
==== Front
Adv Radiat Oncol
Adv Radiat Oncol
Advances in Radiation Oncology
2452-1094
Elsevier

S2452-1094(24)00136-2
10.1016/j.adro.2024.101573
101573
Scientific Article
Carbon Ion Beam Radiation Therapy as Part of a Trimodal Therapy for Non-small Cell Superior Sulcus Tumors: The INKA Study
Weykamp Fabian MD fabian.weykamp@med.uni-heidelberg.de
abcde⁎
Schaub Lukas MD abc
Eichhorn Martin MD f
Winter Hauke MD f
Schirmacher Peter MD, PhD g
Thomas Michael MD h
Haberkorn Uwe MD i
Ellerbrock Malte d
Adeberg Sebastian MD abcde
Debus Jürgen MD, PhD abcdej
Herfarth Klaus MD abcdej
a Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
b Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany
c National Center for Tumor Diseases (NCT), Heidelberg, Germany
d Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
e Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
f University Hospital Heidelberg, Thoraxklinik, Department of Surgery, Heidelberg, Germany
g University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
h Department of Thoracic Oncology, Thoraxklinik, University of Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
i University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg, Germany
j German Cancer Consortium (DKTK), Partner Site Heidelberg, Germany
⁎ Corresponding author: Fabian Weykamp, MD, INF 400, 69120 Heidelberg, Germany fabian.weykamp@med.uni-heidelberg.de
15 7 2024
9 2024
15 7 2024
9 9 1015733 4 2024
9 7 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Purpose

Superior sulcus tumors are frequently treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery via a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiation therapy (C12-RT) in this regimen.

Methods and Materials

The prospective INKA study included patients with locally advanced non-small cell superior sulcus tumors (<cN3 cM0). Patients received 2 cycles of cisplatin and vinorelbine as per local standard. During the second cycle, 39 Gy(Relative biological effectiveness (RBE)) of hypofractionated C12-RT in 13 fractions were applied. Surgery following fludeoxyglucose F18 positron emission tomography–computed tomography restaging was performed 2 weeks later. The primary endpoint was feasibility and safety measured by the incidence of Common Terminology Criteria for Adverse Events (version 4.0) grade 3/4 toxicity and/or discontinuation because of any reason. Secondary endpoints included the morphologic (Response Evaluation Criteria in Solid Tumors 1.0), metabolic (Positron Emission Tomography Response Criteria in Solid Tumors 1.0), and histopathologic response after nCRT as well as quality of life measurement (QLQ-C30/LC13).

Results

Between 2015 and 2020, 14 patients were included and received nCRT. No grade 3/4 toxicity occurred, with no discontinuation because of toxicity. Before surgery, 8 patients (57%) showed a partial response on computed tomography scan. Thirteen patients showed a metabolic response (metabolic complete remission (mCR), 1; metabolic partial remission (mPR), 12). Three patients (21%) were deemed inoperable after nCRT. In patients with resection, a pathologic Complete remission (CR) was seen in 2 patients (19%) and near-complete remission (<10% vital tumor cells) in 6 patients (55%). Pain score was more than half of that at baseline (mean, 69.2 ± 26.2 vs 30.6 ± 29.1; P = .005) after completion of nCRT and before surgery.

Conclusions

The INKA trial is the first study to evaluate nCRT with C12-RT and showed excellent response, low toxicity, and rapid pain relief.
==== Body
pmcBackground and Purpose

Although lung cancer is one of the most common tumor entities in the world, superior sulcus tumors only represent approximately 3% to 5% of these cases.1 However, superior sulcus tumors in particular are difficult to treat and were regarded as inevitably fatal until the 1950s, when induction radiation therapy and en bloc resection were introduced.2 Shaw et al3 established the sequence of neoadjuvant photon radiation therapy (30-35 Gy over 2 weeks) followed by surgery as the new standard of care, leading to 5-year overall survival (OS) rates of up to 30%. After simultaneous neoadjuvant chemotherapy was introduced in the 1990s, the current standard of care is a trimodal approach leading to 5-year OS rates of up to 40%.4

