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Biomedical subjects

S N Wolff

Publications and source records attributed to S N Wolff.

At least 73 records · Page 4Linked to original sources
PubMed1987

Cerebellar toxicity with high-dose cytosine arabinoside.

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.

Adolescent↗
PubMed1987

High-dose carmustine with autologous bone marrow transplantation for the adjuvant treatment of high-grade gliomas of the central nervous system.

The long-term survival of patients with high-grade gliomas of the CNS is poor despite the use of radiation therapy and chemotherapy. In an attempt to improve the survival of such patients, we administered adjuvant chemotherapy as high-dose carmustine with autologous bone marrow transplantation. Eighteen patients, 15 with glioblastoma multiforme and three with anaplastic astrocytoma, were treated shortly after completion of standard radiation therapy. One course of carmustine was administered at a total dose of 900-1050 mg/m2 iv over 3 days followed in 3 days by the reinfusion of the previously cryopreserved bone marrow. Acute toxicity was mild, but eight patients had severe pulmonary or CNS toxicity of which four episodes of pulmonary toxicity were fatal. For all patients treated, the median survival was 17.5 months from diagnosis and the estimated probability of surviving greater than 27 months was 22% (95% confidence limits of 14%-32%). Presently, there are four long-term survivors, two with progressive tumor, one suffering from severe encephalomyelopathy, and one alive and well. Although, in this series, we have observed long-term survivors, the overall estimated probability of survival is not substantially different from conventional treatment. In addition, the 22% incidence of fatal pulmonary toxicity suggests that this treatment will not measurably add to the treatment of CNS gliomas.

Adult↗
PubMed1987

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: an update.

High-dose (HD) cytosine arabinoside (ara-C) is more effective treatment than conventional-dose ara-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). Previously, we have reported that HD-ara-C administered during the first remission of ANLL has resulted in long remission durations and a high proportion of patients with long-term disease-free survival. In this update, those patients have been observed further and additional patients have been treated, affirming the initial conclusions. Since August 1979, 55 adult patients with ANLL in first remission received one to three courses of HD-ara-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 to 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 to 9). Three patients died of sepsis or hemorrhage during consolidation and 19 patients have relapsed from 5 to 48 months after diagnosis. The remaining 33 patients remain in continued complete remission (CCR) from 5 to 75 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 51% at 75 months with an apparent plateau in the survival curve. Of the first 22 patients is 27 months. Using univariate and multivariate analysis, age is the only statistically significant prognostic parameter with the actuarial CCR of ages less than 25, 25 to 44, and greater than 44 being 100%, 48%, and 23%, respectively. Due to its heightened antileukemic activity, HD-ara-C allows brief but effective consolidation of ANLL in first remission with long-term disease-free survival comparable with other approaches including bone-marrow transplantation.

Acute Disease↗
PubMed1986

Intensive 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma.

Intensive monochemotherapy with carmustine (BCNU) (either 1,050, 1,200, or 1,350 mg/m2) and cryopreserved autologous marrow transplantation was administered to 36 patients with malignant glioma: 27 with progressive disease and nine without progression (adjuvant therapy group). Twelve (44%) of the patients with progressive disease responded; two remain disease free 84 and 60 months after BCNU treatment. In the adjuvant therapy group, three patients remain progression free at 70, 48, and 27 months after BCNU therapy. Tumor progression posttransplantation occurred in 25 patients; six others died of therapy-induced complications. In addition, late neurologic deterioration of unknown cause has developed in two surviving patients. Results from this and other series using intensive BCNU monochemotherapy and autologous marrow transplantation for progressive malignant glioma indicate that prolonged progression-free survival can be produced in an occasional patient, an extremely unusual result with conventional chemotherapy. Although intensive BCNU and autologous marrow transplant regimens are toxic, these results are encouraging. The treatment of patients in an adjuvant fashion with BCNU and other active agents may produce improved results.

Adolescent↗
PubMed1986

Randomized dose-response evaluation of etoposide in small cell carcinoma of the lung: a Southeastern Cancer Study Group Trial.

