Second solid tumors in patients with Hodgkin's disease cured after radiation or chemotherapy plus adjuvant low-dose radiation.

PURPOSE: Late solid tumors (STs) are a significant cause of morbidity and mortality in long-term survivors of Hodgkin's disease. To investigate the carcinogenic potential of two different therapeutic approaches, we measured the relative risk (RR) of STs in patients with early-stage disease cured after primary full-dose (approximately 40 Gy) radiation therapy (RT) and in patients with advanced disease who were treated with chemotherapy followed by low-dose (15 to 30 Gy) involved-field radiation (CMT). PATIENTS AND METHODS: Because therapy-induced STs generally begin after a latency period of 5 to 10 years, we restricted our analysis to patients treated before 1986 who achieved durable remissions. Patients who required salvage chemotherapy or who died of Hodgkin's disease were excluded from analysis. The RR of STs was calculated by dividing the observed number of cases by the expected number in a matched population from the Connecticut Tumor Registry. The actuarial incidence of STs was also measured. RESULTS: A total of 197 patients formed the RT group and 116 the CMT group. The median follow-up period in the RT group was 12.8 years, versus 13.5 years in the CMT group. The overall RR of STs in the CMT group was 1.5 (95% confidence interval [CI], 0.6 to 3.5; P = .122). There were no cases of lung or breast cancer. In the RT group, the overall RR of STs was 3.3 (95% CI, 2.0 to 5.3; P < .001). There were seven cases of lung cancer (RR = 10.8; 95% CI, 5.3 to 22.2; P < .001) and two cases of breast cancer (RR = 2; 95% CI, 0.6 to 7.4; P = .07). All six benign tumors occurred in the RT group. CONCLUSION: In patients cured by initial treatment for Hodgkin's disease, RT was associated with a statistically significant increase in STs, particularly lung cancer. CMT was not associated with a significant increase in STs. These data may have important implications for the design of newer therapies for early-stage Hodgkin's disease.

Combined modality therapy in previously untreated patients with advanced Hodgkin's disease: A 24-year follow-up study.

PURPOSE: To describe the long-term results of treatment with chemotherapy plus adjuvant low-dose, involved-field radiation therapy (CMT) in patients with advanced Hodgkin's disease. Data on disease-free and failure-free survival, second malignancies, and the results of salvage therapy are presented. PATIENTS AND METHODS: From 1969 to 1989, CMT was administered to 186 patients with previously untreated stage IIB, III, and IV Hodgkin's disease. Chemotherapy included MVVPP (47%), MOPP (25%), MOPP/ABVD (26%) and ABVD (2%). After 6 months of chemotherapy, patients received radiation to all involved sites with the exception of the bone marrow. RESULTS: The failure-free survival for all patients was 63% at 5 years, 56% at 10 years, and 40% at 23.5 years, respectively. Significantly worse results were observed in patients older than 40 years and those with stage IV disease. The overall survival of 45 patients after recurrence was 39% at 10 years, but was only 21% if the initial complete remission lasted less than 1 year. Thus far, 21 of 165 patients (12.7%) who achieved complete remission have developed a second malignancy, and 16 have died. CONCLUSIONS: In comparison with comparable chemotherapy programs, chemotherapy plus radiation therapy may improve disease-free survival; however, the results of treatment in patients older than age 40 or with stage IV disease are still poor. Although patients with initial remissions lasting longer than 1 year can have durable second remissions, the long-term disease-free survival is poor and in the current series the majority of failures were due to recurrent Hodgkin's disease.

Second solid malignancies after combined modality therapy for Hodgkin's disease.

