Saul E. Rivkin

Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205

PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. RESULTS A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. CONCLUSION In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.

PURPOSE AND METHODS Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewings sarcoma, Kaposis sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin. RESULTS Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis. CONCLUSION In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.

Dose response evaluation of adriamycin in human neoplasia.

Because patients treated with 60–90 mg/m2 every three to four weeks reach cardiotoxic doses of 550 mg/m2 within 36 weeks, prolonged treatment with Adriamycin is limited. The purpose of this study was to determine whether lower doses could be given over longer periods without loss of efficacy. Good risk patients treated with 75, 60, or 45 mg/m2 had remission rates of 25, 27, and 19%; poor risk patients treated with 50 and 25 mg/m2 had remission rates of 16 and 12% respectively. Although a dose response was identified, there were no statistically significant differences in remission rates, durations of remission, or toxicities in the dose schedules studied. Irreversible congestive heart failure occurred in five patients with cumulative doses of 240–390 mg/m2. Unless rapid remission induction is urgent, we recommend 60 mg/m2 X four doses and measurement of myocardial function if treatment is to continue.

Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group Study (SWOG-8037).

Conservative treatment of esophageal cancer with radiation therapy has afforded few long-term survivors. In order to improve outcome, patients with locoregional disease were treated using a combined modality approach. Patients were treated with chemotherapy consisting of a 96-hour continuous infusion of 5-fluorouracil (5-FU), 1,000 mg/m2/d, days 1 to 4 and days 29 to 32; cisplatin 75 mg/m2, day 1 and 29; and radiation 3,000 rad, days 1 to 19. In the absence of progressive disease, patients underwent esophagectomy. One hundred twenty-eight patients were registered of whom 113 were eligible and 106 were evaluable. Toxicity included gastrointestinal (GI) symptoms, mucositis, and myelosuppression. One hundred two patients completed chemoradiotherapy. Following its completion, 11 patients refused surgery, six were considered poor surgical risks, and 14 had progressive disease. Of the remaining 71 patients, 16 had unresectable disease, 13 had residual disease which was incompletely resected, 24 had disease which could be completely resected, and 18 were without disease on pathologic examination. The overall operability rate was 63% and the overall resectability rate, 49%. Surgical mortality was 11%. Eighty-nine of 113 eligible patients have died, with a median survival of 12 months and a 2-year survival of 28%. The median postsurgical survival for all 71 patients was 14 months and was 32 months for those patients attaining complete remission (CR). Combined modality therapy remains an investigational approach. Attempts should be directed at increasing response rate to initial therapy. A randomized comparison between combined modality treatment and radiation therapy is necessary to definitively determine the usefulness of this more aggressive approach.

Combination chemotherapy and adriamycin in patients with advanced breast cancer. A Southwest Oncology Group study

In January, 1972, the Southwest Oncology Group initiated two randomized studies for patients with advanced breast cancer. The study for patients with prior chemotherapy showed a 33% response rate with adriamycin. The study for patients without previous chemotherapy consisted of three treatment regimens: a weekly repeated combination of cyclophosphamide, methotrexate, 5‐flu‐orouracil, vincristine, and prednisone; these same five drugs given in courses of 5 days repeated every 4 weeks; and adriamycin as a single agent every 3 weeks. For the 283 evaluable patients, the response rates were: weekly combination 63/106 (59%); intermittent combination 39/98 (40%); and adriamycin 31/79 (39%). The median duration of response was 8 months for weekly combination, 10 months for intermittent therapy and only 4 months for adriamycin. Leukopenia was the dose‐limiting toxicity with all three regimens. The weekly combination is the most effective therapy for patients with advanced disease. Extensive trials of combinations that include adriamycin are underway.

