Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin's disease

High doses of radiation administered to children with Hodgkin's disease may be associated with long-term alterations in soft tissue and bone growth. In an attempt to minimize this complication, we initiated a protocol using low doses of radiation in conjunction with six cycles of MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy in newly diagnosed, pathologically staged children with Hodgkin's disease. Of 55 children treated in this fashion, the actuarial survival and freedom from relapse rates are 89% and 90%, respectively, with median follow-up of 7 1/2 years and maximum follow-up of 15 1/2 years. The local control rate is 97%. The previously encountered growth alteration did not occur when lower doses of radiation were used. However, three children developed acute leukemia. This study demonstrates that the vast majority of children with Hodgkin's disease can be cured with combined modality therapy. This experience provides long-term follow-up and thus serves as the basis for new ongoing protocols using low-dose involved field radiation with new drug combinations.     

Postchemotherapy staging laparotomy in Hodgkin's disease.

Seventeen patients with Hodgkin''s disease who had a staging laparotomy (SL) within 2 months of the completion of initial chemotherapy are presented. Only 1 patient had a positive laparotomy. Postchemotherapy SL allows any residual active disease to be assessed, but the incidence of positive finding may be small, and such findings are unlikely to alter subsequent management. SL following chemotherapy is therefore not recommended either for patients in clinical remission or for patients with evidence of relapsed disease.     

Treatment of Hodgkin's disease with MOPP chemotherapy: effect of dose and schedule modification on treatment outcome.

An analysis of the therapy details of 99 patients receiving primary MOPP chemotherapy for Hodgkin's disease revealed that treatment modification was a frequent occurrence. The mean cumulative dose calculated as a percentage of the projected ideal dose was 76%. Dose modifications of individual components of the MOPP combination were, however, variable and in part reflected disease-related factors, e.g. patients with stage 4 disease received significantly less vincristine than those with less advanced disease. An initial univariate analysis of factors influencing remission showed that the remission rate was significantly lower among those patients who had (a) liver involvement and (b) drug doses less than 75% of the ideal cumulative dose. Among the individual drug dosages, modification of the vincristine dose appeared to be the most significant treatment-related factor associated with lower remission rates. In a multivariate analysis where both disease-related and treatment-related factors were taken into account drug dosage remained a significant prognostic factor. The most important factors adversely affecting initial remission were the presence of liver involvement and reduction of the drug intensity index (cumulative dose divided by cumulative time). Disease-free survival was adversely influenced mainly by the presence of B symptoms and to a lesser degree, but still significantly, by a lower cumulative vincristine dose. Total survival was, however, influenced adversely only by the presence of B symptoms. The quality of MOPP therapy appears to play a significant role in determining the outcome of Hodgkin's disease.     

The relevance of a staging laparotomy for Hodgkin's disease in India.

A retrospective analysis of 328 cases of Hodgkin's Disease (HD) subjected to a staging laparotomy at the Tata Memorial Hospital, Bombay, India, from 1974 to 1986 was undertaken to assess its relevance to our setup. Eighty percent of the patients were from clinical stages (CS) I and II, 38% with lymphocyte predominance (LP), and 41% with mixed cellularity (MC) histologies. Staging laparotomy was positive in 60% cases overall, including 50% from CS IA and IIA, 68% from CS IB and IIB, and 53% and 67%, respectively, from LP and MC histologies. Splenic involvement was seen in 54% cases. Operative complications were encountered in 2% of cases and deaths in two cases only. In view of the high propensity for abdominal spread, only selected CS IA and IIA cases would merit a staging laparotomy within which, nearly 50% cases with a negative yield could be offered radical segmental irradiation alone for cure. The majority of our patients would, however, require combination therapy.     

Technique of exploratory laparotomy and staging in Hodgkin's disease

Exploratory laparotomy, splenectomy, liver biopsy, multiple lymph node biopsy, and bone biopsy have been successfully carried out in 76 patients with Hodgkin's disease. The superiority of these procedures for accurate determination of extent of abdominal disease is clear. A surgical technique of staging is described that has, to date, no mortality and insignificant morbidity.     

