Contribution of three-dimensional conformal intensity-modulated radiation therapy for women affected by bulky stage II supradiaphragmatic Hodgkin disease

Early-stage Hodgkin lymphoma treated with a combination of chemotherapy and radiotherapy has an excellent clinical outcome, with overall survival reaching 90% [1‐4]. However, late effects can dramatically affect the quality of life or be life-threatening in these survivors [5]. These late complications, including cardiovascular effects and secondary cancer, are due to large radiation doses and fields and also to chemotherapy, both of which lead to cardiovascular toxicity [6, 7] and increase the risk of secondary cancer [6, 8‐11]. Depending on the follow-up, the incidence rate ranges from 4.6% to 20% [10, 12‐17]. The incidence of hematologic cancers is the most important, with standardized incidence ratios (SIRs) between 1.5 and 30 times higher than for solid tumors [10, 11, 18]. The occurrence of a secondary cancer is more frequent for women than men [10, 19], mainly because of secondary breast cancers. Several risk factors have been associated with radiation-induced breast cancers, such as the age at treatment [20], higher irradiation dose [21, 22] and the irradiation volumes [16, 22].

Because radiotherapy remains a cornerstone in the treatment of Hodgkin lymphoma, some improvements have been developed recently to decrease the risk of side effects: i) decreasing the delivered dose, ii) irradiating the initially involved fields, and iii) using modern radiation techniques, such as intensity-modulated radiation therapy (IMRT) [2, 3, 23‐26]. The decrease in the irradiated volume in the breasts could potentially decrease the risk of secondary breast cancer, thereby improving the prognosis in these patients [8]. We propose to demonstrate that using the helical tomotherapy HiArt system can achieve both the goal of improving the dose distribution to large or bulky PTV and that of sparing organs at risk compared with 3D radiation therapy (3D-RT) in young women who are particularly at risk for secondary breast cancer. We present the results of this study comparing dosimetric plans for 3D-conformal radiation therapy (3D-CRT) and for IMRT by helical tomotherapy (IMRT-HT) in women with Hodgkin disease.

The median follow-up of the 13 patients was 23 months (range: 16–48). The median CTV and PTV were 272 mL (range: 155–950) and 970 mL (range: 512–2666), respectively. We observed two relapses at 15 and 28 months. The first relapse arose in a non-irradiated site (with no fixation of ¹⁸FDG and no adenopathy in the first exam of the site), and the patient was treated with a new irradiation. The patient was alive at 48 months. The second relapse appeared at the irradiated site and was treated by chemotherapy. The two-year progression-free survival was 91.6%, and the 2- and 3-year overall survivals were 100%. The median number of LCVE controls was 2 (1–4). No cardiac dysfunction was observed, with a mean LVEF of 63% (60–70) before irradiation and 63% (55–72) at the last control. The median number of LFT was 2 (1–4). No change of the LFT at 1 year was observed, and no patient complained of breath dysfunction.

This study reports a dosimetric comparison of a series of 13 women with bulky early-stage Hodgkin lymphoma treated with INRT and IMRT using tomotherapy. This study is the third publication comparing IMRT and conformal 3D radiotherapy; a case report previously compared both techniques [41], and one series of 10 women comparing four irradiation plans was recently published [8]. In our series, the volumes were large (bulky tumors) and needed extensive radiation fields, leading to a difficult conformal treatment able to spare numerous organs at risk, such as the heart, lung, thyroid and spine. All plan comparisons were performed before the treatment, and overall the patients were treated with IMRT. Because of the excellent outcome of the patients with early-stage Hodgkin disease and the known risk of ionizing radiation, decreasing the treatment was performed. A decrease in the total dose was the first step [23]; the second step was the adaptation of the irradiated volume from the involved fields to the initial involved node areas [3, 29, 30, 42‐44]. A “Mantelet” field was progressively avoided. The last step to improve the dose distribution was the use of IMRT or proton therapy or of respiratory gating [24, 25, 30, 45‐49]. All these techniques aim to achieve better homogeneity of the target dose distribution, which we proved in our study as the conformity index was reduced by a factor of 2 between 3D-CRT and IMRT.

