan R, Uldrick TS. HIV-associated cancers and related diseases. N Engl J Med. 2018;378(11):1029-1041.
23. Gao SJ, Kingsley L, Li M, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nat Med. 1996;2(8):925-928.
24. Epstein-Barr virus and AIDS-associated lymphomas. Lancet. 1991;338(8773):979-981.
25. Picard A, Badoual C, Hourseau M, et al. Human papilloma virus prevalence in HIV patients with head and neck squamous cell carcinoma. AIDS. 2016;30(8):1257-1266.
26. Minkoff H, Zhong Y, Burk RD, et al. Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Infect Dis. 2010;201(5):681-690.
27. Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: past, present and future. Gynecol Oncol Rep. 2017;21:101-108.
28. Kojic EM, Rana AI, Cu-Uvin S. Human papillomavirus vaccination in HIV-infected women: need for increased coverage. Expert Rev Vaccines. 2016;15(1):105-117.
FDA approves larotrectinib for cancers with NTRK gene fusions
for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.
Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.
NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.
Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.
The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.
Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.
The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.
The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients.
The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.
The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.
for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.
Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.
NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.
Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.
The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.
Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.
The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.
The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients.
The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.
The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.
for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.
Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.
NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.
Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.
The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.
Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.
The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.
The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients.
The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.
The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.
Immunotherapy may hold the key to defeating virally associated cancers
Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.
The link between viruses and cancer
Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.1
The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.2Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.3
In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.
Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.
Viruses hijack the cellular machinery to meet those needs and they can do this either by producing viral proteins that have an oncogenic effect or by integrating their genetic material into the host cell genome. When the latter occurs, the process of integration can also cause damage to the DNA, which further increases the risk of cancer-promoting changes occurring in the host genome.
Viruses can indirectly contribute to carcinogenesis by fostering a microenvironment of chronic inflammation, causing oxidative stress and local tissue damage, and by suppressing the antitumor immune response.4,5
Screening and prevention efforts have helped to reduce the burden of several different virally associated cancers. However, for the substantial proportion of patients who are still affected by these cancers, there is a pressing need for new therapeutic options, particularly since genome sequencing studies have revealed that these cancers can often have distinct underlying molecular mechanisms.
Vaccines lead the charge in HPV-driven cancers
German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).
A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.
HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.6,7
The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).8,9
Other immunotherapies are also being evaluated, including immune checkpoint inhibitors, antibodies designed to target one of the principal mechanisms of immune evasion exploited by cancer cells. The combination of immune checkpoint inhibitors with vaccines is a particularly promising strategy in HPV-associated cancers. At the European Society for Medical Oncology Congress in 2017, the results of a phase 2 trial of nivolumab in combination with ISA-101 were presented.
Among 24 patients with HPV-positive tumors, the majority oropharyngeal cancers, the combination elicited an overall response rate (ORR) of 33%, including 2 complete responses (CRs). Most adverse events (AEs) were mild to moderate in severity and included fever, injection site reactions, fatigue and nausea.14
Hepatocellular carcinoma: a tale of two viruses
The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.
The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.
HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.15,16
Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.
Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).
At the current time, the treatment strategy for patients with HCC is independent of etiology, however, there are significant ongoing efforts to try to tease out the implications of infection for treatment efficacy. A recent meta-analysis of patients treated with sorafenib in 3 randomized phase 3 trials (n = 3,526) suggested that it improved overall survival (OS) among patients who were HCV-positive, but HBV-negative.21
Studies of the vascular endothelial growth factor receptor 2-targeting monoclonal antibody ramucirumab, on the other hand, suggested that it may have a greater OS benefit in patients with HBV, while regorafenib seemed to have a comparable OS benefit in both subgroups.22-25 The immune checkpoint inhibitors studied thus far seem to elicit responses irrespective of infection status.
A phase 2 trial of the immune checkpoint inhibitor tremelimumab was conducted specifically in patients with advanced HCC and chronic HCV infection. The disease control rate (DCR) was 76.4%, with 17.6% partial response (PR) rate. There was also a significant drop in viral load, suggesting that tremelimumab may have antiviral effects.26,27,28
Adoptive cell therapy promising in EBV-positive cancers
More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.
EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.29
The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).
