Sarcoma & GIST

Osteosarcoma (OS) is a rare disease with approximately 800- 900 newly diagnosed cases each year in the United States. Of those, the majority occur about the knee. The distal femur is the most common site, followed by the proximal tibia, with the proximal humerus being a distant third. OS of the clavicle has been reported, with the earliest case report dating from 1975.1 Since then, additional case reports of high-grade OS of the clavicle have been published.^2,3 We describe the case of a 16-year-old female who presented with a mass on her right medial clavicle, which was confirmed to be a low-grade central OS.

Case Presentation

The patient is a 16-year-old female who presented to the Emergency Department (ED) for evaluation of a mass on her right clavicle, after being evaluated by her primary care physician (PCP). She noted an enlarging mass over the previous 2 months but stated that it had been asymptomatic until 4 days prior to presentation to her PCP, at which time she had developed tenderness to palpation and pain with range of motion of the right arm. X-rays were obtained at the PCP’s office and she was referred to the ED for further evaluation. She denied constitutional symptoms.

At the ED visit, she was noted to have an area of erythema and tenderness over the medial aspect of the right clavicle with increased bony prominence. A chest x-ray demonstrated medial clavicle enlargement with periosteal reaction and sclerosis (Figure 1).

MRI demonstrated a 6-cm x 3.8-cm x 4.1-cm mass arising from the right medial clavicle with cortical destruction and concomitant displacement of the right subclavian and brachiocephalic veins (Figure 2). A CT-guided biopsy was performed 1 week later and demonstrated low-grade OS. The pathologist was concerned about the possibility of sampling error and the presence of a higher-grade component, as low-grade OS of the clavicle had not been reported.

The patient was evaluated by a pediatric hematologist/oncologist 2 weeks later after having obtained the biopsy and a PET/CT scan. At that time, the PET/CT showed an FDG-avid mass at the clavicle without evidence of pulmonary metastatic disease (Figure 3). She was subsequently evaluated by orthopedic oncology, at which time a discussion was had regarding further treatment. There was essentially no literature to guide the surgical and medical teams, as low-grade clavicular OS is unknown. Based on the evidence of localized, low-grade disease, the determination was made to proceedwith surgical resection. In the event that high-grade disease was identified at the time of final pathological evaluation, the pediatric hematology/oncology team felt that administering all of the patient’s chemotherapy postoperatively would be acceptable and not affect her long-term prognosis. CT and CT angiogram were obtained for further operative planning (Figure 4).

Given the intimacy of the mass to the subclavian vessels, she was also seen preoperatively by pediatric general and cardiothoracic surgeons. The plan was formulated to have them in the operating room for mobilization of the subclavian vessels and in the event that a sternotomy was required for proximal control of the vessels. Following this visit, the case was discussed at the multidisciplinary pediatric tumor board and the consensus was to proceed with surgical resection.

Surgical Technique

General endotracheal anesthesia was administered without complication. The patient was positioned supine with a soft bump under her shoulders to place her neck in slight extension and thus facilitate access to the clavicle and great vessels. A 14-cm oblique incision was made over the subcutaneous clavicle extending to the contralateral sternoclavicular joint. Dissection was carried down to the fascia and the biopsy site was excised with the skin paddle. Dissection was carried through the sternocleidomastoid superiorly and the pectoralis major inferiorly, to 8 cm lateral from the right sternoclavicular joint. The clavicle was osteotomized well lateral of the palpable tumor and a marrow margin was sent for frozen section, which was found to be negative.

Dissection was continued circumferentially. Assistance from pediatric general and cardiothoracic surgery was required at the inferior aspect of the mass to assist with exposure and control of the subclavian vein (Figure 5A). A large branch of the subclavian vein near its junction with the internal jugular vein was found to be involved with the tumor and thus required suture ligation. The subclavian vein was noted to be intimate with the mass and somewhat friable. With the vein mobilized, a cuff of normal tissue was obtained inferiorly and superiorly to the mass. Medially, the sternoclavicular joint was disarticulated (Figure 5B). At this point, the specimen was delivered from the operative field and tagged in the usual fashion (Figure 5C). A medial soft tissue margin from the sternal side of the sternoclavicular joint was also sent and found to be negative for tumor. The wound was closed in layered fashion over a ¼” Penrose drain. A soft dressing was placed, and the patient was successfully extubated and transferred to the post-anesthesia care unit in stable condition.

Postoperative Course

The patient was found to be neurologically and vascularly intact on postoperative exam and was discharged on postoperative day 1.