Carbon ion radiation therapy (C12-RT) is predominantly used for inherently radioresistant tumors with highly radiosensitive anatomic structures in close vicinity (eg, skull base chordoma or chondrosarcoma and adenoid-cystic carcinoma). Lung cancer is a rather infrequent indication for C12-RT and the respective study landscape is almost exclusively of Japanese origin. In the early 2000s, Miyamoto et al5 successfully evaluated the feasibility of 52.8 Gy(Relative biological effectiveness (RBE)) and 60.0 Gy(RBE) C12-RT in 4 fractions for stage I non-small cell lung cancer (NSCLC). No toxicity higher than grade 3 was described.5 Nonetheless, particle therapy in lung cancer is rather challenging because respiratory motion in combination with surrounding lung tissue hinders a reliable calculation of the dose distribution.6 Superior sulcus tumors represent the ideal lung tumor entity for evaluation of C12-RT because of their anatomic localization. Per definition, superior sulcus tumors are located near radiosensitive structures, and at the same time, the lung apex is less prone to respiratory motion. We sought to evaluate the scientific utilization of carbon ions within the trimodal therapy of non-small cell superior sulcus tumors.

Methods and Materials

The INKA study was a monocentric phase 2 pilot study evaluating the safety and feasibility of neoadjuvant hypofractionated C12-RT in patients with non-small cell superior sulcus tumors (T3-4 N0-2 M0). The detailed study protocol has been published earlier (https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1163-7). Eligible patients were aged between 18 and 75 years and amenable to standard of care concurrent cisplatin/vinorelbine chemotherapy (Karnofsky Performance Score ≥70, no decompensated medical disease). The initial fludeoxyglucose F18 (FDG) positron emission tomography (PET)–computed tomography (CT) scan was not allowed to be older than 6 weeks. No previous thoracic radiation therapy or active medical devices without approval for particle therapy (eg, cardiac pacemakers) were allowed.

Treatment characteristics

Except for the use of hypofractionated carbon ion instead of photon radiation therapy, treatment corresponded to local standard of care. Neoadjuvant chemoradiation therapy (nCRT) included 2 cycles of chemotherapy (day 1, cisplatin 80 mg/m2 and vinorelbine 25 mg/m2; day 8, vinorelbine 25 mg/m2). Concurrently with the second cycle, C12-RT was applied (39 Gy[RBE]) in 13 fractions using active raster scanning). Vinorelbine dose was reduced to 15 mg/m2 during the second, concurrent cycle. Two weeks after completion of radiation therapy and an FDG-PET-CT restaging, surgery was performed (including systemic mediastinal lymphatic node dissection).

Target volumes were delineated as follows: the gross tumor volume (GTV) comprised the macroscopic visible primary tumor and the PET-positive lymph nodes if present. The clinical target volume was defined as the GTV with a safety margin of 6 mm. Based on the 4-dimensional planning CT, an internal target volume was generated. During treatment planning, 95% of the internal target volume should receive 39 Gy(RBE) in 13 fractions (5-6 fractions a week), leading to an equivalent dose at 2 Gy (α-to-β ratio, 10Gy) of 42.3 Gy. The esophagus, lungs, brachial plexus, and spinal cord were contoured as organs at risk. The local effect model 1 was used for calculation of the biological dose of the carbon ion irradiation.7 During the local effect model 1 calculation, an α-to-β ratio of 10 Gy was assumed for the GTV and an α-to-β ratio of 2 Gy was assumed for organs at risk.

Study endpoints

The primary endpoint was safety and feasibility, characterized by the incidence of grade 3/4 toxicities (Common Terminology Criteria for Adverse Events, version 4.0) excluding hematologic toxicities or treatment-related interruptions (grade 1-4). The secondary endpoints included the morphologic response (Response Evaluation Criteria in Solid Tumors 1.0) based on CT scan, the metabolic response (Positron Emission Tomography Response Criteria in Solid Tumors 1.0) described by Wahl et al8 based on FDG-PET, the histopathologic tumor regression according to the Junker classification (grade 1, no or only slight tumor regression; grade 2a, >10% vital tumor cells; grade 2b, <10% vital tumor cells; grade 3, complete tumor regression),9 and health-related quality of life based on the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires QLQ-C30 and QLQ-LC13. In a post hoc analysis local control (LC), distant control (DC) progression-free survival (PFS), and OS were calculated, starting from the first day of irradiation.

