Leonard R. Farber

Long term remissions with combined modality therapy for advanced Hodgkin's disease†

A new treatment program for advanced Hodgkins disease employing five‐drug combination chemotherapy and low dose radiation to the sites of bulk disease (nodal or parenchymal) was designed in 1969. Eighty patients have now been treated, 60 of whom have achieved a complete remission. More significantly, only 5 of the 60 complete responders have relapsed with followup from 1–6 years. The cumulative survival at 5 years of patients entering complete remission is 92%. For those patients not sustaining a complete remission, it is 19% at 2 years. This program has resulted in substantially lower relapse rates than previously reported by other investigators, probably because of the administration of radiotherapy in the manner described. Hopefully, a significant number of these patients may be cured of their disease.

Combination sequential chemotherapy in advanced reticulum cell sarcoma

Based on studies of the chemotherapy of human leukemia and late stage animal neoplasms which may be kinetically analogous to disseminated reticulum cell sarcoma, a therapy program was devised using sequential cyclophosphamide‐vincristine followed by weekly methotrexate‐cytosine arabinoside. Each cycle of therapy consisted of cyclophosphamide 1.5 g/m2 on day 0 and vincristine 1.4 mg/m2 on days 1, 8, and 15; subsequently, 8 weekly doses of IV cytosine arabinoside 300 mg/m2 and oral methotrexate 120 mg/m2 over 24 hours were given followed by “Leucovorin rescue.” Fifteen patients received 3 such cycles with intervening 2‐week recovery periods. Nine patients achieved complete remission, and 6 had a partial response. Median remission duration was 10 months. Median survival from onset of disease was 15+ months and from beginning of therapy was 14+ months. Five of 7 patients who have relapsed are dead. Toxic manifestations included neutropenia below 1000/mm3 in 10 patients; of these, there were recurrent episodes of sepsis in one. Alopecia occurred in 10, and reversible neurotoxicity in 8 patients.

Supradiaphragmatic Hodgkin's disease: significance of large mediastinal masses.

Abstract In order to assess the significance of large mediastinal masses in patients with Hodgkins disease, we analyzed all patients with pathological stage (PS) IA or IIA disease evaluated and treated at Yale between 1969 and 1978. There were 131 such patients treated initially with radical radiotherapy only, combination chemotherapy being reserved for those who failed radiation. Actuarial 5 and 10 year survivals were 95%. The presence of a mediastinal mass reglardless of size did not affect survival. Relapse-free survival was 77% at 5 years, 74% at 10 years in the entire group. Patients with any mediastinal involvement had a 65% relapse-free survival, 72% if the mass was 33%. These differences are suggestive of a greater tendency of such patients to fail radiotherapy but the differences were not statistically significant. Patients who did fail radiotherapy were for the most part successfully retreated with combined modality therapy (chemotherapy and radiation), accounting for the overall survival of 95%. Only 6 patients died of causes related to Hodgins disease and 2 of these deaths were related to combined modality therapy complications. Because of the serious potential long term consequences of combined modality treatment, it should be used with great caution and on an individual basis only in PSIA and IIA patients.

Avascular necrosis of bone in Hodgkin's disease patients treated with combined modality therapy.

Avascular necrosis of bone developed in eight patients with advanced Hodgkins disease who had been treated with combined modality therapy and were in complete remission from their disease. A ninth patient not on protocol but treated with the combined modality program also developed avascular necrosis. The cumulative incidence was 10% among long‐term survivors. The etiology is unclear. Prolonged corticosteroid administration has been implicated but usually in much larger doses than the patients in this series received. The possible roles of the other chemotherapeutic agents for Hodgkins disease, and radiation are discussed. Considerable disability resulted for almost all patients. Three of seven patients primarily with avascular necrosis of the femoral heads had bilateral hip replacements with surgery anticipated in four others. The two patients primarily with humeral head involvement have limited use of their arms. This condition must be added to the known possible serious consequences of combination chemotherapy for Hodgkins disease. It is uncertain if the frequency of avascular necrosis is higher in patients treated with both radiation and chemotherapy compared with chemotherapy alone. Further studies are needed from other institutions to clarify the frequency and cause of this problem.

