Paul V. Woolley

The Modulation of Fluorouracil With Leucovorin in Metastatic Colorectal Carcinoma A Prospective Randomized Phase III Trial

The authorship of the report The Modulation of Fluorouracil With Leucovorin in Metastatic Colorectal Carcinoma: A Randomized Phase III Trial, published in the October 1989 issue (J Clin Oncol 7:1419–1426, 1989) should have read: by the Gastrointestinal Tumor Study Group. The following appendix should also have appeared at the end of the report:

5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer.

Sixty-two patients with advanced measurable gastric cancer were treated with a combination chemotherapy program of 5-fluorouracil, doxorubicin, and mitomycin (FAM). Forty-two percent of patients achieved an objective partial response. The median duration of remission was 9 months and the median survival for responding patients, 12.5 months. The median survival for nonresponding patients was 3.5 months; all patients were dead by 8 months after initiation of therapy. The median survival of all 62 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor, and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, producing only moderate bone marrow suppression. These results show that patients with metastatic gastric cancer can be effectively palliated with FAM chemotherapy. The efficacy of this regimen should now be tested in patients with less advanced stages of this disease.

5‐Fluorouracil, adriamycin, and mitomycin‐C (FAM) chemotherapy for advanced adenocarcinoma of the pancreas

Thirty‐nine patients with advanced metastatic adenocarcinoma of the pancreas were treated with a combination of 5‐fluorouracil, Adriamycin, and mitomycin‐C (FAM). Twenty‐seven of these patients had measurable disease, and ten (37%) achieved a partial response. An additional three patients had evidence of disease stabilization. The median survival period of responding patients was 12 months, compared with 3.5 months for nonresponders (P < 0.01). The median survival period for all patients was 6 months. Moderate myelosuppression constituted the treatment‐limiting toxicity. The FAM combination is an active and well‐tolerated regimen for pancreatic cancer and may have an application in the management of patients with less advanced disease.

Phase II trial of streptozotocin, mitomycin-C and 5-fluorouracil (SMF) in the treatment of advanced pancreatic cancer

Ten of 23 patients with advanced measurable adenocarcinoma of the pancreas achieved an objective response after treatment with a regimen consisting of streptozotocin, mitomycin‐C and 5‐fluorouracil (SMF). The median duration of response is in excess of 7 months, and responding patients have lived significantly longer than patients with progressive disease (7.5+ months vs. 3 months). The SMF regimen was adequately tolerated. Principal toxicities included myelosuppression, which was generally mild, nausea and vomiting. There was reversible nephrotoxicity in the form of proteinuria in 30% of patients and persistent azotemia in 9% of patients.

Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein A immunoperfusion.

Plasma perfusion over filters containing staphylococcal protein A (SPA) was used to treat 11 patients with adenocarcinoma who developed a hemolytic uremic syndrome. Immunoperfusion resulted in complete clearance of pretreatment elevated levels of circulating immune complexes in eight of the 11 patients with normalization of complement values depressed at the start of the therapy in seven. A significant rise in platelets and erythrocyte counts was achieved in nine patients, and stabilization of progressive renal impairment was achieved in six. The response was incomplete and short lived in three patients with clinically evident tumor recurrence, whereas long-term control of the syndrome was demonstrated in seven patients in complete tumor remission (no recurrence with median follow-up of 9 months). SPA immunoperfusion appears to be an effective form of therapy for this otherwise fatal syndrome.

Extranodal presentation of non-Hodgkin's lymphomas in the testis

The clinical and pathologic features of six patients, each of whom exhibited a testicular mass as the first sign of a lymphoma, are discussed. All underwent extensive staging procedures. Retroperitoneal lymph nodes and bone were frequent sites of extratesticular involvement early in the disease. Later widespread dissemination to multiple organs occurred in five of six patients. CNS involvement was a prominent feature of advancing disease. One patient was apparently cured by orchiectomy alone. Although the others exhibited partial responses to chemotherapy and radiation, the disease was fatal to all of them within a year of orchiectomy. Early, aggressive systemic treatment of these patients appears necessary.

5‐fluorouracil, adriamycin, and mitomycin‐C (FAM) chemotherapy for adenocarcinoma of the lung

Twenty‐five patients with advanced measurable adenocarcinoma of the lung were treated with combination chemotherapy consisting of 5‐fluorouracil, adriamycin, and mitomycin‐C (FAM). Objective response (1CR, 8PR) was obtained in 36% of patients. The median duration of response was 7.0 months and the median survival for responders is greater than 8.5 months. Five responders are alive 5.5 to 23.5 months after starting therapy. Three of four patients evidencing stabilization of disease are alive at 10–23 months. Nonresponding patients had a median survival of 2.5 months and none lived beyond seven months. Tumor response and survival suggested correlation with initial performance status and limited disease. The FAM regimen was tolerated well, with moderate bone marrow suppression and gastrointestinal symptoms being the only clinically significant toxicities. These results indicate that patients with advanced pulmonary adenocarcinoma can obtain objective tumor regression with FAM chemotherapy.

