Saul A. Rosenberg

The Natural History of Initially Untreated Low-Grade Non-Hodgkin's Lymphomas

To learn more about the natural history of low-grade non-Hodgkins lymphoma, we have studied 83 patients in whom the advanced disease was initially managed without therapy. Actuarial survival was 82 per cent at 5 years and 73 per cent at 10 years. The median time until therapy was required was three years. Spontaneous regressions occurred in 19 untreated patients (23 per cent), including 30 per cent of patients with nodular, poorly differentiated lymphocytic lymphoma. Histologic transformation to an intermediate-grade or high-grade lymphoma occurred both before and after primary therapy. The actuarial risk of transformation among the initially untreated patients was similar to that in a group of patients treated at this institution immediately after diagnosis. Neither the time to histologic transformation nor the incidence of transformation was influenced by when therapy was started.

Non-hodgkin's lymphomas iv. clinicopathologic correlation in 405 cases

An analysis is presented of the histopathologic, clinical, and prognostic features in a series of 405 previously untreated patients with non‐Hodgkins lymphomas referred to Stanford University Medical Center between 1960 and 1971. All biopsies were histologically classified according to the criteria of Rappaport et al. and clinical extent of disease was thoroughly evaluated prior to treatment and staged according to the Ann Arbor Classification. Nodular lymphomas constituted 44% of the group and diffuse lymphomas 56%. Patients under the age of 35 years and those over 60 tended to have diffuse lymphomas. Although 39% of the patients had Stage IV disease at presentation, localized forms (Stage I, IE, II, IIE) were observed in 37%. Localized extralymphatic involvement occurred more often in patients with diffuse than nodular lymphomas (p < 0.001). Systemic symptoms occurred in 24% of patients with diffuse and 17% of those with nodular lymphomas; however, their presence did not adversely affect survival. Mediastinal adenopathy was noted in 24% of diffuse and 18% of nodular lymphomas (P = NS), and mediastinal “skipping” was observed in 20% of diffuse and 40% of nodular lymphomas (p < 0.05). By the criteria used, 81% of evaluable patients (Stages II through IIIE) with nodular lymphoma and 90% of those with diffuse lymphoma had contiguous sites of involvement (p = 0.07). Two frequently observed sites of initial extralymphatic involvement were bone marrow and gastrointestinal; the former was observed more often in advanced lymphocytic lymphomas, whether nodular or diffuse, and the latter in advanced, diffuse lymphomas. Actuarial survival correlated strongly with the histopathologic type of lymphoma; in each cellular category, patients with nodular lymphomas survived significantly longer than those with diffuse lymphomas (p < 0.05). Age at presentation also influenced survival in relation to certain histologic patterns. Patients with diffuse lymphocytic or mixed lymphomas who were less than 40 years of age had a worse prognosis than those over 40 (p = 0.02). In contrast, older patients with nodular lymphocytic and mixed lymphomas fared worse than those under 40 (p < 0.01). Patients with either initial bone marrow or gastrointestinal involvement survived longer if their lymphoma had a nodular pattern. It is concluded that histopathologic classification proposed by Rappaport et al. and the Ann Arbor Staging Classification are both useful guides to the management and prognosis of the non‐Hodgkins lymphomas.

Hematologic neoplasia in patients treated for Hodgkin's disease.

We studied 680 patients with Hodgkins disease, treated at Stanford University Medical Center from July 1, 1968, through December 31, 1975, to determine the risk of development of hematologic neoplasia. Six cases of leukemia occurred in patients in clinical remission, one 7 1/2 years after diagnosis. Two additional cases occurred in patients with active Hodgkins disease. No cases were seen in 320 patients treated with radiotherapy alone or in 30 treated with chemotherapy alone. A single case of subacute leukemia occurred in a patient treated initially with radiation therapy and colloidal gold. The actuarial probability of development of leukemia at five and seven years is 1.5 and 2.0 per cent for the entire group and 2.9 and 3.9 per cent for the 330 patients treated with combined radiation and chemotherapy. The medium survival after diagnosis is four months, with no patient living beyond six months.

