Combined modality therapy for stage II and stage III pancreatic carcinoma.

PURPOSE: To study the outcome achieved with three-drug chemotherapy and split-course external-beam radiotherapy as a treatment for unresectable stage II and III pancreatic carcinoma. PATIENTS AND METHODS: Radiotherapy was given in three cycles of 2 Gy/d on days 1 to 5 and 8 to 12 (total dose, 54 Gy) concurrently with fluorouracil (FU) 1,000 mg/m2/d by continuous infusion for 4.5 days, streptozocin (STZ) 300 mg/m2 on days 1, 2, and 3 and cisplatin (P) 100 mg/m2 on day 3 of each every-28-day cycle. Subsequent treatment consisted of leucovorin (LV) 200 mg/m2 and FU 600 to 1,000 mg/m2 every 14 days. RESULTS: The median survival time for the 35 patients was 15 months and 26% of patients were alive at 24 months. Fifteen patients (42.8%) had objective responses to therapy. Six (17%) had a complete response (CR). Three of nine patients with partial responses (PRs) achieved a radiographic CR within the next 3 months. Nine patients underwent attempts at surgical resection: five were resected (median survival time, 31 months; range, 12.8 to 44.7+), two had no residual disease found at complete resection, and three others also had a complete resection. Of four others who could not be resected, three underwent intraoperative radiotherapy and one had occult metastatic disease. Of primary tumors, 91% did not produce either back pain or local gastrointestinal complications for 2 years. The rates of severe side effects were stomatitis 15%, anemia 14%, granulocytopenia 6%, and thrombocytopenia 6%. CONCLUSION: Palliation and survival compare favorably with other series, including many surgical series. The response findings encourage studies of both unresectable and (as neoadjuvant therapy) resectable tumors.

Survival after combined modality therapy for pancreatic cancer.

Twenty consecutive patients with unresectable, locally advanced pancreatic cancer were treated with split courses of radiotherapy (RT) and simultaneous multidrug chemotherapy consisting of 5 fluorouracil, continuous infusion, streptozotocin, and cisplatin. A separate, retrospective study identified a group of 28 contemporary patients with less advanced pancreatic cancers, all of which were successfully resected. The survival rate of the two groups were similar over the first 2 years, although it initially favored the unresectable group. This pattern of survival among patients treated with combined modality therapy provides a basis for new studies. At the two clinical extremes, these include treatment of unresectable tumors previously considered ineligible for this treatment and initial treatment before resection of stage I tumors.

Combined modality therapy increasing local control of pancreatic cancer.

Twenty patients with inoperable locally advanced Stage II and III pancreatic cancer were treated with combined modality therapy. Radiotherapy consisted of split courses of 2000 cGy each and, as needed, an additional 1400 cGy, separated by 2-week intervals. Simultaneous multidrug regimen chemotherapy consisted of 5-fluorouracil, continuous infusion, 1 g/m2 days 1-5; streptozotocin, 300-500 mg/m2 days 1, 2, 3; and cisplatin, 100 mg/m2 day 3 of every 4-week radiotherapy course (RT-FSP). Primary tumors decreased more than 50% in volume in 11 of 20 patients. Computed tomography scans demonstrated apparent complete disappearance of the primary tumor in 7 patients. Only 3 patients had tumor regrowth within the radiotherapy field, all after the end of radiotherapy. Local control improved as measured by increased frequency of tumor shrinkage and decreased frequency of primary tumor growth, recognizing the limitations of a pilot study and comparisons to best historical results achieved with standard short 5-fluorouracil schedules and radiotherapy. Successful local control largely eliminates the most common cause of refractory pain and may decrease the need for some forms of early palliative surgical intervention. Tumor shrinkage sometimes downstages tumors, creating frequent investigational opportunities for either elective extirpative surgery or intraoperative radiotherapy. This pilot experience also supports testing of expanded eligibility staging criteria for combined modality treatment and testing of new drugs as part of 5-fluorouracil-radiotherapy-based regimens.

Circulating pancreatic polypeptide in patients with adenocarcinoma of the bile duct.

