Abstract

Background: This study aims to investigate the factors associated with pathological complete response following neoadjuvant treatment and to examine the prognostic value of pathological complete response in patients with non-small cell lung cancer undergoing surgical resection.

Methods: Between February 2009 and January 2016, a total of 112 patients (96 males, 16 females; mean age 60±8 years; range, 37 to 85 years) with the diagnosis of non-small cell lung cancer who underwent anatomical pulmonary resection after neoadjuvant treatment were retrospectively analyzed. Demographic, clinical, radiological, and pathological characteristics of the patients were recorded. The patients were classified as pathological complete response and nonpathological complete response according to the presence of tumors in the pathology reports. Predictive factors for pathological complete response and its prognostic significance were analyzed.

Results: The mean follow-up was 35±20 (range, 0 to 110) months. Of the patients, 30 (27%) achieved a pathological complete response. Reduction rate in tumor size was significantly higher in the responsive group (32.5±21.6% vs. 19.2±18.8%, respectively) and was a predictor of pathological complete response independent from the T and N factors (p=0.004). Survival of the responsive patients was significantly longer than unresponsive patients (75±9 vs. 30±4 months, respectively; p<0.001). During follow-up, tumor recurrence was seen in 30 patients. Recurrence was observed in only one patient in the responsive group, while 29 patients in the unresponsive group had recurrence or metastasis.

Conclusion: Tumor shrinkage rate after neoadjuvant treatment in non-small cell lung cancer is a predictive factor for pathological complete response. Survival of patients with a pathological complete response is also significantly longer than unresponsive patients.

Lung cancer is the most common cancer in both genders and is responsible for more than 25% of all cancer-related deaths. Among these cases, the five-year survival rate is below 21%.[1-3] Primary lung cancer mainly consists of small cell lung cancer and non-small cell lung cancer (NSCLC) and the latter represents approximately 85% of the whole.[4] Surgical anatomical resection is the gold-standard treatment option in patients with early stage NSCLC. Only 25% of the lung cancers are eligible for surgery, and the other treatment options of chemotherapy and radiotherapy have been increasingly applied in recent years.[3]

In locally advanced disease, complications of surgical treatment alone have resulted in locoregional failure and distant metastasis and, therefore, neoadjuvant treatment before definitive local treatment has been initiated.[5] In Stage IIIA(N2), progressionfree survival is reported to be longer with surgery after chemoradiotherapy with no significant survival advantage.[6] Further studies have proved survival benefit with neoadjuvant chemotherapy.[5] The role of adding neoadjuvant radiotherapy to chemotherapy is not yet clear, since a clear survival benefit compared to sole chemotherapy has not been proven.[7] However, the treatment decision in locally advanced disease is challenging, as it includes a widely heterogeneous patient group and the effective treatment decision should be made by a Medical Council.

Other t han Stage III disease, Stage II NSCLC patients may benefit from neoadjuvant treatment.[8] The main advantages of neoadjuvant therapy include diminished tumor volume and improved micrometastasis control, leading to accurate assessment of sensitivity and resistance of the agents and providing better treatment tolerability and earlier cessation of smoking.[9]

Following neoadjuvant treatment, the assessment of pathological response and the prognostic importance of pathological complete response (pCR) in surgical specimens have been questioned recently.[9-11] In cases where the surgical specimens contain no viable tumor cells, naming pCR, the prognosis is reported to be significantly better.[11-13]

The reported pCR rates varies in a wide range. The width of this range mostly depends on the study method, pCR definition, and patient selection criteria. In a series of 127 patients, Coroller et al.[10] reported pCR in 21% and Mouillet et al.[11] in 8 %. In local advanced NSCLC, patients with pCR were shown to have a better prognosis than non-pCR patients and were recommended to be restaged in the TNM classification.[14]

These improved survival rates observed in pCR patients have led to the factors associated with complete response to be questioned. Varied results have been published in a limited number of studies investigating this issue and yet, there is no predictor for a better response to neoajuvant treatment. The tumor type is the mostly argued issue that both adenocarcinoma and squamous cell carcinoma are found to be associated with pCR.[11,15,16]

In the present study, we aimed to investigate the factors associated with pCR following neoadjuvant treatment and to examine the prognostic value of pCR in NSCLC patients undergoing surgical resection.