Statistical methods

EORTC questionnaires QLQ-C30 and QLQ-LC13 as well as toxicity assessment were completed at baseline, at the beginning of radiation therapy, 2 weeks post radiation therapy as well as 3 and 6 months after surgery.10,11 The obtained raw item data from the EORTC questionnaires were linearly transformed to a standardized range of 0 to 100 as described in the third edition of the EORTC QLQ-C30 Scoring Manual.12 Higher scores represent a higher level of functioning. However, regarding the symptom burden, higher scores represent a higher degree of symptoms. The Wilcoxon rank sum test was used to compare the calculated means. Additionally, a comparison with a German norm population was performed.13 LC, DC, PFS, and OS (beginning on the first day of radiation therapy) were estimated with the Kaplan-Meier method. Each was calculated and assessed with the log-rank test. A P value less than .05 was considered statistically significant. All statistical analyses were performed with SPSS software (IBM SPSS version 28.0).

The INKA study was approved by the ethics committee of (https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1163-7). Written informed consent was obtained from all included patients. The trial is registered at (https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1163-7).

Results

Fourteen patients were included in the INKA trial and were treated between February 2015 and September 2020. Figure 1 provides an overview including study visits and response assessment. Enrolment was prematurely closed in February 2022 because of slow accrual, after 14 of 20 initially planned patients were included and treated.Figure 1 Scheme of the INKA trial, including the number of patients treated at each treatment step and response assessment.

Abbreviations: CT = computed tomography; FDG = fludeoxyglucose F18; NSCLC = non-small cell lung cancer; PET = positron emission tomography.

Figure 1

In terms of the primary endpoint, no grade 3/4 toxicities or treatment-related interruptions (grade 1-4) occurred. Demographic data, tumor stage, and radiation therapy details are shown in Table 1. Toxicity was low and is shown in Fig. 2 (additional details shown in Table E1). No patient developed grade 3 to 5 events at any time. Tumor response is shown in Table 2. The CT-graphic response was partial response in 8 patients (57%) and stable disease in 6 patients (43%) 2 weeks after completion of radiation therapy. The metabolic response was complete in 1 patient (7%), partial in 11 patients (79%), stable in 1 patient (7%), and not assessable in another patient (7%) because of lack of cross-calibration between the initial PET scan and restaging PET scan. The patient having had complete metabolic remission also showed complete tumor regression in the surgical specimen as shown in the case study (Fig. 3). Three patients were deemed inoperable after completion of the study treatment and were therefore not available for the histopathologic response endpoint. Histopathologic tumor regression according to the Junker classification was grade 2a (>10% vital cells) in 3 specimens (27%), grade 2b (<10% vital cells) in 6 specimens (54%), and grade 3 (pathologic complete remission) in 4 specimens (19%). Nine patients (82%) had complete resection (R0). Two patients (18%) had microscopic residual tumor (R1). One of these patients received additional 5 fractions of 2 Gy intensity modulated photon radiation therapy. The other patient refused additive treatment. Both patients did not show local recurrence during their latest follow-up of 12 and 42 months, respectively.Table 1 Demographic data, tumor stage, and radiation therapy details

Table 1Age (y)	56 (47-69)	
Karnofsky performance index	90% (70%-100%)	
Female	3 (21%)	
Male	11 (79%)	
Adenocarcinoma	5 (36%)	
Squamous cell carcinoma	3 (22%)	
NOS	4 (28%)	
Other	2 (14%)	
n = 1 pleomorphic; n = 1 sarcomatoid	
T3	10 (71%)	
T4	4 (29%)	
N0	12 (86%)	
N1	1 (7%)	
N2	1 (7%)	
Primary tumor diameter (cm)	5.8 (4.6-8.5)	
CTV volume (mL)	218 (88-449)	
Plexus brachialis Dmax (Gy)	40 (29-42)	
Spinal cord Dmax (Gy)	28 (0-34)	
Esophagus Dmean (Gy)	8 (0-16)	
Ipsilateral lung Dmean (Gy)	4 (0-14)	
Contralateral lung Dmean (Gy)	0 (0-4)	
Data are reported as median (range) or n (%).

Abbreviations: CTV = clinical target volume; NOS = not otherwise specified.

Figure 2 Toxicity according to Common Terminology Criteria for Adverse Events (version 4.0): grade 0 (none), grade 1 (mild), grade 2 (moderate), and grade 3 (severe).

