Stage I to IIB Hodgkin's disease: the combined experience at Stanford University and the Joint Center for Radiation Therapy

The treatment records of 180 patients with pathological stage (PS) IB to IIB Hodgkin's disease treated at Stanford University Medical Center (SUMC) or the Joint Center for Radiation Therapy (JCRT) were reviewed. Pretreatment characteristics were analyzed to assess their influence on survival and freedom from relapse (FFR). The two most important disease characteristics predictive of relapse were the number and type of B symptoms present and the mediastinal mass ratio (MMR). Patients with both fevers and weight loss had a 7-year survival and FFR of only 57% and 48%, respectively. The poor prognosis in this group was apparent for treatment with either radiation (XRT) alone or combined modality therapy (CMT). Patients with night sweats only had no adverse effect of B symptoms on outcome. Patients with a MMR greater than 1/3 had a 7-year FFR of only 58% after XRT, but 79% after CMT (P = .12). The 7-year survivals for these patients were 85% and 88%, respectively. CMT improved the FFR of the entire group of 180 patients when compared with XRT (7-year FFR 86% and 74%, respectively, P = .02); however, survival in the two treatment groups was similar (88% and 89%). Among patients treated with radiation alone, there was a similar survival and FFR irrespective of whether pelvic irradiation was included in the initial treatment fields.     

Stage IA to IIB mediastinal Hodgkin's disease: three-dimensional volumetric assessment of response to treatment

From 1979 to 1986, the response to treatment of 53 patients with stage IA to IIB mediastinal Hodgkin's disease was evaluated by three-dimensional volumetric analysis using thoracic computed tomographic (CT) scans. The mean initial volume of mediastinal disease in 34 patients treated with mantle and para-aortic irradiation was 166 mL, whereas for 19 patients treated with two to six cycles of multiagent chemotherapy and mantle and para-aortic irradiation the mean initial volume was 446 mL. Preliminary data suggested that patients with mediastinal volumes of less than 200 mL had a lower mediastinal relapse rate (13%) than patients with volumes greater than 200 mL (32%). For 12 patients receiving six cycles of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), those with a greater than 85% reduction in volume 1 to 2 months after chemotherapy had a lower incidence of mediastinal relapse (zero of six, 0%) compared with patients having 85% or less reduction in volume (four of six, 67%). The primary value of this technique is that it provides a sensitive assessment of response to treatment and may aid in monitoring the effectiveness of a given treatment.     

Gonadal status and reproductive function following treatment for Hodgkin's disease in childhood: the Stanford experience

To ascertain the impact of therapy on gonadal function and reproductive outcome among children treated for Hodgkin's disease, we reviewed the experience at Stanford University Medical Center during the years 1965-1986. There were 240 children 15 years of age or younger, 92 girls and 148 boys; with median follow-up of 9 years, maximum follow-up was 26 years. Of this cohort, data on gonadal function were available on 20 boys, 5 of whom were considered prepubescent; they had no clinical evidence of sexual maturation and were less than 13 years of age. Evaluation of the boys included testicular biopsy, semen analyses and the ability to procreate. Serum gonadotropin hormone levels (FSH, LH) were studied in 11 boys who also had semen analyses. Sexual maturation was attained in all boys without the need for androgen replacement. Among the eight boys treated with radiation alone, four were able to father a child (3 following 40-45 Gy pelvic radiation dose, 1 without pelvic radiation) from 3-19 years following treatment. Three others who received 30-44 Gy pelvic radiation were oligospermic when tested at 10 to 15 years post-treatment. Semen analyses in 10 of 12 (83%) boys who had been treated with six cycles of MOPP with or without pelvic radiation revealed absolute azoospermia with no evidence of recovery as along as 11 years of follow-up. Following prolonged azoospermia, 2 of the 12 boys (17%) had recovery of fertility, with normalization of sperm count and/or ability to procreate at 12 and 15 years following treatment. There was no correlation with serum gonadotropin levels and sterility. Data on menstrual history, pregnancy and offspring were available in 86 (92%) of the girls. Seventy-five of the 86 girls (87%) have normal menstrual function. However, none of the females who underwent pelvic radiation without prior oophoropexy has maintained ovarian function. Both the prepubescent and postpubescent boys were affected by 6 cycles of MOPP whether or not pelvic radiation was administered. On the other hand, in girls similarly treated, ovarian injury was directly related to both the number of cycles of chemotherapy and the ovarian radiation dose. The chances of maintaining gonadal function following combined modality treatment are significantly greater among girls than boys. The progeny of patients treated for Hodgkin's disease appear normal and no excess fetal wastage has been noted.     

