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BACKGROUND This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12). RESULTS Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017. © 2017 American Cancer Society.

BACKGROUND Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2016. © 2016 American Cancer Society.

Importance Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog ( KIT ) and platelet-derived growth factor receptor α ( PDGFRA ) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

BACKGROUND Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a

Purpose: Aggressive fibromatoses (AF; desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. The Sarcoma Alliance for Research through Collaboration (SARC) initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or 1 of 10 sarcoma subtypes. Here, we report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib. Experimental Design: Patients ≥10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg twice daily [body surface area (BSA) ≥ 1.5 m2], 200 mg twice daily (BSA = 1.0-1.49 m2), or 100 mg twice daily (BSA < 1.0 m2). Response outcomes at 2 and 4 months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of cKIT, platelet-derived growth factor receptor α (PDGFRα), PDGFRβ, AKT, PTEN, FKHR, and β-catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR. Results: Fifty-one patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of 2- and 4-month progression-free survival rates were 94% and 88%, respectively, and 1-year progression-free survival was 66%. Objective response rate was 6% (3 of 51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available. Conclusion: Imatinib may have a role in the management of unresectable or difficult to resect desmoid tumors. Clin Cancer Res; 16(19); 4884–91. ©2010 AACR.

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

Purpose Preoperative chemotherapy followed by surgery and adjuvant chemotherapy is a standard treatment for most patients with rectal cancer. We aimed to determine efficacy and tolerability of preoperative mitomycin, fluorouracil (5-FU), and leucovorin (LV) concurrent with hyperfractionated radiation therapy (RT) followed by surgery and adjuvant chemotherapy. Patients and Methods Patients with clinical stage II/III disease were treated with mitomycin 10 mg/m2 on day 1, continuous venous infusion 5-FU 600 mg/m2 per day for 96 hours, and oral LV 25 mg every 6 hours on days 1–5. All patients received concurrent RT in fractions of 150 cGy twice daily beginning on day 1. Unfixed tumors received 3000 cGy, whereas fixed tumors received a dose of 4500 cGy. Patients then underwent resection and postoperative adjuvant chemotherapy with oral LV and continuous venous infusion 5-FU 600 mg/m2 per day on days 1–5 on a 28-day cycle for 6 cycles. Primary endpoints were to determine the rate of pathologic response and downstaging, long-term locoregional control, progression-free survival, and overall survival. Results Between the years 1993 and 2000, 83 patients were enrolled. Eighteen patients (31%) were downstaged. Six patients (7%) had pathologic complete response. Median follow-up was 62 months with a 5-year overall survival of 71%. Local control rate was 96%. Treatment was well tolerated with stomatitis, diarrhea, and radiation proctitis being the most common toxicities. Conclusion This regimen is effective in the treatment of rectal carcinoma. The favorable toxicity profile of mitomycin and hyperfractionated RT allows these strategies to be utilized with the newer chemotherapies for this disease.

Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6 -methylguanine-DNA methyltransferase (MGMT). Administration of O 6-benzylguanine (O 6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O 6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma naive to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6 -BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11–25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9–NR). The most common grade 3–4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O 6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

The incidence of breast cancer increases with age. This trial evaluated the efficacy and safety of oral UFT (ftorafur plus uracil) plus leucovorin in elderly patients with advanced breast cancer. Eligibility criteria included ageor =65 years, locally advanced or metastatic breast cancer,or =1 prior chemotherapy regimens in the setting of metastatic disease, performance status 0-2, and adequate end-organ function. UFT at 300 mg/m2 per day as 2 divided doses and 30 mg leucovorin with each dose were administered orally daily for 21 days, followed by a 7-day rest period. Ten patients were accrued. Six patients received treatment in their first relapse and 3 in their second. One patient was chemotherapy-naive. The dose-limiting toxicity was diarrhea with grade 3 or 4 diarrhea occurring more often in the oldest patients (1 of 6 patients between 65 and 69 vs. 3 of 4 patientsor =70 years old). Protocol treatment was discontinued in 2 patients (ages 78 and 83) secondary to severe gastrointestinal toxicity. One patient achieved a partial response. Although UFT/leucovorin had efficacy in 1 patient, toxicity in the patients over 70 years of age was increased. Careful evaluation of anticancer drug toxicity in very elderly patients is important as our population ages.

