Ion therapy within the trimodal management of superior sulcus tumors: the INKA trial

Lung cancer is one of the most common cancers and accounts for 14% of all cancers in men and 13% in women [1]. The probability of lung cancer development during lifetime is 7.6% in men and 6.3% in women. In 2014 there will be approximately 224.210 new cases of lung and bronchial cancer in the United States. The estimated 5-year survival rate is 17% [1]. Superior sulcus tumors are a subtype of lung cancer, localized in the lung apex and commonly of non-small-cell histology. Treatment of choice is a preoperative chemoradiation followed by surgical resection [2]. Rusch et al. reported on preoperative radiotherapy applying 45Gy in combination with cisplatin and etoposide chemotherapy. The results showed 36% histological complete remissions in the surgical specimens. Acute adverse events > CTC °2 were primarily bone marrow suppressions. The trimodal treatment concept in Heidelberg is platin-based as well and applies cisplatin in combination with vinorelbine. The results of an en-block resection of superior sulcus tumors in Heidelberg were published by Pfannschmidt et al. in 2003 [3]. The colleagues did not find an impact on survival stratified by the radiotherapeutical concept, but a complete tumor resection was prognostic. However, most patients in their report did not receive chemotherapy in addition to irradiation.

In the setting of phase I/II studies colleagues in Japan evaluated heavy-ion therapy in stage I non-small-cell lung cancer (NSCLC). A dose escalation trial evaluated initially 47 patients treated in 18 fractions within 6 weeks (>86.4GyE) and later 34 other patients treated in 9 fractions within 3 weeks (72GyE) [4]. Grade 3 pneumonitis was reported in 3/81 patients, but all patients recovered completely and furthermore, the pneumonitis was not dose-limiting. The local control rates were 64% and 84%. The in-field recurrence rates of the initial series were dose-dependent. Applying doses >86.4GyE in 18 fractions or 72GyE in 9 fractions resulted in local control rates of 90% and 95%. Miyamoto et al. reported on heavy-ion therapy in 50 patients suffering from stage I NSCLC applying 72GyE in 9 fractions [5]. All patients were followed-up for at least 5 years or until death. The median follow-up time was 59.2 months and the local control rate 94.7%. No pulmonary toxicity > CTC °3 was reported. Comparable results were published by Hof et al. in 2007 on stereotactic radiosurgery using photon beams in stage I/II NSCLC [6]. Patients were treated with doses of 19 to 30Gy prescribed to the isocenter. The 12-, 24- and 36-months local control rates were 89.5%, 67.9% and 67.9%, and showed an advantage for higher doses. Furthermore, Grutters et al. reported in their meta-analysis on stage I NSCLC comparing photons, protons and heavy-ions a superiority of particles in comparison to conformal radiotherapy, especially regarding the survival probability; however, this survival advantage was comparable to stereotactic radiotherapy [7]. Furthermore, a trend to fewer side effects in particle therapy was seen, even though final conclusions could not be drawn.

Yamamoto et al. analyzed the surgical specimen in 4 patients having had surgical resection following heavy-ion therapy with 18 x 3.3 GyE [8]. Endpoints were tumor response and radiation induced changes within the lung tissue. In 2 patients no surviving tumor cells were found and in 2 other cases only scattered tumor cells. Furthermore, they described pulmonary fibrosis in the tissue surrounding the primary tumor, whereas the intensity decreased with increasing distance from the primary tumor site. Tissue having been irradiated with less than 15GyE did not show signs of pulmonary fibrosis. The authors concluded that their results demonstrated the efficacy and safety of heavy-ion therapy in NSCLC. Another team that evaluated radiographic changes of the lung and pleura following heavy-ion therapy were Nishimura and colleagues [9]. Their analysis showed a correlation of the V20 and V40 with the severity of the pulmonic changes. Furthermore, these changes occurred 3 months after the treatment and the maximum period was 6 months. In contrast, pleural changes occurred median 4 months after the initiation of heavy-ion therapy and correlated significantly with the PTV, V20 and V40. The effect on pulmonary function was evaluated by Kadono et al. [10]. The authors reported a <8% decrease in the forced expiratory volume in 1 second (FEV1) 6 and 12 months after heavy-ion therapy and rated this decrease in the FEV1 as not-severe. The impact of heavy-ion therapy on the migration and invasion of NSCLC-cells (cell lines A549 and EBC-1) was analyzed by Akino et al. [11]. The authors showed that heavy-ion therapy suppresses the metastatic potential in these cell lines.

Lung cancer is one of the most common types of cancer with poor long-term survival rates. High complete response rates were found in histopathologic examinations following surgery with preoperative chemoradiation [2]. Even though a prior report by Pfannschmidt et al. did not show an impact of the chosen radiation technique on survival [3], recent studies demonstrated excellent results for local tumor control (>90%) after hypofractionated heavy-ion beam therapy in early stage NSCLC [4,5]. In addition, these excellent tumor control rates were associated with low treatment related adverse events [4,5,8]. For the dose calculations we assumed an α/β of 10Gy for sulcus superior tumors resulting in a BED2Gy of 42 Gy. To limit possible treatment-related adverse events, the recommendations by Emami et al. and QUANTEC were used [14,15].

Furthermore, high histopathological response rates (50% complete remissions) might be achieved considering the analysis by Yamamoto et al.; however, the number of analyzed specimens was small and higher doses (18 x 3.3GyE up to 16 x 4.5GyE) but without concurrent chemotherapy were applied [8]. Another analysis of heavy-ion beam therapy on the tumor cell migration and invasion suggested a suppression of the metastatic potential in the analyzed cell lines [11]. Recently, colleagues from Chiba reported on respiratory-gated carbon ion therapy in 34 patients treated for lung metastases from colorectal cancer (CRC) [17]. The carbon ion treatment was well tolerated (only Grade 1–2 adverse events) and achieved high local tumor control rates, even though Takeda et al. showed previously that lung metastases from CRC do not respond as well to stereotactic body radiation therapy [18]. Considering those reports we assume that the results of a preoperative heavy-ion beam therapy in combination with chemotherapy followed by surgical tumor resection might improve the outcome following high-linear energy transfer heavy-ion beam therapy in comparison to standard photon beam therapy for example due to biological effects allowing us to optimize the treatment results in the future while keeping treatment related adverse events minimal. Therefore, this prospective single-arm pilot trial is primarily aimed to evaluate the safety and feasibility of heavy-ion beam therapy for sulcus superior tumors in the trimodal setting. Secondary endpoint is the degree of regression in the histopathological specimen. In case of promising results, the information generated in the present trial will be used to plan a confirmatory study.