Radiation Pneumonitis in Association with Internal Mammary Node Irradiation in Breast Cancer Patients: An Ancillary Result from the KROG 08-06 Study

In 2008, the Korean Radiation Oncology Group (KROG) initiated a prospective phase III randomized trial (KROG 08-06) designed to investigate the effect of internal mammary node irradiation (IMNI) on disease-free survival (DFS) and toxicity in breast cancer patients. Until that time, no consensus existed regarding the use of IMNI in postmastectomy radiotherapy or radiotherapy after breast-conserving surgery (BCS). Inclusion of the internal mammary nodes (IMNs) in breast cancer radiotherapy is mainly dependent on the preferences of the treating radiation oncologists. A Korean patternof-care study showed that approximately 50% of patients received IMNI during postmastectomy radiotherapy [1]. Variable patterns of clinical practice regarding IMNI, which were culture-driven not evidence-based, have been reported [2, 3].

Because IMNI may increase radiation exposure to critical organs, new studies must determine whether the expected benefits of elective IMNI is worth the risk of late toxicity to critical organs, such as the lungs and heart [4]. In the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, instances of pulmonary toxicity were significantly higher in the IM-MS (internal mammary and medial supraclavicular chain) treatment group than in the control group [5]. The National Cancer Institute of Canada Clinical Trial Group MA.20 trial demonstrated improved DFS in patients with one to three positive nodes with the addition of regional nodal irradiation, including IMNI. However, this additional irradiation was associated with an increase in the incidence of grade 2 or higher pneumonitis (1.3% vs. 0.2%) [6].

Upon its completion in February 2013, KROG 08-06 had enrolled a total of 747 patients. In this study, we reviewed collected data from the evaluable 722 patients and present the incidence of radiation pneumonitis (RP) reported within 6 months after radiotherapy with or without IMNI.

The use of IMNI has been debated, but several reports have provided evidence that it improves survival in patients with breast cancer [7, 8]. A previous retrospective study from our institution reported a long-term DFS advantage following IMNI in postoperative patients [9]. Although more studies are needed to clearly define the role of IMNI in long-term survival and toxicity, the findings of this retrospective study showed that IMNI was obviously effective in patients with N2 disease and patients with inner/central tumors. However, there is no consensus regarding whether IMNs should be treated, because of the possible increase in the risk for late toxicity. As a result of the anatomic location of IMNs, IMNI increases the exposure of critical organs, such as the lungs and heart, to radiation.

In this study, we investigated lung toxicity, which may lead to deterioration of the patient's performance status or quality of life. We specifically examined RP occurring within 6 months of treatment and its association with IMNI. RP is a common type of toxicity caused by radiation exposure to the lung and usually appears within 6 months of the completion of radiotherapy. Clinical symptoms, including cough and low-grade fever, occur following completion of the radiotherapy course, and can also be seen as nonspecific infiltration on chest X-rays. The rate of pneumonitis may be also influenced by systemic therapy [10, 11]. Various techniques to irradiate the IMN while minimizing normal tissue irradiation have been suggested [12]. We previously reported that the partial wide tangent method is the best technique for patients undergoing BCS because of the IMN coverage involved with this method and because of the reduced dose to the lungs and heart. However, the photon/electron combination method showed better isodose distribution in some patients [13]. The developments in radiotherapy techniques and the availability of three-dimensional (3D) treatment planning have allowed us to more precisely and safely irradiate IMN. In our country, 3D treatment planning with CT simulation has been used since the mid-2000s; therefore, all patients enrolled in this study had undergone CT simulation and 3D treatment planning. In this study, various radiotherapy techniques were allowed at the discretion of the treating radiation oncologists. In the IMNI treatment group, the most commonly used technique was the partial wide tangent method for both MRM and BCS. The reverse hockey stick method was exclusively used for MRM cases, both in the IMNI and non-IMNI groups.