Stage I and II subdiaphragmatic Hodgkin's disease

From January 1971 to December 1986, 521 patients with Hodgkin's disease were evaluated and treated at the Yale University School of Medicine or one of its close affiliates. A total of 258 patients had pathologic stage (PS) I or II disease, with 239 patients having Hodgkin's disease above the diaphragm (ADHD) and 19 patients having Hodgkin's disease below the diaphragm (BDHD). A comparison of patients with BDHD versus patients with ADHD showed that patients with BDHD were older (mean age, 42 versus 28 years of age, P = 0.005), were initially seen less often with nodular sclerosis subtype (32% versus 77%, P = 0.00001), and had a higher male: female ratio (2.8 versus 1.2, P = 0.12). Ten patients with BDHD (53%) had positive findings at staging laparotomy (0 of 4 clinical stage [CS] IA patients and 10 of 15 (67%) CS II patients). Radiation therapy alone was the initial treatment of choice for 74% of patients with BDHD versus 94% of the patients with ADHD. There was no statistical difference in the overall survival or relapse-free survival rates for patients with BDHD versus ADHD (10-year survival rates, BDHD = 73% and ADHD = 81%). However, patients with BDHD who initially had intra-abdominal disease had a statistically significant increase in death rate (60%) due to Hodgkin's disease compared with patients with BDHD who initially had only peripheral nodal disease (0%). Treatment recommendations for patients with BDHD should be tailored to the specific clinical presentation of each patient. For most PS IA/IIA patients initially seen with peripheral nodal disease, radiation therapy alone is a successful treatment program. However, combined modality therapy should be the treatment of choice for patients with BDHD initially seen with intra-abdominal disease.     

Subdiaphragmatic Hodgkin's disease: the University of Florida experience.

PURPOSE: To assess the long-term outcomes and late effects of patients with subdiaphragmatic Hodgkin's disease. METHODS AND MATERIALS: Twenty-one patients with Stage I and II subdiaphragmatic Hodgkin's disease were treated with curative intent between February 1966 and February 1998 at the University of Florida. Patient characteristics were as follows: mean age, 38.7 years (range, 3-75 years); 20 males and 1 female; 33% lymphocyte predominant, 43% nodular sclerosing, 14% mixed cellularity, 5% lymphocyte depletion, and 5% unclassified Hodgkin's disease. Treatment included inverted Y irradiation (InY) (8 patients), total nodal irradiation (TNI) (7 patients), and combined modality irradiation and chemotherapy (CMT) (6 patients). Median follow-up was 12.3 years (range, 3.1-33.6 years). RESULTS: Progression-free survival and overall survival were 80% and 70%, respectively, at 10 years. There were no deaths from Hodgkin's disease. Treatment failures occurred in 1 of 8 patients after InY, 1 of 7 after TNI, and 1 of 6 after CMT. Two of 3 recurrences were in patients with 3 or more sites of involvement and/or splenic involvement; 1 was in-field. There were 5 second malignant neoplasms and 3 cardiac events, including 4 second malignant neoplasms and 2 cardiac events in the 9 patients > or =40 years old at diagnosis and 1 second malignant neoplasm and 1 cardiac event in the 12 patients <40 years old. All 3 second solid malignancies in this study occurred 7-14 years after treatment in areas receiving 10-20 Gy. CONCLUSIONS: Subdiaphragmatic Hodgkin's disease is an uncommon manifestation with excellent disease control achieved with InY, TNI, and CMT. This subgroup of patients with Hodgkin's disease is predominantly male and older than subgroups with other presentations, which may predispose the group to a higher risk for serious adverse events after treatment. We recommend InY with spleen for clinical Stages IA and nodular sclerosis or lymphocyte-predominant clinical Stage IIA, InY alone for pathologic Stages IA and IIA, and CMT for all Stage I/II patients with greater than three involved sites, B symptoms, bulky disease (>6 cm), central (para-aortic) presentation, or splenic involvement.     

