Biomedical subjects
Publications and source records attributed to J A Levi.
A life-threatening haemorrhagic cystitis, which occurred in a patient with metastatic prostatic carcinoma, was controlled with epsilon-aminocaproic acid (EACA) after conventional approaches to treatment failed. EACA administration was both systemic and intravesical, and control of bleeding occurred within 24 hours after initiation of treatment.
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Combination chemotherapy including adriamycin is proving highly effective therapy for advanced breast carcinoma. This trial was designed to determine the response to and toxicity of a combination of cyclophosphamide, adriamycin and 5-fluorouracil (CAF). Twenty-six patients with metastatic breast carcinoma who had measurable sites of disease were evaluated. The over-all response rate was 62% being made up equally of complete (CR) and partial (PR) remittors. An additional 19% of patients had less than 50% tumour regression while only 19% had progressive disease. Patients with predominantly soft tissue or visceral metastases responded regularly to CAF, but bone metastases proved to be somewhat more resistant. Toxicity was not great; leucopenia was the most common manifestation, and no severe infections occurred during the trial. Cardiotoxicity occurred in one patient, who received more than 450 mg/m2 of adriamycin. The median time to relapse for responders (CR + PR) was 18 months. Responding patients have had a significantly longer survival than patients with progressive disease. Median survival time of responding patients (CR + PR) is not yet reached; 50% of the patients are still alive 30 months after commencing the trial, while, for patients with progressive disease, median survival time was only six months and none of the original five patients are alive. These and other reported results are sufficiently encouraging to warrant comparative evaluation of endocrine manipulation, combination chemotherapy, and both modalities concurrently, to define the optimal initial management for metastatic breast cancer.
Thirty-five patients with advanced-stage metastatic or unresectable gastric adenocarcinoma were given combination chemotherapy consisting of fluorouracil, doxorubicin, and 1,3-bis (2-chlorbethyl)-1-nitrosourea. Two patients achieved complete remission and 16 partial remission to give an overall response rate of 52%. Six further patients (17%) had stable disease, while in 11 (31%) the disease showed clear-cut progression despite treatment. The only pretreatment factors that suggested poor prognosis were poor initial patient performance and the stomach as the predominant site of disease. Patients responding to treatment had a significantly longer time to relapse (median 48 weeks) than patients with stable disease (median 16 weeks) and a significantly improved survival time (medians, 52 weeks with 30% of patients' living at 88 weeks and 32 weeks with all dead at 64 weeks respectively). Comparing these results with those in other reports indicated that the three-drug combination chemotherapy consisting of fluorouracil, doxorubicin, and either a nitrosourea or mitomycin was superior to single and two-drug regimens and currently represents the optimum treatment for advanced-stage gastric cancer. Gastric adenocarcinoma should now be considered to be a gastrointestinal malignancy that is relatively susceptible to chemotherapy, and studies of these improved chemotherapeutic regimens as post-surgical adjuvants may lead to further improvements in prognosis.
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Progressive improvements in the management of certain paediatric and haematological malignancies have provided guidelines for the current approaches to the management of the more common solid tumours of adults. These include precise histopathological grading; comprehensive evaluation of extent of disease; staging classifications accurately correlated with prognosis and progressive evaluation of available therapeutic modalities for all stages of disease in an attempt to define the best combination of local and systemic forms of therapy. Breast cancer is reviewed in detail as an example of the more responsive tumours where screening programs; improvements in pathological and clinical staging and the introduction of systemic chemotherapy together with optimal use of other methods of treatment for the various stages of disease gives hope for a significant improvement in long term survival statistics. Lung cancer has also been reviewed as an example of the more resistant types of cancer where screening programmes and current therapy including the use of combination chemotherapy have given minor encouragement but not had a definite influence on long term survival. Some further gains may still be achieved with currently available techniques but major improvements will probably require the development of better therapeutic tools including radiotherapy with high linear energy transfer particles; new chemotherapeutic agents and specific forms of immunotherapy. It is also quite possible that completely different forms of therapy for these resistant tumours will be necessary to reach the desired goal of long term improvements in survival.
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Fifty patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in a 21-day cyclic regimen. Thirty-one patients (62%) achieved a pathologically documented complete remission (CR). Of the 23 previously untreated patients, 13 obtained CR. Twenty-seven patients had been previously treated and 15/19 (79%) of those with prior major radiation therapy and 3/8 (37.5%) of those who had received both irradiation and chemotherapy achieved CR. Sixteen of the patients who attained CR received maintenance therapy with monthly alternating CCNU and vinblastine but as of this report, neither remission duration nor survival is significantly prolonged when compared to the 14 patients followed in remission on no therapy. Patients who received more than six courses of induction therapy (median 9.5, range 8-12) have had significantly fewer relapses and longer remissions than have those patients who received only six courses of therapy. It is concluded that: 1) CVPP is an effective regimen at inducing CR in patients with advanced Hodgkin's disease and has less gastrointestinal and neurologic toxicity than MOPP; 2) maintenance therapy with CCNU and vinblastine to date has not been beneficial; and 3) greater than six courses of induction chemotherapy prolongs remission duration and is associated with fewer disease relapses.