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study

AbstractPurpose: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. Patients and Methods: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. Results: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p=0.45) and overall survival (p=0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins >1 cm, had superior survival compared to cases not meeting these requirements (p<0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). Conclusion: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

Phase II study of CT-2103 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

PURPOSE To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-L-glutamic acid, in heavily pretreated patients with recurrent ovarian, fallopian tube, or peritoneal cancer. PATIENTS AND METHODS Ninety-nine patients with measurable disease received intravenous CT-2103 at 175 mg/m2 of conjugated paclitaxel over 10 minutes every 3 weeks without routine premedications. Platinum-sensitive (n = 42) and platinum-refractory or platinum-resistant patients (n = 57) were enrolled. Thirty-nine patients (39%) had received one or two prior regimens, and 60 patients (61%) had received between three and 12 regimens. RESULTS In 99 patients, the median number of cycles was three (range, one to 14 cycles). The response rate (RR) for all patients was 10% (10 of 99 patients), with median time to disease progression (TTP) of 2 months. The RR (partial response) in platinum-sensitive and platinum-resistant patients was 14% (six of 42 patients) and 7% (four of 57 patients), respectively. In patients with only one or two prior regimens, the RR in platinum-sensitive and platinum-resistant patients was 28% (five of 18 patients) and 10% (two of 21 patients), with a median TTP of 4 and 2 months, respectively. Grade 2 (15 patients) or 3 (15 patients) neuropathy was reported in 30 patients (30%). Grade 2 hypersensitivity occurred in eight patients (8%) who were subsequently treated with premedications; one patient had grade 3 hypersensitivity and was removed. Grade 2 alopecia was absent. CONCLUSION CT-2103 is active in patients with recurrent ovarian cancer. Neurotoxicity in these heavily pretreated patients was more frequent than predicted from phase I trials. Further study to define toxicity and efficacy in patients with less prior therapy is ongoing.

A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study.

Six hundred eighty assessable patients with measureable stage III M1, non-small-cell lung cancer (NSCLC) were randomized to one of five treatment arms including cisplatin, etoposide (VP-16) +/- methylglyoxal bisguanylhydrazone (MGBG; PVp, PVpM); cisplatin, vinblastine (PVe); or PVe alternating with vinblastine, mitomycin (PVeMi); or fluorouracil, vincristine, mitomycin/cyclophosphamide, doxorubicin, cisplatin (FOMi/CAP). The overall response rate was 20% with 3% complete responses and 17% partial remissions. The duration of these responses was not statistically different by treatment regimen and varied from 2.7 months to 5.0 months. The overall median survival for all patients was 5.3 months and is not different by treatment. Toxicity was greater in PVpM. The similarity of results for response, duration of response, and survival does not establish the superiority of any of these platinum-based regimens for standard clinical usage.

A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors. A southwest oncology group study

A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5‐fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC‐S) or the same combination without Adriamycin (FC‐S) in patients with heart disease. Seventy‐four patients were entered and two were ineligible. Sixty‐nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty‐six patients received FAC‐S, and nine received FC‐S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC‐S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.

5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group Study.

In order to determine the clinical applicability of the in vitro observation of enhanced cytotoxicity of 5-fluorouracil (5-FU) in the presence of excess reduced folates, the Southwest Oncology Group (SWOG) performed a randomized trial evaluating two dose schedules of 5-FU and folinic acid (FA) in 128 patients with metastatic colorectal cancer. Of 125 eligible patients, 62 were randomized to receive bolus FA (200 mg/m2 days 1 through 4) in addition to 5-FU (1,000 mg/m2 days 1 through 4) by continuous four-day infusion (infusion arm), while 63 were randomized to receive bolus FA (200 mg/m2 days 1 through 5) in addition to 5-FU (325 mg/m2 days 1 through 5) by bolus injection (bolus arm). The toxicities of the two schedules differed, with stomatitis being more severe in the infusion arm and leukopenia being more severe in the bolus arm. The response rates and survival data for the two arms are nearly identical. The median survival of patients on the infusion arm is 11.0 months and of patients on the bolus arm, 10.3 months. The infusion arm produced one complete response (CR) and 12 partial responses (PRs), for a major response rate of 21% of eligible patients. The bolus arm produced three CRs and 11 PRs, for a major response rate of 22% of eligible patients. The response rate produced is minimally superior to recent cooperative group studies of colorectal cancer, but the response rate and survival experience are within the range of experience for treatment with 5-FU alone.