Paul S. Ritch

Efficacy and Safety of Trabectedin in Patients With Advanced or Metastatic Liposarcoma or Leiomyosarcoma After Failure of Prior Anthracyclines and Ifosfamide: Results of a Randomized Phase II Study of Two Different Schedules

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/m(2) 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m(2) 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.

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkins lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.

Neoadjuvant FOLFIRINOX for Borderline Resectable Pancreas Cancer: A New Treatment Paradigm?

BACKGROUND Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience. METHODS All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival. RESULTS FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months). CONCLUSION FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.

Treatment of intraocular lymphoma with high-dose Ara-C

Ocular lymphoma is an uncommon clinical entity with a propensity for intracranial extension. Palliation has been reported following radiotherapybut the ultimate prognosis is poorand significant treatment‐related morbidity is common. Recent pharmacokinetic studies have suggested that sustained therapeutic drug concentrations are achievable in cerebrospinal fluid after systemic administration of high‐dose cytosine arabinoside (Ara‐C). These data led the authors to attempt treatment of a case of recurrent ocular lymphoma with high‐dose Ara‐C. Therapeutic drug levels were documented in intraocular fluidsand prolonged objective regression of tumor was seen. Systemic high‐dose Ara‐C deserves consideration for the treatment of ocular lymphoma.

Continuous 5-fluorouracil infusion in refractory carcinoma of the breast

Twenty-five patients with refractory, metastatic carcinoma of the breast were treated with continuous ambulatory 5-fluorouracil (5 FU) infusion (200 to 300 mg/m2/day) through a chronic indwelling central venous catheter. All patients had had extensive previous treatment, including hormonal therapy in 20/25 patients (80%), radiation therapy in 18/25 patients (72%), and an average of 4.6 previous chemotherapy drugs per patient (range 1–10). Twenty-three of 25 patients (92%) had had previous bolus 5 FU. Seventeen of 25 patients (68%) had two or more metastatic sites of involvement and 17/25 patients (68%) had visceral involvement. Results: complete remission −1/25 (4%), partial remission −7/25 (28%), stable disease −6/25 (24%), and progressive disease −11/25 (44%), for an overall response rate of 8/25 (32%). Median duration of response was 6 months. Toxicities included hand-foot syndrome, mucositis, diarrhea, and nausea and vomiting, and required treatment interruption and/or dose attenuation in 9/25 patients (36%). No myelosuppression or serious catheter-related problems were seen. We conclude that continuous 5 FU infusion is a potentially effective salvage treatment that may provide meaningful palliation in some patients with carcinoma of the breast, in spite of extensive previous treatment.

Continuous 5-Fluorouracil (5FU) Infusion in Carcinoma of the Pancreas: A Phase II Study

ABSTRACT: Sixteen patients with metastatic carcinoma of the pancreas were treated with continuous ambulatory 5-Fluorouracil (5FU) infusion (200–300 mg/m2/day) through a chronic indwelling central venous catheter. Twelve of sixteen patients (75%) had two or more sites of disease, and eleven of sixteen (69%) had liver metastases. Five patients had previous chemotherapy. Results: partial remission, 3/16 (19%); stable disease, 8/16 (50%); and progressive disease, 5/16 (31%). Improvement in ECOG performance status was observed in 2/3 responding and 6/8 stable desease patients, respectively. Toxicities included hand-foot syndrome, mucositis, diarrhea, and cerebellar ataxia, which required treatment interruption in 9/16 patients (56%). No myelosuppression or catheter related problems were seen. The authors conclude that continuous infusion 5FU is a potentially efficacious palliative therapy in the management of carcinoma of the pancreas.

Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside.

Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.