To evaluate postulated dose-response relationships of etoposide (VP-16) for patients with recurrent small cell carcinoma of the lung, a prospectively randomized study was undertaken. VP-16 was administered iv at three dose levels: 300, 600, and 900 mg/m2. Based on historical information, a 20% response rate was anticipated in the standard-dose level and the study was designed to be able to detect a response rate of 40% in either of the high-dose levels. The planned number of patients required in each arm was 45, with an alpha-level of 0.1 and a beta-level of 0.2. The total number of patients actually entered was less than the planned number due to a low response rate. Seventy-seven of 79 treated patients were eligible, and 26, 27, and 26 patients were treated at each dose level, respectively. Toxicity was predominantly hematologic, with the higher dose levels substantially more toxic. Response to therapy was infrequent, with only four partial responses achieved and distributed between all dose levels. In this study, using previously treated patients, VP-16 at standard-dose or at moderate-dose increments had minimal activity.

Carcinoma, Small Cell↗
PubMed1986

Effects of Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the treatment of lymphoid neoplasms with very poor prognosis.

Treatment results remain very poor for some clinical and histopathologic subsets of patients with aggressive non-Hodgkin's lymphoma. We treated 21 such patients with a high-dose combination chemotherapy regimen [Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)] in an attempt to improve disease-free survival. Neoplasms were classified using the Lukes-Collins system. Eight patients had T-cell lymphomas (convoluted lymphocytic lymphoma, four patients; T-cell lymphoma/leukemia, one; and peripheral T-cell lymphoma, three), eight had B-cell lymphomas (immunoblastic sarcoma, five patients; small noncleaved follicular center cell, one; and large noncleaved follicular center cell, two), and five had nontypable large noncleaved cell lymphomas. All patients were previously untreated; 18 of 21 patients had clinical stage III or IV disease. Following induction therapy (4-8 weeks' duration), 16 patients (76%) achieved complete remission, while three had partial remission. Two patients died of sepsis during induction therapy. Eleven of 16 complete responders (69%) remain in complete remission after a median follow-up of 35 months. The actuarial 3-year survival rate is 51% for the entire group. Myelosuppression with this regimen was severe and prolonged, with a median duration of neutropenia (less than 500 cells/microliter) of 14 days. Seven patients (33%) developed severe neuropathy following induction treatment. High-dose induction therapy with this regimen resulted in a high complete remission rate with manageable toxicity. Survival results are encouraging when compared retrospectively to our patients with similar poor-prognosis histologies treated with standard combination chemotherapy. However, the value of this intensive therapy, relative to newer ("third-generation") regimens, can only be established by prospective randomized studies.

Actuarial Analysis↗
PubMed1986

High-dose pilot studies in extensive-stage small-cell lung cancer.

Small-cell lung cancer is rarely cured with standard chemotherapy, despite initial good responses. The concept of high-dose induction therapy for extensive-stage patients has been explained in a series of pilot studies. The rationale of this approach and the most recent preliminary results will be presented.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Modified cyclophosphamide, vincristine, methotrexate, leucovorin, and cytarabine (COMLA) in intermediate- and high-grade lymphoma: an effective short-course regimen.

Twenty-one patients with intermediate- and high-grade lymphomas were treated with modified cyclophosphamide, vincristine, methotrexate, leucovorin, and cytarabine (COMLA). This regimen utilizes the drugs used in COMLA in similar doses, but cyclophosphamide is given twice as frequently, cytarabine is given by continuous infusion, and the total duration of therapy is reduced to 16 weeks. Complete remission rates were 80% in patients with intermediate-grade lymphomas and 67% in patients with high-grade lymphomas. Persistent complete remission rates were 60% and 33%, respectively, with a median follow-up of 26 months for surviving patients. This regimen was myelotoxic, but there were no toxic deaths. Modified COMLA is a relatively nontoxic regimen producing excellent results in intermediate-grade lymphomas.

Actuarial Analysis↗
PubMed1986

Combination chemotherapy with vindesine, etoposide, and cisplatin in non-small cell lung cancer: a pilot study of the Southeastern Cancer Study Group.

Ninety-two patients with advanced non-small cell lung cancer were treated with a combination chemotherapy regimen containing cisplatin, vindesine, and etoposide. Eighteen patients (20%) achieved major responses to therapy (three complete responders and 15 partial responders). Response rates were similar in each histologic subtype. Initial performance status was an important determinant of response; 42% of the patients with a Karnofsky performance status greater than or equal to 70% responded versus 5% of those with a performance status less than 50%. The median duration of partial response was 21 weeks; complete responders had a median response duration of 50 weeks. The median survival for the entire group was 23.5 weeks. Toxicity with this regimen was acceptable; myelosuppression was the major toxic effect and was severe in only 10% of the patients. This regimen produced response rates comparable to those reported with other combinations containing cisplatin. Survival advantage in patients receiving this treatment is not established.