The value of laparotomy and splenectomy in the staging of Hodgkin's disease.

Experience with 65 patients with biopsy‐proven Hodgkins disease who were subjected to laparotomy, splenectomy, liver biopsy, and para‐aortic lymph node biopsy is presented. There were no major complications. Histologic findings in the para‐aortic nodes, liver, and spleen are presented. A general correlation was observed between the occurrence of systemic symptoms and the extent of involvement below the diaphragm. There was no instance of liver involvement without concomitant splenic involvement. It is concluded that laparotomy with splenectomy is a valuable procedure for the more precise delineation of intra‐abdominal sites of involvement in Hodgkins disease prior to the initiation of extended field megavoltage radiation therapy with curative intent.

Female Reproductive Potential after Treatment for Hodgkin's Disease

Abstract The probability of maintaining ovarian function, becoming pregnant, and delivering a normal child is important to young women anticipating successful therapy for Hodgkins disease. In this study, reproductive function was retrospectively examined in 103 women 40 years old or younger who had undergone treatment for Hodgkins disease with total-lymphoid irradiation (TLI) alone, combination chemotherapy, or combined TLI and chemotherapy. Infertility was directly related to gonadal exposure to therapy and to age at treatment. Twenty women became pregnant after receiving total-nodal irradiation or combination chemotherapy or both. No fetal wastage occurred, and no birth defects were seen in the 24 infants born to these women. Even after intensive treatment programs, women successfully treated for Hodgkins disease have become pregnant and delivered phenotypically normal children. (N Engl J Med. 1981; 304:1377–82.)

Occurrence of Non-Hodgkin's Lymphoma after Therapy for Hodgkin's Disease

We studied the clinical and pathological features of six cases of non-Hodgkins lymphoma (diffuse undifferentiated in four cases and diffuse histiocytic in two cases) occuring in patients treated for Hodgkins disease. All six patients had received both radiation and chemotherapy. Abdominal or gastrointestinal involvement was present in five of the six cases. None of the patients had evidence of Hodgkins disease when the diagnosis of non-Hodgkins lymphoma was made. Five of the six patients were among a study group of 579 patients with Hodgkins disease, prospectively followed since diagnosis. At 10 years the actuarial risk of development of non-Hodgkins lymphoma in this study group is 4.4 per cent (1.2 to 15.0) (per cent probability with 95 per cent confidence limits) and is similar to that of developing acute leukemia: 2.0 per cent (0.3 to 12.9). Non-Hodgkins lymphoma is a second tumor that may occur late in the course of patients treated for Hodgkins disease--particularly in patients who have received both radiation therapy and chemotherapy. Like acute leukemia, non-Hodgkins lymphoma may be another cancer that represents a substantial late risk of combined-modality therapy.

Stanford V and Radiotherapy for Locally Extensive and Advanced Hodgkin’s Disease: Mature Results of a Prospective Clinical Trial

PURPOSE To provide more mature data on the efficacy and complications of a brief, dose-intense chemotherapy regimen plus radiation therapy (RT) to bulky disease sites for locally extensive and advanced-stage Hodgkins disease. PATIENTS AND METHODS One hundred forty-two patients with stage III or IV or locally extensive mediastinal stage I or II Hodgkins disease received Stanford V chemotherapy for 12 weeks followed by 36-Gy RT to initial sites of bulky (> or =5 cm) or macroscopic splenic disease. Freedom from progression (FFP), overall survival (OS), and freedom from second relapse (FF2R) were determined using life-table estimates. Outcomes were analyzed according to the international prognostic score. Late effects of treatment were recorded in follow-up. RESULTS With a median follow-up of 5.4 years, the 5-year FFP was 89% and the OS was 96%. No patient progressed during treatment, and there were no treatment-related deaths. FFP was significantly superior among patients with a prognostic score of 0 to 2 compared with those with a score of 3 and higher (94% v 75%, P <.0001). No secondary leukemia was observed. To date, there have been 42 pregnancies after treatment. Among 16 patients who relapsed, the FF2R was 69% at 5 years. CONCLUSION These data confirm our preliminary report that Stanford V chemotherapy with RT to bulky disease sites is highly effective in locally extensive and advanced Hodgkins disease. It is most important to compare this approach with standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the ongoing intergroup trial (E2496) to determine whether Stanford V with or without RT represents a therapeutic advance.