However, the treatment remains challenging. A recently published trial demonstrated that a combination of ABVD and radiotherapy improved disease-free survival compared with ABVD alone but that the overall survival was worse in the combination group [50]. The main reason for the increase in mortality with the combination treatment was the excess of causes of death other than Hodgkin disease in the combined treatment group [50]. The doses and radiation technique could be responsible for this loss of survival. However, in that study, the RT-fields used in the RT-arm were outdated, i.e., subtotal nodal irradiation, which is known to contribute to increase morbidity and mortality from cardio-toxicity and secondary cancers. Moreover, many of the deaths in the radiotherapy arm were clearly unrelated to radiotherapy [50]. A meta-analysis that pooled the results of trials comparing the combination of chemotherapy and radiotherapy and the same chemotherapy regimens alone showed that combined treatment was associated with a better disease-free survival and a higher survival rate. However, the chemotherapy schedules were not considered optimal [51].

The main causes of death after Hodgkin disease treatment include secondary cancers and lung and heart dysfunction. The cardiac pathologies induced by radiation are highly variable [52], and the delivered dose to the heart is a major factor of these complications [53, 54]. However, the dose relationship that induces cardiac morbidity and cancer is a matter of debate as there is sufficient evidence to suggest a linear dose–response for cardiac mortality [55], with doses < 5 Gy most likely being less at risk than higher doses [56]. Decreasing the dose to the heart is a major goal, which can be reached with IMRT, even if the NTCP (normal tissue complication probability) is low at these doses [41].

For solid secondary neoplasms, breast and lung cancers are the most frequent types of malignant tumor [10, 57]. The increase in the risk for breast cancer has been well described [58‐64]. The roles of dose [64], volume [65] and age [10, 16] are well known. The risk of secondary lung cancer is related to the combined treatment and, specifically for radiotherapy, the function of the dose and irradiated volume [66, 67]. The dose–response relationships for secondary cancers also suggest a linear dose–response, with the exception of thyroid cancer [57, 64].

The follow-up of the patients in this series could be considered to be short, but the risk of relapse is always quick; although we treated large tumors, we did not observe an increase in the relapse rate. Paumier et al. published comparable results with a longer follow-up [24, 25]. Our series is the first study of women treated with tomotherapy IMRT, and we can suggest some conclusions. As expected, IMRT with tomotherapy decreased the median conformity index by twice, from 2.4 for 3D–CRT to 1.2 with IMRT, a highly significant difference. IMRT is feasible and well tolerated in terms of clinical tolerance and heart and pulmonary functions. Large doses were clearly demonstrated as responsible for the complications after Hodgkin disease. The dose distributions were clearly improved by IMRT. This improvement was obtained mainly for the higher doses that cause heart morbidity and induce cancer. For the breasts, doses greater than 20 Gy are at risk of inducing cancer. Van Leeuwen et al. showed a significantly higher breast cancer risk in patients receiving radiotherapy alone at a dose of ≥ 24 Gy [64]. Bhatia et al. also demonstrated that young patients given < 20 Gy to the breasts did not have a significantly higher risk of breast cancer compared with the controls [10]. The V_20Gy, V_25Gy and V_30Gy were 1.5, 2.5 and 3.5 times lower, respectively, for IMRT than for 3D-CRT. For the lung tissues, the V_20Gy and V_30Gy were 2 times and 4.5 times lower, respectively, for IMRT than for 3D-CRT. For the heart, the V_20Gy and V_30Gy were 1.4 and 2 times lower, respectively, for IMRT than for 3D-CRT. For the esophagus, the V_35Gy was 1.7 lower for IMRT than for 3D-CRT, and for the thyroid, the V_30Gy was 1.2 lower for IMRT. Based on this list of classical constraints to critical organs, we demonstrated that IMRT can deliver a higher dose to the PTV and successfully decrease the highest dose in all the critical organs at risk of secondary cancer or dysfunction. The values of lung V_20Gy and heart V_30Gy were comparable with those previously published [8, 24, 41, 48].

However, controlling the secondary appearance of breast cancer by ultrasound CT and magnetic resonance imaging beginning at least five to eight years after the completion of radiation therapy is recommended. For lung cancer, preventing smoking is recommended. Interestingly, the risk of mortality using the estimated 20-year survival for patients with solid secondary cancer was shown to be 72% compared with 80% for those who did not develop any secondary cancer, which was not significantly different [57]. Furthermore, a recently published study reported that conservative treatment followed by irradiation can be efficiently performed in patients with breast cancer after Hodgkin disease [68].