Desmoid tumors frequently reoccur after surgery and radiation. The therapy of recurrent desmoid tumors is often unsatisfactory. Additional surgery may not be feasible. Drug therapy can sometimes be helpful, and even remarkably successful. Unfortunately, the rarity of desmoids precludes conduct of large clinical trials. Most series are small, anecdotal, and lack internal consistency. The lack of real understanding of desmoid biology has meant that therapies have, until now, been empirical rather than rationally designed. Nevertheless, a range of drugs is available to be utilized, including hormonal or hormonal antagonist therapy, cyclooxygenase inhibitors, biologic agents and cytotoxic chemotherapy. This review will utilize a patient case report to illustrate the problems frequently encountered in choosing therapy for patients with recurrent desmoid tumors. Based on this case, the review will explore the options available, as well as the process through which treatment options may be evaluated.

PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

BACKGROUND In a prior Cancer and Leukemia Group B (CALGB) Phase II trial of patients with advanced, previously untreated mesothelioma, dihydro-5-azacytidine (DHAC) demonstrated a 17% response rate, including 1 complete response, with only mild myelosuppression. This Phase II study (CALGB 9031) was conducted to determine the effectiveness of and toxicities that would result from adding cisplatin to DHAC administered to the same patient population. METHODS Thirty-six patients were treated with concurrent DHAC at 1500 mg/m2/day for 5 days by continuous infusion and cisplatin 15 mg/m2 daily for 5 days. Therapy was repeated every 3 weeks. Cisplatin was to be increased to 20 mg/m2 daily in subsequent cycles if toxicity was minimal. Therapy was continued until disease progression or excessive toxicity mandated discontinuation. RESULTS Overall, 5 objective responses were observed in 29 evaluated patients (objective response rate, 17%). The median duration of response was 6.6 months. Median survival was 6.4 months, with a median time to clinical failure of 2.7 months. The major toxicity noted was significant chest/pericardial pain, as was observed with DHAC alone. There were 2 early deaths of unknown cause on Days 9 and 17 of therapy, respectively. Significant leukopenia was observed in 29% of patients, but there were no neutropenic fevers. CONCLUSIONS The addition of cisplatin to DHAC did not increase the response rate over that observed with DHAC alone in patients with mesothelioma; however, it did increase toxicity, especially leukopenia. This combination is not recommended for further studies involving mesothelioma patients. Cancer 1998;82:1578-84. © 1998 American Cancer Society.

PURPOSE We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination. PATIENTS AND METHODS Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed. RESULTS Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies. CONCLUSION Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.

Purpose To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide. Patients and Methods Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m2 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m2 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images. Results Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted. Conclusion Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.

Purpose The purpose of this trial was to assess the efficacy of imatinib in patients with one of 10 different subtypes of advanced sarcoma. Patients and Methods Eligible patients were treated daily with imatinib dosed at 300 mg twice a day (for body-surface area ≥ 1.5 m2). The primary end point was response (clinical benefit response [CBR]), defined as complete (CR) or partial response (PR) at 2 months, or stable disease, CR, or PR at 4 months. Rules for early termination within each disease type were based on a Bayesian hierarchical probability model (BHM) accounting for correlation of the responses of the 10 subtypes. Available tissue samples were analyzed for molecules within the KIT/platelet-derived growth factor receptor (PDGFR) signal transduction pathway. Results One hundred eighty-five assessable patients with one of 10 subtypes of sarcoma were treated. One CR and three PRs were achieved. A CBR was achieved in 28 patients treated overall and by subtype: two angiosarcomas (n = 16), 0 Ewing (n = 13), one fibrosarcoma (n = 12), six leiomyosarcomas (n = 29), seven liposarcomas (n = 31), three malignant fibrous histiocytomas (n = 30), five osteosarcomas (n = 27), one malignant peripheral-nerve sheath tumor (n = 7), 0 rhabdomyosarcoma (n = 2), and three synovial sarcomas (n = 22). Variable expression and mutations within the KIT/PDGFR pathway were observed. Conclusion This is the first phase II study of a new agent in sarcoma to include sufficient patients with each of the common histologic subtypes to permit generalizable conclusions. The BHM is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Although rare dramatic responses were seen, imatinib is not an active agent in advanced sarcoma in these subtypes.