Figure 2

Table 2 Tumor response

Table 2CT-graphic response (RECIST 1.0)		
 Partial response	8 (57%)	
 Stable disease	6 (43%)	
Metabolic response (PERCIST 1.0)		
 Complete metabolic response	1 (7%)	
 Partial metabolic response	11 (79%	
Stable metabolic disease	1 (7%)	
 Not assessable	1 (7%)	
Surgery performed	11 (79%)	
 Complete resection (R0)	9 (82%)	
 Macroscopic complete resection (R1)	2 (18%)	
 Regression rate in specimen (Junker grade)		
  1 (no change)	0 (0%)	
  2a (>10% vital tumor cells)	3 (27%)	
  2b (<10% vital tumor cells)	6 (55%)	
  3 (no vital tumor cells)	2 (18%)	
Abbreviations: PERCIST = Positron Emission Tomography Response Criteria in Solid Tumors; RECIST = Response Evaluation Criteria in Solid Tumors.

Figure 3 Case study: (A) computed tomography scan, (B) positron emission tomography scan, and (C) fused computed tomography/positron emission tomography images before (left column) and after (right column) chemoradiation therapy; the surgical specimen later revealed complete remission (Junker grade 3).

Abbreviations: SUV = standardized uptake value.

Figure 3

Table 3 shows the results of the health-related quality of life (an additional graphic visualization of significant items can be found in Fig. E1). Global health status was significantly reduced after the first cycle of chemotherapy and 4 weeks after surgery. After completion of nCRT, the mean pain score was less then half of that at baseline (69.2 ± 26.2 vs 30.6 ± 29.1; P = .005) and thus reached toward the mean value of the German general population (27.6 ± 30.9). A detailed comparison with the German general population can be found in Table E2. Four weeks after surgery, the mean pain score had relapsed nearly back to baseline (65.4 ± 25.8; P = .667), but significantly declined again 6 months after surgery (39.4 ± 27.1; P = .022). The dyspnea symptom burden was significantly higher 4 weeks after surgery (56.4 ± 28.5; P = .023) and persisted 6 months after surgery with a trend of improvement (48.5 ± 27.3; P = .080).Table 3 EORTC QLQ-C30 quality of life/symptom scale and EORTC QLQ-LC13 symptom scale scores at baseline, before radiation therapy, before surgery, 4 weeks after surgery, and 6 months after surgery