A Phase I/II Study of LY900003, an Antisense Inhibitor of Protein Kinase C-α, in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non–Small Cell Lung Cancer

Purpose: Protein kinase C-α has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C-α antisense oligonucleotide LY900003 (Affinitak, ISIS 3521) and cisplatin, we designed this phase I/II trial of LY900003 with cisplatin/gemcitabine Experimental Design: The safety of the combination, as well as potential pharmacokinetic interactions, was evaluated in the phase I portion of the trial. The phase II portion evaluated the antitumor activity of the combination in previously untreated patients with stage IIIB/IV non–small-cell lung cancer (NSCLC). Results: Seven patients received 18 cycles of the combination during the phase I portion. Dose-limiting toxicity was only observed in one of six evaluable patients (grade 3 fatigue). However, due to a relatively high frequency of thrombocytopenia, cisplatin 80 (mg/m2) and gemcitabine (1,000 mg/m2) were recommended for the phase II portion. Antitumor activity was observed in two patients (one with NSCLC and one with pancreatic carcinoma), and prolonged stabilization was observed in two others. No pharmacokinetic interactions occurred. In the phase II portion, 55 NSCLC patients received the combination at two gemcitabine doses [1,000 mg/m2, n = 44 (original cohort); 1,250 mg/m2, n = 11 (expanded cohort)]. Fourteen of 39 evaluable patients in the original cohort had a response rate (1 complete response and 13 partial responses; response, 36%), whereas 2 of 9 evaluable patients in the expanded cohort experienced partial response (combined response rate, 33%). The median time to treatment failure was 3.9 months, whereas the median time response to progression for the 48 patients with evaluable response was 4.4 months (confidence interval, 3.5–5.5 months). Intent to treat median survival time was 8.9 months. Forty-eight percent of the patients experienced catheter-related events. Conclusions: LY900003 can be administered safely in combination with cisplatin and gemcitabine and is associated with antitumor activity in patients with advanced NSCLC. Better characterization of subsets of patients most likely to benefit from this combination therapy is needed.

Continuous 5-fluorouracil infusion in advanced gastric carcinoma.

Fourteen patients with advanced gastric adenocarcinpma were treated with continuous 5-fluorouracil (5-FU) infusion, 300 mg/m2/day, through an indwelling central venous catheter; 13 were evaluable for response. The results were as follows: Partial remission was seen in 4 of 13 patients (31%), stable disease in 5 of 13 patients (38%), and progressive disease in 4 of 13 patients (31%). The median duration of response was 19 weeks (range, 10–41), and the median survival for all patients from initiation of infusion was 27 weeks (range, 9–54). Treatment interruption and/or dosage attenuation for toxicity was necessary in 7 of 14 patients (50%); however, myelosuppression, alopecia, and nausea and vomiting were not observed. 5-FU infusion is well-tolerated, palliative therapy for patients with advanced gastric carcinoma and may warrant further investigation in combination with other chemotherapeutic drugs.

A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract

A prospective, randomized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract (UAD) was conducted between July 1979 and September 1982. Eighty-three patients with locally advanced Stage III-IV tumors received standard treatment (STD RX; defined as preoperative irradiation and radical excision or irradiation alone), or induction chemotherapy (CTX) followed by STD RX. Chemotherapy consisted of two cycles of bleomycin (30 units/day by continuous infusions Days 1-4), cyclophosphamide (200 mg/m2 IV Days 1-5), methotrexate (30 mg/m2 Days 1 + 5), and 5-fluorouracil (400 mg/m2 IV Days 1-5). Response to CTX was complete in 2 and partial (greater than 50% reduction) in 27; the overall response rate was 68%. Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and/or surgery and in 24/43 CTX patients (17/29 responders, 7/14 non-responders). Freedom from local-regional disease was noted at 2 years in 53% STD RX and 35% CTX patients (p less than .06). CTX patients had a higher proportion of local-regional persistence and recurrence. The difference was apparent only in the subset of patients treated with primary irradiation; local-regional control following irradiation and surgery was equal in STD RX and CTX groups. Survival at 2 years was 43% STD RX and 31% CTX. Disease-free survival in those with clearance was 64% STD RX and 59% CTX. Induction chemotherapy did not improve tumor clearance or survival in this series. Caution regarding local-regional control with CTX and primary irradiation is noted.