The Fourth International Conference on Malignant Lymphoma was held in Lugano, Switzerland, from June 6th to June 9th, 1990. It was attended by over 1100 delegates from around the world. As at previous Conferences, a large number of invited papers, brief presentations, and posters were presented on a wide variety of topics in the field of lymphoma research. A great deal of excitement was generated by the advances presented in the basic science sessions. Although steady progress is being made in the therapy of lymphomas, few major advances were reported in the clinical arena. In contrast, the application of the techniques of immunology and molecular genetics has resulted in fascinating discoveries that are increasing our understanding of the fundamental nature of lymphoproliferative disorders. These discoveries may lead to innovative therapeutic strategies unlike any currently in use.

Purpose: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma. Methods: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m2 immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m2 on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed. Results: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m2 and doxorubicin 60 mg/m2. Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration. Conclusion: The combination of doxorubicin 60 mg/m2 followed by trabectedin 1.1 mg/m2 every 21 days is safe and active in patients with soft-tissue sarcoma.

BACKGROUND. The authors studied a dose-intense regimen of epirubicin and ifosfamide with hypofractionated preoperative radiotherapy for high-risk soft tissue sarcomas. The primary objective was estimation of the rate of ≥95% pathologic necrosis. METHODS. Twenty-five patients with intermediate-grade or high-grade, localized soft tissue sarcomas of the extremity or body wall measuring >5 cm were treated with epirubicin at a dose of 30 mg/m2/day on Days 1 to 4 and ifosfamide at a dose of 2.5 g/m2/day on Days 1 to 4 every 21 days for 3 preoperative and 3 postoperative cycles. A total of 28 grays of radiation was administered over 8 fractions during Cycle 2 of preoperative therapy (epirubicin was omitted). RESULTS. Sixteen patients (64%) completed all chemotherapy cycles and the average delivered dose intensity relative to intended therapy was 69%. Twenty-one patients (84%) experienced grade 4 toxicity (using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 2.0]), which was predominantly hematologic. Notable toxicities included neutropenic fever (40%), ifosfamide-induced encephalopathy (24%), and grade 3/4 anemia (64%). Postoperative wound complications requiring a surgical procedure occurred in 20% of patients. The rate of ≥95% pathologic necrosis was 40% (95% confidence interval [95% CI], 21–59%). Estimates of 2-year overall and disease-free survival were 84% (95% CI, 66–100%) and 62% (95% CI, 37–86%), respectively. CONCLUSIONS. A high rate of ≥95% pathologic necrosis was noted with this aggressive chemoradiotherapy regimen. The occurrence of significant acute toxicities limited the delivery of the intended dose intensity. Cancer 2008. ©2008 American Cancer Society.

Background. Bryostatin 1 is a marinederived macrolactone with antineoplasticactivity modulated through protein kinaseC, and with good activity in in vitro and in vivomodels. There are fewdrugs that offer palliation for metastaticsoft-tissue sarcoma and head and neckcancer, and drugs with new mechanisms ofaction warrant detailed disease specificstudy. Patients and methods. Twophase II studies for patients withincurable soft tissue sarcoma (12), or headand neck cancer (12) were conducted. Patients were treated with bryostatin,120 mg/m2/72 hours every 2 weeks for 3cycles prior to re-evaluation. Mostpatients had received priorchemotherapy. Results. No patientshad objective responses to therapy. Sixpatients had brief periods of diseasestabilization. Toxicity was generallymild, with myalgia being prominent (n=8). Hyponatremia, not previously described,occurred in 5 patients. The mechanism ofthis toxicity was unclear. Conclusions. Bryosytatin 1given as a single agent for advanced adult soft tissuesarcoma and head and neck cancer isinactive. Myalgia and hyponatremia werethe predominant toxicities.

UFT 300 mg/m2/day and leucovorin 90 mg/day could be administered safely to patients with advanced biliary cancer with good performance status; however, this combination and schedule of 28-day administration has no activity in this disease.To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced biliary (gallbladder and bile duct) carcinoma.Thirteen patients with advanced measurable biliary carcinoma were enrolled onto the trial. All patients had a Karnofsky performance statusor = 60%, platelet countor = 75,000/microL, total bilirubinor = 2.0x institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT scan or ultrasound examination. None of these patients previously received cytotoxic chemotherapy or radiation therapy for advanced disease. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Objective tumor response, the primary endpoint of this trial, was evaluated after two courses of therapy. Other endpoints included toxicity, time to progression, and overall survival.All patients were evaluable for response and toxicity. No complete or partial responses were observed in this trial. Four patients had stable disease lasting 17, 30, 33, and 35 weeks, respectively. The median (range) time to progression and survival were 9 (1-35) and 28 (1-61) weeks, respectively. Treatment-related toxicity was mild with severe (grade 3 or 4) diarrhea seen in 2 (15%). Grade 3-4 hyperbilirubinemia (31%) and nausea/vomiting (31%) were observed and likely related to the underlying disease. Grade 1 and 2 toxic effects included mainly anorexia and fatigue.UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days repeated every 35 days is ineffective in the treatment of advanced biliary carcinoma.

Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in divided doses administered every 8 hours for 28 days repeated every 35 days could be administered safely to patients with advanced hepatomas and good performance status, this combination and schedule has limited activity in treating advanced hepatoma.Biochemical modulation of 5-fluorouracil has yielded higher response rates in hepatoma when compared to treatment with 5-fluorouracil as a single agent, although the impact on survival has been negligible. This study was conducted to determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced hepatocellular carcinoma (hepatoma).Sixteen patients with advanced measurable hepatocellular carcinoma were enrolled onto the trial. All patients had a Karnofski performance statusor = 60%, platelet countor = 75,000/micro L, total bilirubinor = 2.0 x institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT or ultrasound examination. None of these patients received prior cytotoxic chemotherapy or radiation therapy for advanced disease. Fourteen patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Two patients registered for the trial but did not receive study medication. Objective tumor response, the primary purpose of this trial, was evaluated after two courses of therapy. Other end-points included toxicity, time to progression, and overall survival.Fourteen patients were evaluable for response and toxicity, respectively. No complete or partial responders were observed in this trial. Three patients had stable disease lasting 17 to 22 weeks. Toxicity was mild with severe (grade 3 or 4) liver pain, diarrhea, anorexia/nausea, fatigue, dyspnea, hyperbilirubinemia, anemia, and edema seen in 3 (21%), 2 (14%), 3 (21%), 2 (14%), 1 (7%), 1 (7%), 1 (7%) and 1 (7%) patients, respectively. The most frequent grade I and 2 toxic effects included fever of unknown origin, dyspnea, nausea, vomiting and diarrhea.UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate antitumor activity against advanced hepatomas. Further treatment using this regimen is not recommended for this disease.

Summary Purpose: We designed a phase I—II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-smallcell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. Patients and methods: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m 2 /day x 3 and vinorelbine 20-25 mg/m 2 /day x 3 and escalating doses of paclitaxel at 100-175 mg/m 2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. Results: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m 2 and 150 mg/m 2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m 2 with ifosfamide 1.2 g/m 2 /day on days 1-3 and vinorelbine 20 mg/m 2 / day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. Conclusions' This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Purpose : The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. Methods and Materials : Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation (7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and ≥10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy) ; however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. Results : Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of ≥ 5 cm (p = 0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with m 10 cm margins (100%) (p = 0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving ≥ 60 Gy (p = 0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4%) vs. those receiving 64-66 Gy (87.0%) (p = 0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses ≥63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p < 0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. Conclusions : Our data confirm the importance of maintaining an initial field margin of at least 5 cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins ≥10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

PURPOSE To review the clinical pharmacology and clinical trials that have used intravenous (IV) high-dose melphalan (HDM). METHODS We reviewed the mechanism of action, clinical pharmacology, and clinical studies of HDM with and without autologous bone marrow support (ABMT) or peripheral-blood progenitor cells (PBPCs) in the following disease areas: myeloma, ovarian cancer, malignant lymphoma, breast cancer, neuroblastoma, Ewing's sarcoma, and acute leukemia. RESULTS HDM has a distribution half-life (t1/2 alpha) of 5 to 15 minutes and an elimination half-life (t1/2 beta) of 17 to 75 minutes at doses of 140 to 180 mg/m2, with significant intrapatient variability. At these doses, a wide range of areas under the concentration/time curve (AUC) have been reported, ie, 146 to 1,515 mg/min/mL. HDM has significant clinical activity in patients with multiple myeloma in relapse or when used as consolidative therapy in relapsed ovarian cancer, relapsed Hodgkin's disease, breast cancer, and relapsed neuroblastoma. Additional studies are required to determine the activity of HDM in Ewing's sarcoma or acute leukemia. Toxicities of HDM include myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease. CONCLUSION HDM has become an established and effective salvage regimen for children with relapsed neuroblastoma, as well as an effective consolidative treatment for children with high-risk disease (stage IV). HDM is emerging as an active and effective mode of treatment in patients with stage II and III myeloma. The favorable toxicity profile of HDM and the availability of PBPCs allows for repetitive therapy.

