End-of-treatment but not interim PET scan predicts outcome in nonbulky limited-stage Hodgkin's lymphoma.

BACKGROUND: Early interim positron emission tomography (PET) scans appear powerfully predictive of outcome in Hodgkin's lymphoma (HL), particularly in advanced-stage disease where it has been predominantly studied. The prognostic value of interim PET in limited-stage patients with nonbulky disease has not been well established. PATIENTS AND METHODS: Ninety-six patients with nonbulky limited-stage HL were identified who had interim and end-of-treatment PET scans. Response rate, overall survival (OS), and progression-free survival (PFS) were calculated. RESULTS: Four-year PFS and OS for the entire cohort were 88% and 97%, respectively. Interim PET did not predict outcome, with PFS in positive and negative patients 87% versus 91% (P=0.57), respectively. End-of-treatment PET result was predictive of outcome, with PFS of 94% in end PET-negative patients versus 54% in end PET-positive patients (P<0.0001). Four-year OS was 100% in end PET-negative patients and 84% in end PET-positive patients (P<0.0001). CONCLUSIONS: Interim PET scans were not predictive of outcome, compared with scans carried out at completion of therapy. End-of-treatment PET was highly predictive of PFS and OS, regardless of interim PET result. In this low-risk patient population, even patients with interim positive PET scans show a favorable prognosis.

Recombinant interferon-alpha2b added to oral cyclophosphamide either as induction or maintenance in treatment-naive follicular lymphoma: final analysis of CALGB 8691.

Recombinant interferon alpha-2b (IFN-alpha2) has direct and indirect antiproliferative effects in lymphoma, and may augment cytotoxicity when combined with chemotherapy. CALGB 8691 is a randomized study of daily oral cyclophosphamide (CPA) at 100 mg/m2 with or without IFN-alpha2 at 2 x 106 IU/m2 three times per week, followed by a second randomization between IFN-alpha2 maintenance (2 x 106 IU/m2 three times weekly) versus observation in treatment-naïve patients with follicular lymphoma (FL). Five hundred eighty-one patients were randomized to either CPA (n = 293) or CPA plus IFN-alpha2 (n = 288). One hundred five responding patients were randomized to observation and 99 to maintenance IFN-alpha2. With a median follow-up of 11.5 years, the median event-free and overall survival (OS) for CPA induction alone were 2.5 years (95% CI 2.2, 3.0) and 9 years (95% CI 7.7, 10.2), compared to 2.4 years (95% CI 2.1, 3.1) and 8.4 years (95% CI 7.5, 11.1) for the combination arm (p = NS). Patients with a partial response (PR) and randomized to observation had the worst outcome (event-free survival (EFS) 1.8 years versus 3.9 years; p = 0.002). Patients with a PR randomized to IFN-alpha2 had a similar EFS to compared to patients with complete response (CR), but this did not translate into a survival advantage. Myelosuppression was increased in IFN-alpha2-containing arms. Despite the small benefit in EFS in patients with PR randomized to IFN-alpha2 maintenance, we conclude that the addition of low dose IFN-alpha2 did not significantly improve the response rate, duration of response, event-free, or OS obtained with single-agent daily oral CPA in patients with previously untreated FL.

Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804.

BACKGROUND: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m(2), V 20 mg/m(2), and D 15 mg/m(2) for transplant-naive patients, and G 800 mg/m(2), V 15 mg/m(2), and D 10 mg/m(2) for post-transplant patients. RESULTS: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively. CONCLUSIONS: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.

Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up.

BACKGROUND: The most commonly used regimen for the treatment of advanced Hodgkin's disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity. The EVA regimen (etoposide, vinblastine, doxorubicin) is an attempt to substitute a known active agent, etoposide, for bleomycin and dacarbazine. PATIENTS AND METHODS: A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients. RESULTS: EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3-48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity. CONCLUSIONS: The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA.

Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854.

BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.

Persistent symptoms among survivors of Hodgkin's disease: an explanatory model based on classical conditioning.

