Abstract
Background/Aim: The treatment outcome of locally advanced non-small cell lung cancer (LA-NSCLC) has been improved over the past years but local failure is still common for these patients. The purpose of this study is to analyze the pattern of local failure and its risk factor of concurrent chemo-radiotherapy (CCRT) for locally advanced LA-NSCLC. Patients and Methods: We evaluated 77 patients treated with CCRT for LA-NSCLC from July 2007 to December 2017 at our institution. Most of the patients were treated with 60 Gy in 30 fractions of radiotherapy and concurrent chemotherapy. The median follow-up time was 26 months. Results: Among the 77 patients, 50 developed progressive disease during follow-up, including 14 with only local recurrence (LR), 10 with only distant metastasis and 26 with both. Of the 14 patients with only LR, 12 had primary tumor recurrence and 2 had recurrence in lymph nodes. A primary tumor volume of 50 cm3 was identified as the optimal cut-off value that was significantly correlated with primary tumor recurrence and overall survival. Conclusion: Primary tumor recurrence without lymph node and distant metastasis was observed in 12 patients (16%). Primary tumor volume of 50 cm3 was the optimal cut-off value for the prediction of primary tumor recurrence.
Lung cancer is a leading cause of cancer mortality worldwide (1, 2). Concurrent chemo-radiotherapy (CCRT), which combines platinum-based chemotherapy and radiotherapy is the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) (3-7). However, the 5-year overall survival (OS) rate for patients with LA-NSCLC treated with CCRT is reportedly only at 15%-20% (4-6), with distant metastasis as the most common form of recurrence (7). Recently, consolidated blockade therapy using programmed cell death ligand 1 (PD-L1) inhibitor after concurrent chemo-radiotherapy for LA-NSCLC significantly improved progression-free survival and OS. Antonia et al. have reported that for LA-NSCLC patients treated with durvalumab after CCRT an 18-month OS and progression-free survival (PFS) was at 66.3% and 45.5%, respectively, both significantly longer compared to placebo-treated patients (8). Still, in cases where the PFS is significantly improved when consolidated PD-L1 blockade therapy involves durvalumab as maintenance therapy to prevent disease progression after CCRT, local recurrence (LR) remains high (7, 9). Although LR can be classified as a recurrence occurring in the primary tumor, lymph node or both primary tumor and lymph node, only few studies have analyzed LR with respect to the sites it develops. The patterns of local failure and its risk factors should be thoroughly investigated to consider what kind of countermeasure should be taken. Here, we analyzed patterns of local failure and its risk factors among 77 patients with LA-NSCLC who were treated with CCRT at our hospital between July 2007 and December 2017.
Patients and Methods
We retrospectively analyzed patients with LA-NSCLC who underwent CCRT from July 2007 to December 2017 at our hospital. Most primary tumors were histologically diagnosed. However, a few patients could not undergo biopsies for medical reasons. For these patients, their tumors were diagnosed by our hospital's cancer board, based on laboratory and imaging findings. Tumors were clinically staged using i) contrast-enhanced computed tomography (CT), ii) gadolinium-enhanced head magnetic resonance imaging (MRI) and iii) fluorodeoxyglucose-positron emission tomography (FDG-PET) (10), and were classified according to the Union for International Cancer Control (8th edition) classification of malignant tumors (11). Radiotherapy was performed with the help of CT (LightSpeed RT 16, General Electric Company, Fairfield, CT, USA) image simulation, while the tumor respiratory motion was evaluated using four-dimensional CT (Advantage 4D, General Electric Company). Conventional three-dimensional conformal radiotherapy (3D-CRT) was used for all the patients. The prescribed dose was 60 Gy in 30 fractions for most of the patients but an adjusted dose, such as 54 Gy in 27 fractions, 64 Gy in 32 fractions and 66 Gy in 33 fractions were used for few patients by clinicians. The X-ray energy was 10-MV generated by our linear accelerator (CLINAC iX, Varian Medical Systems, CA, USA). GTV in expiratory- and inspiratory-phase CT images were delineated and defined as the internal target volume (ITV). Clinical target volume (CTV) was defined as the ITV + 5-mm margin with an additional prophylactic lymph node area at mediastinum. Planning target volume (PTV) was defined as the CTV + 5-mm margin. Treatment plan was created and calculated using commercially available software (Xio, Elekta, Stockholm, Sweden). The following chemotherapeutic regimens were chosen according to physician's judgment: i) S-1 (Taiho Pharmaceutical Co., Ltd, Tokyo, Japan) at a dose of 80 mg/m2 administered orally twice daily for 14 days plus cisplatin (Nippon Kayaku Co., Ltd, Tokyo, Japan) at a dose of 60 mg/m2 administered on day 1, ii) cisplatin at a dose of 40 mg/m2 plus docetaxel (Sanofi K.K., Paris, France) at 40 mg/m2 on days 1, 8, 29, and 36, iii) paclitaxel (Bristol-Myers Squibb, New York, NY, USA) at 40 mg/m2 plus carboplatin (Nippon Kayaku Co.) at a dose of AUC2 for 6 weeks), iv) carboplatin at a dose of AUC 2 plus docetaxel at a dose of 40 mg/m2 on days 1, 8, 29, and 36), v) low-dose carboplatin at a dose of 30 mg/m2 per day 5 days a week for 20 days. These regimens were concurrently administered with thoracic radiation of 60 Gy.