Two presentations at the American Society of Hematology annual meeting in 2017 detailed ongoing clinical trials of Atara Biotherapeutics’ ATA129 and Cell Medica’s CMD-003. ATA129 was associated with a high response rate and a low rate of serious AEs in patients with posttransplant lymphoproliferative disorder; ORR was 80% in 6 patients treated after hematopoietic stem cell transplantation, and 83% in 6 patients after solid organ transplant.30
CMD-003, meanwhile, demonstrated preliminary signs of activity and safety in patients with relapsed extranodal NK/T-cell lymphoma, according to early results from the phase 2 CITADEL trial. Among 6 evaluable patients, the ORR was 50% and the DCR was 67%.31
Newest oncovirus on the block
The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.
MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.32-34
The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.35 Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.
Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.36
Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.
The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.
The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.
1. Rous PA. Transmissible avain neoplasm. (Sarcoma of the common fowl). J Exp Med. 1910;12(5):696-705.
2. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964;1(7335):702-703.
3. Mesri Enrique A, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host & Microbe. 2014;15(3):266-282.
4. Santana-Davila R, Bhatia S, Chow LQ. Harnessing the immune system as a therapeutic tool in virus-associated cancers. JAMA Oncol. 2017;3(1):106-112.
5. Tashiro H, Brenner MK. Immunotherapy against cancer-related viruses. Cell Res. 2017;27(1):59-73.
6. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40(2):80-85.
7. Tulay P, Serakinci N. The route to HPV-associated neoplastic transformation: a review of the literature. Crit Rev Eukaryot Gene Expr. 2016;26(1):27-39.
8. Smola S. Immunopathogenesis of HPV-associated cancers and prospects for immunotherapy. Viruses. 2017;9(9).
9. Rosales R, Rosales C. Immune therapy for human papillomaviruses-related cancers. World Journal of Clinical Oncology. 2014;5(5):1002-1019.
10. Miles B, Safran HP, Monk BJ. Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11-001. Gynecol Oncol Res Pract. 2017;4:10.
11. Miles BA, Monk BJ, Safran HP. Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy. Gynecol Oncol Res Pract. 2017;4:9.
12. Huh W, Dizon D, Powell M, Landrum L, Leath C. A prospective phase II trial of the listeria-based human papillomavirus immunotherapy axalimogene filolisbac in second and third-line metastatic cervical cancer: A NRG oncology group trial. Paper presented at: Annual Meeting on Women's Cancer; March 12-15, 2017, 2017; National Harbor, MD.
13. Petit RG, Mehta A, Jain M, et al. ADXS11-001 immunotherapy targeting HPV-E7: final results from a Phase II study in Indian women with recurrent cervical cancer. Journal for Immunotherapy of Cancer. 2014;2(Suppl 3):P92-P92.
14. Glisson B, Massarelli E, William W, et al. Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer. Ann Oncol. 2017;28(suppl_5):v403-v427.
15. Ding X-X, Zhu Q-G, Zhang S-M, et al. Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget. 2017;8(33):55715-55730.
16. Ringehan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2017;372(1732):20160274.
17. Abou-Alfa G, Meyer T, Cheng AL, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2017;36(Suppl 4S):abstr 207.
18. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018.
19. Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol. 2018;36(Suppl 4S):Abstr 209.
20. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. Journal of Clinical Oncology. 2017;35(15_suppl):4073-4073.
21. Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials. Journal of Clinical Oncology. 2017;35(6):622-628.
22. Kudo M. Molecular Targeted Agents for Hepatocellular Carcinoma: Current Status and Future Perspectives. Liver Cancer. 2017;6(2):101-112.
23. zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW. Attempts to detect virus-secific DNA in human tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer. 1974;13(5):650-656.
24. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66.
25. Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412-3419.
26. Neparidze N, Lacy J. Malignancies associated with epstein-barr virus: pathobiology, clinical features, and evolving treatments. Clin Adv Hematol Oncol. 2014;12(6):358-371.
27. Ozoya OO, Sokol L, Dalia S. EBV-Related Malignancies, Outcomes and Novel Prevention Strategies. Infect Disord Drug Targets. 2016;16(1):4-21.
28. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-88.
29. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202.
