Correspondence to: Dan L. Longo, M.D., F.A.C.P., National Institute on Aging, Gerontology Research Center, Box 09, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825 (e-mail: longod{at}grc.nia.nih.gov).
Science is simply common sense at its bestthat is, rigidly accurate in observation, and merciless to fallacy in logic.
Thomas H. Huxley
Controversy is an integral part of nearly all major progress in science and medicine. One exception is the development of an active therapy where no previous therapy was effective. A field generally has no problem adopting a novel active treatment. However, when newer approaches are found that are either safer or more effective or both, they sometimes have trouble displacing an established approach. And so it is with the role of radiation therapy in the treatment of Hodgkins disease.
Historically, radiation therapy was the first curative therapy for Hodgkins disease. Technical innovations in radiation equipment and clever designs of radiation fields brought us to the point where patients without B symptoms and with disease localized to one side of the diaphragm could have the Hodgkins disease permanently eradicated in 80%85% of cases. Patients with B symptoms and with more advanced disease fared considerably worse.
In the 1960s and 1970s, genuine advances were made in combination chemotherapy programs that were first tested and confirmed to be active in the group of patients who could not be optimally treated by radiation therapy, namely those with B symptoms and advanced disease. The efficacy of chemotherapy in advanced-stage disease was comparable to the efficacy of radiation therapy in early-stage disease such that by the 1980s, stage was no longer a prognostic factor. Subsequently, the chemotherapy programs were tested in patients usually treated with radiation therapy and were found to be at least as effective as radiation therapy at eliminating the Hodgkins disease.
As patients began to survive longer after the successful treatment of their Hodgkins disease, other problems occurred in these treated patients at a greater frequency than one would expect in an age-matched population that had not been treated for Hodgkins disease. Fortunately, substantial numbers of long-term survivors were produced by radiation therapy and by combination chemotherapy, so it was possible to ascertain which problems were related to the underlying disease and which were related to treatment. For example, an increased risk of B-cell lymphoma, often involving the gastrointestinal tract, was noted in patients treated with radiation therapy, chemotherapy, or both (1); thus, this second malignancy is felt to be a consequence of the Hodgkins disease and its effects on the host rather than a consequence of treatment.
Some consequences have been attributable to chemotherapy specifically. MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, and prednisone) and other alkylating agent-based regimens induce infertility in nearly all men (2) and in women treated after age 30 years and induce premature menopause in those women who do recover their menses after treatment (3). In addition, patients who received MOPP (or a similar regimen) and radiation therapy have an approximately 3% lifetime risk of developing acute leukemia (4), a treatment-related complication that is universally fatal. These late toxicities, together with greater acute toxicity during administration, have led to the virtual replacement of alkylating agent-based regimens with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine), a regimen as active as MOPP (5) but with a nearly spotless record of late toxicityspecifically, it has negligible effects on fertility (6), a very low risk of combined modality acute leukemia (7), and essentially no leukemia when used as a single modality.
By contrast, a number of late effects have been attributed to radiation therapy. Many of these effects are nuisances and quality-of-life issues, such as the poor dentition that arises from salivary gland dysfunction [reviewed in (8)]. However, two groups of radiation therapy complications are life-threatening. Patients who receive mantle field radiation therapy have a threefold increased risk of fatal myocardial infarction (9). In addition, patients treated with radiation therapy have a continuously increasing risk of developing a second solid tumorthe risk is approximately 1% per year (although such tumors dont start appearing until at least 5 years after treatment)and approximately 25% of survivors have been diagnosed with a second malignancy by 25 years after the treatment of their Hodgkins disease (10). From the longest follow-up data [for example, (11)], no hint of a plateau in second cancer incidence can be discerned; the cancers just keep on increasing. The second cancers include lung cancer, melanoma, sarcomas, thyroid and, notably, breast cancer, which is the subject of an important study in this issue of the Journal by van Leeuwen et al. (12).
In one of the most careful analyses of second breast cancer after Hodgkins disease therapy to date, van Leeuwen et al. conducted a casecontrol study of women treated for Hodgkins disease involving 48 women who developed breast cancer and 175 matched controls who did not. The data confirm the previously reported increased risk of breast cancer in women treated with radiation therapy for Hodgkins disease. However, two new findings of great importance also emerged from the study.