Adenocarcinoma↗
PubMed1985

Extensive-stage small-cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose cyclophosphamide plus high-dose etoposide.

Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.

Adult↗
PubMed1985

High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia.

Seventy-eight patients with acute nonlymphoblastic leukemia in relapse were treated with high-dose cytosine arabinoside (3 g/m2 intravenously (IV) every 12 hours for 12 doses) alone, or with three days of anthracycline antibiotics (doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 IV daily) after completing the course of cytosine arabinoside. Consolidation and maintenance therapy was not given. When anthracyclines were added there was no increase in frequency or severity of nonhematologic toxicity including conjunctivitis, photophobia, dermatitis, cerebellar dysfunction, and gastrointestinal disturbance. All 78 patients achieved aplasia of the bone marrow. Five patients in each group died before bone marrow recovery. The use of anthracyclines did not prolong bone marrow recovery, with both groups demonstrating adequate granulocyte and platelet counts about four weeks after beginning treatment. Forty-one (53%) of the total 78 patients achieved a complete remission. In patients not clinically resistant to conventional-dose cytosine arabinoside, both regimens were equally effective inducing a complete remission (high-dose cytosine arabinoside alone, 12/19 [63%]; with anthracycline, 11/17 [65%], P = .270); in patients clinically resistant, the regimen including anthracycline was superior (15/27 [56%] v 3/15 [20%], P = .022). The duration of unmaintained response was similar (median, five months), but the longest remissions occurred when anthracyclines were used. Thus, high-dose cytosine arabinoside is effective in producing remissions in relapsed patients with acute nonlymphoblastic leukemia, and the addition of an anthracycline enhances this effect.

Acute Disease↗
PubMed1985

High-dose etoposide (VP-16) in small-cell lung cancer.

Etoposide (VP-16) is one of the most active drugs against small-cell lung cancer. There may be a steep dose-response relationship, and we have explored the use of etoposide as a single agent in a high dose (1,200 mg/m2) without bone marrow transplantation, for patients with very bulky, extensive-stage disease. This therapy is well tolerated in patients having good performance status, with myelosuppression representing the major toxicity. Our data suggest there may truly be a steep dose-response relationship. We have continued to explore intensive induction therapy for selected very poor-prognosis patients by adding high-dose cyclophosphamide (100 mg/kg) to high-dose etoposide. This combination is also very myelotoxic, but quite similar to etoposide alone. Our current study adds cisplatin (120 mg/m2) to the high-dose cyclophosphamide-etoposide schedule in an attempt to take advantage of the synergism seen with these drugs in various other circumstances. This series of studies will give us information regarding the feasibility of intensive induction therapy and provide data for the design of phase III studies.

Adult↗
PubMed1985

Chemotherapy of small-cell lung cancer.

Combination chemotherapy has become the cornerstone of management for patients with small-cell lung cancer. Although the majority of patients are palliated, most continue to die of their disease. Studies designed to improve treatment results and to understand the basic biology of this neoplasm are continuing. Several strategies are now being investigated, including the use of non-cross-resistant chemotherapy, dose intensification, manipulation of the duration of therapy, combined modality therapy, and salvage chemotherapy. Studies in these areas have not yet yielded results that have definitively improved response rates or survival. It appears that further therapy after remission induction has not yet proven beneficial. This paper will review selected areas of therapeutic investigation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Treatment of metastatic malignant melanoma with intensive melphalan and autologous bone marrow transplantation.

Twenty patients with metastatic malignant melanoma were treated with melphalan (180-225 mg/m2 iv over 3 days) followed by re-infusion of previously harvested and cryopreserved autologous bone marrow. Granulocyte (greater than 500/microliter) and platelet (greater than 20,000/microliter) count recovery occurred a median of 14 days (range, 12-22) and 19.0 days (range, 12-28) after bone marrow transplantation, respectively. Three patients died due to hemorrhage or infection. One of these patients and another (who ultimately achieved a complete response), both with brain metastases, developed intralesional hemorrhage when the platelet count was only moderately reduced. Complete responses occurred in six patients and ranged from 4 to 14 months, with a median of 5 months. Six patients achieved a partial remission lasting 2-5 months. High-dose melphalan and autologous bone marrow transplantation are a promising therapy for patients with metastatic malignant melanoma.

Adult↗