Data collection, definitions of terms and patients' consent. To evaluate treatment efficacy and adverse events, patients were required to visit our hospital every 2-3 months for the first year and every 3-6 months thereafter. Diagnostic imaging, such as CT, MRI, or FDG-PET was performed every 2-3 months for the first 2 years and every 3-6 months thereafter. Adverse events were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (12). We defined OS as the time between starting the treatment and the last follow-up date or death. Local control (LC) of the tumor was defined as the absence of recurrence at the originally irradiated site. Local recurrence was classified as the recurrence of the primary tumor and/or the one in the associated nearby lymph node. Primary tumor control was defined as being free from primary tumor recurrence. PFS was defined as the duration of freedom from local and distant recurrence or death. This study was approved by our hospital's institutional review board (approval number: 18095). An opt-out consent was obtained from all patients by giving information regarding this study on posters around the hospital and in the website of the hospital.
Statistical analyses. We calculated LC, PFS, OS, and primary tumor control rates using the Kaplan–Meier method. Factors considered to affect primary tumor recurrence were compared to one another using the log-rank test. Receiver operating characteristic (ROC) curves were calculated to find the optimal cut-off values for predicting primary tumor recurrence. Values of p<0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 25.0 (SPSS Inc., Armonk, NY, USA).
Results
A total of 77 patients received CCRT during July 2007 to December 2018. Their median follow-up period was 26 months (range=6-132 months). Patient and treatment characteristics are summarized in Table I. Two-year cumulative rates in this cohort were i) LC=52%, ii) PFS=39% and iii) OS=73%. Of the 77 patients, 50 developed progressive disease (PD) during their follow-up period, including 14 with only LR, 10 with only distant metastasis and 26 with both. Of the 14 patients with only LR, 12 had recurrent primary tumors and 2 had recurrence at lymph nodes (one in the hilar lymph nodes and one in the subcarinal lymph nodes) (Figure 1). Among the twelve patients (16%) that developed only primary tumor recurrence after CCRT, 11 patients received chemotherapy thereafter and 1 patient received best supportive care. At the last follow up, 6 patients with only primary tumor recurrence had died of the disease. Primary tumor recurrence was observed in 35 of the 77 patients (45%). In the univariate analysis, only primary tumor volume was significantly correlated with primary tumor recurrence. In the ROC analysis, primary tumor volume of 50 cm3 was the optimal cut-off value that could predict primary tumor recurrence; patients with smaller tumors (<50 cm3) had a 2-year cumulative primary tumor control rate of 84.5%, compared to 32.9% for patients with larger tumors (≥50 cm3) (Figure 2). Lymph node recurrence was observed in 13 patients (17%). There were no significant factors for lymph node recurrence in the univariate analysis. Only the primary tumor volume was significantly correlated with overall survival. These results are summarized in Table II.
Patient and treatment characteristics (N=77).
Pattern of failure including lymph node recurrence, primary tumor recurrence and distant metastasis. Among 77 patients, 50 developed progressive disease during follow-up, including 14 with only local recurrence (LR), 10 with only distant metastasis and 26 with both. Of the 14 patients with only LR, 12 had recurrent primary tumors only and 2 had recurrence at lymph nodes only.