OBJECTIVE Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine. METHODS We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by continuous intravenous infusion over 120 hours and vinblastine was administered by continuous infusion from hour 12 to hour 108. Sixty-two patients entered the trial, of whom 60 were evaluable. RESULTS Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduced to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxicity at higher cyclosporine doses. The maximum tolerated dose of cyclosporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Significant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lower than this maximum tolerated dose and was not cyclosporine dose dependent. Myelosuppression, neurotoxicity, and transient hyperbilirubinemia were observed and were cyclosporine dose dependent. CONCLUSIONS. Cyclosporine by continuous infusion may be safely given in high doses concurrently with continuous-infusion vinblastine. Plasma levels of cyclosporine > or = 1 mumol/L can be sustained during vinblastine administration. No sustained effect on T-cell subsets was observed. Vinblastine toxicity is enhanced by cyclosporine in a dose-dependent fashion and correlates with cyclosporine-induced hyperbilirubinemia.

10027 Background: Between 2005 and 2009, 1404 pts with advanced STS were enrolled in an Expanded Access Program (EAP) of Tr in the United States, Canada and Israel, and were treated with Tr 1.5mg/m...

10009 Background: Advanced high grade sarcomas resistant to standard chemotherapy are usually rapidly fatal. Few drugs with antisarcoma activity are available. Molecular studies of sarcomas suggest that SRC and downstream focal-adhesion kinase are active in sarcoma and may contribute to malignant phenotype. Dasatinib is an orally-administered kinase inhibitor of SRC-family of kinases that exhibited anti-sarcoma activity in preclinical models. SARC undertook a phase II study of dasatinib in advanced sarcoma. Results of patients (pts) treated for high grade subtypes are presented. Methods: An open-label, single-arm study of dasatinib was conducted for pts with incurable sarcoma including 7 histologic subtypes of high grade sarcoma. A Bayesian hierarchical model was used to “borrow strength” statistically across the subtypes. Dasatinib 100 mg bid was initially administered but was reduced to a starting dose of 70 mg bid because of toxicity. Primary endpoint was objective response within or stable disease at ...

10563 Background: P inhibits activation of the Akt pathway which results in apoptosis and block cancer cell proliferation. Since AKT is a molecule downstream of Kit, its inhibition may overcome Kit-dependent imatinib resistance. We performed a phase II trial to assess antitumor activity of perifosine in patients with advanced GIST who were refractory to imatinib mesylate. Methods: Pts with Kit(+) advanced GIST who have PD on IM were eligible. Pts continued their current dose of IM and were randomized to one of two dosing schedules of P (Arm A: 100 mg p.o. qd x 28 + IM or Arm B: 900 mg [300 mg p.o tid] qweekly + qd IM). A Bayesian approach was utilized to assess a target response rate or 20% with an unacceptable toxicity rate of 15% or less. Response was measured at q8 wk intervals by RECIST and Choi criteria. The primary endpoint was to determine the efficacy of P with IM in pts with advanced GIST with PD while receiving IM. Results: From 8/2005 to 7/2008, 41 pts were accrued. After 1 pt exclusion and 2 cross-overs, 22 pts were in Arm A and 18 pts in Arm B. Median age was 58 (range, 32–82), 51% were male, and median ECOG PS was 1. The most common primary site of disease and metastasis was the stomach (29%) and liver (66%), respectively. KIT genotype was available for 22 pts(54%); 5(12%) WT, 13(32%) exon 11 mutations, and 4(10%) exon 9 mutations. The median number of cycles was 2 (range, 1–24). By Choi and RECIST, 30 pts(73%) and 36 pts(87%) were available for response, respectively. No CR was identified but the PR rate was 4/36 (11%) by Choi (4 PR, 9 SD) and 0/36 (0%) by RECIST (16 SD). 4/5 (80%) of pts with WT KIT appeared to benefit (Choi: 1 PR, 3 SD; RECIST: 4 SD). Median PFS and OS for 40 pts were 2.2 months and 18.3 months. No difference in PFS was noted for the 2 schedules. Toxicity was assessed in 39 pts; 46 grade 3 events and 4 grade 4 events (ALT elevation, blurred vision, fatigue, and mood alteration) were noted. The most common grade 3 event was fatigue (20%). Three pts (7%) were removed from the study for toxicity (Arm A:1 pt, Arm B:2 pts). Conclusions: The addition of P to IM has minimal activity in IM-refractory GIST although its activity in GIST with WT KIT may be further investigated. No significant financial relationships to disclose.

