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Radiation for Early-Stage Hodgkin’s Disease?

Yale Cancer Center New Haven, CT

To the Editor:Ng et al¹ present a Sophist argument for the continued use of radiation in early-stage Hodgkin’s disease based on a model constructed with antiquated studies and nonvalidated assumptions. For example, their baseline estimates suggest that the adjusted risk of second tumors is nearly the same after chemotherapy or radiation but that the risk is substantially higher after combined-modality therapy (CMT). In fact, there are no data to suggest that currently used chemotherapy or chemotherapy with or without low-dose radiation is associated with an increased relative risk of solid tumors, whereas abundant information points to higher doses and larger volumes of radiation as the main culprit in causing late solid tumors. For example, Salloum et al² showed that while chemotherapy followed by low-dose, involved-field radiation was not associated with a significant increase in the relative risk for second tumors, there was a significantly increased risk in the group that received extended-field, standard-dose radiation. Similarly, data from Stanford showed that 93% of tumors developed in areas that had been irradiated to at least 35 Gy, and there were no cases of breast cancer in patients who received a dose of radiation less than 40 Gy.³ The article’s assumptions on cardiac mortality after CMT also are incorrect if lower doses of adjuvant radiation are used, because an increase in cardiac mortality is only demonstrable in patients who have received more than 30 Gy to the mediastinum.⁴ In recognition of the dangers posed by higher doses of radiation as well as consistent randomized data showing the superiority of CMT compared with extended-field radiation in disease-free survival, current ongoing studies from the European Organization for the Research and Treatment of Cancer and the German Hodgkin’s Study Group no longer even include an arm that receives standard extended-field radiation. Importantly, the combined results of both studies should help us to determine the appropriate duration of chemotherapy as well as the dose of adjuvant, involved-field radiation. Thus, while mantle with or without para-aortic radiation remains an effective treatment and an attractive option for some patients, it seems inappropriate to recommend it based on a spurious model.

REFERENCES

1. Ng AK, Weeks JC, Mauch PM, et al: Decision analysis on alternative treatment strategies for favorable-prognosis, early-stage Hodgkin’s disease. J Clin Oncol 17:3577-3585, 1999[Abstract/Free Full Text]

2. Salloum E, Doria R, Schubert W, et al: Second solid tumors in patients with Hodgkin’s disease cured after radiation or chemotherapy plus adjuvant low-dose radiation. J Clin Oncol 14:2435-2443, 1996[Abstract]

3. Wolden SL, Lamborn KR, Cleary SF, et al: Second cancers following pediatric Hodgkin’s disease. J Clin Oncol 16:536-544, 1998[Abstract]

4. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 270:1949-1955, 1993[Abstract]

Response

Brigham and Women’s Hospital
Dana-Farber Cancer Institute
Harvard Joint Center for Radiation Therapy
Harvard School of Public Health Boston, MA

In Reply:The conclusions of our decision analysis are based on a decision-analytic model that has been well validated by long-term clinical data, as outlined in our article.¹ Methods of decision analysis are most useful under circumstances of uncertainty or lack of available data. Sensitivity analysis can be performed by varying uncertain variables in the model to determine how the conclusions are, if at all, affected. It also allows identification of crucial areas that drive the decision of the optimal strategy, and areas that may need more attention and further investigation. Although a large, carefully designed, randomized controlled trial is undoubtedly still considered the source of first-class evidence, a well-validated decision model, which can essentially be viewed as a computer-simulated randomized study, can be a powerful tool in evaluating clinical questions, especially when the conduction of an adequately powered phase III study is not always feasible. Our analysis, however, offered more than just a simulation of a randomized study. Our results in fact suggest that it may not be worthwhile to invest in another randomized controlled trial comparing mantle and para-aortic (MPA) radiation therapy with combined-modality therapy (CMT) in clinically staged, early-stage patients, because of the inability to clearly demonstrate a superior treatment strategy even by improving the uncertainties associated with the treatment-related variables.