First, the induction of premature menopause by MOPP-like alkylating agent-based combination chemotherapy appeared protective against the development of radiation-induced second breast cancers. Although the risk of breast cancer did not decrease to that of an age-matched normal population, the increased risk of breast cancer in women treated with combined modality therapy was only about half that of women treated with radiation therapy alone. These data make a strong argument for radiation therapy as the initiator and physiologic sex hormones as promoters of secondary breast cancer. An unacceptable toxicity of chemotherapy, infertility, ameliorates an unacceptable toxicity from radiation therapy, breast cancer.
Second, the authors performed a thorough analysis of the association of radiation dose with the risk of second breast cancers. They found that the breast cancer risk increased proportionally with the radiation dose. This is the first demonstration of a doserisk relationship in radiation-induced breast cancer. The study is small, but the findings are robust.
Unfortunately, it is possible to misunderstand these data. Advocates of combined modality therapy for all stages of Hodgkins disease (which is increasingly the common practice in the United States) will suggest that combined modality therapy lowers this important radiation toxicity and, therefore, provides an argument for combined modality treatment. However, such a conclusion rests on older forms of chemotherapy. MOPP-like chemotherapy, which is toxic to the ovary, appears to reduce the risk of radiation-induced breast cancer, but it cannot be assumed that the commonly used ABVD chemotherapy would have the same effects, especially in light of its lack of effects on fertility. One cannot extrapolate these data to combined modality regimens that use ABVD chemotherapy. And certainly no one would suggest going back to the alkylating agent-based regimens to sacrifice a womans fertility merely to prevent a radiation therapy toxicity.
A second misinterpretation of the data might occur if physicians assumed the doseeffect relationship to imply that so-called low-dose radiation therapy (20 Gy, which is used as a component of combined modality therapy in the majority of newly diagnosed Hodgkins disease patients today) does not increase the risk of breast cancer. In fact, it has been well established that even doses of radiation as low as 4 Gy substantially increase the risk of breast cancer (13). Even diagnostic levels of radiation increase the risk of breast cancer (14). Indeed, van Leeuwen et al. found that the risk appears to increase linearly at least from 4 to 40 Gy, and no evidence exists for a reduced risk from radiation delivered at therapeutic levels for Hodgkins disease. The only dose of radiation therapy that is not associated with an increased risk of breast cancer is zero.
Perhaps no practice in medicine has been studied more thoroughly than combined modality therapy for Hodgkins disease. Both on a study-by-study level and by meta-analysis, combined modality therapy does not improve survival of patients with Hodgkins disease compared with chemotherapy alone in advanced disease (15) or compared with radiation therapy alone in early-stage disease (16). Yet nearly every new study involves combined modality treatment. Even studies that claim to be evaluating new chemotherapy regimens often require the majority of patients to receive radiation therapy to previously involved nodal sites of disease (17).
The prevailing thinking seems to be as follows: if we give combined modality therapy we can cut back a little on the radiation dose and cut back a little on the chemotherapy cycles, and that should preserve the antitumor effects and minimize the toxicity. Au contraire. No dose of radiation therapy is without life-threatening late sequelae, and six cycles of ABVD alone appears to be extremely effective in all stages of Hodgkins disease without any reported life-threatening toxicity.
A modernization of the "first do no harm" axiom would be to use the minimal therapy necessary to cure the disease. Following that principle, we should reserve radiation therapy for that small subset of patients who require it to control their Hodgkins disease, namely patients with very large mediastinal masses and patients who obtain only a partial response from chemotherapy. Radiation therapy is an important component of the treatment of many malignancies, and we should salute its historical role in the treatment of Hodgkins disease. However, its late effects have made it less useful in treatment of a cancer that can be cured without it in 80%85% of patients. The safest and least therapy that has the best chance of curing Hodgkins disease with the fewest acute and chronic toxicities is ABVD chemotherapy, and it should be the treatment of choice for all stages of Hodgkins disease.
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