Stages IIB and IIIB Hodgkin's disease. Results of combined modality treatment.

Between April 1969, and December 1974, 23 IIB and 26 IIIB surgically staged patients with Hodgkin's disease were treated at the Joint Center for Radiation Therapy. Stage IIB patients received either mantle and para-aortic-splenic pedicle, or total modal irradiation (TNI) alone or with the addition of combination chemotherapy. Relapse-free survival is 83% and overall survival 88%. Eleven patients received combination chemotherapy in addition to mantle and para-aortic irradiation, and both the relapse-free and overall survival are 100%. Of the stage IIIB patients, seven received TNI alone with four relapses, and 19 were treated with TNI and MOPP with two relapses. These relapse rates are significantly different (p less than 0.05). The relapse-free and overall survival for all stage IIIB patients is 66% and 84% respectively. These data imply that irradiation alone is not adequate treatment for stage IIIB Hodgkin's disease, and that with the addition of combination chemotherapy both the disease-free and overall survival is similar to that of early stage Hodgkin's disease without systemic symptoms. The ideal management of stage IIB Hodgkin's disease is less certain; it is our plan to study the efficacy of combined modality treatment.     

Staging laparotomy in Hodgkin's disease: a community hospital experience

Between 1977 and 1984, 50 patients with Hodgkin's disease underwent a staging laparotomy performed by nine surgeons in a community hospital. Adequate procedures were performed in 80% of cases compared to staging laparotomies done between 1969 and 1976 when only 40% were properly performed. Abdominal lymphangiogram had a false-negative rate of 0 but a false positive rate of 70%. Clinical stage III disease was significantly downstaged at laparotomy (65% of cases). Postoperative complication rate was 4% and there were no operative deaths. A subset of patients not requiring laparotomy have been identified. Because the quality of staging laparotomy and lymphangiography was variable, we encourage all centres treating patients with Hodgkin's disease to review their own experience with these techniques before making individual patient treatment decisions.     

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 Hodgkin's 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.     

Stage IA-IIB Hodgkin's disease: staging and treatment of patients with large mediastinal adenopathy

Ninety-two patients with clinically staged (CS) IA-IIB Hodgkin's disease (HD) with large mediastinal adenopathy (LMA) underwent three different staging and treatment approaches between April 1969 and December 1984. These approaches included: (1) staging laparotomy followed by radiation therapy (RT) alone; (2) staging laparotomy followed by combined RT and chemotherapy (CMT); or (3) clinical staging followed by CMT. Patients treated with CMT were more likely to have "B" symptoms, extension into extranodal sites, or stage III disease. Patients treated with RT alone had a significantly higher risk of relapse as compared to patients receiving CMT. No overall survival differences were seen between the three groups of patients. For patients treated with CMT without RT to the spleen or abdominal nodes, the risk of relapse in the abdomen was low (4%). These data suggest that for those CS I-II HD patients with LMA who are treated with CMT, the role for staging laparotomy and abdominal irradiation is limited. RT alone remains an option for some patients with LMA, but careful assessment of the anatomic extent of thoracic disease as well as staging laparotomy is essential if such treatment is recommended.     

The Stanford experience with combined procarbazine, Alkeran and vinblastine (PAVe) and radiotherapy for locally extensive and advanced stage Hodgkin's disease.