Using radioimmunoassay methods, the blood of patients with pancreatic tumors was screened for circulating polypeptide hormones. This screening discovered pancreatic polypeptide in abnormally high concentration in the serum of six of seven patients with adenocarcinomas of the bile duct. The assay appears to be very sensitive finding excessive residual pancreatic polypeptide production after palliative resections. Serum pancreatic polypeptide assays warrant evaluation as an aid in the diagnosis and management of patients with bile duct tumors.

Folate biochemical modulation regimen for the treatment of gastric cancer.

Twenty patients with metastatic gastric cancer were treated with methotrexate (MTX, M), 100 to 160 mg/m2 at 0 h, and, in sequence, 5-fluorouracil (FU, F), 600 to 1000 mg/m2 at 4 h; leucovorin (LV, L), 200 mg/m2 at 18 h, then 20 mg/m2 every 6 h x 12; 5-fluorouracil, 600 mg/m2 at 19 h; and high-dose cisplatin (DDP, P), 100 mg/m2 at 20 h. In addition, they were treated with a continuous 5-fluorouracil infusion, 1000 mg/m2/24 h from 18 h to 114. There were 8 complete and 6 partial responses among the 16 patients with measurable tumors. Five patients, each with one remaining clinical site of disease, received supplementary regional therapy: three received intraperitoneal therapy, two received hepatic arterial therapy. Intraperitoneal therapy and hepatic artery therapy each produced one complete response. Median survival was 16 months for all patients, and 25% survived 2 years. In comparison with matched patients, both response rates and survival improved twofold.

Hexamethylmelamine for the treatment of ovarian cancer--the Mount Sinai experience.

Two regimens were tested, CHAP I and CHAP II, the latter, a hexamethylmelamine dosage-intensive regimen, first as second line (salvage) therapy and then as primary therapy. Both produced the most successful results achieved in the Mount Sinai series up to the time of their introduction, when compared to their predecessor regimens: CAP, AP and P. In an overall interim comparison, CHAP II was significantly superior to historical AP and CAP as primary therapy, as was CHAP I vs. AP in several important subgroups compared as part of a randomized trial. CHAP II overall progression-free survival was improved in spite of added new sensitive test methods. Salvage therapy also improved markedly with the addition of intensive hexamethylmelamine. Several biological and treatment characteristics strongly influenced outcome, especially young age and adding hexamethylmelamine. Other possible factors included: poor tumor grade, poor performance status, and extent of surgical debulking, even to intermediate residual, 2-6 cm size [CHAP II only]; extensive (optimum) surgery [CHAP I only]. The hexamethylmelamine-containing regimens interact favorably with some of these factors, better than did the preceding regimens. Five-year follow-up analyses weakened slightly for extensive surgery, intermediate size and poorly differentiated tumors. It confirmed and strengthened several findings favoring CHAP I & II, the hexamethylmelamine-containing regimens.

Dose-dependent leucovorin efficacy with an intermittent high-dose 5-fluorouracil schedule.

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.

Schedule and dosage modification of a cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin combination chemotherapy regimen for refractory ovarian cancer.

A cyclophosphamide, hexamethylmelamine, doxorubicin and cisplatin (CHAP II) regimen produced median survival of 15 and 17 months. All patients had prior chemotherapy, 26 with cisplatin in the former group, and 27 without cisplatin in the latter group. Treatment employed both a novel sequential schedule of cisplatin (usually in the evening) 24 h before cyclophosphamide-doxorubicin and novel stepwise escalation, first of doxorubicin, then of hexamethylmelamine until either nadir white blood counts fell to 1000-1500/mm3 or platelets to 75,000-100,000/mm3. Compared to prior Mount Sinai experience: (i) survival was significantly improved; (ii) with and without prior cisplatin, response rates approached a significant improvement, 12% and 29% complete and 24% and 35% partial. Five of seven additional patients with progression during unmaintained remission also responded, two with pathologically complete remissions. Findings suggest: (i) the importance of maximum dose intensity in ovarian cancer treatment; (ii) the responsiveness of patients failing first line treatment to dose intensive treatment; (iii) the possible importance of schedule, and sequential or circadian timing of cisplatin, and other drugs; (iv) and testing revised clinical criteria of resistance to drugs.