Increased Mortality after Successful Treatment for Hodgkin's Disease

Reviewers: John Han-Chih Chang, MD
Source: Journal of Clinical Oncology, November 1998, Volume 16 (Number 11): pages 3592 ? 3600

Introduction

Advances in the treatment of pediatric Hodgkin's disease (HD) have improved cure rates tremendously. Long-term survival free of disease has become very common in this population with chemotherapy and/or radiation therapy. When patients are cured of their disease, they are living long enough to experience some of the long-term toxicities of treatment. The intent of this article was to detail the long-term impact of treatment toxicity on pediatric HD patients that were treated at the St. Jude Children's Research Hospital on prospective trials from 1968 ? 1990.

Materials and Methods

Three hundred and eighty-seven patients on 4 consecutive prospective trials (HD-68, HD-72, HD-80 and HD-80A) were analyzed. The specifics of the treatment regimens of each trial are summarized in table 1 of the Journal article but beyond the scope of this discussion. Suffice to say that initially standard dose radiation treatment (35 ? 44 Gy) was combined with chemotherapy (COPP ? cytoxan, an oncovin or vincristine, procarbazine and prednisone). Later trials compared radiation therapy with combined modality (COPP and radiation therapy). Finally, COPP alternating with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) was analyzed combined with low dose (20 Gy) involved field radiation therapy in HD-80A. Overall, of the entire cohort, 4% had chemotherapy alone, 30% radiation therapy alone and 66% had combined modality treatment.

Stages ranged from IA to IV disease. The cohort was 85% white and 57% male. Most of the earlier patients had splenectomies (62% of entire cohort).

Events were recorded as relapse or progression of disease, death (due to HD, treatment related complications, injury, eg. accident or suicide) and second malignancies. Overall survival (OS) and event free survival (EFS) were calculated from the date of diagnosis.

Results

Median age at diagnosis was 14.4 years. Three hundred and sixteen survivors had a median follow-up of 15.1 years. The estimated 5-year OS was 92%, and the 20-year rate was 78%. The EFS at 5 years was 80% and dropped to 63% at 20 years. Failure from HD was 21% at both 10 and 20 years following treatment. Approximately 70% of those who failed did so by 3 years from treatment, while only one failure was seen after 10 years.

There were 119 first events in the entire cohort. Twenty-two had non-neoplastic deaths (infections, cardiac, accident or suicide), 9 had progressive disease, 21 had second cancers and 67 relapsed. All patients who had progressive disease succumbed to their disease. Twenty-six of those who relapsed have died of their disease or treatment related causes (one fatal infection and one cardiac disease).

Ten fatal infections were seen when all had splenectomies. Three were fatal infections during and due to HD treatment. Compared to national death rates, the standardized mortality ratio (SMR) was 18.4 (meaning it was 18.4 times more likely to have a fatal infection after HD treatment than the general population). Six deaths were due to cardiac disease (cardiac arrest from myocardial infarction in five or sudden death in one with uncontrolled hypothyroidism). All were males who died at a median of 19 years (median of 34 years old) after being treated with at least standard doses of radiation therapy and to an extended field. Three were also given Cytoxan. The SMR for death from cardiac causes was 22.2.

Second malignancies ranged from leukemias, non-Hodgkin's lymphoma, breast carcinomas, basal cell carcinomas and sarcomas. Leukemia had a shorter latency period than solid tumors (median 3.3 years versus 14.7 years, respectively). The estimated cumulative incidence of second malignancy in these study patients is 2% at 10 years and 12% at 20 years with a median latency of 14 years from the diagnosis of Hodgkin's disease. The incidence of malignancy after treatment for Hodgkin's disease in these patients was nearly 12 times the rate of the general population (for breast cancer and leukemias ? approximately 30 times the risk of the general population).

Conclusions

This article evaluates the long-term effects of treatment for Hodgkin's disease. It has demonstrated that patients' major mortality still remains their primary Hodgkin's disease, when it progresses or recurs. The second most significant cause of mortality is from second malignancies. Many prior publications have detailed the leukemogenic effects of and high incidence of breast carcinoma after Hodgkin's disease treatment. Noted above the latency period for leukemia is short, and the incidence plateaus after 5 ? 10 years. In a recent issue of the New England Journal of Medicine, the Late Effects Study Group reported a breast cancer incidence of 35% at 40 years post Hodgkin's disease treatment.

Fatal non-neoplastic treatment complications have also been the next major cause of mortality in this cohort. Cardiac disease and infections have nearly a 20 fold higher incidence of causing mortality than in the general population. This may not be the case currently since modern technology has improved methods of diagnosis and intervention in each area.

The authors have strongly recommended increased use of increased preventative measures against the sequelae of treatment. Pediatric oncologists should communicate with primary physicians about the type of treatment the childhood Hodgkin's disease survivor has undergone and potential adverse long-term effects. Standard screening guidelines should be intensified. The authors' recommendation has been for a baseline mammogram at age 25 and every 2 ? 3 years thereafter until 40 (then annually). Monthly breast self examinations along with twice yearly clinical exams after puberty were also recommended. Discussions should be made on lifestyle effects (tobacco use, diet, unprotected sun exposure, etc?) and their possible increased risk of deleterious synergistic effects with the prior Hodgkin's disease treatment.

The bottom-line is that most Hodgkin's disease patients usually have a good prognosis in being disease-free from their primary malignancy, but they and their subsequent physicians must always have a heightened awareness about the long term effects of their treatment.