This report describes the efficacy and toxicity of PAVe (procarbazine, Alkeran, vinblastine) and irradiation (RT) in the management of 159 patients with locally extensive or advanced stage Hodgkin's disease (HD) at Stanford University. Patients received six courses of chemotherapy alternating with RT. The extent of RT and the schedule of treatment varied according to the stage of disease. About 2/3 of patients received PAVe/RT in the setting of prospective, randomized clinical trials. The rate of complete response was 93%. With a median follow-up of seven years (range 2-17), the 15 year actuarial freedom from progression (FFP) is 78% and overall survival is 75%. Ten-year FFP by stage is: 80% for locally extensive stage II, 90% for stage IIIA and 70% for stage IIIB. Excellent and equal results were attained with PAVe/RT vs. MOP(P) (mustard, Oncovin, procarbazine with or without prednisone)/RT in the randomized combined modality studies. Progression or recurrence was documented in 30 patients and was more common in irradiated sites. PAVe was well tolerated acutely. There were no treatment related fatalities. Twenty-three (14%) patients were admitted to the hospital for neutropenic fever. Five second malignancies have occurred after PAVe/RT only: one myelodysplastic syndrome, one acute myelogenous leukemia, one non-Hodgkin's lymphoma and two solid tumors including a case of non-small cell lung cancer and an in situ carcinoma of the cervix. Three patients died from myocardial infarction several years after the completion of treatment. These mature data show that PAVe/RT is effective and well-tolerated therapy for locally extensive stage II and IIIA/B HD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rhabdomyosarcoma: the Stanford experience using a TNM staging system

Seventy-four patients with rhabdomyosarcoma were initially staged according to the Intergroup Rhabdomyosarcoma Study (IRS) grouping classification and then retrospectively using a TNM staging system based on the initial clinical extent of disease. The TNM system includes T1, tumor confined to site or organ of origin; T2, regional extension beyond the site of origin; N0, normal lymph nodes; N1, lymph nodes containing tumor; M0, no evidence of metastases; and M1, distant metastases. All patients received combination chemotherapy, and more than 90% received radiation therapy as part of their initial treatment program with curative intent. Fifty-three of 74 patients (72%) were group III according to the IRS system, indicating unresectable or gross residual tumor. A more uniform distribution was achieved using the TNM system. Freedom from relapse (FFR) was 43% and the actuarial survival rate was 47% for the entire study group at 10 years. All but one relapse occurred within 3 years of initial diagnosis, and only three of 38 relapsed patients were salvaged. All TNM stage I patients are surviving disease free. Among patients having stages II, III, and IV disease by the TNM system, FFR was 53%, 26%, and 11%, and the survival rates were 47%, 36%, and 33%, respectively. Thirty-two of 74 patients (43%) had evidence of lymph node involvement at presentation, and 28 (88%) of these had primary lesions that extended beyond the site of origin (T2 primary). Histologic subtype and primary site had little impact on outcome in a multivariate analysis, and T stage was identified as the single most significant covariate correlated with survival; a model composed of both T stage and M stage was the best one for predicting relapse. The presented data support a study using a prospectively assigned TNM staging system based on the initial clinical extent of disease for use in future therapeutic trials.     

The role of radiotherapy in the treatment of Stage IIIA Hodgkin's disease in children

The report discusses the results of treatment of 54 patients (aged 2-14) with stage IIIA Hodgkin's disease. Radiotherapy was followed by relapse-free period in 60.6% only, although 5-year survival rate was rather high (90.9%). In the chemoradiation treatment group the said rates were 92.3 and 100%, respectively.     

Radiotherapy for stage I Hodgkin's disease: 20 years experience at St Bartholomew's Hospital