She was seen 14 days postoperatively and was doing well at that time, with full range of motion of the shoulder, elbow, wrist, and hand. Final pathology confirmed a low-grade OS with extraosseous extension. All margins were negative except the medial (sternoclavicular joint) margin and the inferior margin adjacent to the subclavian vein. The intraoperative frozen section from the medial margin was negative for tumor.

The pediatric hematology/oncology team determined that, as no high-grade areas were identified, chemotherapy should be deferred. The positive margins were also discussed with the patient and her family specifically regarding further possible treatments. The findings from the pathology were discussed in a multidisciplinary tumor board and it was felt that, given the low-grade nature of the lesion as well as the high morbidity and risk of mortality with further surgery, additional surgery would be potentially more harmful than helpful. Additionally, low-grade OS is extremely resistant to radiotherapy. The plan remains to monitor her for local recurrence as well as metastases with serial imaging.

Discussion

The clavicle is one of the first bones in the body to ossify but one of the last to have final physeal closure. Its unique characteristics have led to various descriptions, such as a “short tubular bone” versus a “flat bone.”^4,5 Of note are its paucity of a true intramedullary space and scanty red marrow, which make it an unlikely site for a primarily intramedullary- based neoplasm to arise.4 However, it has also been noted that malignant lesions are more common in the clavicle than benign lesions, and special attention should be paid to aggressiveappearing lesions in the clavicle.

Radiographs can be misleading as well. Prior studies have demonstrated that low-grade central OS can be readily misdiagnosed as fibrous dysplasia, desmoplastic fibroma, nonossifying fibroma, osteoblastoma, and aneurysmal bone cyst.6 Findings found in low-grade OS can include evidence of cortical interruption, local soft tissue mass development, intramedullary involvement, cortical destruction, and poor margination; however, low-grade OS is typically sclerotic and highly trabeculated. Cross-sectional imaging can help differentiate between OS and other more benign pathologies and should be considered in the clavicle where biopsy may be perilous.⁵

In this case, wide resection was carried out with the subclavian vein as the posterior-inferior margin and the sternoclavicular joint as the medial margin. Though the intra-operative medial margin was clear of disease, final pathology demonstrated focal (microscopic) involvement of the posterior and medial margins. A study of soft tissue sarcoma evaluated positive margins and concluded that the imperative of preservation of vital structures supersedes the need for negative margins.^7,8 The rate of metastasis and overall survival was similar to surgical resections with positive margins. In the case of our patient, further resection would have carried significant morbidity and possibly mortality, including sacrifice of the major vessels to the arm below and entering into the sternum and thoracic cavity. The likely disability as well as the hazards of surgery were deemed to be too great to justify further excision. Frequent cross-sectional imaging will be necessary to evaluate the presence of recurrent or metastatic disease. To our knowledge, this is the first documented case of low-grade clavicle OS. This report demonstrates the need for multidisciplinary sarcoma care at a center of excellence, particularly in instances of unusual diagnoses.

Osteosarcoma (OS) is a rare disease with approximately 800- 900 newly diagnosed cases each year in the United States. Of those, the majority occur about the knee. The distal femur is the most common site, followed by the proximal tibia, with the proximal humerus being a distant third. OS of the clavicle has been reported, with the earliest case report dating from 1975.1 Since then, additional case reports of high-grade OS of the clavicle have been published.^2,3 We describe the case of a 16-year-old female who presented with a mass on her right medial clavicle, which was confirmed to be a low-grade central OS.

Case Presentation

The patient is a 16-year-old female who presented to the Emergency Department (ED) for evaluation of a mass on her right clavicle, after being evaluated by her primary care physician (PCP). She noted an enlarging mass over the previous 2 months but stated that it had been asymptomatic until 4 days prior to presentation to her PCP, at which time she had developed tenderness to palpation and pain with range of motion of the right arm. X-rays were obtained at the PCP’s office and she was referred to the ED for further evaluation. She denied constitutional symptoms.

At the ED visit, she was noted to have an area of erythema and tenderness over the medial aspect of the right clavicle with increased bony prominence. A chest x-ray demonstrated medial clavicle enlargement with periosteal reaction and sclerosis (Figure 1).

MRI demonstrated a 6-cm x 3.8-cm x 4.1-cm mass arising from the right medial clavicle with cortical destruction and concomitant displacement of the right subclavian and brachiocephalic veins (Figure 2). A CT-guided biopsy was performed 1 week later and demonstrated low-grade OS. The pathologist was concerned about the possibility of sampling error and the presence of a higher-grade component, as low-grade OS of the clavicle had not been reported.