Methods

This single-center, retrospective study was conducted in a tertiary referral center for chest diseases and thoracic surgery between February 2009 and January 2016. A total of 112 patients (96 males, 16 females; mean age 60±8 years; range, 37 to 85 years) with the diagnosis of NSCLC who underwent anatomical pulmonary resection after neoadjuvant treatment were included. Patients who were not followed in our center with missing recurrence or metastasis data were excluded. The study flow chart is shown in Figure 1. A written informed consent was obtained from each patient. The study protocol was approved by the Süreyyapaşa Chest Disease and Thoracic Surgery Training and Research Hospital Ethics Committee. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Figure 1: Study flowchart.

Data including demographic, clinical, radiological, and pathological characteristics of the patients, smoking habit, location and size of the tumor, fluorodeoxyglucose (FDG) uptake on positron emission tomographycomputed tomography (PET-CT), diagnostic methods, and histological types of the tumor were recorded. Clinical staging was supplemented according to the current seventh edition of the Tumor, Node, Metastasis (TNM) Classification of Malignant Tumors.[17] The indications for neoadjuvant treatment and treatment regimen, post-treatment tumor size, and radiological stage were investigated. The surgical resection type was recorded based on the additional invasive procedures to investigate N2 lymph node positivity. The tumor size was determined using pathological evaluation of the resected material. In addition, all patients were evaluated for the development of recurrence or metastasis during follow-up until January 2017. Survival status was also checked using the National Death Reporting System.[18]

Oncological evaluation and surgical method
In our center, a Medical Council including specialists in chest diseases, thoracic surgery, medical oncology, radiology, pathology, and radiation oncology evaluates cases of lung cancer and gives the decision of neoadjuvant treatment. The eligibility of the patient for surgery after the treatment is also evaluated by the Medical Council. After a radiological evaluation, the diagnostic procedures are indicated. These procedures include bronchoscopy, endobronchial ultrasonographic endoscopy (EBUS), transthoracic fine-needle aspiration biopsy (TTFNAB), videoassisted thoracoscopic surgery (VATS), thoracotomy, mediastinoscopy, and mediastinotomy. Detection of a lymph node measuring >2 cm in size on the mediastinal long axis or >1 cm in size on the mediastinal short axis on thoracic CT, or a mediastinal lymph node with a maximum standardized uptake value (SUVmax) value of 2.5 on PET-CT is considered metastasis in the radiological staging.[19] Athoracic CT or PET-CT is used for radiological staging after neoadjuvant treatment, and in some cases, staging is performed during a surgical procedure. Re-mediastinoscopy is performed in cases of clinical necessity, since it is advised as a specific and sensitive procedure to avoid unnecessary thoracotomies.[20]

Hematological and biochemical examinations, as well as cardiac and respiratory reserve evaluation are routinely performed before surgery. Anatomical pulmonary resection is performed via thoracotomy or VATS. Either mediastinal lymph node dissection or mediastinal lymph node sampling is performed according to the European Society of Thoracic Surgeons guidelines.[21]

The patients were divided into two groups according to the histopathological examination of the surgical resection material according to the presence of viable tumor cells:

Group 1 (pCR, n=30): Patients without histopathological evidence of tumor cells.

Group 2 (non-pCR, n=82): Patients with histopathological evidence of tumor cells in various sizes.

The clinical and radiological characteristics of all patients were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.[22] The sizes of the tumor before and after neoadjuvant treatment were evaluated, and the TNM stage was compared between the groups. In addition, the development of recurrence or metastasis during followup and survival rates were compared.

