Faculty Bibliography

PURPOSE: A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. METHODS AND MATERIALS: Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. RESULTS: Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. CONCLUSION: This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. METHODS: This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy. RESULTS: The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone. CONCLUSIONS: Concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects

Intraperitoneal (i.p.) 5-fluoro-2'-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32-78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at greater than 3,000 mg x 3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg x 3 days and leukopenia and thrombocytopenia at 5,000 mg x 3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2-4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2-4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage. (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 1 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Eighteen patients with unresectable localized adenocarcinoma of the pancreas were treated by a combination of chemotherapy plus hyperfractionated radiation therapy to the pancreas for 4080 cGy with an additional 960 cGy to the pancreatic tumor and a surrounding margin. One hundred and twenty cGy were given twice daily 4 to 6 hours apart. High-energy photon or electron beams were used with treatment planning based on computed tomographic (CT) scans. Patients were given chemotherapy in the form of 5-fluorouracil (5-FU) at 350 mg/m2 on the first 3 and last 3 days of radiation therapy. On day 53, chemotherapy was given that included 600 mg/m2 IV of 5-FU, 1 gm/m2 of streptozotocin, and 10 mg/m2 IV of mitomycin C. The 5-FU and streptozotocin were repeated on days 60, 81, and 88, and the stretozotocin and mitomycin (SMF) cycles were repeated every 8 weeks until progression. Radiation toxicity was generally tolerable with one of 18 evaluable patients having severe nausea and vomiting and two of 18 patients having severe diarrhea. One patient had total liver failure and died 3 months after initiation of therapy. Six patients had severe hematopoietic toxicity during chemotherapy. Overall, the severe toxicity rate was higher (67%) than in previous studies. Median survival was 35 weeks, the 1-year survival rate was 39%, and the patient who survived the longest died at 68 months. Although this schedule of hyperfractionated radiation and chemotherapy was disappointing, combined experimental radiation approaches plus chemotherapy for localized unresectable adenocarcinoma of the pancreas deserve additional research.

Although epidermoid cancer of the anus is an uncommon tumor, it has served well as a model for several disciplines within oncology. Advances in understanding the epidemiology and the definitive therapeutic role of combined radiation therapy and chemotherapy for anal tumors have encouraged many investigators to study similar applications in the more common epithelial malignancies. In this monograph, the anatomy of the anal area is reviewed emphasizing the differences in natural history and prognosis between anal margin and anal canal cancers. Treatment does not depend on the specific histologic variant of the epidermoid tumors which arise in this region. The roles of viruses, of immunodeficiency syndromes, and of a history of benign anal disease and trauma in the etiology and epidemiology of this tumor are discussed. Current staging will be critically reviewed stressing that invasive (pathologic) staging by surgery is not indicated, but noninvasive staging has definite limitations. Small superficial tumors may be definitively treated with either limited surgery or radiation. While regional treatments such as surgery and radiation offer cure to between 45% and 60% of nonselected patients, initial treatment with combination radiation and chemotherapy produces cure rates between 65% and 85% for similar groups of patients. The rationale for combined modality therapy is presented and recommendations for therapy by stage of the cancer are made. Finally, we present questions that remain for future research in the clinic and laboratory regarding epidermoid tumors of the anus.

A clinical trial was designed to find the maximally tolerated dose of weekly leucovorin (LV) that could be combined with 4 weeks of protracted infusion (PI) of 5-fluorouracil (5FU) at a fixed dose of 200 mg/m2. A total of 36 patients with disseminated gastrointestinal malignancies were treated; 9 either progressed or died before receiving 4 weeks of treatment leaving 27 patients evaluable for toxicity and response. 5FU was given as a protracted infusion using an ambulatory infusion pump and indwelling venous access. LV doses included 20, 25, 50, and 75 mg/m2 given as an i.v. push at the time of weekly pump fill with 5FU. In all, 72% of the patients tolerated LV at 20 mg/m2 for 4 continuous weeks, whereas the higher doses required treatment rests prior to 4 weeks. The dose-limiting toxicity at all doses was stomatitis. No significant myelosuppression was seen; diarrhea was infrequent. Overall, 40% of the patients with measurable cancer had partial responses. In view of evidence of biologic and therapeutic effects of these weekly doses of 20 mg/m2 LV with 200 mg/m2 5FU per day given as a protracted infusion over 4 weeks, phase II trials and multimodality studies for patients with gastrointestinal malignancies are being initiated at our institution using this dose and schedule.

Forty-one evaluable patients with localized squamous cell carcinoma of the thoracic esophagus were treated by a course of radiation therapy (3000 cGy in 3 weeks), 5-Fluorouracil (5-FU) and Cis-platinum (Pt). This was followed by an esophagectomy in medically eligible patients who agreed to the procedure and who had no evidence of extrathoracic tumor. If tumor was found in the specimen, an added 2000 cGy of radiation therapy and additional 5-FU and Pt were given. One-year survival was 44%, 2-year survival 15%, and 3-year survival 8%. All 3-year survivors had tumor-free specimens, but one patient with tumor in the thorax and subdiaphragmatic metastasis survived 2 years

Based on the surgical pathology and survival for patients in previous trials using a neoadjuvant program of chemotherapy (5-fluorouracil [5-FU]-cisplatin) and radiation (3,000 cGy) before surgery for squamous-cell cancer (SCC) of the esophagus, a nonoperative pilot trial was designed to test if survival and recurrence would differ from our historical controls if routine esophagectomy was eliminated. Twenty patients were treated. The protocol called for the delivery of 5-FU infusion (1,000 mg/m2/d X 4 d) days 1 to 4 and 29 to 32 with cisplatin (100 mg/m2) day 1 and 29 sandwiched around external beam radiation (3,000 cGy over 3 weeks). Mitomycin C (10 mg/m2) day 57 was administered with bleomycin infusion (20 U/d X 4 d) days 57 to 60 and 78 to 81. A radiation boost of 2,000 cGy was administered 200 cGy/d days 99 to 103 and 106 to 110. Clinical pulmonary toxicity forced withdrawal of bleomycin and mitomycin C in the last four patients treated; two further courses of 5-FU-cisplatin were administered instead. The median measurement of the 20 esophageal lesions by barium swallow was 7 cm. Four patients underwent salvage surgery to prevent life-threatening aspiration pneumonia. The median survival for the 20 patients is 22 months, with a range from 6 to 39+ months. The six patients clinically without cancer are alive 22+ to 39+ months (median, 35+ months). Three patients died manifesting only local (infield) recurrence; five died manifesting only distant recurrence; and five developed local and distant recurrence. While the toxicity of the four drug regimen as administered was prohibitive, the survival and quality of survival is superior to the regimen previously used, which routinely used surgery after preoperative chemotherapy and radiation.