The incidence of symptomatic RP (grade ≥2) was reported as 2.3% after whole breast and supraclavicular lymph node treatment without IMNI, and 3% after breast irradiation using the partial wide tangent technique, which includes the first three IMNs, in single-institution studies [14, 15]. As a multi-institutional study, we showed that the incidence of RP, when patients were treated without IMNI, was 3.3% (n=12/366), with the BCS group accounting for 2.2% and the MRM group accounting for 4.3%. In addition, the incidence rates of grade 1 and 2 RP after using the partial wide tangent method were 4.9% (n=9/185) and 2.2% (n=4/185), respectively. In the MRM group, the risk of RP can be reduced by using the reverse hockey stick method, in which the anterior chest wall is irradiated with an electron beam using an individualized stepbolus. However, 13.7% of patients experienced RP, which may have resulted from improper administration of the step-bolus. The results of the current study are in line with previous reports on pulmonary toxicity associated with breast radiotherapy [5, 16, 17]. Although the incidence of RP, including asymptomatic radiologic changes, was significantly increased with IMNI, the clinical impact was minimal. In the EORTC 22922/10925 trial, researchers found no significant difference between the deterioration of the performance status and increased lung toxicity [5]. Thus, we suggest that IMNI can be applied without any significantly increased risk.

The incidence of RP correlates with the irradiated lung volume and radiation dose. A previous study suggested that if the ipsilateral lung irradiation volume is less than 12%, then the risk of pneumonitis is minimal, even with coverage of the supraclavicular area [18]. In general, the MLD and V20 are related to RP, and the ipsilateral V20 can predict the risk of pulmonary toxicity [19]. In the current study, each patient underwent CT-based simulation; therefore, we obtained and analyzed the relationship between the dosimetric parameters and the incidence of RP with or without IMNI. MLD and V20 (17.66±5.33 Gy and 34.94%±12.15%, respectively) in the IMNI group were higher than in the non-IMNI group (13.29±4.37 Gy and 25.49%±10.53%, respectively). Other lung dosimetric parameters such as V10, V30, and V40 also exhibited statistically significant differences between the two groups. A previous single-institution study showed that the incidence of RP was higher in patients with MLD ≥20.5 Gy or a normal tissue complication probability ≥23% [15]. Through this large prospective trial, we confirmed that the incidence of RP, as evaluated using chest X-ray, increased with higher doses of radiation to the lung, which was associated with IMNI. However, clinically meaningful grade 2 RP was not predictable on the basis of dosimetric parameters. Other patient factors that increase the risk of RP can also be considered. It has been reported that RP is more likely to occur when certain chemotherapy drugs are administered along with radiation. However, because all the patients in our trial received chemotherapy, we could not evaluate the effect of chemotherapy.

One drawback of this study is that the chest X-ray follow-up visit could occur at any time within 6 months after RT. Considering that most radiologic changes in this study were found at 2 or 3 months after RT, the heterogeneity of the follow-up time among patients may have caused an underestimation of asymptomatic grade 1 RP. Furthermore, we did not assess the change in performance status between the enrollment and post-RT periods, which may have helped to evaluate the effect of IMNI on quality-of-life. In this study, we focused only on short-term RP incidence; we did not plan to investigate radiation-related cardiac disease, because late cardiac toxicity often appears 10 to 15 years after radiotherapy, meaning long-term follow-up is required [20, 21, 22]. Nilsson et al. [23] reported that radiation to the supraclavicular lymph nodes and IMNs increased the risk of stroke. The EORTC trial 22922/10925 assessed the impact of elective internal mammary and medical supraclavicular lymph node irradiation on the well-known toxicities of breast cancer radiotherapy, including lung, skin, and heart toxicity [5]. In contrast, they found that increased lung toxicity with IMNI was the only statistically significant factor between the two treatment groups at 3 years.

With newer treatment techniques, such as the breath-hold technique, intensity-modulated RT, particle therapy, and volumetric-modulated arc therapy, IMNI can be delivered at even lower doses to the organ at risk, especially in left-sided breast cancer [24, 25, 26]. Consequently, the incidence of RP and dose parameters with IMNI estimated in this study can be further decreased by including these newer methods.

In conclusion, results from this large data collection study clearly showed that treatment of IMNs resulted in increased radiation to the lungs and a higher rate of RP, but the incidence and severity of RP was minimal. Therefore, we suggest that IMNI is well tolerated with a very low risk of symptomatic RP; however, future analyses should assess whether this minor impact on morbidity could affect long-term survival outcomes.