30. Prockop S, Li A, Baiocchi R, et al. Efficacy and safety of ATA129, partially matched allogeneic third-party Epstein-Barr virus-targeted cytotoxic T lymphocytes in a multicenter study for post-transplant lymphoproliferative disorder. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
31. Kim W, Ardeshna K, Lin Y, et al. Autologous EBV-specific T cells (CMD-003): Early results from a multicenter, multinational Phase 2 trial for treatment of EBV-associated NK/T-cell lymphoma. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
32. Schadendorf D, Lebbé C, zur Hausen A, et al. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. European Journal of Cancer. 2017;71:53-69.
33. Spurgeon ME, Lambert PF. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology. 2013;435(1):118-130.
34. Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: An update and review: Current and future therapy. J Am Acad Dermatol. 2018;78(3):445-454.
35. American Cancer Society. Key Statistics for Merkel Cell Carcinoma. 2015; https://www.cancer.org/cancer/merkel-cell-skin-cancer/about/key-statistics.html#written_by. Accessed March 7th, 2017.
36. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology.17(10):1374-1385.
Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.
The link between viruses and cancer
Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.1
The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.2Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.3
In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.
Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.
Viruses hijack the cellular machinery to meet those needs and they can do this either by producing viral proteins that have an oncogenic effect or by integrating their genetic material into the host cell genome. When the latter occurs, the process of integration can also cause damage to the DNA, which further increases the risk of cancer-promoting changes occurring in the host genome.
Viruses can indirectly contribute to carcinogenesis by fostering a microenvironment of chronic inflammation, causing oxidative stress and local tissue damage, and by suppressing the antitumor immune response.4,5
Screening and prevention efforts have helped to reduce the burden of several different virally associated cancers. However, for the substantial proportion of patients who are still affected by these cancers, there is a pressing need for new therapeutic options, particularly since genome sequencing studies have revealed that these cancers can often have distinct underlying molecular mechanisms.
Vaccines lead the charge in HPV-driven cancers
German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).
A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.
HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.6,7
The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).8,9
Other immunotherapies are also being evaluated, including immune checkpoint inhibitors, antibodies designed to target one of the principal mechanisms of immune evasion exploited by cancer cells. The combination of immune checkpoint inhibitors with vaccines is a particularly promising strategy in HPV-associated cancers. At the European Society for Medical Oncology Congress in 2017, the results of a phase 2 trial of nivolumab in combination with ISA-101 were presented.
Among 24 patients with HPV-positive tumors, the majority oropharyngeal cancers, the combination elicited an overall response rate (ORR) of 33%, including 2 complete responses (CRs). Most adverse events (AEs) were mild to moderate in severity and included fever, injection site reactions, fatigue and nausea.14
Hepatocellular carcinoma: a tale of two viruses
The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.
The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.
HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.15,16
Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.
Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).
At the current time, the treatment strategy for patients with HCC is independent of etiology, however, there are significant ongoing efforts to try to tease out the implications of infection for treatment efficacy. A recent meta-analysis of patients treated with sorafenib in 3 randomized phase 3 trials (n = 3,526) suggested that it improved overall survival (OS) among patients who were HCV-positive, but HBV-negative.21
Studies of the vascular endothelial growth factor receptor 2-targeting monoclonal antibody ramucirumab, on the other hand, suggested that it may have a greater OS benefit in patients with HBV, while regorafenib seemed to have a comparable OS benefit in both subgroups.22-25 The immune checkpoint inhibitors studied thus far seem to elicit responses irrespective of infection status.
A phase 2 trial of the immune checkpoint inhibitor tremelimumab was conducted specifically in patients with advanced HCC and chronic HCV infection. The disease control rate (DCR) was 76.4%, with 17.6% partial response (PR) rate. There was also a significant drop in viral load, suggesting that tremelimumab may have antiviral effects.26,27,28
Adoptive cell therapy promising in EBV-positive cancers
More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.
EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.29
The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).
Two presentations at the American Society of Hematology annual meeting in 2017 detailed ongoing clinical trials of Atara Biotherapeutics’ ATA129 and Cell Medica’s CMD-003. ATA129 was associated with a high response rate and a low rate of serious AEs in patients with posttransplant lymphoproliferative disorder; ORR was 80% in 6 patients treated after hematopoietic stem cell transplantation, and 83% in 6 patients after solid organ transplant.30
CMD-003, meanwhile, demonstrated preliminary signs of activity and safety in patients with relapsed extranodal NK/T-cell lymphoma, according to early results from the phase 2 CITADEL trial. Among 6 evaluable patients, the ORR was 50% and the DCR was 67%.31
Newest oncovirus on the block
The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.
MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.32-34
The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.35 Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.
Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.36
Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.
The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.
The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.
Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.
The link between viruses and cancer
Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.1
The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.2Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.3
In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.
Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.
Viruses hijack the cellular machinery to meet those needs and they can do this either by producing viral proteins that have an oncogenic effect or by integrating their genetic material into the host cell genome. When the latter occurs, the process of integration can also cause damage to the DNA, which further increases the risk of cancer-promoting changes occurring in the host genome.
Viruses can indirectly contribute to carcinogenesis by fostering a microenvironment of chronic inflammation, causing oxidative stress and local tissue damage, and by suppressing the antitumor immune response.4,5
Screening and prevention efforts have helped to reduce the burden of several different virally associated cancers. However, for the substantial proportion of patients who are still affected by these cancers, there is a pressing need for new therapeutic options, particularly since genome sequencing studies have revealed that these cancers can often have distinct underlying molecular mechanisms.
Vaccines lead the charge in HPV-driven cancers
German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).
A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.
HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.6,7
The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).8,9
Other immunotherapies are also being evaluated, including immune checkpoint inhibitors, antibodies designed to target one of the principal mechanisms of immune evasion exploited by cancer cells. The combination of immune checkpoint inhibitors with vaccines is a particularly promising strategy in HPV-associated cancers. At the European Society for Medical Oncology Congress in 2017, the results of a phase 2 trial of nivolumab in combination with ISA-101 were presented.
Among 24 patients with HPV-positive tumors, the majority oropharyngeal cancers, the combination elicited an overall response rate (ORR) of 33%, including 2 complete responses (CRs). Most adverse events (AEs) were mild to moderate in severity and included fever, injection site reactions, fatigue and nausea.14
Hepatocellular carcinoma: a tale of two viruses
The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.
The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.
HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.15,16
Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.
Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).
At the current time, the treatment strategy for patients with HCC is independent of etiology, however, there are significant ongoing efforts to try to tease out the implications of infection for treatment efficacy. A recent meta-analysis of patients treated with sorafenib in 3 randomized phase 3 trials (n = 3,526) suggested that it improved overall survival (OS) among patients who were HCV-positive, but HBV-negative.21
Studies of the vascular endothelial growth factor receptor 2-targeting monoclonal antibody ramucirumab, on the other hand, suggested that it may have a greater OS benefit in patients with HBV, while regorafenib seemed to have a comparable OS benefit in both subgroups.22-25 The immune checkpoint inhibitors studied thus far seem to elicit responses irrespective of infection status.
A phase 2 trial of the immune checkpoint inhibitor tremelimumab was conducted specifically in patients with advanced HCC and chronic HCV infection. The disease control rate (DCR) was 76.4%, with 17.6% partial response (PR) rate. There was also a significant drop in viral load, suggesting that tremelimumab may have antiviral effects.26,27,28
Adoptive cell therapy promising in EBV-positive cancers
More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.
EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.29
The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).
Two presentations at the American Society of Hematology annual meeting in 2017 detailed ongoing clinical trials of Atara Biotherapeutics’ ATA129 and Cell Medica’s CMD-003. ATA129 was associated with a high response rate and a low rate of serious AEs in patients with posttransplant lymphoproliferative disorder; ORR was 80% in 6 patients treated after hematopoietic stem cell transplantation, and 83% in 6 patients after solid organ transplant.30
CMD-003, meanwhile, demonstrated preliminary signs of activity and safety in patients with relapsed extranodal NK/T-cell lymphoma, according to early results from the phase 2 CITADEL trial. Among 6 evaluable patients, the ORR was 50% and the DCR was 67%.31
Newest oncovirus on the block
The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.
MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.32-34
The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.35 Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.
Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.36
Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.
The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.
The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.
1. Rous PA. Transmissible avain neoplasm. (Sarcoma of the common fowl). J Exp Med. 1910;12(5):696-705.
2. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964;1(7335):702-703.
3. Mesri Enrique A, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host & Microbe. 2014;15(3):266-282.
4. Santana-Davila R, Bhatia S, Chow LQ. Harnessing the immune system as a therapeutic tool in virus-associated cancers. JAMA Oncol. 2017;3(1):106-112.
