Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.     

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 Hodgkin's disease. We compared these regimens as initial chemotherapy for Hodgkin's disease. PATIENTS AND METHODS: Adult patients (N = 856) with advanced Hodgkin's 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 Hodgkin's 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 Hodgkin's disease.     

Predictive value of the early response to chemotherapy in high-risk stages II and III Hodgkin's disease

A series of 60 patients with "high risk" Stage II and III Hodgkin's disease (B symptoms, or large mediastinal mass, or E lung disease) were staged without laparotomy and treated with combined modality treatment: mechlorethamine, vincristine, procarbazine, and prednisone (6 MOPP) plus radiotherapy. Patients were restaged after the first three courses of MOPP and the status of response to therapy at that time was called early response to chemotherapy (ERC). The rate of nitrogen mustard and procarbazine delivery (MRD) during the first three cycles of chemotherapy also was assessed. At the completion of the therapy patients were restaged and the final response was assessed. Fifty-two (86.7%) patients entered complete remission (CR). Forty-eight percent of the complete responders achieved CR in the first three courses of MOPP. Eight-year survival and disease-free survival (DFS) rates of the patients achieving CR were 71% and 73%, respectively. Survival and DFS were significantly better for the patients who achieved CR in the first three cycles of chemotherapy than for patients who entered CR at a later stage of therapy: 8-year survival 90% versus 55% (P = 0.00); 8-year DFS 87% versus 59% (P = 0.01). The attainment of a complete ERC was adversely affected by lymphocyte depletion (LD) histologic type (P = 0.01) and MRD less than 65% (P = 0.04). However, when a multivariate regression analysis was used, ERC was the only significant prognostic variable for survival and DFS and its predictive value was confirmed even after correction by MRD. These data suggest that the rapidity of response to chemotherapy could be an important prognostic factor in high-risk Stage II and III Hodgkin's disease.     

Second malignancies after chemotherapy and radiotherapy for Hodgkin disease

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.     

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.     

Treatment of lower torso stages I and II Hodgkin's disease with radiation with or without adjuvant mechlorethamine, vincristine, procarbazine, and prednisone

From 1956 to 1987, 60 patients with either lymphangiogram-staged or laparotomy-staged I-II lower torso presentations of Hodgkin's disease were treated with radiation with or without Mustargen (mechlorethamine), vincristine, procarbazine, and prednisone (MOPP). In 22 with inguinal/femoral or pelvic disease and 24 with abdominal disease, treatment consisted of radiation only. Fourteen other patients with abdominal disease received MOPP chemotherapy before radiotherapy. In 11, the chemotherapy was limited to two cycles. At 10 years, the determinate survival and freedom from progression rates for all patients were 82% and 72%, respectively. For patients with inguinal/femoral or pelvic disease who were treated with radiation only, the corresponding rates were 90% and 86%. For patients with abdominal disease who received radiation only, the determinate survival and the freedom from progression rates were only 66% and 50%, respectively. However, corresponding results for 14 patients with abdominal disease who were treated with MOPP and radiation were 100% and 92% (P = 0.033 and P = 0.009, respectively.     

Second malignancy in patients with Hodgkin's disease treated at the Royal Marsden Hospital.

Risk of second primary malignancy was assessed in follow-up to June 1991 of 1039 patients first treated for Hodgkin''s disease at the Royal Marsden Hospital during 1963-91. A total of 77 second malignancies occurred. There were significantly raised risks of stomach [standardized incidence ratio (SIR)=4.0], lung (SIR=3.8), bone (SIR=26.5), soft tissue (SIR=16.9) and non-melanoma skin (SIR=3.9) cancers, non-Hodgkin''s lymphoma (SIR=4.6), and acute and non-lymphocytic leukaemia (SIR=31.3), with a relative risk of 3.3 for all second cancers other than non-melanoma skin cancer. Solid cancer risk was raised to a similar extent in patients treated only with radiotherapy (SIR=2.6, P<0.001), only with chemotherapy (SIR=2.1, P=0.08) and with both (SIR=3.1, P<0.001). Leukaemia risk was raised only in those receiving chemotherapy, whether alone or with radiotherapy. The relative risk for solid cancers was much greater in patients who were younger at first treatment (trend P<0.001), whereas leukaemia risk was greatest for those first treated at ages 25-44. For solid cancers (P<0.001) but not leukaemia (P=0.05) there was a strong gradient of greater relative risks at younger attained ages. The relative risk of second cancers overall was 27.5 at ages under 25 and 2.0 at ages 55 and above. Leukaemia and solid cancer risks in patients treated with chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) were not significantly greater than those in patients treated with mustine, vincristine, procarbazine and prednisone (MOPP). Number of cycles of chemotherapy was significantly related to risk of leukaemia (P<0.001), and there was a trend in the same direction for solid cancers (P=0.07). The study adds to evidence that alkylating chemotherapy may increase the risk of solid cancers, and that ChlVPP does not provide a less carcinogenic alternative to MOPP chemotherapy. The very large relative risks found for solid cancers at young attained ages and in patients treated when young may have important implications as, in the long term, the majority of second malignancies after Hodgkin''s disease are solid cancers. The risks of solid malignancies need clarification by larger collaborative epidemiological studies.     

