the Department of Radiation Oncology, Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC.

    ABSTRACT

    PURPOSE: The treatment of early-stage Hodgkin's disease (HD) has evolved from radiotherapy alone (RT) to combined-modality therapy (CMT) because of concerns about late adverse effects from high-dose subtotal nodal irradiation (STNI). However, there is little information regarding the long-term results of CMT programs that substantially reduce the dose and extent of radiation. In addition, lowering the total radiation dose may reduce the complication rate without compromising cure. This retrospective study compares the long-term results of STNI with CMT using modestly reduced RT dose in the treatment of early-stage HD.

    PATIENTS AND METHODS: Between 1982 and 2002, 111 patients with stage IA and IIA HD were treated definitively with RT (mean dose, 37.9 Gy); 70 patients were treated with CMT with low-dose involved-field radiotherapy (LDIFRT; mean dose, 25.5 Gy). Median follow-up was 11.7 years for RT patients and 8.1 years for the CMT group.

    RESULTS: There was a trend toward improved 20-year overall survival with CMT (83% v 70%; P = .405). No second cancers were observed in the CMT group; in the RT group the actuarial frequency of a second cancer was 16% at 20 years. There was no difference in the frequency of cardiac complications (9% v 6%, RT v CMT).

    CONCLUSION: In this retrospective review, CMT with LDIFRT was effective in curing early-stage HD and was not associated with an increase in second malignancies. For RT alone, a moderate dose seemed to reduce cardiac complications but did not lessen second malignancies compared with higher doses used historically.

    INTRODUCTION

    For approximately four decades, the ability of radiotherapy (RT) to cure the great majority of patients with early-stage Hodgkin's disease (HD) has been recognized.1-3 For the last 10 years, however, there have been increasing concerns about the long-term effects of such therapy. With longer follow-up, it has become apparent that RT as it is typically used for primary treatment of early-stage HD (subtotal nodal irradiation at doses of approximately 40 Gy) conveys a substantial risk for both second malignancies and cardiac disease.4-11 The relative risk (RR) for both of these occurrences ranges from 2 to 8. In several long-term series, deaths as a result of second cancers and heart disease now exceed those as a result of HD.4,7,9

    Because of these data and the well-recognized success of combination chemotherapy (CT) in treating advanced HD, a paradigm shift has occurred. The great majority of early-stage HD patients are now treated with combined-modality therapy (CMT).12,13 Many questions remain, however, regarding long-term efficacy and adverse effects of this approach, such as the appropriate duration of CT and the choice of RT field size and dose. Ongoing phase III trials, particularly from the German Hodgkin's Study Group, may resolve some of these issues.12

    At Duke University Medical Center, we have long been proponents of lesser doses of RT for HD, alone or in combination with CT.14 In this study we hypothesized that RT doses below 40 Gy would be curative for early-stage HD and might result in reduced cardiac complications and second malignancies, and that doses in the range of 20 to 30 Gy delivered only to sites of disease present before CT, in combination with CT, would be curative for the great majority of patients with early-stage HD, without increasing the risk of long-term complications.

    To test these hypotheses, we analyzed our 20-year experience treating early-stage HD, first with RT alone and now largely with CMT. Compared with larger cooperative group trials or registry data, this series has the advantage of a uniform treatment philosophy, rigorous quality control, detailed follow-up over long time periods, and analysis by the physicians caring for these patients, so that patterns of relapse, complications, and causes of death could be ascertained precisely. It has the obvious disadvantage of smaller numbers of patients for analysis.

    PATIENTS AND METHODS

    Between January 1982 and December 2002, 181 consecutive patients with stage IA and IIA HD were treated at our facility. Data were analyzed as of October 2004. One hundred eleven patients were treated with RT alone and 70 were treated with CT followed by low-dose involved-field radiation (LDIFRT; CMT). The patients were analyzed for prognostic factors, response to treatment, survival (failure free, cause specific, and overall), and complications. Patients who experienced relapse and subsequently received CT were analyzed based on their original treatment group.

    Patients were staged using the standard modalities of the time. Lymphangiogram and staging laparotomy were more common early in the study time interval. Gallium and positron emission tomography scans became more common in the latter 10 years. Chest and abdomen computed tomography imaging were employed throughout the study period.

    Response to treatment was based on physical examination and imaging studies. Complete response (CR) was defined as the disappearance of all signs of disease but also included patients with residual imaging abnormalities on computed tomography scans (who might be classified as having unconfirmed CR or partial response in other series). Those not achieving CR were classified as experiencing induction failures. The category partial response was not used. All patients experiencing induction failure had obvious progression of disease during treatment. There were no instances of patients with a positive gallium or positron emission tomography scan only at completion of induction therapy without positive findings on other imaging modalities.