5. Tashiro H, Brenner MK. Immunotherapy against cancer-related viruses. Cell Res. 2017;27(1):59-73.
6. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40(2):80-85.
7. Tulay P, Serakinci N. The route to HPV-associated neoplastic transformation: a review of the literature. Crit Rev Eukaryot Gene Expr. 2016;26(1):27-39.
8. Smola S. Immunopathogenesis of HPV-associated cancers and prospects for immunotherapy. Viruses. 2017;9(9).
9. Rosales R, Rosales C. Immune therapy for human papillomaviruses-related cancers. World Journal of Clinical Oncology. 2014;5(5):1002-1019.
10. Miles B, Safran HP, Monk BJ. Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11-001. Gynecol Oncol Res Pract. 2017;4:10.
11. Miles BA, Monk BJ, Safran HP. Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy. Gynecol Oncol Res Pract. 2017;4:9.
12. Huh W, Dizon D, Powell M, Landrum L, Leath C. A prospective phase II trial of the listeria-based human papillomavirus immunotherapy axalimogene filolisbac in second and third-line metastatic cervical cancer: A NRG oncology group trial. Paper presented at: Annual Meeting on Women's Cancer; March 12-15, 2017, 2017; National Harbor, MD.
13. Petit RG, Mehta A, Jain M, et al. ADXS11-001 immunotherapy targeting HPV-E7: final results from a Phase II study in Indian women with recurrent cervical cancer. Journal for Immunotherapy of Cancer. 2014;2(Suppl 3):P92-P92.
14. Glisson B, Massarelli E, William W, et al. Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer. Ann Oncol. 2017;28(suppl_5):v403-v427.
15. Ding X-X, Zhu Q-G, Zhang S-M, et al. Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget. 2017;8(33):55715-55730.
16. Ringehan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2017;372(1732):20160274.
17. Abou-Alfa G, Meyer T, Cheng AL, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2017;36(Suppl 4S):abstr 207.
18. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018.
19. Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol. 2018;36(Suppl 4S):Abstr 209.
20. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. Journal of Clinical Oncology. 2017;35(15_suppl):4073-4073.
21. Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials. Journal of Clinical Oncology. 2017;35(6):622-628.
22. Kudo M. Molecular Targeted Agents for Hepatocellular Carcinoma: Current Status and Future Perspectives. Liver Cancer. 2017;6(2):101-112.
23. zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW. Attempts to detect virus-secific DNA in human tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer. 1974;13(5):650-656.
24. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66.
25. Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412-3419.
26. Neparidze N, Lacy J. Malignancies associated with epstein-barr virus: pathobiology, clinical features, and evolving treatments. Clin Adv Hematol Oncol. 2014;12(6):358-371.
27. Ozoya OO, Sokol L, Dalia S. EBV-Related Malignancies, Outcomes and Novel Prevention Strategies. Infect Disord Drug Targets. 2016;16(1):4-21.
28. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-88.
29. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202.
30. Prockop S, Li A, Baiocchi R, et al. Efficacy and safety of ATA129, partially matched allogeneic third-party Epstein-Barr virus-targeted cytotoxic T lymphocytes in a multicenter study for post-transplant lymphoproliferative disorder. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
31. Kim W, Ardeshna K, Lin Y, et al. Autologous EBV-specific T cells (CMD-003): Early results from a multicenter, multinational Phase 2 trial for treatment of EBV-associated NK/T-cell lymphoma. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
32. Schadendorf D, Lebbé C, zur Hausen A, et al. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. European Journal of Cancer. 2017;71:53-69.
33. Spurgeon ME, Lambert PF. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology. 2013;435(1):118-130.
34. Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: An update and review: Current and future therapy. J Am Acad Dermatol. 2018;78(3):445-454.
35. American Cancer Society. Key Statistics for Merkel Cell Carcinoma. 2015; https://www.cancer.org/cancer/merkel-cell-skin-cancer/about/key-statistics.html#written_by. Accessed March 7th, 2017.
36. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology.17(10):1374-1385.
1. Rous PA. Transmissible avain neoplasm. (Sarcoma of the common fowl). J Exp Med. 1910;12(5):696-705.
2. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964;1(7335):702-703.