The patient was evaluated by a pediatric hematologist/oncologist 2 weeks later after having obtained the biopsy and a PET/CT scan. At that time, the PET/CT showed an FDG-avid mass at the clavicle without evidence of pulmonary metastatic disease (Figure 3). She was subsequently evaluated by orthopedic oncology, at which time a discussion was had regarding further treatment. There was essentially no literature to guide the surgical and medical teams, as low-grade clavicular OS is unknown. Based on the evidence of localized, low-grade disease, the determination was made to proceedwith surgical resection. In the event that high-grade disease was identified at the time of final pathological evaluation, the pediatric hematology/oncology team felt that administering all of the patient’s chemotherapy postoperatively would be acceptable and not affect her long-term prognosis. CT and CT angiogram were obtained for further operative planning (Figure 4).

Given the intimacy of the mass to the subclavian vessels, she was also seen preoperatively by pediatric general and cardiothoracic surgeons. The plan was formulated to have them in the operating room for mobilization of the subclavian vessels and in the event that a sternotomy was required for proximal control of the vessels. Following this visit, the case was discussed at the multidisciplinary pediatric tumor board and the consensus was to proceed with surgical resection.

Surgical Technique

General endotracheal anesthesia was administered without complication. The patient was positioned supine with a soft bump under her shoulders to place her neck in slight extension and thus facilitate access to the clavicle and great vessels. A 14-cm oblique incision was made over the subcutaneous clavicle extending to the contralateral sternoclavicular joint. Dissection was carried down to the fascia and the biopsy site was excised with the skin paddle. Dissection was carried through the sternocleidomastoid superiorly and the pectoralis major inferiorly, to 8 cm lateral from the right sternoclavicular joint. The clavicle was osteotomized well lateral of the palpable tumor and a marrow margin was sent for frozen section, which was found to be negative.

Dissection was continued circumferentially. Assistance from pediatric general and cardiothoracic surgery was required at the inferior aspect of the mass to assist with exposure and control of the subclavian vein (Figure 5A). A large branch of the subclavian vein near its junction with the internal jugular vein was found to be involved with the tumor and thus required suture ligation. The subclavian vein was noted to be intimate with the mass and somewhat friable. With the vein mobilized, a cuff of normal tissue was obtained inferiorly and superiorly to the mass. Medially, the sternoclavicular joint was disarticulated (Figure 5B). At this point, the specimen was delivered from the operative field and tagged in the usual fashion (Figure 5C). A medial soft tissue margin from the sternal side of the sternoclavicular joint was also sent and found to be negative for tumor. The wound was closed in layered fashion over a ¼” Penrose drain. A soft dressing was placed, and the patient was successfully extubated and transferred to the post-anesthesia care unit in stable condition.

Postoperative Course

The patient was found to be neurologically and vascularly intact on postoperative exam and was discharged on postoperative day 1.

She was seen 14 days postoperatively and was doing well at that time, with full range of motion of the shoulder, elbow, wrist, and hand. Final pathology confirmed a low-grade OS with extraosseous extension. All margins were negative except the medial (sternoclavicular joint) margin and the inferior margin adjacent to the subclavian vein. The intraoperative frozen section from the medial margin was negative for tumor.

The pediatric hematology/oncology team determined that, as no high-grade areas were identified, chemotherapy should be deferred. The positive margins were also discussed with the patient and her family specifically regarding further possible treatments. The findings from the pathology were discussed in a multidisciplinary tumor board and it was felt that, given the low-grade nature of the lesion as well as the high morbidity and risk of mortality with further surgery, additional surgery would be potentially more harmful than helpful. Additionally, low-grade OS is extremely resistant to radiotherapy. The plan remains to monitor her for local recurrence as well as metastases with serial imaging.

Discussion

The clavicle is one of the first bones in the body to ossify but one of the last to have final physeal closure. Its unique characteristics have led to various descriptions, such as a “short tubular bone” versus a “flat bone.”^4,5 Of note are its paucity of a true intramedullary space and scanty red marrow, which make it an unlikely site for a primarily intramedullary- based neoplasm to arise.4 However, it has also been noted that malignant lesions are more common in the clavicle than benign lesions, and special attention should be paid to aggressiveappearing lesions in the clavicle.

