|Ahead of print
Local failure patterns after radical resection and adjuvant chemotherapy in patients with pN2 nonsmall-cell lung cancer: A retrospective analysis
Chenyu Wang1, Haixia Li1, Yongshun Chen2, Hong Ge1
1 Department of Radiation Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
2 Department of Oncology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
|Date of Submission||23-Oct-2018|
|Date of Decision||11-Feb-2020|
|Date of Acceptance||28-Mar-2020|
|Date of Web Publication||20-Jul-2020|
Department of Radiation Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou
Source of Support: None, Conflict of Interest: None
Background: The patterns of local failure in stage pN2 nonsmall-cell lung cancer (NSCLC) patients undergoing radical resection and adjuvant chemotherapy are controversial.
Methods: The sites of local failure were compared in subgroups of patients with relevant clinicopathologic features (e.g., location and size of primary lesions).
Results: Totally 75 patients with local failure after radical resection and adjuvant chemotherapy for pN2 NSCLC were included in the analysis. Thirty-seven (49.3%) patients had distant metastasis. The median duration from surgical resection to local failure was 11 months (range: 3–45 months). Sites with ≥10% failure rate in all subgroups based on the location of the primary lesions included 4R, 7, the ipsilateral hilum, and the stump. Additional sites with ≥10% failure rate included 2R, 2L, 4L, and 5 for lesions in the left upper lobe; 4L and 5 for lesions in the left lower lobe; and 2R and 3P for lesions in the right upper-middle lobe. Squamous cell carcinoma affected the stump failure rate compared to adenocarcinoma (56.3% vs. 18.0%, P = 0.003). Tumor diameter ≥5 cm affected the stump failure rate compared to tumor diameter <5 cm (44.0% vs. 18.0%, P = 0.016). Skip N2 metastasis affected the ipsilateral hilum failure rate compared to nonskip N2 metastasis (7.5% vs. 31.4%, P = 0.008)
Conclusions: For pN2 NSCLC patients undergoing radical resection and adjuvant chemotherapy, different lung lobes had different high-risk failure sites. Left lung cancer is prone to bilateral mediastinal lymph nodes recurrence, while right lung cancer mainly recurs with ipsilateral mediastinal lymph nodes. Moreover, the local failure patterns are influenced by pathological type, tumor size, and skip N2 metastasis.
Keywords: Nodal recurrence, nonsmall cell lung cancer, pN2, postoperative radiotherapy
|How to cite this URL:|
Wang C, Li H, Chen Y, Ge H. Local failure patterns after radical resection and adjuvant chemotherapy in patients with pN2 nonsmall-cell lung cancer: A retrospective analysis. Indian J Cancer [Epub ahead of print] [cited 2020 Aug 9]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=290275
| » Introduction|| |
Nonsmall-cell lung cancer (NSCLC) is the most common type of lung cancer. The 5-year survival rate after radical resection of pN2 NSCLC varies widely between 10% and 39%, suggesting the highly heterogeneous nature of pN2 NSCLC disease.,, The varying prognosis also highlights the need for tailored therapy of pN2 NSCLC patients.
Postoperative adjuvant chemotherapy confers a survival benefit on pN2 NSCLC patients and has become an integrated part of the treatment strategies.,,, However, local relapse occurs in 20%–40% of these patients. Postoperative radiotherapy (PORT) is not recommended for patients with N0 and N1 disease., Several studies indicated that PORT could reduce the risk of local relapse ,, and confer a survival benefit in patients with N2 NSCLC.,, The size of the radiation field is directly proportional to radiation-related injury. As a result, a radiation oncologist must balance potential harms versus benefits when choosing the appropriate clinical target volume (CTV). Two analyses confirmed that the delineation of CTV varies at different hospitals, even among different physicians at the same hospital as well., Fortunately, when detailed delineation guidelines are followed, these variances will be largely reduced. However, it is still controversial which lymph node regions should be included in the PORT CTV for the treatment of pN2 NSCLC patients receiving radical resection and adjuvant chemotherapy.