Central Nervous System Involvement in non-Hodgkin 's Lymphoma: An Analysis of 105 Cases

Records of 105 patients with central nervous system (CNS) lymphoma were analyzed in order to better define the incidence, setting, and management of CNS lymphoma and the role for CNS prophylaxis. Survival was best for patients under 30 years of age treated with whole‐brain irradiation and intrathecal (IT) chemotherapy whose CNS involvement was an isolated event (median survival time, 1.8 years). Survival was worst for patients over 30 years of age whose CNS invasion occurred at a time of progressive systemic lymphoma (median time ten weeks if treated with whole‐brain irradiation with or without IT chemotherapy). The risk of CNS invasion was greatest for those with lymphoblastic lymphoma. Among patients with Stage IIE, III, or IV histiocytic lymphoma, the risk of CNS involvement was greatest for those with progressive or relapsing disease or involvement of the testes, peripheral blood, or epidural space of the spinal cord.

The evolution and summary results of the Stanford randomized clinical trials of the management of Hodgkin's disease: 1962–1984

This is a summary report of the Stanford randomized clinical trials of the management of Hodgkins disease, initiated in 1962. There have been four major changes in the treatment protocols during this 22 year period. Between 1962-67, 132 patients with CS I, II and III disease were enrolled on various radiation trials. Between 1968-74, 367 patients were enrolled on studies primarily evaluating the role of adjuvant MOPP chemotherapy. Between 1974-80, variations in the chemotherapy regimen and the sequences of the combined modality programs were studied. The current studies, initiated in 1980, have enrolled 102 patients, and test a new mild adjuvant chemotherapy, VBM, (vinblastine, bleomycin and methotrexate) and utilizes ABVD in combined modality and alternating regimens. During the two decades of these studies, involving more than 800 patients, the initial remission rate and duration and the survival of all patients treated have progressively improved.

Histologic conversion in the non-Hodgkin's lymphomas.

Between July 1, 1971 and December 31, 1978, 150 patients with favorable subtypes of non-Hodgkins lymphoma [nodular poorly differentiated lymphocytic (NLPD), nodular mixed, or diffuse well differentiated lymphocytic] were entered into prospective randomized clinical trials at Stanford University. Treatments included involved field, total lymphoid, or whole body irradiation, single alkylating agent chemotherapy, combination chemotherapy with cyclophosphamide, vincristine and prednisone (CVP) or with cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP), or various combinations of chemotherapy and irradiation. The initial complete response rate (CR) was 79%. Among patients who achieved a CR, 31% later relapsed. There were 78 patients who either failed to achieve a CR or achieved a CR and later relapsed. Histologic conversion (change from initially favorable to an unfavorable subtype of non-Hodgkins lymphoma) was documented in 22/78 patients (28%). However, the actuarial risk for conversion was actually much greater (60% at 8 yr). The median time to documentation of conversion was 51 mo. The most common type of histologic conversion was from NLPD to diffuse histiocytic lymphoma. Documented histologic conversion was often associated with a more aggressive clinical behavior of the lymphoma, and the median survival after conversion was less than 1 yr. However, those patients who achieved a CR after conversion had a more favorable outcome (actuarial survival 75% at 5 yr). No specific risk factors predictive of histologic conversion could be identified.