Persistent symptoms of nausea, distress, and vomiting triggered by reminders of cancer treatment were examined among 273 Hodgkin's disease survivors, 1 to 20 years posttreatment. Prevalence rates were high for distress and nausea but low for vomiting. Retrospective report of anticipatory symptoms during treatment was the strongest predictor of persistent symptoms, suggesting that treatment-induced symptoms are less likely to persist if conditioning does not occur initially. Time since treatment was also a significant predictor, with patients more recently treated more likely to experience persistent symptoms. Thus, an explanatory model based on classical conditioning theory successfully predicted presence of persistent symptoms. Symptoms also were associated with ongoing psychological distress, suggesting that quality of life is diminished among survivors with persistent symptoms. Recommendations for prevention and treatment of symptoms are discussed.

Burnout: caring for the caregivers.

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Burnout describes the end result of stress in the professional life of a physician or caregiver and combines emotional exhaustion, depersonalization and low personal accomplishment. This problem is common in health care workers in every specialty and may affect not only personal satisfaction, but also the quality of care delivered to patients. Burnout is particularly relevant in oncology where caregivers work closely with patients who have life-threatening illnesses and therapy often has only a limited impact. Burnout was discussed in the rounds with an emphasis on factors which precipitate or prevent stress among health care workers. Presentations were made by Dr. Canellos of the Dana Farber Cancer Institute, and Dr. Picard of the Institute for Health Professions. Staff discussed the main issues contributing to burnout including the health care system, lack of time and inadequate training. They considered preventative measures including psychological support of the health care team, communication and management skills, and effective coping mechanisms.

The lymphomas.

The history of therapeutic advances in the lymphomas is reviewed. The initial studies that led to the cure of Hodgkin's disease and diffuse large B-cell lymphomas set a paradigm of cancer treatment broadly applicable to a number of malignancies. In recent times our knowledge of the biology of the Immune system has clarified the origin of subsets of lymphomas and provided specific targets of future therapeutic approaches.

Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group.

Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkin's lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.

Sequential chemotherapy (etoposide, vinblastine, and doxorubicin) and subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features: A phase II Cancer and Leukemia Group B Study (9051).

BACKGROUND: The aim of this study was to evaluate a regimen of sequential chemotherapy and radiotherapy for patients with Hodgkin disease. METHODS: The Cancer and Leukemia Group B conducted a Phase II study of three cycles of etoposide, vinblastine, and doxorubicin (EVA) chemotherapy followed by subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features. Fifty-nine patients were enrolled in the study. Fifty-three patients met all study eligibility criteria; 48 of them (91%) had mediastinal disease and 29 (55%) had bulky mediastinal disease. RESULTS: A complete response (CR) occurred in 35 of the patients (66%). Of all patients who had CR, 26% had the CR after the chemotherapy and before the radiation, and 74% after the chemotherapy and radiation. Twenty percent of the patients who had CR experienced disease progression; in these patients, the progression was outside the radiotherapy field in the lung and involved widespread disease. CONCLUSIONS: EVA offers a nonbleomycin-containing alternative for patients in whom preexisting pulmonary disease may be exacerbated by bleomycin and radiation therapy. EVA, as given in this study (in three cycles), was insufficient chemotherapy for patients who had disease in areas outside the radiation fields (occult disease).

Phase II trial of topotecan in advanced breast cancer: a Cancer and Leukemia Group B study.

The topoisomerase I inhibitor topotecan had demonstrated good antitumor activity in several murine tumor systems and in human clonogenic assays by 1993. In that year, the Cancer and Leukemia Group B (CALGB) began a phase II trial to determine its activity in patients with breast cancer who had previously received one course of chemotherapy for advanced breast cancer. Between April 1993 and June 1994, 53 patients of performance status 0-2 entered the study, of whom 47 were eligible and 40 were evaluable. Topotecan was given at a dose of 1.5 mg/m2 over 30 minutes daily for 5 days every 21 days. In the absence of progression or withdrawal of consent, therapy was continued indefinitely. The median age was 58 years (range 30-79). There were no complete responses and four partial responses, resulting in an objective response rate of 10% (95% CI: 3-24%). Responses were noted in lymph nodes, liver, and skin. The median duration of response was 5 months. The median survival was 12 months. Life-threatening toxicities were almost exclusively hematologic. However, myelosuppression was not cumulative. It was concluded that topotecan has only modest activity among women with advanced breast cancer who have previously received one course of chemotherapy. Given its modest activity and predominant hematologic toxicity, it does not appear to be a promising drug for either single-agent or combination chemotherapy in the salvage setting of advanced breast cancer.

Mediastinal large cell lymphoma: prognostic significance of CT findings at presentation and after treatment.