Table 3	Baseline	Before radiation therapy	Before surgery	Four weeks after surgery	Six months after surgery	
	n	Mean ± SD	n	Mean ± SD	P	n	Mean ± SD	P	n	Mean ± SD	P	n	Mean ± SD	P	
EORTC QLQ-C30															
 Global health status	13	65.4 ± 9.5	13	50.6 ± 19.1	.036	12	64.6 ± 23.1	.671	12	52.8 ± 19.9	.029	10	62.5 ± 18.1	.310	
 Functional scales															
  Physical functioning	13	75.4 ± 22.5	14	81.0 ± 16.9	.192	12	80.0 ± 17.3	.344	13	62.6 ± 28.1	.265	11	73.9 ± 21.6	.944	
  Role functioning	12	51.3 ± 37.6	14	73.8 ± 23.3	.011	12	68.1 ± 27.9	.151	13	38.5 ± 31.4	.301	11	56.1 ± 30.1	.288	
  Emotional functioning	12	55.1 ± 26.0	14	63.1 ± 31.1	.212	12	67.4 ± 61.2	.050	13	63.5 ± 31.5	.181	11	66.7 ± 19.8	.123	
  Cognitive functioning	13	78.2 ± 24.9	14	84.5 ± 20.1	.272	12	86.1 ± 17.1	.306	13	80.8 ± 21.3	.679	11	78.8 ± 24.9	1.000	
  Social functioning	13	58.9 ± 37.6	14	53.6 ± 26.2	.833	12	66.7 ± 30.9	.724	13	50.0 ± 36.6	.164	11	56.0 ± 29.1	.717	
 Symptom scales															
  Fatigue	13	35.9 ± 18.8	14	39.7 ± 25.3	.671	12	33.3 ± 21.7	.765	13	50.4 ± 24.7	.105	11	27.3 ± 25.9	.125	
  Nausea/vomiting	13	3.8 ± 10.0	14	3.6 ± 7.0	1.000	12	6.9 ± 15.0	.680	13	9.0 ± 23.0	.680	11	3.0 ± 10.1	.785	
  Pain	13	69.2 ± 26.2	14	51.2 ± 31.7	.049	12	30.6 ± 29.1	.005	13	65.4 ± 25.8	.667	11	39.4 ± 27.1	.022	
  Dyspnea	13	25.6 ± 24.7	14	19.1 ± 21.5	.257	12	30.6 ± 30.0	.783	13	56.4 ± 28.5	.023	11	48.5 ± 27.3	.080	
  Insomnia	13	41.1 ± 33.7	14	38.1 ± 36.6	.366	12	30.6 ± 26.4	.131	13	48.7 ± 32.2	.796	11	36.4 ± 34.9	.431	
  Appetite loss	13	0 ± 0	14	14.3 ± 31.2	.180	12	8.3 ± 15.0	.083	13	23.1 ± 31.6	.024	11	3.3 ± 10.1	.317	
  Constipation	13	10.3 ± 21.0	14	31.0 ± 33.2	.038	12	13.9 ± 26.4	.655	13	12.8 ± 21.7	.793	11	6.1 ± 23.1	.414	
  Diarrhea	13	2.6 ± 9.2	14	4.8 ± 12.1	.317	12	2.8 ± 9.6	1.000	13	7.7 ± 19.9	.414	11	3.1 ± 10.05	1.000	
  Financial difficulties	13	20.5 ± 21.7	14	21.4 ± 28.0	.562	12	13.9 ± 22.9	.564	13	35.9 ± 34.4	.083	11	33.3 ± 36.5	.160	
EORTC QLQ-LC13															
 Symptom scales															
  Dyspnea	13	11.1 ± 12.8	14	17.3 ± 21,6	.102	12	14.4 ± 16.5	.244	13	39.3 ± 27.0	.005	11	31.3 ± 19.1	.009	
  Coughing	13	33.3 ± 30.4	14	30.9 ± 30.6	.414	12	33.3 ± 25.9	.480	13	30.8 ± 9.2	.480	11	39.4 ± 13.4	1.000	
  Hemoptysis	13	2.6 ± 9.2	14	2.4 ± 8.9	1.000	12	0 ± 0	.317	13	0 ± 0	.317	11	0 ± 0	.317	
  Sore mouth	13	10.3 ± 16.0	14	7.1 ± 14.2	.317	12	3.0 ± 10.1	.317	13	2.6 ± 9.2	.083	11	3.0 ± 10.1	.157	
  Dysphagia	13	2.6 ± 9.2	14	4.8 ± 12.1	.317	12	9.1 ± 15.6	.157	13	0 ± 0	.317	11	3.0 ± 10.1	.317	
  Peripheral neuropathy	13	20.5 ± 29.0	14	16.7 ± 21.7	.564	12	15.2 ± 22.9	.680	13	33.3 ± 27.2	.426	11	30.3 ± 37.9	.550	
  Alopecia	13	2.6 ± 9.2	14	19.0 ± 36.3	.102	12	21.2 ± 34.2	.066	13	15.4 ± 32.2	.180	11	6.1 ± 13.4	.157	
  Pain in chest	13	46.2 ± 28.9	14	31.0 ± 24.3	.084	12	21.2 ± 22.5	.054	13	38.9 ± 27.8	.414	11	27.3 ± 35.9	.256	
  Pain in arm or shoulder	13	66.7 ± 36.0	14	42.9 ± 40.1	.034	12	24.2 ± 26.2	.011	13	51.3 ± 32.2	.321	11	42.4 ± 42.4	.048	
  Pain in other parts	13	16.7 ± 33.3	14	23.9 ± 33.1	.546	12	3.3 ± 10.1	.197	13	35.9 ± 39.5	.436	11	24.2 ± 42.4	.671	
Abbreviation: EORTC = European Organisation for Research and Treatment of Cancer; QLQ = Quality of Life Questionnaire.

Bold = statistically signifcant.

Three patients were deemed inoperable after neoadjuvant therapy. Two patients had a tumor response; however, they persisted to be technically inoperable after neoadjuvant treatment. One patient had a worsened pulmonary condition, which was not associated with an adverse event during neoadjuvant treatment. The 3 inoperable patients received additional therapies instead of surgery. Two patients received additional C12-RT with 6 fractions of 3 Gy(RBE) without concurrent or sequential chemotherapy. One patient received 2 additional cycles of cisplatin/vinorelbine without further irradiation. These 3 patients are also included in the long-term follow-up evaluation.

LC, DC, PFS, and OS were 93%, 86%, 79%, and 86% after a median follow-up of 42 months (Fig. E2). One patient had local recurrence in a right upper paratracheal node (station 2R) after 7 months. One patient developed brain metastases after 6 months. Another patient developed contralateral lung cancer after 46 months. Two patients died after 20 months and 23 months, respectively.

