High-dose concurrent chemo–proton therapy for Stage III NSCLC: preliminary results of a Phase II study

The aim of this report is to present the preliminary results of a Phase II study of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. We concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC.


INTRODUCTION
The prognosis of unresectable advanced non-small-cell lung cancer (NSCLC) remains poor despite advances in radiotherapy and medication. Concurrent chemoradiotherapy is the first treatment choice for unresectable advanced NSCLC. In the 2000s, dose escalation studies were encouraged, and doses > 70 Gy were delivered with concurrent chemotherapy [1][2][3][4][5][6]. The prognoses were favorable in many Phase I/II studies, with median survivals of > 20 months and toxicities that appeared tolerable [3][4][5][6]. However, in the Phase III study, there was no apparent survival benefit [7]. While the reason was unclear, cardiopulmonary toxicities were suspected as potential contributors [8]. Proton beam therapy (PBT) has been utilized in advanced lung cancer [9][10][11].
Proton beams can reduce the doses for normal lung tissues because of the penetration energy peak, the 'Bragg peak'. Therefore, we hypothesized that high-dose PBT with concurrent chemotherapy might be well tolerated and lead to favorable results. We initiated a Phase II study in 2010 to evaluate the safety and efficacy of high-dose PBT with concurrent chemotherapy for unresectable or medically inoperable advanced NSCLC. Herein, we report the preliminary results.
Patients with contralateral hilar lymph node metastasis, intrapulmonary metastasis in the same lobe, obvious interstitial pneumonitis on imaging, or uncontrollable hypertension and diabetes were excluded. Patients who had undergone thoracic radiotherapy or chemotherapy in the past five years, patients with lung cancer within the past two years and those with a malignant tumor at another site were also excluded.

Proton beam therapy
For treatment planning, chest CT images were obtained in 5-mm thick slices in the treatment position, with a respiratorygated system during the end-expiratory phase. The gross target volume (GTV) was defined as the primary tumor and clinically positive lymph nodes. The clinical target volume (CTV)-1 encompassed the primary tumor and the locoregional lymph nodes where clinically positive lymph nodes existed. Prophylactic lymph nodes were not included. Clinically positive lymph nodes were defined as nodes ≥ 1 cm on a CT scan or as PET-positive lymph nodes. The planned target volume (PTV)-1 covered the CTV-1 with a 7-10-mm margin in all directions and an additional 5-mm margin in the caudal direction to compensate for respiratory motion. CTV-2 was defined as only the primary tumor, and PTV-2 was settled as well. The treatment doses of 74 Gy RBE in 37 fractions and 66 Gy RBE in 33 fractions were delivered to PTV-2 and PTV-1, respectively. The targets were delineated as maximal contour on the lung and mediastinum window. The RBE of the proton beam was assigned a value of 1.1 [12]. Adapted planning was made with reduction in tumor volume.
Treatment beams were delivered during the end-expiratory phase using a respiratory gating system controlled by a laser range finder that monitors the movement of the patient's body surface. The patient's body was immobilized using a custom-shaped body cast (ESFORM, Engineering System Co., Matsumoto). Prior to each treatment, the patient's position was confirmed by fluoroscopy.
The termination criteria of PBT were as follows: WBCs < 1000/μl, NTRs < 500/μl, PLTs < 5000, fever ≥ 38°C . PBT was stopped when radiation pneumonitis was observed, and the patients were withdrawn from this study when PBT could not be reinitiated within 14 d, or disease progression was observed.

Chemotherapy
All patients received monthly concurrent cisplatin (CDDP) and vinorelbine (VNR) as intravenous infusions during PBT. CDDP was administered at 80 mg/m 2 on Day 1 and VNR was administered at 20 mg/m 2 on Days 1 and 8. The two courses of chemotherapy were administered during PBT. While neoadjuvant (induction) chemotherapy was not allowed, adjuvant (consolidation) was allowed in this study.

Follow-up
Patients were evaluated at least weekly during treatment, and every 2-3 months after the PBT for 1 year, and 3-6 months, thereafter. Acute and late toxicities were defined as evaluated and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3 [13]. Acute toxicities were defined as occurring during and within 6 months after the chemo-proton therapy, and late toxicities were defined as those appeared 6 months after the completion of chemo-proton therapy. The survival and recurrence were calculated from the date of the start of chemoradiotherapy.
The response rate was evaluated and classified into complete response (CR), partial response (PR), progressive disease (PD) and stable disease (SD), according to the modifications of the Response Evaluation Criteria in Solid Tumors (RECIST) [14]. Local recurrence was defined as an increase in tumor size > 20%, or significant positive accumulation on the PET imaging.

Statistical analysis
The primary endpoint was toxicity, and the secondary endpoints were overall survival, progression-free survival, local control rate and response rate. The survival was analysed using the Kaplan-Meier method (SPSS, IBM Inc., NY, USA).