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-Hodgkins lymphoma) in patients with Hodgkins 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 Hodgkins 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-Hodgkins 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.

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 Hodgkins 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.

Curative potential of combined modality therapy for advanced Hodgkin's disease

During the period from 1969 through 1977, 124 patients with advanced Hodgkins disease underwent treatment with combination chemotherapy and radiotherapy. Sixty‐three cases were previously untreated, and 61 were relapses following radical radiotherapy for localized Hodgkins disease. No patient in this series had received prior chemotherapy. Of 102 patients (84%) who have entered complete remission, 92 remain in complete remission with a median follow up time of five years, 10 patients having relapsed, and acute leukemia having developed in 2. The cumulative survival rate for all 124 patients is 80% at five years; the relapse‐free survival rate is 74%. In many, if not most cases, the Hodgkins disease appears to be cured. We have also identified two subgroups of patients for whom the prognosis is worse than for patients with advanced‐stage disease as a whole. Patients over the age of 40 years have a five‐year survival rate of only 45%, compared with 89% for all other patients. Those Stage IV patients with multiple extranodal sites of involvement have a five‐year survival rate of 48%, compared with 81% for other Stage IV patients with only a single extranodal site involved.

Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer.

The standard q8h high-dose interleukin-2 (IL-2) regimen produces clear benefit for a subset of patients, but has limited acceptance because of its substantial acute toxicity including hypotension requiring pressors in 30% to 50%, the schedule is inconvenient for medical staff who must assess patients before each dose, and in some hospitals, the limited availability of monitored beds. We initiated a high-dose IL-2 program with a modified twice daily dosing schedule, limited the total number of doses per course to 8, and treated patients in an oncology ward without cardiac monitoring. Hypotension was managed preferentially with normal saline fluid boluses and/or delay in treatment. We conducted a retrospective chart review of 41 consecutive metastatic melanoma (n=33) and renal cancer (n=8) patients treated with the modified high-dose IL-2 regimen. The median number of IL-2 doses administered in the first cycle was 15. Overall toxicity was similar to published data for the q8h schedule, but only 9.79% of patients required pressors. Twenty-four percent of patients were transferred electively or emergently to the intensive care unit. There were no treatment-related deaths. The objective response rate was 12.5% and 0% in melanoma and renal cancer, respectively. Responses were durable, and 2 additional melanoma patients with mixed responses remain disease-free after resection of residual or recurrent sites of disease. In summary, the twice-daily IL-2 regimen has meaningful activity, may be more convenient to administer, reduces the need for elective monitored beds, and may be preferable for development of combinations with newer immune modulators.

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.

A follow-up of a randomized study comparing two chemotherapy treatments for advanced diffuse histiocytic lymphoma.

In 1976 we began a randomized study for the treatment of patients with stage III and IV diffuse histiocytic lymphoma. The therapy was either ACOMLA (doxorubicin, cyclophosphamide, vincristine [oncovin], methotrexate with leucovorin rescue, and cytarabine) or CHOP-B (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [oncovin], prednisone, and bleomycin). A complete response (CR) was achieved in 13 (65%) of 20 patients treated with ACOMLA and in 20 (71%) of the 28 patients treated with CHOP-B. Four patients achieving CR with ACOMLA and three patients treated with CHOP-B have relapsed for an overall relapse rate of 21%. Partial response (PR) was obtained in four patients treated with ACOMLA and five patients treated with CHOP-B. Median follow-up time is 36 months for the combined treatment groups. Multiple regression analysis demonstrated that those patients who were classified by the Lukes-Collins criteria as having histiocytic lymphoma not of follicular center-cell origin (combined T- and B-cell immunoblastic sarcoma) had a significantly worse survival as compared to patients classified with follicular center-cell origin lymphoma (large cell noncleaved, large cell cleaved, and large cell unclassified) with a 40% five-year survival versus an 80% five-year survival (P = .011). The CR rate however for these two large categories of patients was 63% v 73% respectively, and the relapse rates were equivalent. The increased survival in the follicular center-cell origin lymphomas may be related to a longer survival of PRs and relapsed patients as compared to the patients with nonfollicular center-cell lymphomas.