As postoperative prophylaxis, the PORT CTV of NSCLC should include high-risk recurrence areas after radical resection and postoperative adjuvant chemotherapy. Kelsey et al. performed an analysis of postoperative failure patterns of 61 patients with stage I to III disease, which provided a reference for the design of CTV. However, these patients are not representative of pN2 patients who are most likely to benefit from PORT. Then, Feng et al. performed a postoperative recurrence pattern analysis of 54 patients with completely resected pN2 NSCLC, but not all of these patients received postoperative adjuvant chemotherapy, and the effect of postoperative adjuvant chemotherapy on postoperative recurrence patterns was unclear. In the current study, we examined the sites of local failure in a group of pN2 NSCLC patients receiving radical resection and adjuvant chemotherapy. Failure pattern was analyzed in subgroups of patients with relevant clinicopathologic features (e.g. the location and size of primary lesions).
| » Patients and Methods|| |
We screened all patients receiving radical resection of NSCLC at Zhengzhou University Cancer Hospital between January, 2011 and December, 2015. NSCLC was staged using the Union for International Cancer Control (UICC) 7th edition. For inclusion in the final analysis, subjects must meet the following criteria: 1) radical resection with systematic mediastinal lymph node dissection (subcarinal lymph node station and at least 2 other mediastinal lymph node stations, plus hilar and intrapulmonary lymph node stations), 2) histologically proven pN2 NSCLC, 3) R0 resection margin, 4) postoperative adjuvant chemotherapy, and 5) first treatment failure involving local relapse, with or without concurrent distant metastasis. Patients receiving neoadjuvant therapy or PORT were excluded from the analysis. Patients having concurrent or subsequent second primary cancer were also excluded. The study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Zhengzhou University Cancer Hospital.
Treatment failure was determined by reviewing electronic medical records in the clinic, including imaging reports and pathology reports. Local failure was defined as disease recurrence involving the bronchial stump, ipsilateral hilar lymph nodes, and ipsilateral or contralateral mediastinal lymph nodes (except lymph node station 1). Distant metastasis was defined as distant recurrences at all other failed sites, including lymph node station 1, contralateral hilar lymph nodes, and distant organs., New or enlarged lymph node found in follow-up CT, measuring ≥1 cm in the short axis, was considered indicative of nodal failures. For patients who also underwent an FDG-PET/CT, hypermetabolism in lymph nodes or soft tissues, regardless of size, was also considered an indicator of recurrence. Pathologic verification of recurrence was not mandatory. Imaging data were reviewed by one of the authors. Grouping of the lymph nodes was based on the 2009 International Association for the study of Lung Cancer (IASLC) lymph node map.
Statistical analysis was performed by using SPSS (version 22; SPSS Inc., Chicago, IL). The failure rate was compared by χ2 test. A value of P < 0.05 was considered statistically significant.
| » Results|| |
The study flowchart is shown in [Figure 1]. Between January, 2011 and December, 2015, totally 2,570 patients underwent surgical resection of lung cancer at our hospital and 295 (11.5%) of them had pN2 NSCLC. Seventy patients were excluded due to loss to follow-up, and 62 patients were excluded because they received neoadjuvant chemotherapy (n = 22) or PORT (n = 40). Twenty-three patients who did not receive postoperative adjuvant chemotherapy were also excluded. Furthermore, 42 patients with only distant metastasis, 21 patients with no recurrence at the last day of follow-up (December 2017), and 2 patients with a second primary cancer were excluded. Finally, 75 patients were included in this retrospective analysis. The characteristics of the study cohort are shown in [Table 1]. The median age was 62 years (range: 39–75 years) and 59% of the patients were male. Recurrence was confirmed pathologically in 28% (21 of 75), PET (GE Discovery ST16 PET-CT) in 40% (30 of 75), and by CT (Bright Speed GE 16 Row CT) in all patients. Sixty-seven percent of the patients had adenocarcinoma and 21% had squamous carcinoma. Most patients had T1 (28%) or T2 (59%) NSCLC. All patients received 1 to 4 cycles of postoperative adjuvant chemotherapy. Thirty-seven (49.3%) patients had both local and distant recurrences, and 38 (50.7%) patients only had local failure. The median duration from surgical resection to local failure was 11 months (range: 3–45 months). Forty-eight patients (64%) received salvage treatment, of which 11 patients received local radiotherapy, 22 patients received palliative chemotherapy, and 15 patients received targeted therapy. All of these patients were evaluated. There were 2 patients with complete response (CR), 22 patients with partial response (PR), 17 patients with stable disease (SD), and 7 patients with progressive disease (PD).