The estimates for second malignancy risks used in our model needed to be based on data in which some of the treatment methods used were outdated, because in order to have any meaningful second tumor data, particularly solid tumors, long follow-up time is needed. This is one of the situations in which sensitivity analysis is useful. Because of the uncertainty associated with the solid tumor risks after different treatment modalities, we performed a sensitivity analysis to assess how the treatment choices are affected by changing the absolute risks over wide ranges. We reported in our Results that the decision between MPA radiation therapy and CMT in pathologically staged patients is not affected by changes in values of any of the variables in the model. On the other hand, for clinically staged patients, as shown in Table 3, the solid tumor risks after CMT only needed to be slightly lowered to a value that may very well be within a clinically plausible range for CMT to become favored over MPA radiation therapy. This type of analysis is helpful in showing what type of threshold value is needed in order for the optimal strategy to change from one to another. We are still somewhat in the dark as to the actual magnitude of solid tumor risks using modern chemotherapy regimens (either given alone or in conjunction with low-dose or conventional-dose radiation therapy). Although radiation therapy clearly increases the long-term risk of solid tumor development, it is presumptuous to ignore the contribution of chemotherapy to secondary solid tumors. Studies have shown a significantly increased risk for solid tumor, particularly lung cancer, after treatment with methotrexate/vincristine/procarbazine/prednisone alone.^2-4 We are not aware of any data that specifically address the risk of solid tumor after doxorubicin/bleomycin/vincristine/dacarbazine alone, and longer follow-up is needed to know whether it is indeed a safe regimen.

Cardiac mortality is no longer as great a concern with the use of modern radiation therapy techniques.⁵ For pathologically staged patients, as noted above, none of the variables in the model, including cardiac mortality, had an impact on the decision between MPA radiation therapy and CMT. For clinically staged patients, if the cardiac mortality associated with CMT is lowered to 17/10,000 person-years while that associated with MPA radiation therapy remains at 20/10,000 person-years, the optimal strategy changes from MPA radiation therapy to CMT. However, the long-term toxicities of chemotherapeutic agents known to have dose-related cardiotoxicity, and their potential synergistic effects with radiotherapy, are yet to be defined.

Although the current style is to use CMT in early-stage Hodgkin’s disease, and most no longer advocate use of extended-field radiation therapy because of the large field sizes involved, there are very little data that compare the late toxicities associated with the two approaches. We look forward to results from the ongoing European Organization for the Research and Treatment of Cancer and German Hodgkin’s Study Group trials, which will provide us with efficacy data in the next 5 years, comparing different chemotherapy and radiation doses, but it will be at least 10 to 15 years before late toxicity results will be available. Finally, the results of our model do not "argue for" use of radiation therapy alone over CMT in early-stage Hodgkin’s disease. The model merely reinforces the lack of evidence for any meaningful survival differences between the two treatment strategies.

REFERENCES

1. Ng A, Weeks J, Mauch P, et al: Laparotomy versus no laparotomy in the management of early-stage, favorable prognosis Hodgkin’s disease. J Clin Oncol 17:241-252, 1999[Abstract/Free Full Text]

2. Swerdlow A, Douglas A, Vaughan Hudson G, et al: Risk of second primary cancer after Hodgkin’s disease in patients in the British National Lymphoma Investigation: Relationships to host factors, histology and stage of Hodgkin’s disease, and splenectomy. Br J Cancer 68:1006-1011, 1993[Medline]

3. Swerdlow A, Barber J, Horwich A, et al: Second malignancy in patients with Hodgkin’s disease treated at the Royal Marsden Hospital. Br J Cancer 75:116-123, 1997[Medline]

4. Kaldor J, Day N, Bell J, et al: Lung cancer following Hodgkin’s disease: A case-control study. Br J Cancer 52:677-681, 1992

5. Constine L, Schwartz R, Savage D, et al: Cardiac function, perfusion and morbidity in irradiated long-term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 39:897-906, 1997[Medline]

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