A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer.

This ongoing study evaluates the efficacy of oral 9-nitrocamptothecin (9NC), or RFS-2000, in the treatment of advanced pancreatic cancer. Patients received 9NC orally for 5 days/week; 8 weeks of therapy is required to achieve minimum effective dose. Starting dose was 1.5 mg/m2/day, with adjustments made as necessary. Patients were analyzed for changes in tumor size by CT scan, changes in serum CA 19-9 tumor marker levels, quality of life, and survival. 107 consecutive patients with advanced adenocarcinoma of the pancreas were enrolled before November 3, 1997. Of this group, 47 patients did not receive the minimum 2 courses of treatment necessary to induce response, leaving 60 evaluable patients. Primary dose-limiting toxicities were myelosuppression and interstitial cystitis. No deaths were attributed to 9NC. Median survival was 6.5 months for the 107 total patients and 8.7 months for the 60 evaluable patients, with one patient surviving at 44+ months. Of the 60 evaluable patients, 31.7% were responders (median survival 18.6 months; range 6.5-44.7+ months), 31.7% were stable (median survival 9.7 months), and 36.6% were non-responders (median survival 6.8 months). Fifty-seven previously untreated patients had a median survival of 7.3 months compared to 4.7 months for the 50 previously treated patients. Thirty-three patients who failed gemcitabine therapy prior to 9NC treatment had a median survival of 4.7 months. 9NC is safe and efficacious as first-line therapy for the treatment of advanced pancreatic cancer. It also shows some modest success as second-line therapy in treating gemcitabine failures.

Phase I clinical and pharmacological studies of 20-(S)-camptothecin and 20-(S)-9-nitrocamptothecin as anticancer agents.

Groups of 52 and 29 patients with refractory cancers received either native camptothecin (CPT) or 9-nitrocamptothecin (9NC), respectively, in Phase I clinical trials designed to determine the maximum tolerated dose, toxicity and potential efficacy of orally administered camptothecins. Favorable responses occurred with both compounds (11% after CPT, 24% after 9NC). Although both agents could be taken safely for extended periods, dose limiting toxicities were substantial. Diarrhea was the major clinical problem with CPT, and myelosuppression with 9NC. Both compounds could cause hemorrhagic cystitis. The antitumor activity demonstrated suggests that further investigation of orally administered camptothecin analogs is warranted.

Heterotransplantation of human breast carcinomas in nude mice. Correlation between successful heterotransplants, poor prognosis and amplification of the HER-2/neu oncogene.

Four hundred and thirty-three human breast carcinomas and 23 cell lines derived from human breast carcinomas were heterotransplanted in nude mice. Twenty-eight tumors and 13 cell lines took and could be serially transplanted. Their human origin was established by isozyme analysis performed on successive passages. Sixteen primary infiltrating duct-cell carcinomas (PIDC) took, from a total of 262 transplanted (6.1%). This is in striking contrast to the greater than 50% rate of takes of most major cancers of epithelial origin. All 16 PIDC growing in nude mice were highly cellular and lacked desmoplastic hyperplasia. The clinical prognosis of the PIDC patients whose tumors were successfully transplanted was poor. Ten of 16 (63%) died of their disease within 3 years, compared to only 49 (20%) of the 246 PIDC patients whose tumors did not take in nude mice. This could not be attributed to later stage disease of the tumors that took, because only 15% of these patients had 4 or more positive axillary lymph nodes as opposed to 28% of the patients whose tumors did not take. Sixty-four percent of the breast carcinomas growing in nude mice exhibited amplification of the HER-2/neu oncogene which is also correlated with poor prognosis in human breast cancer. It is possible that the nude mouse is more susceptible to a population of highly invasive and lethal breast carcinomas.

Treatment of cancer of the liver. Twenty years' experience with infusion and resection in 414 patients.

The factors influencing survival for patients with cancer of the liver were studied by reviewing the records of 414 patients operated on in a private oncology practice. Approximately half (47%) had colorectal metastasis; 17% had metastatic breast carcinoma, 14% had malignant hepatoma, 5% had metastatic melanoma, and the remainder had a variety of primary cancers. Eighty-two per cent of all patients had advanced liver disease when first diagnosed. One quarter of the patients had some type of resection; the remainder had abdominal exploration plus insertion of an infusion catheter into the hepatic artery. The postoperative mortality rate after liver resection for 108 patients was 6.5%. After resection, the most important prognostic factor influencing survival was the presence or absence of extrahepatic metastases. When possible, resection was by far the best treatment available, and the best results were seen in patients who had resection of a solitary lesion. For advanced disease, when resection was not possible, intra-arterial chemotherapy, primarily with 5-fluorouracil (5-FU), was associated with response rates of 36% for colorectal cancer, 45% for breast cancer, 13% for hepatocellular cancer, 12% for melanoma, and 14% for metastases from other primary sites. The patients who responded to infusion lived longer than those who did not respond. For example, at 18 months, 26% of the responders with colorectal cancer were alive, as were 50% of the responders with breast cancer and 40% of the responders with hepatocellular cancer. In contrast, at 18 months, there were no survivors among the nonresponders with colorectal, breast, or hepatocellular cancer. For those patients treated solely by infusion chemotherapy, the extent of disease in the liver was the most reliable factor in predicting the length of survival. However, very few patients treated in this manner lived longer than 3 years.