|Table 1: Demographic and clinicopathologic characteristics of the study population|
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Outcomes by sites of initial tumor are shown in [Figure 2] and [Table 2]. For all patients (n = 75), the most common site of failure was 4R (44%), followed by 7 (43%), the stump (27%), and the ipsilateral hilum (19%). For left upper lobe lung cancer (n = 13), 29 sites of local failure were observed, and sites with a failure rate ≥10% included 7, 4R, the ipsilateral hilum, 2R, 2L, 4L, 5, and the stump. Six patients had isolated recurrence. For left lower lobe lung cancer (n = 16), 30 sites of local failure were recorded, and sites with a failure rate ≥10% included 4R, 7, 4L, 5, the ipsilateral hilum, and the stump. All patients had multiple sites of recurrence. For right upper-middle lobe lung cancer (n = 25), 43 sites of local failure were recorded, and sites with a failure rate ≥10% included 4R, 7, 2R, 3P, the stump, and the ipsilateral hilum. Eleven patients had isolated recurrence. For right lower lobe lung cancer (n = 21), 37 sites of local failure were documented, and sites with a failure rate ≥10% included 7, the stump, 4R, and the ipsilateral hilum. Ten patients had isolated recurrence.
|Figure 2: Sites of local failure after surgical resection and adjuvant chemotherapy of left upper, left lower, right upper-middle, and right lower lobe tumors. Single recurrent site and simultaneously multiple recurrent sites within the thorax are represented by open stars and solid stars, respectively. Ao = Aorta; PA = Pulmonary artery|
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In addition, the stump failure rate of squamous cell carcinoma patients was significantly higher than that of adenocarcinoma patients (56.3% vs. 18.0%, P = 0.003). The stump failure rate of patients with a tumor diameter ≥5 cm was markedly higher than that of patients with a tumor diameter <5 cm (44.0% vs. 18.0%, P = 0.016). Compared with patients with nonskip N2 metastasis, patients with skip N2 metastasis had a significantly lower failure rate in the ipsilateral hilum (7.5% vs. 31.4%, P = 0.008) [Table 3].
|Table 3: Patterns of failure based on pathological type, tumor size, and skip N2 metastasis|
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| » Discussion|| |
At present, a number of large retrospective studies have shown that PORT can improve the overall survival of pN2 NSCLC patients with modern technology.,, However, currently, there is no consensus on CTV. The purpose of our study was to evaluate the local failure patterns after radical resection and adjuvant chemotherapy in patients with stage pN2 NSCLC and provide a basis for designing a reasonable PORT CTV.
Hata  mapped lung lymphatic drainage in 179 healthy volunteers by lymphatic scintigraphy after injecting the lung segments with a tracer. The results showed that the right upper lobe lymph was drained to 4R and 2R. The left upper lobe lymph was mainly drained to the 5, 6, and 4L, and can also be drained to the contralateral mediastinal venous angle. Left and right lower lobe lymph was drained to the ipsilateral hilum and 7, and further to 4R and 2R, and the lower left lobe lymph can also be drained to 4L and 2L. Lin et al.analyzed the postoperative pathological data of 810 patients with operable NSCLC, showing that the lymph node metastasis rate was the highest (41.2%) regardless of primary tumor site, and right upper lung cancer often metastasized to 2-4, while right lower lung cancer often metastasized to 2-4 and 7. Left upper lung cancer often metastasized to 2-4, and left lower lung cancer often metastasized to 5 and 7. The above studies are based on lymphatic imaging and postoperative pathological data. Although these data provide information on the pathways and risks of lymph node metastasis, they do not actually reflect the most likely sites of recurrence after radical surgery.