10078 Background: T is a novel marine-derived DNA minor-groove binder that interferes with gene activation, nucleotide excision repair, and induces DNA strand breaks and cell cycle arrest in S and G2. T is active in STS and exhibits preclinical synergy with D. The objective of this study was to determine the combination regimen that is tolerable and associated with manageable neutropenia. Other objectives included safety, clinical activity and pharmacokinetics (PK) Methods: This was a dose escalation phase I study. Eligible patients (pts) had metastatic or recurrent STS, PS 0–1, and adequate organ function. Pts with more than 1 prior chemotherapy, prior anthracyclines or radiation to more than 20% of bone marrow were excluded. On day 1 of each 3-week cycle, pts received D starting at 60 mg/m2 followed by T starting at 0.9 mg/m2. Incremental doses were explored. D was discontinued after 6–8 cycles. Treatment was administered as an outpatient. PK samples were collected. A modified dose escalation and dose modifications were implemented Results: Forty one pts were treated in three sequential cohorts. In cohort 1 (D60 mg/m2 + T0.9 mg/m2), 4/11 pts without G-CSF experienced unmanageable neutropenia and subsequently prophylactic G-CSF was instituted. No unmanageable neutropenia was seen in the subsequent18 evaluable pts in this cohort. 1/13 and 2/6 DLTs were seen in cohort 2(D60 mg/m2 + T1.1 mg/m2) and cohort 3(D60 mg/m2 + T1.3 mg/m2) respectively. The most frequent grade 3/4 AEs were: neutropenia(71%), ALT elevation(46%), thrombocytopenia34%), AST(24%), anemia (22%), Febrile neutropenia (17%). One pt discontinued due to grade 3 asthenia. The MTD and recommended dose is D60 mg/m2 + T1.1 mg/m2. Anti-tumor activity included 17% ORR (1 CR and 6 PR), 80% stable disease (45% SD>6 months). Median PFS is 8.9 months (95% CI 5.6–11.8). 3-month and 6-month PFS are 85.4% and 58.2% respectively. Mature overall survival and PK data will be presented Conclusions: The combination of T and D with G-CSF support is safe, tolerable and active in pts with metastatic or recurrent STS [Table: see text]

9055 Background: Pathologic necrosis after preoperative (pre-op) chemoradiotherapy is an independent predictor of survival for STS (Eilber JCO 2001;19:3203–9). This is a pilot phase II study of a dose-intense regimen of epirubicin and ifosfamide with pre-op radiation for patients with high-risk STS of the extremities or body wall. The primary endpoint is rate of complete (≥95%) pathologic necrosis. Secondary endpoints include toxicty, disease-free and overall survival. Methods: Eligibility criteria: >5 cm localized STS, intermediate or high-grade, extremity or body wall site. Chemotherapy: epirubicin 30 mg/m2/day D1–4, ifosfamide 2.5 g/m2/day D1–4 with mesna and pegfilgrastim repeated every 21 days for 3 pre-op and 3 post-op cycles. Radiation: 28 Gy over 8 fractions (3.5 Gy/fx) during cycle 2 (epirubicin omitted during radiation) with a post-op boost of 12 Gy over 6 fractions for positive margins. Results: As of December 2004, 22 patients have been enrolled. 15 eligible patients have completed treatment t...

