The influence of antineoplastic chemotherapy on antipyrine metabolism in man.

When either Doxorubicin or Mitomycin-C was administered to patients, antipyrine clearance was respectively unaltered or increased. Antipyrine was administered to patients two days prior to and one day after their first course of the chemotherapeutic drug. Antipyrine clearance increased an average of 11.2% in the 5 patients that received Doxorubicin (not significant) and 15.2% in the six patients that received Mitomycin-C (P = 0.033, students t-test). The altered clearance is likely due to a rapid induction of the mixed function oxidase system by the chemotherapy as other parameters that could influence clearance were stable throughout the study (volume of distribution, weight, creatinine clearance and liver function tests). It is unlikely that the prechemotherapy antipyrine dose accounted for this change. The administration of these two antitumor antibiotics in humans may modestly increase the mixed function oxidase activity that is responsible for the metabolism of antipyrine. These findings are in direct contrast to markedly decreased mixed-function oxidase activity observed in the rodent pretreated with the same chemotherapy.

A phase II trial of PALA + dipyridamole in patients with advanced soft-tissue sarcoma.

A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m2 N-phosphonacetyl-L-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m2 dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma.

Phase II trial of methyl-CCNU, vincristine, 5-fluorouracil, and streptozotocin (MOF-Strep) in patients with disseminated pancreatic carcinoma.

A phase II trial of methyl-CCNU, 5-fluorouracil (5-Fu), vincristine, and streptozotocin (MOF-Strep) was conducted on 20 patients with pancreatic carcinoma. There were two partial remissions (10%) lasting 3 and 10 months. In addition, there were two minor responses. The predominant toxicity was gastrointestinal, although hematologic and renal toxicity were also seen. Since the response rate to MOF-Strep does not appear to exceed that to 5-Fu alone, the usefulness of this combination in patients with pancreatic carcinoma is limited.

Phase II trial of methylglyoxal-bis-guanylhydrazone (methyl-GAG) in patients with soft-tissue sarcomas.

A phase II study of Methylglyoxal-bis-guanylhydrazone (Methyl-GAG) was conducted on 20 previously treated patients with soft-tissue sarcomas. No major responses were seen among 18 adequately treated patients. Toxicity including severe fatigue, muscle pains, and pharyngitis was noted in most patients. Methyl-GAG does not have significant antitumor activity in previously treated patients with soft-tissue sarcomas.

Phase II trial of menogarol in the treatment of advanced adenocarcinoma of the pancreas.

Fifteen patients with advanced adenocarcinoma of the pancreas were treated with menogarol 150-225 mg/m2 i.v. every 3 weeks. All patients had bidimensionally measurable disease. This regimen and dosage schedule are well tolerated, with minimal toxicity that included myelosupression; median white blood cell (WBC) count nadir of 2,700 cells/mm3 (range 1,400-7,100 cells/mm3) and median platelet nadir of 162,000 cells/mm3 (range 53,000-390,000 cells/mm3). Anorexia occurred in one patient, nausea or vomiting in six, phlebitis in one, and alopecia in six patients. No patients responded. At this dosage and schedule, there is no role for menogarol in the treatment of advanced pancreatic adenocarcinoma.

Etoposide (VP-16) in the treatment of advanced adenocarcinoma of the pancreas.

Twenty-six patients with advanced adenocarcinoma of the pancreas were treated with etoposide (VP-16), 100-180 mg/m2 i.v., days 1, 2, and 3, monthly. Twenty-five had bidimensionally measurable disease and one had evaluable disease only. This regimen and dosage schedule were well tolerated, with minimal toxicity including myelosuppression; a median WBC count nadir of 3,600 cells/mm3 (range 200-2,400); and a median platelet nadir of 215,000 cells/mm3 (range 15,000-405,000). However, no patients responded and only two had stable disease for 3.5 and 4 months, respectively. At this dosage and schedule, there is no role for VP-16 in the treatment of advanced pancreatic adenocarcinoma.

Phase II evaluation of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) in patients with gastric adenocarcinoma.

A phase II study of m-AMSA in patients with gastric adenocarcinoma was conducted. Twenty-three patients received m-AMSA, 90-120 mg/m2, every 3 weeks. There were no major responses among 20 evaluable patients, although one patient experienced a minor response. Depression of the white blood count was the most prominent toxicity. m-AMSA has little activity in patients with gastric adenocarcinoma.

Phase II evaluation of m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) in patients with adenocarcinoma of the pancreas.

m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide, a substituted acridine derivative, was administered to 27 patients with adenocarcinoma of the pancreas. The dose ranged from 90-210 mg/m2/course. The toxic effects were primarily hematologic. Twenty-four of the patients were evaluable for response. These patients received a median of 2 doses (range 1-7). The median time from diagnosis to therapy was 2 months (range 0-16). Two patients achieved an MR lasting 4 and 2 months, respectively. Two patients had stabilization for 6 and 3 months. The median survival for all patients was 3 months. Survival distribution for patients with prior chemotherapy versus no previous therapy was not significantly different (p = 0.5). This study suggests that m-AMSA has little value as a single agent in the treatment of adenocarcinoma of the pancreas.

