Correspondence to: Dan L. Longo, MD, FACP, National Institute on Aging, National Institutes of Health, Gerontology Research Center, Box 09, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825 (e-mail: longod{at}grc.nia.nih.gov)
Near the end of "Butch Cassidy and the Sundance Kid," the heroes, surrounded by the Bolivian cavalry, are about to charge out to meet their fate when Butch asks Sundance, "You didnt see Lefors out there, did you?" Joe Lefors was the leader of the highly skilled posse that had tracked the two across much of North America. "Lefors? No," answers Sundance. "Good. For a moment there, I thought we were in trouble." Butch and Sundance did not accurately assess their risks, overestimating a small risk and underestimating a huge one.
Aleman et al. make two major points. First, radiation therapy may help people who do not achieve a complete response with chemotherapy alone. I agree. The first study to show this benefit was Southwest Oncology Group (SWOG) Study 7808 (1). Second, ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) cannot cure 85% of patients with Hodgkins disease. If ABVD alone were as good as MOPP (mechlorethamine, vincristine, procarbazine, prednisone) alone, it would achieve a 92% 10-year survival in early-stage disease (2). The study cited by the authors reports a 5-year survival of 82% in advanced-stage Hodgkins disease. If chemotherapy cannot cure 80%85% of all patients with Hodgkins disease, it comes close.
According to Surveillance, Epidemiology, and End Results (SEER)1 Program data (3), 5-year survival from Hodgkins disease for the period 1992 through 1998 was 84%. Despite this high level of successful treatment and the very long period of time that the most successful treatment tools have been available (radiation therapy since the 1960s, MOPP since 1970, ABVD since 1975), a paucity of long-term follow-up data exist to assess the impact of treatment on cured patients.
So far, perhaps because radiation therapists have done a better job of studying the impact of their treatment, the late effects of radiation therapy appear to be alarmingly serious and frequent. Ng et al. (4) showed that more of their patients treated for Hodgkins disease with radiation therapy have died from effects of the treatment (101 deaths) than have died from Hodgkins disease (60 deaths). They project about 10% of patients dying from second cancers and 3% from heart disease at 20 years after treatment, based on a median follow-up of only 12 years. Other studies have documented a second cancer risk of about 1% per year extending at least 25 years after treatment and possibly beyond.
Comparable data from patients treated with chemotherapy alone are even more sparse. Long-term follow-up of MOPP-treated patients does not suggest any late death or toxicity when chemotherapy alone is used. Patients receiving therapy with MOPP plus radiation have a 3% lifetime risk of acute leukemia, and all the risk occurs in the first decade after treatment (5). In patients who survive beyond 10 years after treatment, the risk of leukemia appears to be no greater than in people who never had Hodgkins disease. Other life-threatening late toxicities are anecdotal or unsupported by data from large groups of patients.
Data on ABVD-treated patients are virtually nonexistent other than occasional anecdotes. Acute toxicity appears lower with ABVD than with MOPP (the Cancer and Leukemia Group B [CALGB] mortality data quoted by Aleman et al. are several times higher than those reported from other centers). Of course, absence of evidence is not evidence of absence but, given more than 28 years of use, it would be surprising if a life-threatening late toxicity from ABVD affecting as many as 10% of the patients would have been missed.
No one contests the attribution of late toxicity to radiation therapy. However, the magnitude of the risk has not been widely appreciated. I doubt that any research protocol using radiation therapy actually informs the patients that their risk of dying from a radiation therapyrelated complication exceeds their risk of dying from Hodgkins disease. Instead, the approach has been to hope that lowering the dose of radiation therapy and/or limiting the field size will reduce the enormous late risks of second cancer and heart disease. This approach is not currently supported by data. Upton (6) demonstrated more than 40 years ago that the risk of cancer in animals receiving radiation follows a bell-shaped doseresponse curve. Thus, lowering radiation doses might actually increase the risk of a second cancer. In the absence of data, one cannot assume that lower doses of radiation therapy are safer.
We sorely need additional data on long-term effects of treatment in patients with Hodgkins disease. In the interim, on the basis of current information, the safest approach to managing these patients is to avoid the routine use of radiation therapy in all patients. Cure as many patients as you can with chemotherapy alone, reserving radiation therapy for two subgroups: those who fail to obtain a complete response to chemotherapy, and those with very large mediastinal masses. Patients who relapse should be rescued with high-dose chemotherapy (without radiation therapy, if possible) and autologous hematopoietic stem cells. This approach needs to be compared in large-scale studies with combined modality treatment approaches for response rate, relapse rate, complications, and survival. To continue with a treatment approach that exposes every patient to the risks of radiation therapy is to repeat the error in judgment of Butch and Sundance: underestimating a huge risk and overestimating a small one.
NOTES
1 Editors note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
REFERENCES
1 Fabian C, Dahlberg S, Miller T, Jones S, Grozea P, Morrison F, et al. Efficacy of low dose involved field (LDIF) XRT in producing and maintaining CR following PR induction with MOP-BAP chemotherapy in Hodgkins disease [abstract 987]. Proc ASCO 1989;8:253.
2 Longo DL, Glatstein E, Duffey PL, Young RC, Hubbard SM, Urba WJ, et al. Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkins disease: seven year results of a prospective randomized trial. J Clin Oncol 1991;9:90617.[Abstract]
3 Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:526.
4 Ng AK, Bernardo MP, Weller E, Backstrand KH, Silver B, Marcus KC, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkins disease treated at age 50 or younger. J Clin Oncol 2002;20:21018.
5 Blayney DW, Longo DL, Young RC, Greene MH, Hubbard SM, Postal MG, et al. Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkins disease. N Engl J Med 1987;316:7104.[Abstract]
6 Upton AC. Dose-response relation in radiation-induced cancer. Cancer Res 1961;21:71729.[ISI][Medline]
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