Bronchogenic cysts above and below the diaphragm: report of eight cases.

Bronchogenic cysts are developmental foregut anomalies usually located within the mediastinum. Although typically asymptomatic, infection or compression of adjacent structures may become prominent. Surgical excision is recommended to establish diagnosis, alleviate symptoms if present, and prevent future complications. We report our recent experience with bronchogenic cysts including 7 located within the mediastinum and a rare instance of a cyst below the diaphragm.

A ten year study of partial mastectomy for carcinoma of the breast.

Since 1970, 334 patients have undergone partial mastectomy, axillary dissection and irradiation for treatment of invasive carcinoma of the breast. The average follow-up period is 59 months. Survival curves were calculated for the entire study group and for patients classified by tumor size, nodal status and stage of disease. The five year over-all survival rate for 334 patients is approximately 87 per cent; the ten year survival rate is approximately 64 per cent. Of the 334 patients, 247 (74 per cent) have been observed for at least two years. Fourteen of these patients (5.7 per cent) have had a recurrence of carcinoma develop within the treated breast.

Exceptional lethality for nude mice of cells derived from a primary human melanoma.

BRO human melanoma cells, obtained from a biopsy of a highly aggressive and malignant primary tumor, were grown as xenografts in nude mice and in cell culture. These cells were exceptionally tumorigenic and malignant for nude mice. NIH-II nude mice survived 11.0 +/- 0.4 (S.E.) and 14.1 +/- 0.4 days after i.p. inoculation of 10(7) or 10(6) BRO cells, respectively, and lethal tumors developed in all mice inoculated i.p. with only 10(3) cells. The doubling time (2.3 days) of the volume of tumors formed after s.c. inoculation was comparable to the doubling time of these cells in culture. After i.p. or s.c. inoculation, BRO cells metastasized to the diaphragm and lungs, causing respiratory failure in most of the host mice. The original tumor and the cell line derived from it had undifferentiated structures with prominent nuclei and very large nucleoli. Karyotype abnormalities included a gigantic A group chromosome, a large D group chromosome, and an unusual double centromere chromosome not found typically in human melanoma cells. Due to the short and reproducible survival times of nude mice inoculated i.p. with BRO cells, this model system may be useful for rapidly determining the effects of experimental treatment on the survival of hosts bearing human tumor cells.

Results of eleven years' experience with heated perfusion for melanoma of the extremities.

Eleven years have elapsed since we first added heat to regional perfusion for treatment of melanoma of the extremities. This report describes briefly our laboratory findings and our technique of hyperthermic perfusion and brings up to date the survival figures for the 165 patients (185 perfusions) which were originally reported in 1975 (Stehlin et al., Surg. Gynecol. Obstet., 122: 3--14, 1966). A dramatic increase in the survival rate is documented for those patients with recurrent melanoma confined to the extremities.

Soft tissue sarcomas of the extremity. Multidisciplinary therapy employing hyperthermic perfusion.

Cultured human sarcomatous cells that have been tested in our laboratory are more sensitive to the lethal effects of heat than are the normal cells from which they are derived. During an eight year period from March 1967 to March 1975, thirty-seven patients with soft tissue sarcomas of the extremities were treated with hyperthermic perfusion and, when possible, radiation therapy and radical local excision. Despite the fact that these tumors arise on the extremity, diagnosis was often delayed. With meticulous attention to all details, hyperthermic perfusion was performed with a minimum of morbidity and mortality. The combined use of hyperthermic perfusion, radiation therapy, and delayed excision has greatly reduced the necessity for amputation. Many useful limbs, heretofore not considered salvageable, can be saved with this method of treatment. Also, the possibility exists that destruction of tumor within the extremity followed by delayed excision enhances the immune response of the patient.

Results of hyperthermic perfusion for melanoma of the extremities.

Our studies show that the malignant melanoma cell in human beings is more sensitive to the lethal effect of heat than its normal counterpart, the melanocyte. Malignant melanoma of the extremities presents unique problems; at times, local control can be extremely difficult. The addition of heat to regional perfusion with melphalan has dramatically improved the objective response of melanoma. Complications rise as the tempreature and duration of perfusion increase. These risks must be weighed carefully against the volume and extent of tumor. One hundred and eighty-five hyperthermic perfusions have been perfomed on 165 patients. When done with meticulous attention to details, this procedure is accompanied by minimal morbidity and mortality. Hyperthermic perfusion is currently the best treatment for recurrent melanoma of the extremities and has almost eliminated the necessity for amputation. Perfusion is recommended as a prophylactic measure for the more deeply invasive primary lesions. It reduces the incidence of regional recurrence. A retrospective statistical analysis of survival rates of patients treated with nonheated and heated perfusion for recurrent melanoma, State IIIA, was conducted. If the experience of the heated group continues, which from a clinical standpoint appears likely, then a striking advantage of heated perfusion over nonheated perfusion will be demonstrated. This superiority in survival rates for the heated group is now three to one or 300 per cent. The most reasonable explanation for the improvement in survival time of patients in State IIIA is stimulation of the immune response. As a result of our experience with heated perfusion of limbs, we are investigating the possibility that systemic hyperthermia may enhance the antitumor effects of various chemotherapeutic agents on melanoma.