Phase-II trial of tamoxifen in advanced breast cancer

SummarySeventy-eight advanced breast cancer patients, most of whom had had prior treatment, were treated with the synthetic antiestogen tamoxifen. The overall objective response rate was 27% (21/78). An additional 19% (15/78) showed disease stabilization. Sixty-seven percent (14/21) of the responses were in soft tissue sites, 24% (5/21) on bony sites and one each occurred in liver and nodular lung disease. Forty percent of patients with soft-tissue disease alone responded, while 10% of patients with visceral disease showed responses in visceral sites. The response rate was 28% among patients with a known positive estrogen receptor (ER) assay. It was 21% among patients who had previously received cytotoxic drugs. Toxicity was mild and was seen in nausea and vomiting, hot flushes and vaginal bleeding, and occasional myelosuppression. One patient was withdrawn from the study because of a rash. In two patients the disease flared, once with concomitant hypercalcemia. Tamoxifen is a useful agent for advanced breast cancer even in some patients with visceral disease.

A controlled trial of the effect of 4-hydroxypyrazolopyrimidine (allopurinol) on the toxicity of a single bolus dose of 5-fluorouracil.

We have evaluated, in a controlled study, the modification of the toxicity of a single bolus dose of 5-fluorouracil (5-FU) by allopurinol. Patients first received a single dose of 5-FU and were monitored for toxicity. If a measurable nadir in WBC or platelet count occurred, then the same dose of 5-FU was repeated with concurrent allopurinol, given for four consecutive days at an initial dose of 300 mg twice daily, starting the day before the administration of 5-FU. With this schedule, each evaluable patient received courses of 5-FU with and without allopurinol that could be compared for toxicity. Twenty patients received initial 5-FU doses of either 1,200 mg/m2 or 1,500 mg/m2 and later had the same dose repeated with allopurinol. Nineteen of these patients had a higher WBC count with allopurinol than without it. In several patients who received a further course of 5-FU with 900-mg/d allopurinol, the WBC count was yet higher than with 600-mg/d allopurinol. The myelosuppression produced by 5-FU was characterized by a decrease in granulocyte levels that was much greater than the decrease in lymphocyte levels, and the result of allopurinol treatment was to attenuate this effort on granulocytes. In a second part of the trial, the goal was to establish the maximum tolerated dose of 5-FU given with concurrent allopurinol. In this part of the study, all patients entered were given 5-FU, usually 1,200 mg/m2, with allopurinol, usually 600 mg/d for four days. Escalations of one or the other drugs were made on subsequent treatments. The data for 22 patients showed that 1,800 mg/m2 of 5-FU was well tolerated if given with 600 to 1,200 mg of allopurinol per day, and that the WBC count nadirs were no more severe than those of 1,200-mg/m2 5-FU without allopurinol. Neurotoxicity became limiting in some patients treated at these higher doses. We conclude that allopurinol given in the proper dose and schedule can diminish the granulocytopenia produced by bolus doses of 5-FU, thereby allowing a 50% increase in the maximal tolerated dose of 5-FU.

Delayed radiation necrosis of brainstem related to fast neutron beam irradiation: case report and literature review.

A 42‐year‐old man developed necrosis of the brainstem 10 months following fast neutron irradiation of a recurrent adenocystic carcinoma of the right submandibular salivary gland. The neoplasm had been diagnosed 15 years earlier. Neck dissection and several local excisions failed to control local extension, so that 7000 rad 4.8 MeV x‐rays were administered. The right mandible and part of the tongue and palate were resected for recurrence and chemotherapy and transfer factor were given. Because of cranial neuropathy and erosion of the skull base, fast neutron radiation (2.080 rads) was administered five and one‐half years after the x‐ray therapy, but to a nonoverlapping field. Ten months later, rapidly progressive symptoms and signs of multiple cranial nerve palsies on the right side and left hemihypesthesia and hemiplegia appeared. Clinical manifestations of brainstem necrosis lasted 4 months. Postmortem examination demonstrated radionecrosis of pons and upper medulla, predominantly on the right side. This case illustrates the efficacy of neutron radiation in eradicating local carcinoma and also the serious complications of this therapeutic modality. Cancer 44:473‐479, 1979.