A dose and time response analysis of the treatment of Hodgkin's disease with MOPP chemotherapy

A dose-response analysis of the results of MOPP chemotherapy in 132 patients with Hodgkin's disease was carried out. Complex statistical methods were utilized including 40 different dose-time variables and multivariate logistic analyses of 21 clinical variables, both simply and in stepwise regression. These covariates were not independent, and in stepwise regression analysis only B-symptoms and the mean three-cycle rate of drug delivery significantly influenced complete remission attainment. Two parameters, bone marrow involvement (negative) and lung involvement (positive), significantly influenced the duration of complete remission. Survival was influenced adversely by pleural involvement (effusion), advanced age, and B-symptoms. Analyses indicate that the dose of all three drugs (mustard, vincristine, and procarbazine), and the rate of drug delivery during the first three cycles are important in achieving maximal complete response rates, especially for patients with B-symptoms.     

Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy

The sperm production of 25 patients with Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy was studied retrospectively. All but two patients also received radiotherapy treatment to pelvic and/or non-pelvic fields. Sperm counts were obtained from patients treated either with three or fewer (MOPP-2 group) or with five or more (MOPP-6 group) chemotherapy cycles. Recovery of spermatogenesis following treatment-induced azoospermia was significantly higher among the MOPP-2 patients (Mann-Whitney rank sum test, p = 0.001). Patients in this group who did not receive pelvic irradiation appeared to have greater recovery rates (p = 0.06). The results suggest that three cycles of MOPP chemotherapy represent a maximum exposure compatible with the recovery of spermatogenesis.     

Stages I--III Hodgkin's disease in children: results of staging and treatment.

Fifty-two children with clinical stages I-III Hodgkin's disease were evaluated for disease extent between April 1969 and March 1975. All underwent laparotomy and splenectomy. Two patients with liver involvement were excluded. Thirty of 31 patients with pathologically staged IA-IIA disease have been continuous complete remission after mantle and para-aortic irradiation. There have been no extensions into the untreated pelvis. Fourteen of 15 patients with pathologic stages IIB and IIIB disease show no evidence of relapse after TNI and MOPP. Three of four patients with stage IIIA disease developed nodal relapse after irradiation; all are alive without evidence of disease after re-irradiation (3) and MOPP (2). Thus 45 of 50 patients (90%) have remained continuously free of disease after completion of the planned treatment, and overall 49 of 50 (98%) are alive, without evidence of disease. Such results justify continuation of our staging and treatment philosophy in children with Hodgkin's disease.     

Anticoagulation and high dose liver radiation: a preliminary report.

Two groups of patients were observed for evidence of acute radiation hepatitis during "high dose" radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.     

Involved field radiation therapy for early stage Hodgkin's disease in children: preliminary results.

Twenty Stage I and II children with Hodgkin's disease were treated with involved field radiation therapy. Twelve patients were Stage I. The histologic types were:nodular sclerosis(seven cases), mixed cellularity (two) and lymphocyte predominant (three). There were eight Stage II patients (six nodular sclerosis and two of mixed cellularity). One Stage I and 4 Stage II patients had class B disease. Involved field irradiation was used in these children after staging laparotomy showed no disease below the diaphragm. Eight of the 20 patients relapsed, five in lymph nodes adjacent to the primary site, two in areas across the diaphragm; the other had both local and distant extension. The median time to relapse after completion of radiation therapy for Stage I and II were 15 and 5 months, respectively. Two of the eight children with recurrent disease are dead. The other six were retreated and are alive and free of disease for periods ranging from 24 to 68 months after original treatment (median, 36 months). Two of the six survivors in this group received irradiation to the site of the recurrent disease only, one was given total nodal irradiation, and three had chemotherapy. The other 12 patients are in continuous first remission. They have been followed for a median time of 26 months. The actuarial relapse-free survival and survival rates at 3 years are 57 and 89%, respectively.     

Transient optic neuropathy secondary to MOPP chemotherapy in Hodgkin's disease: report of a case

The authors describe a case of optic neuropathy in a child undergoing MOPP chemotherapy for Hodgkin's disease stage IIISA. Visual acuity improved after substitution of the aforementioned regimen with ABVD chemotherapy, and reached 1 during maintenance therapy with vinblastine. Various neurologic deficits have been ascribed to vincristine, a well-known neurotoxin. This case of optic neuropathy is supposed to be a rare example of involvement of the 2nd cranial nerve due to vinca alkaloids. The absence of neurotoxicity of vinblastine in this case is emphasized.     