9001 Background: The success of imatinib (Gleevec) in gastrointestinal stromal tumor (GIST) is proof that a small oncogene targeted molecule can have significant benefit in a solid tumor. Sarcomas, other than GIST, also overexpress one or more of the tyrosine kinases inhibited by imatinib. We are performing a multi-institutional study to evaluate imatinib activity in nine different sarcoma subtypes and desmoid tumors. Methods: Patients ≥10 years old with a sarcoma subtype not curable by multidisciplinary management were eligible. Imatinib was prescribed at 300 mg BID (BSA≥1.5m2), 200 mg BID (BSA=1.0–1.49m2), or 100 mg BID (BSA

9000 Background: Trabectedin (Yondelis), a marine-derived alkaloid, has shown antitumor activity as therapy for advanced STS in pts refractory to conventional chemotherapy. LMS and LPS pts were selected for further study since these subtypes appeared to have somewhat higher rates of clinical benefit than other STS subtypes. Methods: To evaluate the efficacy and tolerability of ET-743 administered either as a 3-hr IV infusion given weekly for 3 consecutive weeks in a 4 week cycle (Arm A) or as a 24-hr IV infusion q 3 weeks (Arm B) to pts following progression despite prior doxorubicin plus ifosfamide chemotherapy. Pts with PS 0–1, normal bilirubin and alkaline phosphatase (AP) levels, and measurable LMS or LPS were eligible for study. Patients were pretreated with dexamethasone.The ET-743 dose was reduced if any abnormal elevation of bilirubin or AP was noted between cycles, or if any other unacceptable toxicity occurred. Histology will be centrally reviewed and patients whose diagnosis cannot be confirmed...

9013 Background: Desmoid tumors (aggressive fibromatosis) are rare clonal neoplastic proliferations of connective tissues. Although classified as benign, local aggressiveness can lead to significant impairment. Standard treatment involves wide surgical resection and/or radiation therapy. In cases of unresectable or recurrent disease, tamoxifen, chemotherapy, and NSAIDs have been used with varying success. We and others have previously reported desmoid tumors expressing c-kit, PDGFRα, and/or PDGFR. We reported two patients with extraabdominal desmoid tumors treated with the selective tyrosine kinase inhibitor imatinib (Gleevec) with significant shrinkage. SARC, in association with the Connective Tissue Oncology Society, initiated a prospective phase II trial in patients with desmoid tumors, or one of nine sarcoma subtypes. Here, we report specifically on patients with desmoid tumors. Methods: Patients ≥ 10 years old with desmoid tumors that were not curable by surgical management or in whom curative surger...

Intraarterial administration of chemotherapeutic agents provides greater local concentration at the tumor site without increased systemic toxicity. Although intravenous infusion of cisplatin is known to cause peripheral neuropathy and intraarterial administration has been reported to cause lumbosacral plexopathy, brachial plexopathy has not been described. We present a case in which infusion of cisplatin into the axillary artery resulted in permanent neurological damage to the posterior cord of the brachial plexus. Proper positioning of the infusion catheter is necessary to minimize potential neural damage.

In vitro radiobiologic survival parameters have been determined for 7 human osteosarcoma, 5 human soft tissue and bone sarcomas, and 4 Ewing's sarcoma cell lines. The mean D 0 values were 99.5 ± 11.6 cGy, 90.5 ± 7.7 cGy and 95.8 ± 7.9 cGy for osteosarcomas, soft tissue and bone sarcomas and Ewing's sarcomas, respectively. These in vitro survival data do not predict the clinical radiation resistance generally attributed to osteosarcomas and soft tissue and bone sarcomas, and do not differ substantially from the results obtained with the clinically radioresponsive Ewing's sarcomas.

In a significant fraction of patients with NHL or HD, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In HD, remissions can be achieved in approximately half of the patients with relapsed advanced disease. This may also be true in patients with NHL who do not respond to conventional regimens. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, suggesting failure of the conditioning regimen rather that an infusion of occult tumor cells in the autologous bone marrow had occurred. Thus, the role of marrow purging in this therapy needs to be further evaluated and compared with findings involving nonpurged marrow reinfusion. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used (1) in patients with HD who experience relapse after MOPP/ABVD or equivalent regimens and (2) in patients with intermediate or high-grade NHL whose disease recurs or is resistant to conventional regimens. Potential areas for development include the use of this modality as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. The role of high-dose chemotherapy of ABMR in the nodular lymphomas is not known at this point. Finally, high-dose ABMR therapy has a definite role in salvaging patients with malignant lymphomas. Many issues need to be resolved, including (i) the optimal timing of this approach, (ii) the optimal conditioning regimen, and (iii) the need for purging bone marrow prior to reinfusion. The past 10 years have led to significant gains. During the next 10 years, it may be possible to refine this therapy and find solutions to the above issues.

Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of 5 patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumors. In 3 of the cases no evidence of tumor was found at autopsy. Both an acute and a long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional 16 collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.