Thirteen patients with advanced mycosis fungoides received induction therapy with Adriamycin, 60/m2 I.V. repeated at 21-day intervals. Ten patients had extensive skin tumors; all patients had lymph node enlargement with mycosis fungoides involvement in eight; four patients had biopsy-proven visceral involvement. Only two patients had received no prior therapy. The overall response rate with Adriamycin therapy was 85% with three patients (23%) achieving a biopsy-proven complete remission and five patients (39%) partial remissions. The median number of courses to maximum response was two (range two to four). The principle toxicity was myelosuppression, but this was not severe and the entire group received more than 90% of the intended doses of Adriamycin. One patient developed probable Adriamycin cariotoxicity. Maintenance therapy for patients achieving a remission was methotrexate 15 mg/m2 I.M. twice weekly and cyclophosphamide 750 mg/m2 I.V. every 21 days. The median duration of complete remission was 32+ weeks (range 16+-40+ weeks) while the median duration of partial remission was 18 weeks (range 8-111+ weeks). Adriamycin has proven to be an effective induction agent in the treatment of advanced mycosis fungoides and its incorporation into combination chemotherapy regimens is warranted.
In an effort to determine the most appropriate initial therapy for patients with stage IIIA Hodgkin's disease, a comparative analysis was undertaken of 13 pathologically staged IIIA Hodgkin's disease patients whose abdominal disease was localized to the spleen (IIIsA); 17 IIIA patients with spleen and abdominal lymph node involvement (IIIs+n+A) and 44 stage IIA patients. The three groups were treated concurrently with either extended field irradiation alone or limited field irradiation followed by MOPP chemotherapy. Relapse rates after irradiation alone were 17% for the IIIsA patients; 63% for the IIIs+n+A patients and 25% for the stage IIA patients. Following therapy with irradiation and chemotherapy no relapses occurred among the IIIsA and IIIs+n+A patients while 2/16 (13%) stage IIA patients relapsed. After irradiation alone stage IIIs+n+A patients had a significantly shorter remission duration and survival than the stage IIA patients (p = 0.03 and 0.002, respectively) but remission duration and survival were similar for the IIIsA and IIA patients. When therapy was irradiation and chemotherapy no significant differences in remission duration or survival were noted for the three groups. The most common sites of relapse for the IIIs+n+A patients were extralymphatic (60%) while no extralymphatic relapse have occurred among the IIIA patients (p less than 0.02). The only relapse among the IIIsA patients was at an extralymphatic site. These data have shown that patients with IIIsA Hodgkin's disease have a similar prognosis to stage IIIA disease but after therapy with irradiation along stage IIIs+n+A patients have a poorer prognosis. Combined irradiation and chemotherapy should, therefore, be considered for stage IIIs+n+A Hodgkin's disease when abdominal nodal disease cannot be included in the initial radiation port.
Seventeen patients with advanced, previously treated Hodgkin's disease received therapy with a combination of streptozotocin 500 mg/m2/day i.v. days 1--5, CCNU 100 mg/m2 orally day 1, adriamycin 45 mg/m2 i.v. day 1, and bleomycin 15 mg/m2 i.m. days 1 and 8 at 28-day intervals (SCAB). The overall response rate was 59% with six patients (35%) achieving complete remission and four patients (24%) entering partial remissions. No maintenance therapy was given and the median duration of complete remission was 8+ months (range 2+-18+ months), while the median duration of partial remission was only 2 months (range 2-3 months). The median duration of survival from the start of therapy for the complete responders was 16+ months (range 5+-25+ months) while the median survival for the partial and nonresponders was only 5 months (range 2-13 and 3-11+ months, respectively). Toxicity was a major problem with this drug combination. Myelosuppression occurred regularly and was severe after 25% of courses. There were two deaths directly related to drug-induced myelosuppression. Other serious toxicities included bleomycin-induced pulmonary toxicity in three patients, with one death; renal tubular dysfunction secondary to streptozotocin in three patients; hepatic dysfunction in three patients and severe weight loss in three. SCAB has proven to be an active although toxic combination which is not cross-resistant to MOPP-type regimens. Alterations in drug dosages and scheduling are being evaluated in an effect to ameliorate toxicity and preserve efficacy.