    Patients were observed regularly for recurrence and for treatment-related complications. When complications occurred, they were graded using the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema.15

    Statistics

    Median follow-up for all patients was 10.1 years (range, 0.3 to 21.9 years) and 11.2 years for survivors (range, 1.9 to 21.9 years). Median follow-up for the RT group was 11.7 years; median follow-up was 8.1 years for the CMT group. Curves of overall survival (OS), failure-free survival (FFS), and cause-specific survival (CSS) were generated using Kaplan-Meier analysis.16 OS was calculated from time of diagnosis until death as a result of any cause. The end points for FFS were relapse of HD or failure to achieve a CR (with non-HD deaths censored). The end point for CSS was death as a result of HD. Statistical significance for prognostic variables between the RT and CMT groups were determined using the log-rank test,17 with the upper limit of significance defined as a P value of .05. Frequency of complications was analyzed using the 2 test.

    This study was approved by the Duke University Medical Center Institutional Review Board.

    RESULTS

    Patient Characteristics

    Characteristics for the RT and CMT groups are listed in Table 1. As expected, the CMT group contained a higher percentage of patients with prognostic factors generally regarded as adverse.

    Treatment

    For patients who received RT alone, the mean dose was 37.9 Gy (median, 38.6 Gy; range, 20.8 to 49.8 Gy), with 68% receiving less than 40 Gy. Standard RT treatment was 30 to 35 Gy to the primary field, with a smaller field boosted to a total dose of 35 to 40 Gy. For those who received CMT, the mean dose was 25.5 Gy (median, 24.3 Gy; range, 18 to 44 Gy), with 74% receiving less than 30 Gy.

    Details of CT are listed in Table 2. Two thirds of patients received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or in combination with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).

    Response to Treatment and Survival

    The complex pathways of outcome that HD patients follow are shown for the RT and CMT groups in Figures 1 and 2. In the RT group, 109 of the 111 patients entered remission. One patient died as a result of radiation pneumonitis during the course of treatment; one patient had progressive disease during radiation and eventually died as a result of HD. Of these 109 patients, 19 experienced relapse. Most of these received successful salvage CT, so that only six patients ultimately died as a result of HD; one patient remains alive with disease. Sixteen patients died as a result of other causes.

    In the CMT group, 64 of 70 patients entered CR. One patient died shortly after induction CT of bleomycin-related pulmonary toxicity; five patients experienced induction failure. Of these five, one received salvage RT and two received salvage bone marrow transplantation. The remaining two died as a result of HD. None of the three CMT patients who experienced relapse after CR received successful salvage therapy. At last follow-up, 62 CMT patients were alive without any evidence of disease, two had died as a result of HD, and two had died as a result of other causes.

    The survival data are shown in Figures 3, 4, and 5. FFS and CSS are essentially the same for the two groups (15-year FFS, 81% v 86%; 15-year CSS, 93% v 89% for RT and CMT groups, respectively). OS, however, shows an interesting pattern. At 10 years, OS is the same for both groups (85% for RT and 87% for CMT) but then seems to diverge, with the curve for the CMT group flattening, whereas the RT curve continues to decline (83% v 70% at 20 years). Thus far, the differences are not statistically significant (P = .405).

    Patterns of Relapse

    Twenty-six patients have experienced relapse: seven in the CMT group and 19 in the RT group (P = .478). In the RT group, three relapses occurred within the radiation field: 10 at distant sites, and six both within and outside the field. In the CMT group, four relapses occurred in field, two occurred out of field, and one had both in field and distant disease. All treatment failures occurred within 8 years of treatment.

    Causes of Death

    Thirty-one patients died overall (23 in the RT group and eight in the CMT group). Table 3 lists all causes of death. Only 11 of the deaths were as a result of HD (six in the RT group and five in the CMT group).

    In the RT group, deaths unrelated to HD were more common than deaths as a result of HD. Fifteen RT patients died as a result of non-HD related causes: two of direct treatment consequences (one from radiation pneumonitis and one from sepsis 4 years after splenectomy). Of the 15 deaths unrelated to HD, eight were a result of a second malignancy, three were a result of coronary artery disease (CAD), two were a result of pulmonary emboli, and one was the result of a perforated duodenal ulcer. One additional patient died at age 89 of uncertain causes 147 months after treatment for HD with no sign of relapse; death was attributed to old age.

    In the CMT group, there were five HD deaths, one treatment-related death as a result of pneumonitis, and two deaths as a result of cardiac disease (myocardial infarcts).

    Complications

    The type and frequency of significant late complications for the two groups are listed in Table 4. Eighty-nine patients developed a complication as a consequence of treatment, with fewer complications in the CMT group (P = .010). In the RT group, 63 patients developed 84 complications. In the CMT group, no patient developed more than one complication.