The frequency of translocations after treatment for Hodgkin's disease.

We studied the frequency of translocations in peripheral blood lymphocytes of patients with Hodgkin's disease to determine the extent of chromosome changes induced by radiation or radiation and chemotherapy. Comparisons were made to patients with second cancers to determine if this population is more susceptible to the effects of treatment. Group one included six patients with newly diagnosed Hodgkin's disease who were treated with radiation only. Group two included Hodgkin's disease patients who were treated 12-24 years previously and have been continuously free of disease. Five of these patients were treated with radiation only and five patients received radiation and mechlorethaminehydrochloride, oncovin, procarbazine, prednisone (MOPP) chemotherapy for six cycles. Group three included three patients who developed a second cancer after successful treatment for Hodgkin's disease. Two of these patients had a sarcoma within the radiation field and one had breast cancer. Metaphase spreads were obtained from cultured lymphocytes and hybridized with a chromosome 4 specific probe. After fluorescein staining, approximately 1000 metaphases were scored per patient. In group one only one patient in six demonstrated translocations in chromosome 4 before treatment for a mean frequency of .0009. After treatment the frequency of translocations increased to a mean of .016 (p = .036) (range .006-.034). Group two patients treated with radiation only had a mean translocation frequency of .012 (range .004-.022) in comparison to the radiation/mechlorethaminehydrochloride, oncovin, procarbazine, prednisone chemotherapy treated patients who demonstrated a mean frequency of .016 (p = .425) (range .0009-.023). The third group of second cancer patients showed inconsistent translocation frequencies of .002, .020, and .035. Of these patients, the one who demonstrated the greatest frequency of translocations (.035) was treated with mechlorethaminehydrochloride, oncovin, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, decadron) and radiation. Our data demonstrates a statistically significant increase in translocations detected after radiation. When compared to combined modality therapy a greater mean frequency of translocations is observed over radiation alone; however, this was not statistically significant. In the three patients who developed second cancers in our series we saw no consistent increase in translocation frequency compared to Hodgkin's disease patients who did not develop a second cancer.     

Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.

PURPOSE: To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION: Age at treatment has a major effect on risk of second malignancy after Hodgkin's disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease require detailed investigation.     

Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology.

PURPOSE: With the aim of decreasing undesirable side effects of therapy, we investigated the reduction of both chemotherapy and radiation therapy (RT) in children with Hodgkin's disease, and compared Adriamycin (doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France), bleomycin, vinblastine, and dacarbazine (ABVD) alone to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in favorable cases and assessed the effectiveness of low-dose RT (20 Gy) after good response to chemotherapy. PATIENTS AND METHODS: A French national study began in 1982 that included 238 pediatric patients with Hodgkin's disease. Initial staging was clinical and without laparotomy. In patients with localized disease (IA-IIA), an equivalence trial compared the effectiveness of four cycles of ABVD with two cycles of ABVD that were alternated with two cycles of MOPP. Patients with more advanced disease (IB-IIB-III-IV) received three courses of MOPP that was alternated with three courses of ABVD. All of the patients who achieved a good remission after chemotherapy were administered 20 Gy RT, which was limited to the initially involved areas for localized disease, and encompassed the paraaortic nodes and the spleen as well for more advanced stages. When a good remission was not obtained, 40 Gy RT was administered. RESULTS: At the completion of chemotherapy, 227 patients (97%) were considered good responders, whereas 11 did not achieve a good remission. With a median follow-up of 6 years, the 6-year actuarial survival was 92% and the disease-free survival was 86%. The relapse-free survival in favorable stages was 90% in the ABVD arm and was 87% in the MOPP and ABVD arm. In June 1987, inclusion of stage IV patients was discontinued because of poor results. CONCLUSIONS: Present findings indicate that (1) in favorable stages, ABVD alone and alternating MOPP and ABVD are equivalent, and (2) chemotherapy followed by 20 Gy RT represents a valid therapeutic approach in the vast majority of children with Hodgkin's disease.     