OBJECTIVE: Primary mediastinal large cell lymphoma is a distinctive subtype of non-Hodgkin's lymphoma. Computed tomography (CT) has become an integral part of the evaluation of these patients at presentation and after completion of therapy. The purpose of this study is to identify CT features that predict increased risk of relapse. METHODS: A retrospective study of patients with primary mediastinal large cell lymphoma who underwent CT scans of the thorax. RESULTS: Tumor volume greater than 100 ml after completion of therapy was a statistically significant predictor of increased risk of relapse (p=0.02, Fisher exact test). Other measurements (obtained at presentation and after completion of treatment) were not statistically significant in predicting relapse. CONCLUSION: CT plays an important role in predicting outcome in primary mediastinal large cell lymphoma. Large residual tumor volume after completion of treatment predicts an increased risk of relapse.

Comparison of psychosocial adaptation of advanced stage Hodgkin's disease and acute leukemia survivors. Cancer and Leukemia Group B.

BACKGROUND: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. PATIENTS AND METHODS: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). RESULTS: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. CONCLUSIONS: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.

Treatment of relapsed Hodgkin's disease: strategies and prognostic factors.

The major points in salvage therapy of patients in relapse following combination chemotherapy for advanced disease are: (1) success of any second-line approach is determined by prognostic factors which include age, duration of the initial remission, and quantity of disease at relapse; (2) induction failures (progression without remission or incomplete remission and short initial remission) require innovative therapy which currently entails high-dose chemotherapy with peripheral or bone marrow autologous support; (3) late relapse still retains an order to sensitivity to chemotherapy and can be treated with conventional dose combination with complementary radiation therapy to previously unirradiated bulky sites. The choice of regimen is empiric and can include a repeat of the regimen used for the original remission or induction. The relative advantage of HDC in this favorable group is uncertain.

Stage IA-IIB Hodgkin's disease: management and outcome of extensive thoracic involvement.

PURPOSE: To examine the presentation, management, and outcome of patients with extensive intrathoracic involvement in early-stage Hodgkin's disease. PATIENTS AND METHODS: One hundred seventy-two patients with clinical Stage IA-IIB Hodgkin's disease and extensive intrathoracic involvement were studied. Extensive intrathoracic disease was defined as either large mediastinal adenopathy (LMA, defined as the width of the mass greater than one-third the maximum thoracic diameter, n = 154) or as extensive (> 10 cm) cephalocaudad intrathoracic disease that did not fulfill formal chest radiograph criteria for LMA (n = 18). Patients were divided into three groups based on staging and extent of treatment. Forty-seven patients were treated with radiation alone after a laparotomy (RT-lap), 47 patients received combined modality therapy after laparotomy (CMT-lap), and 78 patients were treated with combined modality therapy without staging laparotomy (CMT-no lap). MOPP was used in 82% of the CMT patients. Low-dose whole-cardiac RT was used in nearly 50% of patients treated either with RT or CMT. RESULTS: The 10-year actuarial freedom from relapse rates were 54% with RT alone and 88% with CMT (p = 0.001); overall survival rates were 84 and 89%, respectively (p = NS). The median time to relapse was only 17 months. Over 80% of relapses occurred within the first 3 years. The most common site of relapse in all patients was the mediastinum. Relapses below the diaphragm were rare, even in CMT patients who did not receive abdominal radiation treatment. The principal acute morbidity was symptomatic pneumonitis, which occurred in 29% of patients receiving any part of their chemotherapy after RT, compared to 13% if all the chemotherapy was given before RT and 11% if RT alone was administered. There was a low late risk of myocardial infarction (3%) in the two groups with the longest follow up (RT-lap, CMT-lap), but a higher risk of second malignancy in the CMT-lap group (21%) compared with the RT-lap group (2%). CONCLUSION: Extensive intrathoracic involvement is a distinctive presentation of early-stage HD that has a high relapse risk if treated with RT alone. The introduction of CMT has been associated with improvements in freedom from relapse. The low rate of peripheral relapse with CMT suggests that reductions in field size may be achievable. The use of low-dose whole-heart RT with modern techniques is not associated with a high risk of late cardiac complications and should be used in patients who present with extensive pericardial disease or cardiophrenic lymphadenopathy. The high rate of second malignancy in the CMT group with the longest follow-up suggests that careful long-term surveillance for such patients is warranted.