PURPOSE: To determine the actuarial incidence (AI) and relative risk (RR) of second solid malignancies (SSM; solid tumors and non-Hodgkin's lymphoma) in patients with Hodgkin's disease who were treated with chemotherapy and adjuvant, low-dose radiation (combined modality therapy; CMT). PATIENTS AND METHODS: From 1969 to 1983, 102 patients with previously untreated advanced Hodgkin's disease (group A) and 81 patients with recurrent disease after radiation (group B) were treated with CMT. Patients were observed for the development of solid tumors (ST) and non-Hodgkin's lymphoma (NHL), and the AI and RR were calculated. RESULTS: Nearly half of the patients entering remission were observed for greater than 15 years. At 20 years, the AI for SSM was 12% in group A versus 41% in group B (P = .009). The overall RR for developing a ST in group A was 1.88 (not significant) versus 8.84 in group B (95% confidence interval, 5.3 to 15.4). The difference in the RR between groups A and B was significant (P < .001). The RR for developing NHL was significantly increased in both groups, but the difference between groups was not significant. CONCLUSION: Previously untreated patients with advanced disease who were treated with CMT (group A) had a modest but not significant increase in the RR of ST; however, patients treated with CMT for recurrent disease (group B) had a highly significant increase in the RR of ST. Possible explanations for the increase in ST in group B include more cumulative radiation or a greater carcinogenic effect of chemotherapy in previously irradiated patients, but it also is possible that the increase is due to a longer follow-up time.

Gallium scans in patients with mediastinal Hodgkin's disease treated with chemotherapy.

PURPOSE: To determine the predictive value of gallium scans in patients with mediastinal Hodgkin's disease treated with chemotherapy or combined modality treatment. PATIENTS AND METHODS: A retrospective study was performed of 48 patients with mediastinal Hodgkin's disease treated with chemotherapy or combined modality therapy. Patients were monitored with whole-body planar scans (34 patients) or chest single-photon-emission computed tomography (SPECT) plus planar abdominal imaging studies (14 patients). Scans were performed at diagnosis, following three to eight cycles of chemotherapy, and after the end of treatment. The value of gallium scans in modifying treatment and predicting outcome was assessed. RESULTS: All patients studied at the time of diagnosis had abnormal gallium accumulation in the mediastinum. After chemotherapy, four patients had residual mediastinal activity; two patients with persistent activity on planar scans failed to enter remission and died of disease; two other patients with abnormal activity only seen on SPECT had therapy modified and remain in remission. After chemotherapy, 44 patients had a normal gallium scan. Twelve patients with negative scans relapsed, including nine patients with recurrence above the diaphragm. CONCLUSION: The use of gallium scans after several courses of chemotherapy resulted in a modification of treatment in four patients, including two patients who are apparently cured. However, after negative scans, 20% of patients relapsed above the diaphragm. These results suggest that gallium imaging, including SPECT, is of limited value in predicting disease sterilization, although the number of patients studied with SPECT was small. At present, the major value of gallium scans is to identify patients who may benefit from a modification of treatment.

The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).

Mediastinal irradiation in combined modality therapy for Hodgkin's disease.

Patients with Hodgkin's disease who present with large mediastinal masses in the setting of either early or advanced stage disease are frequently treated with combined modality therapy. Policies for radiation dose to the mediastinum in these settings range from no radiation to doses in the 3600-4000 cGy range. We reviewed the charts of 50 patients treated with radiation therapy following remission induction with chemotherapy between 1979 and 1983 to determine whether the dose of radiation to the mediastinum could be correlated with mediastinal control, relapse-free, and overall survival. Patients were divided into groups with small (SM, 30 pts.) and large (LM, 20 pts.) mediastinal masses and analyzed according to whether they had received low dose (LD, less than or equal to 2500 cGy) or high dose (HD, greater than 2500 cGy) radiation to the mediastinum. The 5-year relapse-free survival (RFS) for all 50 patients was 84% (+/- 8%, 95% confidence limits). For the patients with small mediastinal masses, 5-year RFS was 81% +/- 20%, and for the patients with large mediastinal masses, 89% +/- 16%. No clear dose-response effect was observed when the outcomes of the low dose and high dose patients were compared. This was true even in the patients with large mediastinal masses although the high dose subset of this group included patients felt to be at a higher risk for relapse following chemotherapy. Nine of eleven patients with large mediastinal masses treated with chemotherapy and low dose radiation remain disease-free. There was only one isolated mediastinal relapse in the entire group of patients. Treatment was well tolerated with no acute treatment-related deaths. Two patients developed second malignancies. We conclude that combined modality therapy using low dose radiation results in excellent 5-year relapse-free survival for most small and many large mediastinal mass patients, and that it is not necessary to treat all chemotherapy patients who present with mediastinal disease with high dose radiation to achieve these relapse-free survival rates.

Procainamide-induced circulating anticoagulants in a congenitally-deficient factor XI patient.