    Thyroid. Hypothyroidism requiring pharmacologic replacement was common, occurring in 43 patients (39%) receiving RT alone and 16 patients (23%) receiving CMT (P = .027). Five-, 10-, 15-, and 20-year actuarial incidence of hypothyroidism was 25%, 39%, 45%, and 45%, respectively. Hyperthyroidism was rare but did occur.

    Cardiac. Cardiac events occurred in nine patients (8%) in the RT group and five patients (7%) in the CMT group (P = .551). For all patients (RT and CMT combined), the actuarial incidence of a cardiac event at 5, 10, 15, and 20 years was 2%, 6%, 10%, and 16%.

    In the RT group, three of the nine cardiac events were fatal. These three patients were all older (61, 68, and 72 years of age); two of these patients had a prior cardiac history. The six patients who developed nonfatal cardiac events ranged from age 37 to 60 (mean age, 48 years at the time of the complication). Of the nine events in the RT group, two were valvular and the remaining seven were CAD.

    In the CMT group, two of five patients with cardiac events died as a result of myocardial infarcts (at ages 51 and 75 years). Of the three living patients, two had CAD and one had doxorubicin-related cardiomyopathy at ages 67, 67, and 37 years, respectively. One of these patients had not received chest RT.

    Pulmonary. Pulmonary events occurred in 6% and 2% of patients receiving RT and CMT, respectively. Three patients in the RT group developed fatal pulmonary events (one occurrence of radiation pneumonitis and two pulmonary emboli). The emboli occurred in a 75-year-old woman 9 months after treatment and in a 73-year-old man 124 months after treatment. In the CMT group, one patient died as a result of pneumonitis, which developed during CT. Other pulmonary complications were less than European Organisation for Research and Treatment of Cancer grade 3.

    Second malignancies. There was a significant difference between the RT and CMT groups with regard to second cancers. No second malignancies occurred in the CMT group, whereas 12 second (or third) cancers were diagnosed in 10 patients in the RT group (P = .014). Figure 6 shows the incidence of second malignancies; the actuarial frequency of a second cancer was 3%, 10%, 12%, and 16% at 5, 10, 15, and 20 years, respectively. Nine second cancers occurred within the RT field (three sarcomas, four non–small-cell lung cancers, one small-cell lung cancer, and one melanoma). Three second cancers occurred outside of the RT field (one prostate cancer, one squamous cell cancer of the lip, and one breast cancer [this patient received only infradiaphragmatic radiation]). The lip cancer was not fatal; the two patients with breast and prostate cancer initially were cured of those malignancies but later died as a result of sarcoma and non–small-cell lung cancer, respectively. Four of the five patients who developed lung cancer had been smokers.

    Other. A wide variety of other complications were also more common in the RT group (P = .034). In the RT group, five patients developed small bowel obstruction, two had herpes zoster, and one patient died as a result of bacterial sepsis. The bowel obstructions and infectious complications all occurred in patients who had undergone splenectomy. One patient developed a fatal duodenal ulcer and one had significant dental problems. In the CMT group, two pediatric patients noted growth delay and one patient developed arm edema.

    DISCUSSION

    This study reaffirms the efficacy of both RT alone and CMT in the treatment of early-stage HD, with regard to cure. CSS and FFS data are similar for the two groups. For patients receiving RT alone, the 15-year FFS and CSS are 80% and 93%, respectively, reflecting the ability of CT to provide salvage therapy to patients initially treated with RT who subsequently experience relapse.

    These data must be considered with the caution that, as a retrospective study, the two groups were not randomly assigned and follow-up is shorter for the CMT group. In addition, although patients in both groups were treated by a small number of physicians at the same institution, there was some variation in the RT dose and CT (when used).

    However, our data are comparable to recent updates from Stanford University and Harvard University, as well as a 1998 meta-analysis.18-20 Generally, patients treated with RT alone have 10-year OS ranging from 75% to 95% and FFS ranging from 70% to 85%, depending on the type of patients (favorable v unfavorable prognostic factors). Patients treated initially with CMT tend to have less frequent relapses compared with those initially receiving RT, with FFS in the range of 85% to 90%. However, OS generally is equivalent because of salvage CT, at least in the first 10 years. With follow-up beyond 10 years, significant complications generally attributable to full-dose extended-field radiotherapy become apparent, most notably second malignant tumors and heart disease.

