Bruce A. Chabner

Chemotherapy and the war on cancer

The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs. Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers.

Histone Deacetylase Inhibitors in Cancer Therapy

PURPOSE Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. METHODS In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. RESULTS HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. CONCLUSION HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

The Pharmacology and Clinical Use of Methotrexate

METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkins lymphoma, oste...

ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA, A POTENTIALLY CURABLE DISEASE: RESULTS WITH COMBINATION CHEMOTHERAPY

Twenty-seven patients with advanced diffuse histiocytic lymphoma (reticulum-cell sarcoma) were treated with combination chemotherapy utilising nitrogen mustard (or cyclophosphamide), procarbazine, vincristine, and prednisone. Elven (41%) achieved a complete remission and only one of these has had a recurrence of tumour. The remaining ten complete responders were free of all evidence of tumour when last seen 26-105 months from the end of treatment. In contrast, all non-responders or partial responders have died. An interpretation of published survival data suggests that this virulent disease evolves quickly and is usally rapidly fatal if treatment is unsuccessful. Survival free of disease beyond 2 years from the end of treatment may be considered tantamount to cure. This definition of cure, previously applied only to patients treated with radiotherapy, seems applicable to patients who acheive complete remissions with modern drug treatment.

Diffuse Aggressive Lymphomas: Increased Survival After Alternating Flexible Sequences of ProMACE and MOPP Chemotherapy

A new treatment program was developed in an attempt to increase the complete remission rate and survival of previously untreated patients with advanced stages of diffuse aggressive lymphomas. A flexible number of cycles of ProMACE chemotherapy (prednisone, methotrexate, doxorubicin, cyclophosphamide, and epipodophyllotoxin VP-16) was alternated with a flexible number of cycles of MOPP chemotherapy (mechlorethamine, vincristine sulfate, procarbazine, and prednisone), and finally late intensification with ProMACE therapy was given. The duration of each phase of treatment was determined by the patients rate of tumor response. Complete remissions were achieved in 55 of 74 patients (74%) with a median duration of follow-up exceeding 2 1/2 years. Only ten of the complete responders (18%) have had relapse. The dose-limiting toxicity is myelosuppression, and eight patients (10%) died from sepsis. Median survival for all patients has not been reached but is predicted to exceed 4 years with 65% of patients alive at 4 years. Previously we achieved a 46% complete remission rate with 38% of all patients alive at 4 years; relapse-free survival beyond 2 years was tantamount to cure. Therefore, ProMACE-MOPP chemotherapy represents a substantial improvement in treating patients with diffuse aggressive lymphomas.

Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma.

A new combination chemotherapy program for patients with diffuse histiocytic and mixed histiocytic-lymphocytic lymphoma was designed to prevent tumor recurrence during the recovery period of each treatment cycle. A myelosuppressive phase consisting of adriamycin, cyclophosphamide, and vincristine was followed by the nonmyelosuppressive agents bleomycin and prednisone to suppress regrowth of lymphoma while allowing for a return in bone marrow function. Twelve of 25 patients (48%) with advanced, previously untreated, diffuse histiocytic lymphoma achieved a complete remission as determined by restaging 1 month after discontinuation of treatment. The median duration of complete response after completion of therapy is in excess of 1 year (range, 5 to 30 months), and no patient has relapsed. Based on previous experience, it is anticipated that the majority of these patients will achieve an extended disease-free survival for what had previously been regarded as an invariably fatal disease.

Use of Plasma Pharmacokinetics to Predict and Prevent Methotrexate Toxicity

To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drugs clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.

Neurotoxicity and Elevated Cerebrospinal-Fluid Methotrexate Concentration in Meningeal Leukemia

Abstract Cerebrospinal-fluid methotrexate concentration was measured in 25 patients receiving intrathecal therapy for prophylaxis or treatment of meningeal leukemia. In 20 patients with no manifestations of neurotoxicity, the mean antifolate value in the cerebrospinal fluid was 1.7 X 10–7 M two days after administration of 12 to 15 mg per square meter of intrathecal methotrexate, and declined thereafter with a half-life of 12 to 18 hours. Five patients with severe neurotoxicity had cerebrospinal-fluid methotrexate concentrations averaging 13.8 times higher than the mean, and these concentrations were consistently higher than the range of antifolate values in the asymptomatic patients. One patient with values 20 to 100 times greater than the mean in asymptomatic patients sustained a fatal myelopathy, and in another, with an apparent antifolate half-life of 48 hours, irreversible neurologic sequelae developed. These observations suggest that the neurotoxicity associated with intrathecal methotrexate may be ...

Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Abstract Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination — hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil — with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P<0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P<0.02) but more severe toxicity than occurred with melphaIan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P<0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma. (N Engl J Med 299:...

Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered

Induction therapy is now successful in producing a complete remission in more than 90 per cent of patients with acute lymphoblastic leukemia.1 , 2 However, maintenance of remission remains a major ...