Discussion

Sulcus superior tumors are frequently painful, and curative treatment is particularly difficult because of the involvement of sensitive anatomic structures. The prospective phase 2 INKA trial sought to evaluate the feasibility of neoadjuvant hypofractionated C12-RT together with standard of care chemotherapy. Our study demonstrated excellent results with low toxicity, rapid pain mitigation after nCRT, and very good pathologic response already 2 weeks after the neoadjuvant treatment. No nonhematologic grade 3/4 toxicities or treatment-related interruptions occurred. The absence of pneumonitis grade 2 or higher in our study is not surprising given the fact that even high-dose C12-RT in a definitive-intent treatment led to pulmonary grade 3 toxicity of less than 4%.14 The majority of patients showed at least partial morphologic and metabolic response before surgery (57% and 79%). Every surgical specimen showed at least partial tumor response. Pathologic complete remission was 19% in the presented study and, therefore, within the range of the 3 other prospective trials in the field that investigated comparable treatment schemes.5,15,16 Complete pathologic response and near-complete response taken together were surprisingly high in the INKA trial (74%). Table E3 provides details regarding treatment schemes and response rates in comparison with the presented INKA study. One has to keep in mind the shorter interval in the INKA trial between completion of nCRT and surgery (2 weeks), leaving less time for the tumor to regress completely. Moreover, the INKA trial used hypofractionated radiation therapy (13 fractions instead of 25 fractions), which further decreased the time for the tumor to regress completely by more than 2 weeks. None of the aforementioned prospective studies investigated patient-reported outcome measures. Thus, the presented study provides unique insights. Shortly after completion of nCRT, pain was drastically reduced, but recurred after surgery. Patients who did not undergo surgery had better quality of life and less toxicity. However, there were not enough data available to perform statistical comparison, and thus, no definitive conclusion can be drawn. Moreover, the significant differences in quality of life after surgery in terms of pain and dyspnea might originate from other factors, which were not controlled for. There was no pain medication surveillance and no monitoring of underlying pulmonary diseases and their respective therapy. None of the 3 patients who did not undergo surgery died or had any recurrence during their follow-up (Fig. E2). However, their median follow-up was less mature (26 vs 46 months). The main limitation of the INKA trial is its prematurely closure because of slow patient accrual, with 14 instead of 20 patients available for final analysis. However, difficulties with accruing patients in this rare NSCLC subset were not unexpected, as described by Kernstine et al,17 who stated that it required 76 surgeons from all over North America in order to accrue 110 superior sulcus tumor patients for the SWOG 9416 study. The currently ongoing JCOG 1807C study (DEEP OCEAN) evaluates cisplatin-based polychemotherapy together with photon radiation therapy (66 Gy/2 Gy, including 22 Gy/2 Gy sequential boost prescribed to the clinical target volume). Two cycles of durvalumab are given sequentially after nCRT and again after surgery for approximately 1 year.15 Given the excellent results with durvalumab consolidation after definitive chemoradiation therapy in patients with NSCLC in the PACIFIC trial, the DEEP OCEAN protocol seems to be promising.18 Nonetheless, 66 Gy appears to be a dose escalation compared with the current standard of 45 Gy for neoadjuvant photon radiation therapy. Assuming an α-to-β ratio of 10 Gy for superior sulcus tumor cells, the 39 Gy(RBE) prescribed in our INKA trial corresponds to a 42.3 Gy equivalent dose at 2Gy. This dose is even slightly below the current standard of practice and still achieved excellent results including low toxicity, which could be attributed to the superior biological effect of C12-RT. Of note, this higher biological effect still allowed for simultaneous administration of chemotherapy without unexpected or aggravated toxicity.

Conclusions

The INKA trial is the first study in its field and showed excellent histopathologic response and low toxicity after neoadjuvant chemotherapy with concurrent C12-RT. These encouraging results should lead to further investigations, and multicentric efforts should be made to evaluate this regimen in further trials in the future.