Radiographs can be misleading as well. Prior studies have demonstrated that low-grade central OS can be readily misdiagnosed as fibrous dysplasia, desmoplastic fibroma, nonossifying fibroma, osteoblastoma, and aneurysmal bone cyst.6 Findings found in low-grade OS can include evidence of cortical interruption, local soft tissue mass development, intramedullary involvement, cortical destruction, and poor margination; however, low-grade OS is typically sclerotic and highly trabeculated. Cross-sectional imaging can help differentiate between OS and other more benign pathologies and should be considered in the clavicle where biopsy may be perilous.⁵

In this case, wide resection was carried out with the subclavian vein as the posterior-inferior margin and the sternoclavicular joint as the medial margin. Though the intra-operative medial margin was clear of disease, final pathology demonstrated focal (microscopic) involvement of the posterior and medial margins. A study of soft tissue sarcoma evaluated positive margins and concluded that the imperative of preservation of vital structures supersedes the need for negative margins.^7,8 The rate of metastasis and overall survival was similar to surgical resections with positive margins. In the case of our patient, further resection would have carried significant morbidity and possibly mortality, including sacrifice of the major vessels to the arm below and entering into the sternum and thoracic cavity. The likely disability as well as the hazards of surgery were deemed to be too great to justify further excision. Frequent cross-sectional imaging will be necessary to evaluate the presence of recurrent or metastatic disease. To our knowledge, this is the first documented case of low-grade clavicle OS. This report demonstrates the need for multidisciplinary sarcoma care at a center of excellence, particularly in instances of unusual diagnoses.

Osteosarcoma (OS) is a rare disease with approximately 800- 900 newly diagnosed cases each year in the United States. Of those, the majority occur about the knee. The distal femur is the most common site, followed by the proximal tibia, with the proximal humerus being a distant third. OS of the clavicle has been reported, with the earliest case report dating from 1975.1 Since then, additional case reports of high-grade OS of the clavicle have been published.^2,3 We describe the case of a 16-year-old female who presented with a mass on her right medial clavicle, which was confirmed to be a low-grade central OS.

Case Presentation

The patient is a 16-year-old female who presented to the Emergency Department (ED) for evaluation of a mass on her right clavicle, after being evaluated by her primary care physician (PCP). She noted an enlarging mass over the previous 2 months but stated that it had been asymptomatic until 4 days prior to presentation to her PCP, at which time she had developed tenderness to palpation and pain with range of motion of the right arm. X-rays were obtained at the PCP’s office and she was referred to the ED for further evaluation. She denied constitutional symptoms.

At the ED visit, she was noted to have an area of erythema and tenderness over the medial aspect of the right clavicle with increased bony prominence. A chest x-ray demonstrated medial clavicle enlargement with periosteal reaction and sclerosis (Figure 1).

MRI demonstrated a 6-cm x 3.8-cm x 4.1-cm mass arising from the right medial clavicle with cortical destruction and concomitant displacement of the right subclavian and brachiocephalic veins (Figure 2). A CT-guided biopsy was performed 1 week later and demonstrated low-grade OS. The pathologist was concerned about the possibility of sampling error and the presence of a higher-grade component, as low-grade OS of the clavicle had not been reported.

The patient was evaluated by a pediatric hematologist/oncologist 2 weeks later after having obtained the biopsy and a PET/CT scan. At that time, the PET/CT showed an FDG-avid mass at the clavicle without evidence of pulmonary metastatic disease (Figure 3). She was subsequently evaluated by orthopedic oncology, at which time a discussion was had regarding further treatment. There was essentially no literature to guide the surgical and medical teams, as low-grade clavicular OS is unknown. Based on the evidence of localized, low-grade disease, the determination was made to proceedwith surgical resection. In the event that high-grade disease was identified at the time of final pathological evaluation, the pediatric hematology/oncology team felt that administering all of the patient’s chemotherapy postoperatively would be acceptable and not affect her long-term prognosis. CT and CT angiogram were obtained for further operative planning (Figure 4).

Given the intimacy of the mass to the subclavian vessels, she was also seen preoperatively by pediatric general and cardiothoracic surgeons. The plan was formulated to have them in the operating room for mobilization of the subclavian vessels and in the event that a sternotomy was required for proximal control of the vessels. Following this visit, the case was discussed at the multidisciplinary pediatric tumor board and the consensus was to proceed with surgical resection.

Surgical Technique

General endotracheal anesthesia was administered without complication. The patient was positioned supine with a soft bump under her shoulders to place her neck in slight extension and thus facilitate access to the clavicle and great vessels. A 14-cm oblique incision was made over the subcutaneous clavicle extending to the contralateral sternoclavicular joint. Dissection was carried down to the fascia and the biopsy site was excised with the skin paddle. Dissection was carried through the sternocleidomastoid superiorly and the pectoralis major inferiorly, to 8 cm lateral from the right sternoclavicular joint. The clavicle was osteotomized well lateral of the palpable tumor and a marrow margin was sent for frozen section, which was found to be negative.