MIFA III (mitomycin-C, 5-fluorouracil, and adriamycin) chemotherapy for advanced adenocarcinoma of the pancreas.

Twenty-nine patients with advanced adenocarcinoma of the pancreas were treated with a combination of mitomycin-C, 5-fluorouracil, and adriamycin (MIFA III). Four of these patients achieved a partial response, and two achieved a minor response. An additional seven patients had evidence of disease stabilization. The median survival period from initiation of therapy for responders was 13.5 months as compared to 7.6 months for those with stable disease and 3.2 months for nonresponders (p = 0.001). Myelosuppression was the primary toxicity. Prolongation of survival was demonstrated in responding patients who had failed prior chemotherapy. The MIFA III regimen is active, well tolerated, and warrants further investigation in previously untreated patients.

Scanning with L-(13 N) glutamate: Assessment of the response to chemotherapy of a patient with embryonal rhabdomyosarcoma.

The use of (13) N-labeled L-glutamate as an imaging agent in a patient with embryonal rhabdomyosarcoma is described. Localization of (13)N in a large, poorly defined tumor of the left pectoral region was seen, and clinically occult right axilliary metastases were also detected. A marked reduction in uptake in these areas occurred after chemotherapy, paralleling the clinical disappearance of tumor. These changes were verified on gallium scan. (13)N-labeled glutamate may be useful as an imaging agent, especially in patients with soft-tissue sarcomas.

Central venous catheter complications in sarcoma patients receiving adjuvant chemotherapy.

As part of a prospective randomized study in patients with high grade soft tissue sarcoma (STS), 47 patients received post-operative adjuvant Adriamycin. The method of administration was randomized to intravenous bolus (B) or to continuous 72 hour infusion (CI) via a Silastic right atrial catheter. Both groups received 60 mg/m2 every 3 weeks. There were nine hospital admissions for treatment related complications in four of the 26 CI patients compared to none in the 21 B patients (P = 0.03). All of the admissions related to complications involving the central venous catheter (CVC). This apparent increased risk for hospital admission secondary to treatment related complications in patients treated with CI must be considered in the planning of future therapeutic trials.

Malignant mesothelioma in children: report of seven cases and review of the literature.

Seven children with malignant mesothelioma have been seen at Memorial Hospital since 1953. In six, the origin was at the pleura and in one at the peritoneum. None of the patients related a history of exposure to asbestos. Two patients lived more than five years. The other five patients died within two years of the diagnosis. Distant metastases were seen in four of the patients, including three who had metastases to brain. Surgery or radiotherapy were not effective in controlling the disease in most of the patients. One patient had a complete response to a combination of Adriamycin, cyclophosphamide, and vincristine and has remained free of disease for 5 1/2 years. The seven cases are reviewed, as are the other 42 cases of malignant mesothelioma in children reported in the literature.

Chemotherapy for soft tissue sarcoma.

Adriamycin is the only active single agent for patients with metastatic sarcoma; combination chemotherapy regimens that omit Adriamycin are ineffective in adults. Despite early success with CYVADIC, there have been recent doubts regarding its efficacy. No other chemotherapeutic combination has provided consistently better results than CYVADIC. As complete responses occur in less than 15 per cent of patients there is a need for further evaluation of new regimens. It is necessary to evaluate new regimens in prospective, randomized studies. Response criteria should be consistent and reproducible. Attenuation schedules and data relating to the total administered dosage should be provided. It would also be beneficial to analyze prognostic variables so that patients liable to an unfavorable outcome could be identified before commencement of treatment.

Recurrent epidermoid cancer of the anus.

Of 83 patients with recurrent epidermoid cancer of the anus, 67 had tumors in the anal canal and 16 had tumors at the anal margin. Local pelvic or perineal recurrence after abdominoperineal resection of tumors in the canal had a poor prognosis. Median survival after combination chemotherapy and megavoltage irradiation was 14 months. With irradiation alone, median survival was 7 months, although nearly half of these patients had been treated with orthovoltage techniques. Untreated patients with visceral metastases had a median survival of 8 months, but no improvement in survival was seen after treatment with chemotherapy. In contrast, patients who had metastases in inguinal lymph nodes had a 55% 5-year survival rate after inguinal dissection. Patients with tumors at the anal margin did not have visceral metastases. This is an important difference between tumors arising in the canal and those arising at the anal margin. Local excision was satisfactory treatment for 90% of the patients who had local recurrence in the perianal skin; abdominoperineal resection was rarely required. Inguinal lymph node metastases from margin cancer are uncommon, but three of five such patients survived 5 years after groin dissection. A combination of 5-fluorouracil, mitomycin C, and radiation therapy was used for patients with pelvic recurrence after abdominoperineal resection of epidermoid cancer of the anal canal. In this study, there was no evaluation of the role of megavoltage irradiation alone at the recommended doses of 5500 to 6000 rad for these patients. Some patients with visceral metastases respond to combination chemotherapy, but median survival is not improved; evaluation of new chemotherapeutic regimens is required. Patients with canal tumors metastatic to inguinal nodes should be treated by groin dissection as their prognosis is relatively good. Local recurrence of tumors at the anal margin can be satisfactorily treated by further local excision; those patients with margin tumors metastatic to inguinal nodes require groin dissection.