Disclosures

Fabian Weykamp received speaker fees from Merck Sharp & Dohme, Varian Medical Systems, and AstraZeneca and travel fee from Varian Medical Systems Hauke Winter has received payments for lectures, presentations, speaker fee, manuscript writing, and educational events from BMS, MSD, AstraZeneca, Intuitive, Medtronic, and Roche and for expert testimony from Intuitive and support for attending meetings/travel from Roche, Intuitive, and MSD and reports participation on Data Safety Monitoring/Advisory Boards for AstraZeneca and Intuitive, all outside the submitted work. Michael Thomas has received research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Roche, and Takeda; personal fees for speakers bureaus and advisory boards from Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; and support for attending meetings and/or travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda, all outside the submitted work. Sebastian Adeberg participated on advisory boards for Accuray Inc, Sanofi Genzyme, Novartis, and Novocure GmbH; received grants and laboratory equipment from Novocure; received consulting fees from Accuray; received support for attending meetings and/or travel from Merck and Novocure; and received honoraria from Accuray Inc, AstraZeneca GmbH, Bristol-Myers Squibb GmbH & Co, MSD, Novocure GmbH, Merck KGaA, Fakultät Heidelberg, and Sanofi, all outside the submitted work. Jürgen Debus received grants from View Ray Inc, CRI—The Clinical Research Institute GmbH, Accuray Inc, Accuray International Sàrl, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, AstraZeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Merck Serono GmbH, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. All other authors report no disclosures.

Appendix Supplementary materials

Supplementary File.docx

Image, application 1

Acknowledgments

In loving memory of Renate Haselmann, our long-term study nurse. Fabian Weykamp was responsible for statistical analysis.

Sources of support: This research is in part funded by the Deutsche Forschungsgemeinschaft (DFG): KFO214: HE 2499/4-1 .

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.adro.2024.101573.
==== Refs
References

1 Panagopoulos N Leivaditis V Koletsis E Pancoast tumors: Characteristics and preoperative assessment J Thorac Dis 6 suppl 1 2014 S108 S115 24672686
2 Rusch VW Management of Pancoast tumours Lancet Oncol 7 2006 997 1005 17138221
3 Shaw RR Paulson DL Kee JL Treatment of superior sulcus tumor by irradiation followed by resection Ann Surg 154 1961 29 40 17859668
4 Marulli G Battistella L Mammana M Calabrese F Rea F Superior sulcus tumors (Pancoast tumors) Ann Transl Med 4 2016 239 27429965
5 Miyamoto T Baba M Sugane T Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week J Thorac Oncol 2 2007 916 926 17909354
6 Liao Z Lin SH Cox JD Status of particle therapy for lung cancer Acta Oncol 50 2011 745 756 21767170
7 Elsässer T Scholz M Cluster effects within the local effect model Radiat Res 167 2007 319 329 17316069
8 Wahl RL Jacene H Kasamon Y Lodge MA From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors J Nucl Med 50 suppl 1 2009 122S 150S 19403881
9 Junker K Thomas M Schulmann K Klinke F Bosse U Müller KM Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment J Cancer Res Clin Oncol 123 1997 469 477 9341895
10 Aaronson NK Ahmedzai S Bergman B The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology J Natl Cancer Inst 85 1993 365 376 8433390
11 Aarsonson 1993 EORTC QOL30. https://pubmed.ncbi.nlm.nih.gov/8433390/.
12 Bergman B Aaronson NK Ahmedzai S Kaasa S Sullivan M The EORTC QLQ-LC13: A modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life Eur J Cancer 30A 1994 635 642 8080679
13 Fayers PM An BK Groenvold M Curran D Bottomley A EORTC QLQ-C30 Scoring Manual 3rd ed. 2001 European Organisation for Research and Treatment of Cancer
14 Nolte S Waldmann A Liegl G Updated EORTC QLQ-C30 general population norm data for Germany Eur J Cancer 137 2020 161 170 32777715
15 Rusch VW Giroux DJ Kraut MJ Induction chemoradiation and surgical resection for superior sulcus non–small-cell lung carcinomas: Long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160) J Clin Oncol 25 2007 313 318 17235046
16 Kunitoh H Kato H Tsuboi M Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: Report of Japan Clinical Oncology Group trial 9806 J Clin Oncol 26 2008 644 649 18235125
17 Kernstine KH Moon J Kraut MJ Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-intergroup trial S0220 Ann Thorac Surg 98 2014 402 410 24980603
18 Aokage K Tsuboi M Zenke Y Study protocol for JCOG1807C (DEEP OCEAN): A interventional prospective trial to evaluate the efficacy and safety of durvalumab before and after operation or durvalumab as maintenance therapy after chemoradiotherapy against superior sulcus non-small cell lung cancer Jpn J Clin Oncol 52 2022 383 387 34999817