Dissection was continued circumferentially. Assistance from pediatric general and cardiothoracic surgery was required at the inferior aspect of the mass to assist with exposure and control of the subclavian vein (Figure 5A). A large branch of the subclavian vein near its junction with the internal jugular vein was found to be involved with the tumor and thus required suture ligation. The subclavian vein was noted to be intimate with the mass and somewhat friable. With the vein mobilized, a cuff of normal tissue was obtained inferiorly and superiorly to the mass. Medially, the sternoclavicular joint was disarticulated (Figure 5B). At this point, the specimen was delivered from the operative field and tagged in the usual fashion (Figure 5C). A medial soft tissue margin from the sternal side of the sternoclavicular joint was also sent and found to be negative for tumor. The wound was closed in layered fashion over a ¼” Penrose drain. A soft dressing was placed, and the patient was successfully extubated and transferred to the post-anesthesia care unit in stable condition.

Postoperative Course

The patient was found to be neurologically and vascularly intact on postoperative exam and was discharged on postoperative day 1.

She was seen 14 days postoperatively and was doing well at that time, with full range of motion of the shoulder, elbow, wrist, and hand. Final pathology confirmed a low-grade OS with extraosseous extension. All margins were negative except the medial (sternoclavicular joint) margin and the inferior margin adjacent to the subclavian vein. The intraoperative frozen section from the medial margin was negative for tumor.

The pediatric hematology/oncology team determined that, as no high-grade areas were identified, chemotherapy should be deferred. The positive margins were also discussed with the patient and her family specifically regarding further possible treatments. The findings from the pathology were discussed in a multidisciplinary tumor board and it was felt that, given the low-grade nature of the lesion as well as the high morbidity and risk of mortality with further surgery, additional surgery would be potentially more harmful than helpful. Additionally, low-grade OS is extremely resistant to radiotherapy. The plan remains to monitor her for local recurrence as well as metastases with serial imaging.

Discussion

The clavicle is one of the first bones in the body to ossify but one of the last to have final physeal closure. Its unique characteristics have led to various descriptions, such as a “short tubular bone” versus a “flat bone.”^4,5 Of note are its paucity of a true intramedullary space and scanty red marrow, which make it an unlikely site for a primarily intramedullary- based neoplasm to arise.4 However, it has also been noted that malignant lesions are more common in the clavicle than benign lesions, and special attention should be paid to aggressiveappearing lesions in the clavicle.

Radiographs can be misleading as well. Prior studies have demonstrated that low-grade central OS can be readily misdiagnosed as fibrous dysplasia, desmoplastic fibroma, nonossifying fibroma, osteoblastoma, and aneurysmal bone cyst.6 Findings found in low-grade OS can include evidence of cortical interruption, local soft tissue mass development, intramedullary involvement, cortical destruction, and poor margination; however, low-grade OS is typically sclerotic and highly trabeculated. Cross-sectional imaging can help differentiate between OS and other more benign pathologies and should be considered in the clavicle where biopsy may be perilous.⁵

In this case, wide resection was carried out with the subclavian vein as the posterior-inferior margin and the sternoclavicular joint as the medial margin. Though the intra-operative medial margin was clear of disease, final pathology demonstrated focal (microscopic) involvement of the posterior and medial margins. A study of soft tissue sarcoma evaluated positive margins and concluded that the imperative of preservation of vital structures supersedes the need for negative margins.^7,8 The rate of metastasis and overall survival was similar to surgical resections with positive margins. In the case of our patient, further resection would have carried significant morbidity and possibly mortality, including sacrifice of the major vessels to the arm below and entering into the sternum and thoracic cavity. The likely disability as well as the hazards of surgery were deemed to be too great to justify further excision. Frequent cross-sectional imaging will be necessary to evaluate the presence of recurrent or metastatic disease. To our knowledge, this is the first documented case of low-grade clavicle OS. This report demonstrates the need for multidisciplinary sarcoma care at a center of excellence, particularly in instances of unusual diagnoses.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were 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). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could 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 the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-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.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

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 therapy patients received was 4 (range 2-6) and the median number of cycles 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.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose 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. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 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, reporting at CTOS 2018.

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/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). 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, or 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.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

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%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were 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). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could 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 the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-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.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

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 therapy patients received was 4 (range 2-6) and the median number of cycles 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.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose 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. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 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, reporting at CTOS 2018.

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/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). 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, or 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.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

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%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were 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). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could 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 the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-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.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

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 therapy patients received was 4 (range 2-6) and the median number of cycles 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.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose 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. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 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, reporting at CTOS 2018.

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/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). 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, or 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.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

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%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.