Prolonged disease-free survival in MOPP-resistant Hodgkin's disease after treatment with adriamycin,bleomycin, vinblastine and dacarbazine (ABVD)

Summary Twenty-one patients with advanced Hodgkin's disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, prednisone) were treated with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). ABVD induced complete remission in 13 patients (62%) and partial remission in 2 (9.5%). In particular, complete response to ABVD was obtained in 7 of 13 patients who failed to respond to primary MOPP chemotherapy. After six cycles, no further therapy was given to patients in complete remission. At 36 months from starting ABVD, 69.7% of complete responders remain alive and free of disease, with a total survival of 73.4%. In contrast, none of the patients in whom partial response or nonresponse was observed was alive at 18 months. ABVD for six cycles was accompanied by mild and reversible toxicity. The results indicate that there is no cross-resistance between MOPP and ABVD. ABVD appears a simple, effective, and tolerable multiple-drug chemotherapy for use in patients who are resistant to MOPP.     

A comparison of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) vs. nitrogen mustard in advanced Hodgkin's disease.

A randomized study of patients with advanced Hodgkin's disease was designed to determine whether the improved therapeutic effectiveness of combination chemotherapy was due to the use of a combination of drugs or might be achieved with a single agent if given as intensively and for as long a period. A combination of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) was compared with nitrogen mustard (HN2) alone. Treatment with both regimens was given to tolerance on cylic basis and was continued for six cycles of treatment. Sixty-one evaluable patients were treated with MOPP and 47 with HN2. The complete remission rate of 47.5% with MOPP was significantly better than the 12.8% with HN2 (p less than .05). Complete remission lasted a median of 15 months after MOPP and 12 months after HN2. The survival of patients initially treated with MOPP was significantly better than that of those initially treated with HN2.     

Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute

The aim of this study was to assess the long-term therapeutic outcome and risk of treatment-related complications in Hodgkin's disease. From May 1973 to September 1990, four randomised studies have been activated at the Milan Cancer Institute using nitrogen mustard, vincristine, procarbazine and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimens, with or without irradiation, involving a total of 811 patients with intermediate and advanced Hodgkin's disease. Overall, ABVD contributed to significantly reduce the relative risk of lymphoma progression and death compared with the MOPP regimen. With a prolonged follow-up, a total of 106 patients (75 of whom were in continuous complete remission after first-line chemotherapy) developed a variety of cancers, resulting in a total risk of 22.2%. Our 25 years of experience re-emphasises that ABVD can cure a high fraction of patients with Hodgkin's disease. However, patients in continuous complete remission, are at a high risk of developing second cancers, especially when the treatment strategy includes extensive irradiation. The main focus of future trials should be on reducing treatment sequelae to improve the quality of life of long-term survivors.     

MOPP treatment of resistant Hodgkin's disease following ABVD failure

Fourteen patients with Hodgkin's disease resistant to ABVD were treated with MOPP chemotherapy (nitrogen mustard, vincristine, procarbazine, prednisone). Complete remission was obtained in 6 patients (43%). Four of the 6 complete responders are disease free after 5, 20, 23, 35 months. The actuarial median survival after MOPP of all patients is 20 months. These data confirm that there is no "cross-resistance" among the drugs included in the two schedules.     

Increased risk of secondary acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy for Hodgkin's disease

The purpose of this study was to evaluate the influence of the number of mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP) cycles and the extent of irradiation on the risk of secondary acute nonlymphocytic leukemia (SANLL) after a single combined treatment for Hodgkin's disease (HD). Between April 1972 and May 1980, 462 patients with HD clinical stage (CS) I, II, and III were prospectively treated with three or six cycles of MOPP and supra- and/or infradiaphragmatic irradiation (40 Gy). Four hundred forty-one patients achieved complete remission (CR). By January 1988, 237 patients had been followed-up in first CR for at least 10 years. Ten patients developed SANLL between the 34th and 123rd month of CR. The 15-year SANLL risk is 3.5% +/- 2.7%. Cox's stepwise regression analysis performed with all initial and treatment covariates (sex, age, histology, splenectomy, MOPP chemotherapy, and irradiation extent) showed that the only significant explanatory variable of SANLL risk was the irradiation extent (P less than .002). Using the log-rank test, SANLL risk ranged from 2.2% for supradiaphragmatic irradiation alone to 9.1% for subtotal (STNI) or total nodal irradiation (TNI) (P less than .001). These results strongly suggest that extended high-dose irradiation and MOPP chemotherapy should not be combined for the treatment of HD.     