Subdiaphragmatic Hodgkin's disease: laparotomy and treatment results in 49 patients

The clinical records of 1,616 patients with previously untreated Hodgkin's disease were reviewed. Forty-nine of these patients (3%) presented with disease limited to sites below the diaphragm and underwent laparotomy as part of their staging evaluation. The clinical and histological characteristics of this group of patients with subdiaphragmatic Hodgkin's disease are compared with those who presented with supradiaphragmatic disease. Splenectomy in 47 patients revealed splenic involvement in 16 (39%), and bulky splenic involvement (more than five gross nodules) in ten (24%). The final pathological stage (PS) distribution was PS I = 8, PS II = 37, PS IV = 4. No clinical stage (CS) IA patients and only two of 20 patients with negative paraaortic nodes on lymphogram had splenic involvement in contrast to eight of nine CS IIB patients. Freedom from relapse and survival were similar to patients with equivalent stage supradiaphragmatic disease. Splenic involvement and bulky splenic involvement were associated with a significantly decreased survival. Twelve out of 44 PS IA to IIB patients relapsed. In eight of these 12 patients, relapse was limited to sites above the diaphragm and another two patients relapsed both above and below the diaphragm. Patients who received total lymphoid irradiation were less likely to relapse above the diaphragm than patients who received no supradiaphragmatic irradiation. We recommend that CS IA and IIA patients with subdiaphragmatic disease undergo staging laparotomy and receive supradiaphragmatic irradiation as part of their treatment. Laparotomy may not be necessary for CS IIB patients who are at high risk for splenic disease if chemotherapy is planned as part of their treatment program.     

Prognostic factors for Stage IV Hodgkin's disease treated with MOPP, with or without bleomycin

Prognostic factors for 53 previously untreated patients with Stage IV Hodgkin's disease were analyzed for their effects upon complete remission rate, survival, and disease-free survival following treatment with mechlorethamine, Oncovin (vincristine), procarbazine, and prednisone (MOPP) or MOPP plus bleomycin (MOPP-Bleo). Although 75% of those patients with only one site of extranodal disease achieved complete remission, only 25% of those with more than one site of involvement entered complete remission. Seven of the eight patients with more than one extranodal site were dead of disease at 4 years, compared with a 5-year survival of 75% for those with only one site of involvement. Disease-free survival from complete remission was dependent upon the percentage of planned doses of nitrogen mustard actually administered. Patients who received higher doses of nitrogen mustard had significantly longer freedom from relapse and survival after attaining complete remission than those who received reduced doses. Age, symptoms, pathologic features, and presence or size of mediastinal disease did not affect the couple remission rate, survival, or disease-free survival. Patients with Stage IV disease treated with MOPP alone should receive the highest tolerable dose of nitrogen mustard early in their treatment, since those receiving lower doses have a higher risk of relapse.     

Early supradiaphragmatic Hodgkin's disease. High-dose gallium scanning obviates the need for staging laparotomy

Experience with 16 sequential patients with Stage IA/IIA supradiaphragmatic Hodgkin's disease who had no evidence of intra-abdominal disease using high-dose gallium and computerized tomography scanning is reported. Subsequent staging laparotomy also was negative in all these patients and did not alter management decisions. It is suggested that high-dose, whole-body gallium scanning and other noninvasive staging procedures give reliable data for therapeutic decisions.     

Treatment of advanced Hodgkin's disease with B-CAVE following MOPP failure.

Between March 1973, and December 1976, 22 patients who developed disease progression during or after MOPP therapy were treated with a new combination, B-CAVe (Bleomycin 5 mg/m2 iv days 1, 28, 35; CCNU 100 mg/m2 po day 1; adriamycin 60 mg/m2 iv day 1; and vinblastine 5 mg/m2 iv day 1). Objective responses were achieved in 17 of 22 patients (77%) and 11 of 22 responses were complete (50%). The actuarial survival for all patients is 16.4 months. For complete responders the median is 24 months with 2 complete responders dead without evidence of Hodgkin's Disease. Median relapse free survival for complete responders has not been reached at 35+ months while that for partial responders is 14 months. Significant adriamycin cardiotoxicity was encountered in two patients. There were no life threatening bacterial infections during B-CAVe. Two patients died of Pneumocystis carinii several months after cessation of therapy. B-CAVe is effective in the therapy of advanced Hodgkin's disease after MOPP failure, and this regimen is comparable to other previously reported MOPP salvage combinations.