Some discussions have criticized the risk of secondary cancer with respect to the “bath” of low-to-moderate doses delivered to the patient’s body [49]. However, some arguments can reassure patients and physicians. The first complication in Hodgkin disease in cases similar to those in our series is cardiac side effects up to cardiac death. The decrease in the dose in this organ at risk is assumed to decrease the chance of this type of death or morbidity. The same conclusion can be reached for lung function complications. Some authors have translated the decrease in the dose in NTCP (normal tissue complication probabilities), showing the clear impact of the decrease in the dose in lowering complications [41, 48].

Notably, the question of radiation-induced carcinogenesis remains controversial. In particular, the phenomenon of radiation hormesis at low radiation doses has attracted increasing attention [69]. Radiation hormesis is considered to be an adaptive response to the external stress of radiation exposure and is manifested in several cell lines in the form of reduced chromosomal aberrations and increased longevity.

Recently, Weber et al. showed by calculating the excess relative risk that decreasing the irradiation fields leads to a dramatic decrease in radiation-induced cancer. However, for comparable irradiation fields, the risks appeared higher for IMRT than for 3D-CRT. These calculations have been performed with linear and non-linear models, taking into account mainly the low dose volume risk [8]. However, two major clinical series for breast cancer demonstrated a dose-risk relationship [63, 64]. Furthermore, clinical data have suggested that only a minority of tumors developed inside (<10%) or outside (11%) the PTV [70, 71]. Rather, the majority of secondary cancers have been observed within the margin of the PTV [71] or at the field periphery [71, 72]. This region of the dose or penumbra is rarely studied in the dose distribution and can highly vary according to the photon energy used for irradiation. This observation could suggest that radiation-induced cell death becomes dominant over carcinogenic mutations radiation dose increases. This hypothesis, thus, appears to contrast with the dose reduction developed recently and to not correlate with the clinical observation of Kirova et al., who showed that the dose levels at which secondary cancers are most likely to occur have not yet been clearly established. The authors showed that most reported cases of radiation-induced sarcomas after breast irradiation occurred at sites that had received doses of 60–80 Gy, with a minimal dose of 10 Gy [9].

Extrapolating the risk of radiation-induced carcinogenesis is an uncertain exercise. Data on radiation carcinogenesis are mainly derived from retrospective studies, with variable patient populations exposed to variable radiation doses with dosimetry that is often uncertain. In addition, a heightened risk of secondary malignancies may exist in these patients. In an extensive review of the literature, Suit et al. concluded that the experimentally observed heterogeneity in the induced secondary cancer risk indicated a large genetic role in the determination of risk in the individual [73]. Furthermore, due to the quite large and undefined heterogeneity in the patient populations studied, no precise quantification of the risk of radiation-induced secondary cancer is available at present [73]. Most of these series had difficulties in differentiating the pathological subtypes and dose distributions, which seems to be important data to take into account to ameliorate the predictive analysis. With respect to the risk of complications, a large series of children treated with ionizing radiation demonstrated that the risk of cancer induction was not clearly related to the dose. One third of those cancers arose in areas that received a low dose, one third in areas receiving a moderate doses, and one third in areas receiving a high dose [74]. In our series, specially conducted in women, we showed that IMRT was able to significantly avoid large tissue volumes receiving moderate to large doses at the cost of increasing the volume receiving a low dose. However, the integral dose is not increased by the IMRT technique with tomotherapy compared with 3D-CRT, as shown previously [41, 75].

Another factor of confusion could have appeared because decreasing the dose to non-tumoral tissues will likely lead to a decrease in radiation-related non-cancerous disease. Thus, the absolute number of cancers could increase in the future by improving the survival of the global population.

A better understanding of the dose distributions and inducible secondary cancer for each organ is necessary to perform dosimetry with real dose constraints to protect against the development of secondary cancers. Additionally, a prudence principle is required. With respect to this goal, radiation oncologists are able to demonstrate some advantages of IMRT compared with 3D-RT.

IMRT is an elegant treatment to irradiate large Hodgkin disease in women. It allows good local control to be achieved and has no acute side effects. Because of the decrease in the higher dose in most organs at risk, this therapy will hopefully decrease late complications. However, a longer follow-up is needed to definitively evaluate such an outcome.

Written informed consent was obtained from the patient.