Kelseyet al. first analyzed postoperative failure patterns of 61 patients with NSCLC and found that surgical stump (44%) was the most common local failure site and the common failure sites included the stump, 10L, 5, and 4R in left upper lung cancer, 7 and 4R in left lower lung cancer, 4R and the stump in right upper lung cancer, and 10R and 4R in right lower lung cancer. Patients in the study by Kelseyet al. had stage I to III lung cancer, rather than patients with pN2 NSCLC who were most likely to benefit from postoperative radiotherapy. However, it provides a method for subsequent research. Feng et al.analyzed the failure patterns of 54 patients with completely resected pN2 NSCLC and showed that the common failure sites were 4R, 7, 4L, 10L, 6, and 5 in left lung cancer and 2R, 4R, 10R, and 7 in right lung cancer. However, the study by Feng et al.included patients who did not receive postoperative adjuvant chemotherapy, and the effect of postoperative adjuvant chemotherapy on local recurrence patterns was unclear; therefore, the findings from the study are not representative of local failure patterns in patients with pN2 NSCLC who underwent radical surgery and postoperative adjuvant chemotherapy. PORT as a preventive treatment should include high-risk postoperative failure sites (≥10%) in its CTV. The results of this study showed that the high-risk failure sites (≥10%) were 7, 4R, the ipsilateral hilum, 2R, 2L, 4L, 5, and the stump in the left upper lobe, 4R, 7,4L, 5, the ipsilateral hilum and the stump in the left lower lobe, 4R, 7, 2R, 3P, the stump, and the ipsilateral hilum in the right upper-middle lobe, and 7, the stump, 4R, and the ipsilateral hilum in the right lower lobe. The results of this study showed that cancer at different lung lobes had different high-risk failure sites. It is recommended that radiation oncologists should choose high-risk failure sites for PORT based on different lung lobes.
Our study found that the local failure site of left lung cancer is usually in the bilateral mediastinum, while the local failure site of the right lung cancer is usually in the ipsilateral mediastinum. Our findings appear to be consistent with normal lung lymphatic drainage.
Feng  suggested that the CTV of postoperative radiotherapy for NSCLC should include not only the hilum but also the stump, the ipsilateral mediastinum, subcarinal lymph node station, and part of the contralateral mediastinum. Kelsey et al. believed that postoperative recurrence of NSCLC is mainly in the stump and mediastinum, and 59% of recurrences are only mediastinal recurrence without hilar recurrence. This study found that the rate of hilum failure in patients with skip N2 metastasis was lower than that in patients with nonskip N2 metastasis, which suggests that for these subgroups of patients with skip N2 metastasis, the hilum might not be in CTV, but it needs to be confirmed by prospective studies. Martini et al. reported that squamous cell carcinoma is prone to local recurrence and that local recurrence is associated with T stage. This study shows that squamous cell carcinomas are more likely to have stump failure than adenocarcinomas; tumors with a diameter ≥5 cm are more likely to have stump failure than those with a diameter <5 cm as well. This may be due to the fact that squamous cell carcinoma is mostly center type and adjacent to the trachea and large blood vessels. When the tumor is large, local invasion and metastasis are easy to occur; hence, the stump is more likely to relapse. This suggests that we should strengthen regional therapy of stump in patients with squamous cell carcinoma and a large tumor diameter.
However, our study has several limitations. First, this is a retrospective study based on a relatively small sample size. There are some limiting factors that may lead to potential biases. Second, imaging studies have a certain false-positive rate for lymph node recurrence. Although 28% of the patients in our study were pathologically confirmed, 40% of the patients underwent PET-CT. One study showed that the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET-CT in the diagnosis of mediastinal lymph node metastasis were 94.4%, 95.7%, 95.1%, 95.7%, and 94.4%, respectively. PET-CT can detect lymph node metastases <1 cm, which is more sensitive and accurate than CT. In addition, according to the evaluation of the efficacy of salvage treatment, we indirectly proved the failure of local lymph nodes.
| » Conclusions|| |
In conclusion, for pN2 NSCLC patients undergoing radical resection and adjuvant chemotherapy, different lung lobes had different high-risk failure sites. Left lung cancer is prone to bilateral mediastinal lymph nodes recurrence, while right lung cancer mainly recurs with ipsilateral mediastinal lymph nodes. Moreover, the local failure patterns are influenced by pathological type, tumor size, and skip N2 metastasis.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]