A 70 year old male patient admitted for coronary bypass surgery presented with a procainamide-induced lupus syndrome. This syndrome included a LLAC with a positive IgM ACA titer as well as a factor XII inhibitor. These drug-induced inhibitors were superimposed upon the patient's congenital deficiency of factor XI. The methods used to identify these abnormalities are described together with the replacement therapy employed to cover the surgical procedure. The long-term withdrawal of procainamide was associated with correction of all coagulation abnormalities except the factor XI deficiency.

Combined modality therapy for advanced Hodgkin's disease: 15-year follow-up data.

From 1969 through 1982, 184 patients with advanced Hodgkin's disease (HD) were treated with combined modality therapy (CMT) at Yale University. The data were reanalyzed in November 1986, with a mean follow-up of 10 years. The patient population consisted of 102 newly diagnosed stages IIIB and IV patients, and 82 patients who had relapsed after initial radical radiotherapy. From 1969 through 1978, the treatment program was induction chemotherapy with nitrogen mustard, vincristine, vinblastine, procarbazine, and prednisone (MVVPP) for three cycles (6 months) followed by low-dose radiation (1,500 to 2,500 cGy) for patients who had achieved complete remission (CR), to all disease sites present before the onset of chemotherapy. From 1978 to 1982, selected "poor-risk" advanced-stage patients received nitrogen mustard, vincristine, procarbazine, prednisone plus Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (MOPP-ABVD) induction chemotherapy, while the remaining patients were randomized between MVVPP and MOPP. One hundred fifty-one patients have achieved CR (82%); 23 (15%) of these 151 have relapsed, with the remaining 128 patients in continuous CR. A total of 62 patients have died, 45 due to HD, and 17 due to other causes. Twelve of these 17 patients died of second malignancies. The 15-year actuarial survival of all patients is 54%. It is 71% if deaths due only to HD are considered. Within the overall group of advanced HD patients, age and multiple extranodal sites of involvement continue to constitute adverse risk factors. The three drug programs used were all equivalent. No improvement resulted from the use of MOPP-ABVD in the poor-risk patients. These results compare favorably with those recently published by the National Cancer Institute (NCI). CMT resulted in an approximate 20% improvement in survival with no increase in second malignancies when compared with chemotherapy alone.

Pretreatment hematocrit as an independent prognostic variable in Hodgkin's disease.

Pretreatment hematocrit in 117 advanced-stage Hodgkin's disease patients treated with a combined modality therapy program was evaluated as an independent prognostic variable with regard to survival and relapse-free survival. Age greater than 40 years, and multiple extranodal sites of involvement were found to be statistically significant independent negative prognostic factors with regard to survival. Pretreatment hematocrit, however, was not an independent negative prognostic variable.

Prognostic indicators in diffuse large-cell (histiocytic) lymphoma.

Identification of prognostic groups among patients with diffuse large-cell (histiocytic) lymphoma (DHL) would help to select specific therapy for individual patients and allow comparisons among combination chemotherapy clinical trials. The Ann Arbor staging system is of limited value in predicting outcome in diffuse histiocytic lymphoma. Prognostic factors have been examined by various groups without a consensus of reliable prognostic indicators. This study was undertaken to examine the validity of a predictive model for response to treatment and survival in DHL. Eighty-six patients with the diagnosis of DHL treated with combination chemotherapy between the years 1976 and 1982 were examined for prognostic variables influencing response to treatment and survival. The variables examined included: age, sex, presence or absence of systemic symptoms, serum lactic dehydrogenase (LDH), sites of disease involvement, bulk of disease, prior therapy, stage of disease, according to the Ann Arbor classification, and pathological criteria, according to the Lukes Collins classification. Factors achieving a p-value in the 0 to 0.05 range with univariate analysis for predicting response were age and systemic symptoms. Factors significant for overall survival were age and bone marrow involvement. These factors have been found to influence survival in previous studies, but there has not been a consistency regarding the importance of these factors. Large numbers of patients must be examined for various factors in order to allow identification of prognostic groups among patients with DHL.

Second neoplasms in patients with Hodgkin's disease following combined modality therapy--the Yale experience.