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Thirty-five episodes of localized infection among 20 patients with acute leukemia and granulocytopenia (less than 1000 cells/microliter) were treated with intensive supportive care including systemic antibiotics. In a double blind randomization, 17 of the episodes also received 400 rads of megavoltage irradiation to the site of the lesion given as a single dose and repeated 7 days later. No significant differences were observed in response rates between the irradiated and nonirradiated lesions. Overall, 65% of the irradiated infections and 44% of the nonirradiated lesions responded completely, a difference which is not significant. The median number of days required to achieve maximum clinical response was similar whether or not irradiation was given (10 versus 12 days). Management of such localized infections should include early diagnosis with prompt institution of intensive supportive care including appropriate systemic antibiotics, but low-dose irradiation cannot be recommended as part of the routine management of these lesions.
Adults with previously treated acute nonlymphocytic leukemia received either 5-azacytidine or guanazole in a randomized study. Eighteen patients were treated with 5-azacytidine at a dosage of 200-250 mg/m2/day X 5 intravenously (i.v.) and six achieved a remission (five complete). The median duration of complete remission was 100 days. Among the 12 patients who received guanazole, at a dosage of 25-30 g/m2/day X 5 by continuous i.v. infusion, only one partial remission ensued. Pm 600 WBC/mm3) than nonresponders (median 1700 WBC/mm3). Both the time taken to reach the nadir white blood coung (median, 14 days) and theduration of the nadir (median, 17 days) were long after each course of 5-azacytidine, particularly for those patients who achieved a remission. Principal toxicities seen after 5-azacytidine administration were gastrointestinal tolerance, fever, and neuromuscular toxicity. Fever was the principal toxicity observed after guanazole therapy; one patient developed erythema nodosum with arthralgias and another, recurrent pulmonary infiltrates. Survival from the start of therapy was clearly longer for the patients receiving 5-azacytidine (median 140 days) because of the prolongation of survival seen in the responding patients (median 266 + days). 5-Azacytidine has significant activity as an induction agent in adults with acute nonlymphocytic leukemia, but guanazole does not appear to be of particular value for patients with this disease.
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.
67Gallium scans were performed as part of the initial evaluation in 45 patients with non-Hodgkin's lymphoma. Eighteen of these patients underwent staging laparotomy and splenectomy. In addition, scans were performed either shortly after therapy was completed or during subsequent followup in 10 patients. The initial scans were found most useful for patients with histiocytic lymphoma: in detecting sites of involvement above the diaphragm and the high para-aortic/mesenteric region, and when tumors were greater than 2 cm in diameter. The addition of 67Ga scanning to the pre-operative clinical evaluation reduced the number of incorrectly staged patients from 8 to 4. Reversion of previously positive 67Ga scans to negative in 3 patients with suspected persistent or recurrent disease was associated with fibrosis and no lymphoma when biopsied. Five other patients had histologically documented positive 67Ga scans post-therapy; in 1 the 67Ga scan was only definitive noninvasive procedure. Despite the occurrence of both false-positive and false-negative 67Ga scans, this procedure appears to be a useful supplement to the pretreatment evaluation of patients with non-Hodgkin's lymphoma, especially the histiocytic form. Confirmation of its ability to detect high para-aortic/mesentric involvement may subsequently result in a reduction of the number of staging laparotomies necessary. For the post-treatment followup of these patients 67Ga scans may prove to be valuable noninvasive investigation.
Current knowledge concerning the course of mycosis fungoides and recognized prognostic factors have been reviewed. Those factors with prognostic significance at the time of biopsy diagnosis include age and the clinical findings of skin tumors, ulceration or palpable lymphadenopathy. During the course of disease, the development of skin tumors, ulceration or palpable lymphadenopathy were each associated with a poor prognosis and median survival was only 12 months if all those clinical parameters were present. Patients who developed overt visceral mycosis fungoides rarely survived more than a few months. Lymphocytopenia and the presence of malignant lymphoma in biopsied lymph nodes were also poor prognostic findings. The various modalities of therapy for proven mycosis fungoides were reviewed. Topical therapy and external irradiation were generally of symptomatic benefit only, but two recent studies have shown that aggressive use of topical nitrogen mustard and electron beam therapy are associated with long-term responses in patients with disease confined to the skin. Single agent chemotherapy often resulted in transient responses in advanced and refractory mycosis fungoides. Future approaches to the management of mycosis fungoides have been suggested. These include a thorough review of the histological features, a thorough and systematic pretreatment evaluation and randomized studies of the various treatment modalities including combination therapy in appropriately staged patients.