George P. Canellos

Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas

Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkins lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.

A Prognostic Score for Advanced Hodgkin's Disease

BACKGROUND Two thirds of patients with advanced Hodgkins disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. METHODS Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkins disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. RESULTS The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. CONCLUSIONS The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkins disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD

BACKGROUND AND METHODS MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkins disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkins disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen. RESULTS Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose. CONCLUSIONS In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkins disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Dose: A critical factor in cancer chemotherapy

Abstract The effect of dose and dose rate of cancer chemotherapeutic agents in experimental in vivo systems and in various clinical situations has been reviewed. In experimental in vivo systems, the dose-response curve for most chemotherapeutic agents is steep. Although the dose response curve may be linear for cytokinetically homogeneous experimental tumors, it deviates from linearity as a result of tumor heterogeneity. The steepness of the dose-response curve is related to the sensitivity of the tumor to a given drug. Thus, for highly sensitive tumors, the curve is very steep and generally linear; whereas for relatively insensitive tumors, dose may have little effect on response. These observations in general apply to the clinic. When dose has been a randomized variable, a dose-response curve is generally evident in sensitive tumors, such as the leukemias, the lymphomas, testicular cancer and small cell lung cancer. In contrast, when the difference in dose is in the range of twofold, the evidence for superiority of the high dose in such situations as 5-fluorouracil for colorectal cancer and dimethyl-triazeno-imidazole-car☐amide (DTIC) for melanoma is less impressive. The use of relatively low dose maintenance treatment following four to six courses of intensive combination chemotherapy for such diseases as testicular cancer and lymphoma may prolong the duration of remission but probably will not increase the cure rate. In adjuvant chemotherapy situations, in which prolonged disease-free survival is improved, the dose-response curve would appear to be quite steep. Conservative dosing in this setting may compromise the cure rate, and the proposed approach is to maintain full dose therapy and consider reducing the total duration of treatment. When high doses or concentrations of antitumor therapy can be achieved, such as in the marrow transplant situation and in isolation perfusion or regional infusion studies, there is in general clear evidence that a substantial increase in response rate occurs.

Randomized Comparison of ABVD and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report of an Intergroup Trial

PURPOSE In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkins disease. We compared these regimens as initial chemotherapy for Hodgkins disease. PATIENTS AND METHODS Adult patients (N = 856) with advanced Hodgkins disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkins disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkins disease.

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.

Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkins disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkins disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkins disease appears to be curable by chemotherapy.

Long-Term Survival and Competing Causes of Death in Patients With Early-Stage Hodgkin’s Disease Treated at Age 50 or Younger

PURPOSE To analyze the long-term survival and the pattern and timing of excess mortality in patients with early-stage Hodgkins disease. PATIENTS AND METHODS Between 1969 and 1997, 1,080 patients age 50 or younger were treated for clinical stage IA to IIB Hodgkins disease. Overall survival was determined, and prognostic factors were assessed. Relative risk and absolute excess risk (AR) of mortality were calculated for the entire cohort and by prognostic groups (on the basis of B symptoms, mediastinal status, and number of sites, modified from the European Organization for Research and Treatment of Cancer). RESULTS The median follow-up was 12 years. The 15- and 20-year Kaplan-Meier survival estimates were 84% and 78%, respectively. Cox proportional hazards models showed that number of involved sites (P =.006), mediastinal status (P =.02), and histology (P =.02) were independent predictors of death from all causes. The AR of mortality in patients with a favorable prognosis increased over time, whereas for those with an unfavorable prognosis, the AR peaked in the first 5 years, predominantly from Hodgkins disease. The relative risk of mortality from all causes, causes other than Hodgkins disease, second tumors, and cardiac disease remained significantly elevated more than 20 years after treatment. CONCLUSION Patients treated for early-stage Hodgkins disease have a sustained excess mortality risk despite good control of the disease. Treatment reduction efforts in patients with early-stage, favorable-prognosis disease should continue, but for patients with an unfavorable prognosis, modified treatment may not be advisable. The excess mortality noted beyond two decades underscores the importance of long-term follow-up care in patients treated for Hodgkins disease.

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.

Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M- BACOD)

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.