    An increased frequency of second malignant neoplasms has been reported by a number of investigators.4,6,7,9-11,21,22 In general, the observed actuarial frequency has been approximately 1% per year, with RR ranging from 2 to 8. Most reports show an increased risk for patients treated at a younger age.22-24 A wide variety of second cancers are observed but are most often those common in the general population. Cocarcinogens may also be important. Smokers reportedly have a risk 20 times that of nonsmokers for treatment-related lung cancer.25

    Most published reports also show an approximately equal or even increased risk of a second cancer from CMT.26,27 However, few have used LDIFRT, as in this study. Furthermore, many reports of increased second cancers after CMT include patients treated initially with RT alone who then experienced relapse and received CT, a situation particularly prone to the development of a second cancer.27

    The frequency of a second malignancy in patients treated with RT alone in this study was 12% and 16% at 15 and 20 years, respectively—comparable to what has been reported in the literature despite somewhat smaller doses of RT used in our study. No second cancers were observed, however, among the CMT patients who received LDIFRT.

    Similar observations were made by the group at Yale University.28 For patients treated with LDIFRT, they described an actuarial frequency of second malignant tumors of 5.3% at both 15 and 20 years, and an RR of 1.5, which is not statistically significantly different from the control population. Most patients in this series had been treated with MOPP CT or a related regimen. The 16 second malignant tumors included nine patients with leukemia or myelodysplastic syndrome; thus the frequency of second solid tumors was quite low.

    Travis et al29 have suggested that the risk of treatment-related breast cancer may be reduced by therapies that suppress ovarian function. In our series, only six of 26 premenopausal women sustained permanent ovarian ablation from CT; thus in most of our patients, ovarian suppression did not play a major role in the failure to develop a second cancer.

    A large recent study from Greece analyzed 368 patients with early-stage HD treated with CMT using LDIFRT.30 With a median follow-up of 84 months, eight leukemias and nine second solid tumors were observed (none of the nine second tumors occurred within the radiation field). Six of eight leukemias occurred in patients treated with MOPP.

    Bonadonna et al31 compared ABVD plus subtotal nodal irradiation versus ABVD plus involved-field RT (IFRT) in 136 patients. Full doses of RT were used in both groups. With a median follow-up of 9 years, no second malignant tumors were observed in the IFRT group, suggesting the importance of volume irradiated.

    The German Hodgkin's Study Group32 compared IFRT with extended-field radiotherapy after four cycles of cyclophosphamide, vincristine, procarbazine, and prednisone plus ABVD. In both arms, patients received 30 Gy plus a 10-Gy boost to bulky disease. With a median observation time of 54 months, the frequency of second malignancies was similar (4.5% in patients receiving extended-field radiotherapy; 2.8% in patients receiving IFRT).

    Collectively, these trials (including our own) suggest a low probability of second malignancy when treating early-stage HD with a doxorubicin-containing regimen and low-dose IFRT.

    The second major complication issue is cardiac disease. Numerous reports have also appeared in the literature regarding this occurrence.5,8,33,34 The RR of a fatal cardiac complication ranges from 2 to 6. Data usually are reported for deaths due to heart disease. Data for any cardiac event are less common. Fatal cardiac events seem primarily related to mediastinal dose. In a large series at Stanford University, no increased risk for cardiac death was seen with doses below 30 Gy.8

    In our series, nine cardiac events occurred in the RT group and five cardiac events occurred in the CMT group, with three fatalities in the former and two in the latter. Two events in the RT group were valvular heart disease, which is a reported complication of radiotherapy.35 The other complications were CAD. The total number of events is small, precluding any definitive statement regarding risk for fatal cardiac events in either the CMT or RT groups.

    Some authors have suggested CT alone for early-stage HD, and a recent phase III trial was reported.36,37 A full discussion of this issue is beyond the scope of this article. Certainly, it is possible that CT alone is sufficient for selected patients. However, the excellent results that are achieved with CMT for early-stage disease must be kept in mind. The addition of LDIFRT to CT does not seem to add significant morbidity and mortality. In view of the difficulties in administering salvage therapy to patients who experience relapse after CT alone,38 trials of CT alone for early-stage HD must be undertaken cautiously.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: John P. Kirkpatrick, Robert W. Clough, Leonard R. Prosnitz

    Administrative support: Robert W. Clough, Jon P. Gockerman, Joseph O. Moore, Leonard R. Prosnitz

    Provision of study materials or patients: Robert G. Prosnitz, Jon P. Gockerman, Joseph O. Moore, Leonard R. Prosnitz

    Collection and assembly of data: Bridget F. Koontz, John P. Kirkpatrick, Robert W. Clough, Leonard R. Prosnitz

    Data analysis and interpretation: Bridget F. Koontz, Robert W. Clough, Leonard R. Prosnitz

    Manuscript writing: Bridget F. Koontz, John P. Kirkpatrick, Robert G. Prosnitz, Leonard R. Prosnitz

    Final approval of manuscript: Bridget F. Koontz, Leonard R. Prosnitz

    NOTES

    Presented at the American Radium Society (ARS) meeting, May 4, 2005, Barcelona, Spain. B.F.K. was the recipient of an ARS Young Oncologist Essay Award.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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