Combination chemotherapy for the treatment of Hodgkin's disease in relapse

Vindesine (desacetyl vinblastine amide sulfate, DVA) was used in combination with CCNU (lomustine) and melphalan (Alkeran) (CAD) to treat 15 heavily pretreated patients with Hodgkin's disease in relapse. The patients were treated with up to six cycles, depending upon their response. Two patients (13%) achieved a complete remission (CR) and five (33%) patients a partial remission (PR). The major toxicity was prolonged thrombocytopenia, which was decreased by a reduction in the initial drug doses for patients who had received extensive prior chemotherapy and radiotherapy (RT). The CAD regimen was then alternated with nitrogen mustard or cyclophosphamide, vincristine, procarbazine, and prednisone (MOPP, C-MOPP) and doxorubicin (Adriamycin), bleomycin, and vinblastine (ABV) for a total of nine cycles in 25 patients with Hodgkin's disease in relapse with somewhat more favorable prognostic features. Two patients also received low-dose RT to areas of bulky nodal disease. Eleven patients (44%) achieved a CR and seven (28%) a PR. Of the 11 CR patients, six remain in remission. The serious toxicity was comparable to that seen with other combination chemotherapy regimens. These results indicated that the CAD/MOPP/ABVD regimen is as active as other so-called 'salvage' regimens for Hodgkin's disease in relapse, and suggest that it might be useful for newly diagnosed Hodgkin's disease.     

Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.

PURPOSE: To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkin's disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. PATIENTS AND METHODS: From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkin's disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). RESULTS: All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). CONCLUSION: We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.     

Analysis of treatment results in advanced Hodgkin's disease: the case for adjuvant radiotherapy

PURPOSE: To assess the treatment results in patients with advanced Hodgkin's disease in a single center and to evaluate the clinical and therapeutic prognostic factors, including verification of the significance of the prognostic score. METHODS AND MATERIALS: Treatment results were analyzed in 133 patients with newly diagnosed Stage IIIB and IV Hodgkin's disease. Treatment consisted of six courses of hybrid chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone [MOPP]/doxorubicin (adriamycin), bleomycin, and vincristine [ABV]) followed by irradiation (RT) in patients with an indication for RT (84 patients). Chemotherapy was then continued for another two cycles. The indications for consolidation RT included bulky disease and/or partial response after six cycles of chemotherapy. In 31 patients, extended-field RT was performed, and in 53, limited fields were irradiated. The median radiation dose was 39 Gy. RESULTS: The median follow-up was 78 months. Complete remission after whole treatment was achieved in 88.7% of patients. The actuarial overall survival rate was 78% and 71%, and relapse-free survival rate was 73% and 65% at 5 and 10 years, respectively. The independent adverse prognostic factors in multivariate analysis appeared to be older age, low serum albumin, low serum gammaglobulin, lower number of chemotherapy cycles, and no RT. The value of the prognostic score was confirmed; the higher the prognostic score, the worse the survival. CONCLUSION: In patients with advanced Hodgkin's disease, consolidation RT improved survival. The best results were achieved with the use of large-volume RT.     

High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin's disease is unlikely to be associated with a major increased risk of secondary MDS/AML.

Hodgkin's disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin's disease from the BNLI and UCLH Hodgkin's databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox's proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49-2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64-7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96-10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66-5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin's disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality.     

Trials in advanced Hodgkin's disease: more than 30 years experience of the British National Lymphoma Investigation

Hodgkin's disease demonstrates an exquisite sensitivity to chemotherapy and radiation therapy. This necessitates investigation of modes of delivering these modalities in the best possible fashion to improve outcomes. The British National Lymphoma Investigation (BNLI) has conducted randomized trials in advanced Hodgkin's disease for > 30 years. The results of BNLI studies have demonstrated that MOPP (mechlorethamine/vincristine/procarbazine/prednisone) chemotherapy is superior to MOP (mechlorethamine/vincristine/procarbazine) chemotherapy; that there are no significant differences between MOPP and B-MOPP (MOPP plus bleomycin); that there is no significant benefit from maintenance therapy with lomustine/vinblastine/bleomycin; that LOPP (chlorambucil/vincristine/procarbazine/prednisone) is as effective as MOPP and has less acute toxicity; that alternating therapy with LOPP and EVAP (etoposide/vinblastine/doxorubicin/prednisolone) is superior to EVAP alone or hybrid LOPP and EVA (etoposide/vinblastine/doxorubicin); that alternating therapy with ChlVPP (a substitute for MOPP) and prednisolone/doxorubicin/bleomycin/vincristine/etoposide regimens is superior to the latter regimen alone; that the Stanford V regimen (doxorubicin/vinblastine/mechlorethamine/vincristine/bleomycin/etoposide/prednisone) combined with disciplined radiation therapy is safe and effective; that hybrid therapy with ChlVPP and EVA and alternating therapy with ChlVPP and prednisolone/doxorubicin/bleomycin/vincristine/etoposide are as effective as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) alone; and that there is no additional benefit from total nodal irradiation or combined-modality therapy compared with MOPP; and that treatment with high-dose BEAM (carmustine/etoposide/cytarabine/melphalan) and autologous bone marrow transplantation is superior to mini-BEAM (lower-dose BEAM not requiring bone marrow rescue) for poor-risk relapsed and refractory disease.