RESULTS
A total of 17 patients were enrolled in this study, and two patients were withdrawn. Obstructive pneumonia could not be controlled in one patient, and the chemotherapy agents were changed before the start of treatment. The other patient could not continue with the PBT because of the Great East Japan Earthquake, and photon radiotherapy was used as an alternative. Therefore, 15 patients were evaluated in this study.
The characteristics of the 15 patients are presented in Table 1. Four and 11 patients had Stage IIIA and III B disease, respectively, and all patients had unresectable NSCLC. The median CTV volume was 191.3 cm 3 .
At the time of analysis, nine patients were alive. The median follow-up period for the survivors was 21.7 months (range: 7-39 months). The mean survival time was 26.7 months (95% confidence interval (CI): 19.5-33.9 months), and the 2-year overall survival time was 51% (95% CI: 21.7-80.3%) (Fig. 1). The median progression-free survival was 10.2 months (95% CI: 8.0-12.4 months), and the 1-and 2-year progression-free survival rates were 24.2% (95% CI: 1.0-48%) and 16.1% (95% CI: 0-36.6%), respectively (Fig. 2). The acute toxicities are presented in Table 2. Among the non-hematologic acute toxicities, Grade 3 pneumonitis was observed in two patients and was diagnosed as infectious pneumonia and obstructive pneumonia on the basis of clinical course and image findings. No severe radiation pneumonitis was observed. Grade 3 esophagitis and skin reactions were observed in one and two patients, respectively. Among the hematologic toxicities, severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, 7 patients and 1 patient, respectively. In particular, Grade 4 neutropenia was observed in four patients (26.7%). The full doses of the first and second courses of chemotherapy were completed in 13 (87%) and eight (53%) patients, respectively.
Late toxicities were evaluated in 13 patients. One patient experienced Grade 3 radiation pneumonitis, and another patient experienced Grade 2 radiation pneumonitis. Grade 1 vasculitis and skin atrophy were also observed in one patient each.
The tumor response upon completion of PBT was PR in 6 and SD in 9. Disease progression was observed in 11 patients during the follow-up period. The first progression site was local in six patients, bone metastasis in two patients, and brain, intrapulmonary and lymph nodes outside the irradiation field in one patient each. All of the local recurrences occurred in the primary tumors, not in the lymph nodes. The course of each patient is shown in Table 3.

DISCUSSION
Dose escalation with concurrent chemoradiotherapy for advanced NSCLC is controversial. The median survival time was 16-26 months in Phase I/II studies of high-dose radiotherapy in combination with concurrent chemotherapy [1][2][3][4][5][6]. However, in a Phase III study, the one-year survival rate was 70.4% in the 74 Gy arm, which was much inferior to the 60 Gy arm (80%) [7]. The reason for the negative results in the Phase III study is not clear. However, Cox et al.
suggested the contribution of cardiopulmonary toxicities [8]. Excellent dose localization of proton beams can reduce normal tissue doses. Roelofs et al. suggested that PBT gave the lowest dose to organs at risk (lung, esophagus, spinal cord and heart) compared with 3D conformal radiotherapy and intensity-modulated radiotherapy, while maintaining doses of 70 Gy to the target [15]. Nichols et al. evaluated the dose distribution in eight patients with Stage III disease and found that PBT led to about a 30% reduction of the normal lung volume receiving 20 Gy (V 20 ) in all patients [16]. Therefore, reduction of the toxicity is anticipated by the use of proton beams, even though high doses are delivered to the tumor. However, there have been few reports of high-dose chemo-proton therapy [17,18]. Recently, Chang et al. reported a Phase II study with high-dose chemo-proton therapy using 74 Gy RBE and weekly carboplatine and paclitaxel. In this study, the median survival period was 29.4 months and the toxicities were considered acceptable [17].
In our series, CDDP and VNR were used as a chemotherapy regimen, according to the studies by the Cancer and Leukemia Group B (CALGB) [19] and Sekine et al. [20]. In the Phase II study by CALGB, gemcitabine (GEM), PTX and VNR were compared as additional agents used with CDDP for concurrent chemoradiotherapy at a dose of 66 Gy. There was a significant difference in median survival time (MST) between the three agents. However, esophagitis and platelet depletion and granulocytopenia occurred frequently in the GEM and PTX groups, respectively [19]. Sekine et al. reported the MST of 30.4 months for unresectable Stage III NSCLC treated concurrently with 60 Gy of photon radiotherapy and CDDP and VNR chemotherapy [20]. Therefore, we conducted chemoradiotherapy with CDDP and VNR, as performed previously (unpublished data), and continued this regimen. We found that radio-toxicities were relatively mild and well tolerated using PBT of 74 Gy with CDDP and VNR. However, nearly half of the patients were unable to complete chemotherapy, and myelosuppression occurred frequently under this chemotherapy regimen.
Meanwhile, local recurrence in the primary lesion was observed in six patients (40%) in our series. This occurred more often than the finding of 5% reported by Hoppe et al. [18] and of 20.5% reported by Chang et al. [17], and this may be due to the fact that the tumors were large and at an advanced stage (IIIB disease in the most patients) in our study with a mean CTV of 191.     High-dose concurrent chemo-proton therapy for Stage III NSCLC 4D CT) plus 8 mm margins [17]. Tumor size may have been assessed differently because additional uniform CTV margins were not added to the GTVs on the CT images obtained at the expiratory phase in our study. In five of the six patients who experienced local recurrence the CTV was > 222 cm 3 . The one patient with a CTV of 99 cm 3 exhibited marginal recurrence. In contrast, there was no in-field lymph node recurrence, even though 66 Gy RBE was delivered in this region. Therefore, it would appear that while 66 Gy RBE was sufficient to control lymph nodes, there are limitations to its ability to control large tumors, even with the high dose of 74 Gy RBE. Because of the short follow-up period, survival has not been assessed to date. However, the current mean survival time of 26.7 months is comparable with previous reports of Phase I/II high-dose concurrent chemoradiotherapy. Most of our patients experienced disease progression, and many received adjuvant therapy, including chemotherapy, molecular-targeted agents, and photon radiotherapy. We consider that improvements in survival for advanced NSCLC could be achieved by multimodality therapy, and our study suggests that 74 Gy RBE of PBT with concurrent CDDP and VNR is safe and useful in the multimodality therapy for unresectable NSCLC.