3. Mesri Enrique A, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host & Microbe. 2014;15(3):266-282.
4. Santana-Davila R, Bhatia S, Chow LQ. Harnessing the immune system as a therapeutic tool in virus-associated cancers. JAMA Oncol. 2017;3(1):106-112.
5. Tashiro H, Brenner MK. Immunotherapy against cancer-related viruses. Cell Res. 2017;27(1):59-73.
6. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40(2):80-85.
7. Tulay P, Serakinci N. The route to HPV-associated neoplastic transformation: a review of the literature. Crit Rev Eukaryot Gene Expr. 2016;26(1):27-39.
8. Smola S. Immunopathogenesis of HPV-associated cancers and prospects for immunotherapy. Viruses. 2017;9(9).
9. Rosales R, Rosales C. Immune therapy for human papillomaviruses-related cancers. World Journal of Clinical Oncology. 2014;5(5):1002-1019.
10. Miles B, Safran HP, Monk BJ. Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11-001. Gynecol Oncol Res Pract. 2017;4:10.
11. Miles BA, Monk BJ, Safran HP. Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy. Gynecol Oncol Res Pract. 2017;4:9.
12. Huh W, Dizon D, Powell M, Landrum L, Leath C. A prospective phase II trial of the listeria-based human papillomavirus immunotherapy axalimogene filolisbac in second and third-line metastatic cervical cancer: A NRG oncology group trial. Paper presented at: Annual Meeting on Women's Cancer; March 12-15, 2017, 2017; National Harbor, MD.
13. Petit RG, Mehta A, Jain M, et al. ADXS11-001 immunotherapy targeting HPV-E7: final results from a Phase II study in Indian women with recurrent cervical cancer. Journal for Immunotherapy of Cancer. 2014;2(Suppl 3):P92-P92.
14. Glisson B, Massarelli E, William W, et al. Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer. Ann Oncol. 2017;28(suppl_5):v403-v427.
15. Ding X-X, Zhu Q-G, Zhang S-M, et al. Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget. 2017;8(33):55715-55730.
16. Ringehan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2017;372(1732):20160274.
17. Abou-Alfa G, Meyer T, Cheng AL, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2017;36(Suppl 4S):abstr 207.
18. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018.
19. Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol. 2018;36(Suppl 4S):Abstr 209.
20. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. Journal of Clinical Oncology. 2017;35(15_suppl):4073-4073.
21. Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials. Journal of Clinical Oncology. 2017;35(6):622-628.
22. Kudo M. Molecular Targeted Agents for Hepatocellular Carcinoma: Current Status and Future Perspectives. Liver Cancer. 2017;6(2):101-112.
23. zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW. Attempts to detect virus-secific DNA in human tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer. 1974;13(5):650-656.
24. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66.
25. Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412-3419.
26. Neparidze N, Lacy J. Malignancies associated with epstein-barr virus: pathobiology, clinical features, and evolving treatments. Clin Adv Hematol Oncol. 2014;12(6):358-371.
27. Ozoya OO, Sokol L, Dalia S. EBV-Related Malignancies, Outcomes and Novel Prevention Strategies. Infect Disord Drug Targets. 2016;16(1):4-21.
28. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-88.
29. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202.
30. Prockop S, Li A, Baiocchi R, et al. Efficacy and safety of ATA129, partially matched allogeneic third-party Epstein-Barr virus-targeted cytotoxic T lymphocytes in a multicenter study for post-transplant lymphoproliferative disorder. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
31. Kim W, Ardeshna K, Lin Y, et al. Autologous EBV-specific T cells (CMD-003): Early results from a multicenter, multinational Phase 2 trial for treatment of EBV-associated NK/T-cell lymphoma. Paper presented at: 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017, 2017; Atlanta, GA.
32. Schadendorf D, Lebbé C, zur Hausen A, et al. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. European Journal of Cancer. 2017;71:53-69.
33. Spurgeon ME, Lambert PF. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology. 2013;435(1):118-130.
34. Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: An update and review: Current and future therapy. J Am Acad Dermatol. 2018;78(3):445-454.
35. American Cancer Society. Key Statistics for Merkel Cell Carcinoma. 2015; https://www.cancer.org/cancer/merkel-cell-skin-cancer/about/key-statistics.html#written_by. Accessed March 7th, 2017.
36. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology.17(10):1374-1385.