Discussion
We analyzed the pattern of local failure and its risk factors in LA-NSCLC patients treated with CCRT. Among the 77 patients who received CCRT, 14 patients (18%) developed only local recurrence, 12 (16%) had recurrent primary tumors and 2 (2%) had recurrence at the lymph nodes. The 2-year effect rates were i) LC: 52%, ii) PFS: 39% and iii) OS: 73%, which are consistent with reported results for CCRT-treated LA-NSCLC patients (3-6, 13).
Differences in LC, PFS and OS between regimens of chemotherapy, such as cisplatin + docetaxel vs. others, carboplatin + paclitaxel vs. others, and carboplatin + docetaxel vs. others were not observed in this study. It would, however, be difficult to interpret differences in local control between regimens of chemotherapy in our results due to the small number of patients. In addition, in the literature, the differences in PFS and OS between regimens of chemotherapy appear controversial (14, 15). During follow-up, 50 of the 77 patients (68%) we treated experienced PD, including 14 with only LR, 10 with only distant metastasis and 26 with both. The most frequent recurrence pattern involved both LR and distant metastasis. Systemic chemotherapy and concomitant PD-L1 blockade therapy has been shown to address both LR and distant metastasis simultaneously (8).
Cumulative primary tumor control rates. A 2-year cumulative primary tumor control rate was approximately at 35% for primary tumors ≥50 cm3.
When possible, salvage surgery should be considered for primary tumor recurrence (16); however, its application is limited due to the poor performance status of the patients or other medical reasons. At the last follow up, 6 of 12 patients with only primary tumor recurrence died from the disease, possibly due to the fact that local recurrence is difficult to salvage.
An increased radiation dose to the primary tumor may represent a measure towards saving patients from primary tumor recurrence and improving their overall survival. However, it must be noted that intense local treatment using dose-escalated radiotherapy was associated with a worse overall survival in the RTOG0617 study, due to the increased levels of toxicity (17). If the high radiation doses would be focused only on the exact location of the primary tumor using intensity-modulated or stereotactic ablative radiotherapy (SABR) with image guidance, the extra dosing to organs at risk, such as the heart or mediastinum, could be minimized. For example, Alexander et al. have reported the feasibility of definitive image-guided intensity modulated radiotherapy (IMRT) combined with SABR in LA-NSCLC patients to increase the dose to the primary tumor (18). In their report, 40-50 Gy in 4 fractions of SABR were delivered to the primary tumor and 63 Gy in 35 fractions of IMRT were delivered to lymph node target volume. The 2-year local, regional, and distant control was 60%, 62%, and 38%, respectively and no local failure was observed in patients following SABR+IMRT, while 23% of patients failed locally following IMRT alone.
Univariate analysis of primary tumor control rate, lymph node control rate and overall survival rate.
Since the primary tumor volume (≥50 cm3) was the only significant factor for primary tumor recurrence such patients with a high risk of recurrence might be good candidates for intense local treatment.
This study has some limitations. First, it is a single-institution retrospective study, which may bias patient selection. Second, if the primary tumor volume correlated with lymph node recurrence, an intense local therapy only on the primary tumor may not lead to an improved outcome. However, in this study the primary tumor volume did not correlate significantly with lymph node recurrence, which might support our idea to intensify local treatment only on the primary tumor. Third, the additional effect of PD-L1/PD-1 blockade therapy on local control is uncertain. The Pacific trial has shown greater PFS with PD-L1/PD-1 blockade therapy after CCRT for LA-NSCLC (8). However, whether the improvement in PFS resulted from an improved control of either the primary tumors, lymph nodes, distant metastasis, or all three, is unclear. If PD-L1/PD-1 blockade therapy significantly suppresses the LR of the primary tumor, the dose-escalation would be unnecessary. Further studies are needed to clarify whether consolidated PD-L1/PD-1 blockade therapy decreases the local control of the primary tumor or not.
Acknowledgements
The Authors thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Footnotes
Authors' Contributions
TA collected data and wrote the manuscript. NK, MI, RH and YK collected data. TA, YR, SS, YM, KK, HK, SN and SK performed treatment and evaluated patients. All Authors read and approved the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this manuscript.
- Received April 20, 2020.
- Revision received May 9, 2020.
- Accepted May 15, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
