Richard T. Hoppe

Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas

Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkins 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.

Revised Response Criteria for Malignant Lymphoma

PURPOSE Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. METHODS The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. RESULTS New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkins and Hodgkins lymphoma. Standardized definitions of end points are provided. CONCLUSION We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

Tolerance and Chimerism after Renal and Hematopoietic-Cell Transplantation

We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donors hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

Cardiac disease following treatment of Hodgkin's disease in children and adolescents.

PURPOSE Cardiac disease is second only to neoplastic disease as a cause of death after treatment for Hodgkins disease. This study evaluates the risks of cardiac disease following treatment of Hodgkins disease during childhood and adolescence. PATIENTS AND METHODS We reviewed records of 635 patients treated for Hodgkins disease before 21 years of age at Stanford University between 1961 and 1991. Mean age was 15.4 years; mean follow-up duration was 10.3 years, representing 6,564 person-years of observation. Relative risks (RRs) of death from cardiac diseases were calculated by comparison with age-, sex-, and race-matched general population rates from United States decennial life-tables. RESULTS Twelve patients have died of cardiac disease (RR, 29.6; 95% confidence interval [CI], 16.0 to 49.3), including seven deaths from acute myocardial infarction ([AMI] RR, 41.5; 95% CI, 18.1 to 82.1), three from valvular heart disease, and two from radiation pericarditis/pancarditis. Thus far, the risk of AMI death was comparable after radiation alone (RO) or after chemotherapy and radiation (CM) (RO-AMI RR, 52.2; 95% CI, 21.1 to 108.7; CM-AMI RR, 21.1; 95% CI, 0.0 to 104.4; P = .6). The risk for other cardiac death (CD) tended to be higher after combined treatment (RO-non-AMI RR, 7.4; 95% CI, 0.0 to 36.5; CM-non-AMI RR, 45.8; 95% CI, 14.4 to 110.6; P = .1). Deaths occurred 3 to 22 years after patients received 42 to 45 Gy to the mediastinum between 9 and 20 years of age. There have been no deaths among patients treated to lower mediastinal radiation doses or without mediastinal radiation. There are no clear trends in the latency of risk. One hundred six nonfatal abnormalities have also been diagnosed. CONCLUSION Mediastinal radiation of 40 to 45 Gy increases the risk of death from coronary artery and other cardiac diseases. The risk increases within 5 years of irradiation. These observations support combined-modality, low-dose irradiation regimens in children and adolescents and suggest the need for careful cardiac screening of treated patients.

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.)

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.

Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.

PURPOSE To evaluate retrospectively the results of radiotherapy for 177 patients with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkins lymphoma (NHL) treated in the Department of Radiation Oncology, Stanford University between 1961 and 1994. PATIENTS AND METHODS Histology was follicular small cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large-cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had extranodal involvement. All patients had received radiotherapy, either to one side of the diaphragm (involved or extended field) or to both sides (total lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy doses ranged from 35 to 50 Gy. RESULTS The median follow-up duration was 7.7 years. The longest follow-up duration was 31 years. Actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37% of patients, respectively, were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. Survival and freedom from relapse (FFR) were significantly worse for older patients. Relapse rates were lower following treatment on both sides of the diaphragm or staging laparotomy. Univariate analysis showed that youth and staging laparotomy were associated with significantly better survival and that FFR was better following treatment on both sides of the diaphragm or laparotomy. CONCLUSION Radiotherapy remains the treatment of choice for early-stage low-grade follicular lymphomas. Patients who have remained free of disease for 10 years are unlikely to relapse.

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.

Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.

Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy†

From 1956 through 1973, 82 patients with carcinoma of the nasopharynx received high dose megavoltage radiation therapy at Stanford University. The actuarial disease‐free (NED) survival was 62% at 5 years and 56% at 10 years. The NED survivals at 5 years for patients with T1, T2, and T3 lesions were 76%, 68%, and 55%, respectively. No T4 patients were salvaged, but two of 10 patients who presented with cranial nerve dysfunction were long‐term survivors. The degree of nodal involvement also had prognostic significance. Involved lymph nodes were successfully controlled in all instances when doses of at least 6500 rads were given. Initial treatment failed in 32 patients. In 24 (75%) this occurred within 18 months. Thirteen patients with initial recurrences in head and neck sites were retreated and three remain alive. Survival after retreatment ranged from 2 months to 10 years, with a median of 16 months. Although nearly one‐third (6/17) of the patients with local recurrences had initial T1 or T2 lesions, there have been no failures in patients treated for these early stages in the last 7 years. This may be attributed to the use of larger treatment fields. Likewise, prophylactic irradiation of the neck was always successful in preventing nodal disease if the primary site was controlled.