Chemotherapy of patients with advanced soft tissue sarcoma with use of DVA (vindesine sulfate), adriamycin and cyclophosphamide (DAC).

Thirty-four patients with advanced soft tissue sarcoma were treated with a three-drug combination including vindesine sulfate (DVA), Adriamycin, and cyclophosphamide (DAC) (S9). Thirty-one patients are evaluable of whom 23 were previously untreated. Among the latter group there were six complete responses (26%) and five partial responses (22%), for a major response rate of 48%. No major responses were seen in the eight previously treated patients. The median duration of responses was 8 months. Leukopenia and peripheral neuropathy were the major complications of treatment. Gastrointestinal toxicity was mild. Adriamycin cardiotoxicity was seen in two patients. Although the overall response rate to DAC is comparable to that of other combinations, it may offer the advantages of an increased complete response rate and less gastrointestinal toxicity.

Extraosseous osteogenic sarcoma. A review of 48 patients.

The clinical records and histologic material of 48 patients with extraosseous osteogenic sarcoma were reviewed. Most patients developed their tumors in the fifth or sixth decades of life. Five patients (10%) developed neoplasms in an area of prior radiation therapy, a median of 15 years after their exposure. Six patients (13%) related a history of trauma to the area where their extraosseous osteogenic sarcoma developed. The course of most patients was that of multiple local recurrences (69%) followed by pulmonary metastases (80%) and death (76%). Amputation or wide resection followed by irradiation appeared to be the most effective types of therapy, with median survivals greater than 60 months for patients receiving these treatments, compared to 28 months for patients initially treated with resection alone. Chemotherapy was not effective for patients with advanced disease; however, adjuvant chemotherapy after surgery may have been of value. Four of five patients who received adjuvant chemotherapy after surgery are alive and disease-free; the only two survivors after development of pulmonary metastases received adjuvant chemotherapy after surgical resection of visible pulmonary metastases.

Phase II trial of cisplatin (CPDD) in previously treated patients with advanced soft tissue sarcoma.

Thirty-six previously treated adult patients with advanced soft tissue sarcomas received CPDD 120 mg/m2 with mannitol diuresis. There were only two (6%) partial responses and five (15%) minor responses in 34 evaluable patients. Toxicity included nausea and vomiting, myelosuppression, mild ototoxicity and mild to moderate, transient nephrotoxicity. CPDD has minimal antitumor activity in previously treated patients with soft tissue sarcomas.

Lymphangiosarcoma.

Forty-four cases of lymphangiosarcoma treated at Memorial Sloan-Kettering Cancer Center were reviewed. With the exception of four patients with primary lymphangiosarcoma of the scalp, all patients had had chronic lymphedema of the involved limb for many years, usually following mastectomy for breast carcinoma, but occasionally due to other cases. Although chronic lymphedema could be implicated in the etiology of lymphangiosarcoma in all patients with neoplasms of an extremity, a significant number of patients did not have a history of radiation therapy at the site where their tumor developed. Histologically, although there were no differences in the lymphangiosarcomas between any of the groups of patients, the morphology of the tumors was influenced in the individual patient by the size and anatomic site of the sarcoma. Early amputation seemed to give the best chance of long-term survival, with responses to wide resection, chemotherapy, and radiation therapy generally only of short duration. Amputation after local recurrence was ineffective in preventing pulmonary metastases and death. At present, early amputation appears to be the treatment of choice for patients with lymphangiosarcoma.

Effect of desacetyl vinblastine amide (DVA) against human sarcomas heterotransplanted in nude mice.

The efficacy of desacetyl vinblastine amide (DVA) was tested against five human sarcomas heterotransplanted into nude mice. Marked antitumor effect was found against a lipoblastic liposarcoma, including complete regressions of tumor in some animals. A lesser, though statistically significant, antitumor effect was observed with a malignant schwannoma. No antitumor activity was seen against a leiomyosarcoma, epithelioid sarcoma, or Ewing's sarcoma. We conclude that DVA deserves study in the treatment of human patients with malignant sarcomas.

Malignant mesothelioma of the pleura: review of 123 patients.

One-hundred-twenty-three cases of malignant pleural mesothelioma were reviewed. Exposure to asbestos or to other industrial dusts or chemicals was an important etiologic factor with 24% of patients relating such a history. A history of prior irradiation or previous lung disease was also occasionally noted. Diagnosis was most often made by exploratory thoracotomy, with pleural biopsy or cytology rarely helpful. Except for nine patients, tumor was confined to the chest at the time of diagnosis, but in 33 of the remaining 114 patients, spread to the abdomen or distant metastasis was seen during the course of disease. Surgery and radiotherapy were ineffective in preventing local recurrence. There were only three major responses to chemotherapy in 111 trials. Median survival was 12 months, and only seven patients (5.6%) lived more than five years. Patients with epithelial mesothelioma and Stage I disease had the most favorable prognosis.