From 1969 to 1982, 183 patients with previously untreated stages IIIB and IV Hodgkin's disease and relapsing Hodgkin's disease after radiation therapy were treated with combination chemotherapy plus low-dose irradiation (CRT). One hundred fifty patients who achieved a complete response (CR) were analyzed for risk of developing a second neoplasm. Median follow-up has been 8.3 years. Actuarial survival of all patients is 74% at 10 years with a relapse-free survival of 68%. An additional 24 patients with stage IIIA disease were also treated with CRT. There were 22 CRs at risk who were analyzed. Median follow-up has been 3+ years with an actuarial survival of 90% at five years and a relapse-free survival of 83%. Second neoplasms have developed in 14 of 172 patients at risk: acute nonlymphocytic leukemia (ANLL; five patients); aggressive histology non-Hodgkin's lymphoma (NHL; three patients); and a variety of solid neoplasms (six patients). Time to second neoplasm diagnosis after initial treatment ranged from 12 to 141 months. Five patients were older than 40 years. At the time of diagnosis of the second malignancy, 11 patients were free of Hodgkin's disease (for 36 to 141 months) and three were receiving therapy for recurrent Hodgkin's disease. The 10-year actuarial risk (%) of developing ANLL was 5.9 +/- 2.8; for NHL, the risk was 3.5 +/- 2.4, and for solid neoplasms, 5.8 +/- 3.0. Our results suggest that combination chemotherapy plus low-dose irradiation does not appear to significantly increase the risk of developing second neoplasms above that already reported for combination chemotherapy when administered as either initial or salvage treatment of Hodgkin's disease.

Primary large cell lymphomas of the mediastinum: an analysis of 20 cases.

Malignant lymphomas originating primarily in the mediastinum consist predominantly of Hodgkin's disease of the nodular sclerosis type, lymphoblastic lymphomas, and large cell non-Hodgkin's lymphomas of diffuse growth pattern (DHL). This analysis of 20 cases of primary mediastinal DHL presents the clinical and pathologic findings in nine patients with T-immunoblastic sarcoma (T-IBS), six with sclerosing variants of follicular center cell lymphoma (FCCL), and five with B-immunoblastic sarcoma (B-IBS). T-IBS patients were predominantly young adult women (mean age 31 years) presenting with relatively well confined mediastinal tumors; four of nine manifested the SVC syndrome. The immunomorphologic findings in T-IBS were similar to those of node-based peripheral T-cell lymphomas. Patients with FCCL and B-IBS were predominantly men, exhibited a broad age range, and presented with larger tumors with a high incidence of contiguous involvement of intrathoracic structures (83% in FCCL, 60% in B-IBS). Chemotherapeutic intervention attained CR in 19 of 20 patients, with 14 of 20 remaining alive in relapse-free CR a median of 26 months after completion of therapy. Durable CR was attained in eight of nine T-IBS patients, in four of six patients with FCCL, and in three of five patients with B-IBS. The morphologic features of these lymphoma subtypes are presented in detail and discussed in relation to the complex differential diagnosis of mediastinal neoplasms.

Treatment selection for stage IIIA Hodgkin's disease patients.

Two treatment policies for the therapy of patients with Stage IIIA Hodgkin's disease are compared. From 1969-1976, 49 newly diagnosed and pathologically staged IIIA patients received total nodal irradiation (TNI) alone (no liver irradiation). Although actuarial survival was 80% at 5 years and 68% at 10 years, actuarial freedom from relapse was only 38% at 5 years. Accordingly, a new treatment policy was instituted in 1976. Patients with either CS IIIA disease, multiple splenic nodules, IIIA with a large mediastinal mass or III2, received combined modality therapy (combination chemotherapy and irradiation). All others received TNI. Thirty-six patients have been treated under the new program. The actuarial survival is 90% at 5 years and the relapse-free survival is 87%, suggesting the superiority of this approach.

Splenectomy in Hodgkin's disease: no therapeutic benefit.

One hundred twenty-four patients with advanced Hodgkin's disease were treated uniformly with combination chemotherapy and radiotherapy. Splenectomy was not performed in 32 patients due to obvious stage IV disease, a medical contraindication, or patient refusal. Comparison of the splenectomy and nonsplenectomy patients revealed no differences in nadir white blood cell counts, platelet counts, or the total dosages of drugs that were administered. Survival and disease free survival curves with a 5-year median follow up also failed to show any difference in the two groups. Splenectomy does not offer a therapeutic advantage in those patients whose treatment would not be altered by splenic histology.