One hundred and one consecutive patients with newly diagnosed stage I Hodgkin's disease (HD) received treatment at St Bartholomew's Hospital, between 1968 and 1987, with a median follow-up of 12 years. Eleven patients have been excluded from detailed analysis because they either received involved field radiotherapy (RT) or radiotherapy with chemotherapy or were lost to follow-up. Actuarial analysis predicts 78% to be alive and without relapse of Hodgkin's disease at 15 years. Ninety evaluable patients (clinical stage (CS) 24; pathological stage (PS) 66) received either mantle or inverted 'Y' RT and form the basis of this analysis. The median age was 33 years (63 men, 27 women). Histology at presentation was nodular sclerosing (39), lymphocytic predominant (27) or mixed cellularity (24). The presenting site was neck (78), axilla (6) groin (4) and mediastinum (2). Complete remission was achieved in all evaluable patients, the actuarial proportion in remission being 75% at 15 years. Factors predictive of a prolonged remission were pathological staging versus clinical staging (P = 0.02) and lymph node size less than 3 cm (P = 0.04). Actuarial overall survival in these 90 patients was 75% at 15 years and none of the above factors correlated with survival. Relapse of HD has occurred in 18 patients (5 within RT field, 10 without and 3 in both). Second remission was achieved in 15/18. The actuarial rate of second remission and survival was 40% at 10 years. Sixteen patients have died, 7 of Hodgkin's disease, 7 of unrelated causes and 2 of second malignancy. A further 3 patients who developed second malignancy are still alive. At 15 years the actuarial mortality related to HD was 12%. These results confirm the importance of long follow up to assess the efficacy of primary therapy.     

Five years' experience with ChlVPP: effective low-toxicity combination chemotherapy for Hodgkin's disease.

Since 1975, 191 patients with Hodgkin''s disease have been treated with a combination of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Complete remission rates were 73% for previously untreated patients, 91% for patients previously treated with radiotherapy and 55% for patients previously treated with chemotherapy. In 59 patients with advanced disease who received no other treatment, a 5-year survival rate of 66% was comparable with that achieved by more toxic mustine-containing combinations. ChlVPP has few side effects, is easily given to outpatients, and can be combined with elective radiotherapy in selected patients.     

Preliminary experience with paclitaxel for the treatment of relapsed and refractory Hodgkin's disease

PURPOSE:: To determine the activity of paclitaxel (Taxol® Bristol-MyersSquibb Co., Princeton, NJ) in patients with relapsed and primarytreatment-refractory Hodgkin's disease. PATIENTS AND METHODS:: Fifteen patients with relapsed (n = 8) or primary treatment-refractory(n = 7) Hodgkin's disease were treated at two cancer centers.Patients received paclitaxel 200 mg/m² intravenously over threehours every three weeks. All patients also received premedicationwith dexamethasone, cimetidine, and diphenhydramine. The medianage was 33 years (range, 19 to 69 years), and the median numberof prior treatment regimens was three. Seven patients had previouslyreceived treatment with autologous bone marrow transplantation. RESULTS:: Fourteen patients were evaluable for response after receivingone to six courses (median, two courses) of paclitaxel. Twopatients (14%) had partial remissions; both of them had relapsedafter achieving a complete remission with high-dose therapyand autologous bone marrow transplantation. One of these patientswas given involved field radiation to consolidate the partialremission and remains free of disease two years after paclitaxeltherapy. Three patients had stable disease, and nine had progressivedisease. Therapy was well tolerated, with a toxicity profilesimilar to that previously reported for paclitaxel in patientswith non-Hodgkin's lymphoma. CONCLUSION:: Paclitaxel, at this dose and schedule, has modest activity inthis group of heavily pretreated patients. Studying its activityin patients with more favorable disease characteristics is warranted. Hodgkin's disease, lymphoma, paclitaxel, Taxol     

Hodgkin's disease: challenges for the future

Clinical investigators of Hodgkin's disease of the recent past have reason to be proud. Tens of thousands of individuals, many of them young, fertile, and productive, have been cured of their life-threatening disease. There are few better examples of the success and rewards of clinical oncology than in the control of Hodgkin's disease by improved diagnostic methods and the appropriate use of radiation and chemotherapy. Yet the clinical investigator of today cannot be satisfied with these successes. The treatment required for high cure rates remains empirical, difficult, and costly. The goal must be to prevent or reverse this fascinating disease, utilizing specific therapy designed from a knowledge of the cause and pathogenesis of the disease. There are sufficient biological clues and methodologies to predict that this will be possible, and in the decade of the 1990s!