The usefulness of the Lukes-Collins classification in identifying subsets of diffuse histiocytic lymphoma responsive to chemotherapy.

Twenty-nine patients with Stage III and IV diffuse histiocytic lymphoma (DHL) were treated prospectively with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone and bleomycin (CHOP-B) or hydroxydaunorubicin, cyclophosphamide, vincristine, methotrexate with leucovorine rescue and cytosine arabinoside (ACOMLA). Twenty-six evaluable patients were reclassified blindly by the Lukes-Collins classification with five large noncleaved follicular center cell (FCC), six large cleaved FCC, three large cell unclassified, seven B-immunoblastic sarcoma and five T-immunoblastic sarcoma patients identified. There was no significant survival advantage between the two combination chemotherapy programs. Survival of the immunoblastic sarcoma patients was inferior to that of the FCC lymphoma patients (P = 0.02). There were no significant survival differences between the large cleaved FCC and noncleaved FCC subtypes. Immunoblastic sarcomas, B- and T-cell types, appear to be more resistant to standard combination chemotherapy programs and new approaches may warrant more aggressive therapy in future protocols. The large cell FCC lymphomas have an excellent prognosis.

Randomized study comparing doxorubicin, cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (ACOMLA) with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B) in the treatment of diffuse histiocytic lymphoma.

Two combination chemotherapy programs, ACOMLA (doxorubicin, cyclophosphamide, vincristine, methotrexate and leucovorin rescue, and cytarabine) and CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), were evaluated in 29 prospective randomized patients with advanced diffuse histiocytic lymphoma. A complete response was achieved in 13 of the 15 patients (87%) treated with CHOP-B and in nine of the 14 patients (64%) treated with ACOMLA. The overall complete response rate was 75%. Two patients treated with ACOMLA and none of the CHOP-B-treated patients have relapsed. Median followup is 32 months for ACOMLA patients and 26 months for CHOP-B patients. Actuarial freedom from relapse at 2 years is 49.9% for ACOMLA and 93.3% for CHOP-B (P = 0.04). Toxicity was substantial, with eight nonfatal episodes of sepsis and three drug-related deaths. There have been no central nervous system relapses. Although patients treated with CHOP-B have a better response rate, the small numbers of patients treated to date preclude definitive conclusions.

Combined modality therapy for advanced Hodgkin's disease: long-term followup data.

From 1969 to 1979, 155 patients with advanced Hodgkin's disease were treated with a combined modality protocol (combination chemotherapy and irradiation to all sites of disease). The actuarial 10-year survival of all patients who started therapy is 78%, and the relapse-free survival is 67%. Within the group of patients with advanced disease, age greater than 40 years and/or stage IV disease with multiple extranodal sites of involvement adversely affected prognosis. Since 1978, these patients have been treated with MOPP-ABVD and irradiation, with a resulting 3-year survival of 87% compared with 58% for those treated with MVVPP in prior years. A comparison between MVVPP and MOPP, also begun in 1978, has thus far yielded no significant differences. Second malignancies have occurred in four patients apparently cured of their Hodgkin's disease: two patients with acute leukemia and two with non-Hodgkin's lymphoma. Avascular necrosis of bone has developed in nine patients. There have not been other serious long-term complications. This combined modality treatment approach appear to offer a significant survival advantage compared with treatment programs using chemotherapy alone.

Bone involvement in Hodgkin's disease.

Eighteen patients with osseous involvement were identified from a series of 124 consecutive patients treated with combined-modality therapy with advanced-stage or relapsing Hodgkin's disease. Multiple lesions were seen as frequently as were solitary lesions. Nodular sclerosing histology was as prevalent as mixed cellularity disease. However, those five cases initially diagnosed at protocol entry were predominantly mixed cellularity (80%) with multiple lesions (80%). Sites of involvement included: the spine, 24; pelvis, 8; ribs, 4; femur, 3; skull, 1; and shoulder 1. Actuarial survival for these patients was 84% at nine years. Only three patients were induction failures and no patient has had a relapse. Patients with bone lesions had favorable responses to combined-modality therapy.