Statistical analysis
Statistical analysis was performed using the SPSS for Windows version 16.0 software (SPSS Inc., Chicago, IL, USA). The quantitative data were expressed in mean ± standard deviation (SD) or median (min-max), while the qualitative data were expressed in number and frequency. For comparative statistics, a t-test was used for the analysis of quantitative data and a chi-square test was used for the analysis of qualitative data. The diagnostic power of the parameters found to be significant in the diagnosis was evaluated according to the sensitivity, specificity, and cut-off values using the Receiver Operating Characteristic (ROC) curve. Logistic regression analysis was used for independent predictors of pCR. The Kaplan-Meier method was used for survival analysis. A p value of <0.05 was considered statistically significant with 95% confidence i nterval (CI).

Results

Of all patients, 70 (63%) were diagnosed via fiberoptic bronchoscopy and 31 (27%) via TTFNAB. Other diagnostic methods were mediastinoscopy (n=6), EBUS (n=3), rigid bronchoscopy (n=1), and VATS (n=1). Patient data are shown in Table 1.

Table 1: Demographic, clinical, radiological, and pathological characteristics of patients

Ninety-five patients (85%) had Stage IIIA, 14 patients (12%) had Stage IIB, and three patients (3%) had Stage IIIB disease prior to neoadjuvant therapy (Table 2). In Stage IIB, neoadjuvant treatment was applied for chest wall tumors and pancoast tumors. Neoadjuvant chemotherapy regimens consisted of paclitaxel and carboplatin (n=54, 48%) and cisplatindocetaxel (n=46, 41%) combinations. The mean radiotherapy dose was 58.5 (range, 45 to 66) Gy.

Table 2: Clinical and pathological staging before and after neoadjuvant treatment*

Neoadjuvant treatment was given due to clinically N2 disease in 75 (67%) and clinical T4 disease in 23 patients (21%). The most common cause of a clinical T4 appraisal was mediastinal invasion with other causes being the presence of an additional nodule or major vessel invasion.

Following neoadjuvant treatment, 55 patients (49%) with a suspected N2 tumor were scheduled for mediastinoscopy, six patients (6%) for re-mediastinoscopy, and three (2%) for extended mediastinoscopy. In addition, resection of aortopulmonary window lymph nodes after VATS was performed in one patient (1%).

After completion of neoadjuvant treatment, the mean resectional surgery duration was 4.2±1 (range, 2 to 7) weeks. Lobectomy was performed in 76 (66%), pneumonectomy in 22 (20%), and bilobectomy in 14 patients (11%). Two patients (2%) underwent a superior sleeve bilobectomy, while two patients (2%) underwent a right upper sleeve lobectomy. The surgical procedure was terminated with an R1 resection in three patients (3%), and an R0 in 109 patient (97%). According to the pathology reports, no tumor cells were found in 30 patients (27%), and they were evaluated as pCR (Table 1).

There was no significant difference in gender (p=0.862), age (p=0.818), smoking habit (p=0.163), tumor characteristics (p=0.355), indications for neoadjuvant treatment (p=0.45), chemotherapy regimens (p=0.361), and treatment modalities (p=0.345) between the pCR and non-pCR groups. Chemotherapy regimens (p=0.361) and radiotherapy doses (p=0.342) had no effect on pCR. There was no statistically significant difference between the groups in terms of resection type (p=0.057) or the development of bronchopleural fistula during follow-up (p=0.128).

The radiological tumor sizes of pCR and non-pCR groups at the time of diagnosis were 5.2±1.9 vs. 4.9±1.9 cm, respectively (p=0.497). Following neoadjuvant therapy, the mean radiological tumor sizes were similar between the groups (3.4±1.5 cm vs. 3.9±1.8 cm, respectively; p=0.662). In five patients, the mean tumor enlargement ratio was 0.26 (range, 0.1 to 0.5) cm after neoadjuvant treatment. One of those patients was grouped as pT0 (the tumor was 2.0 cm at the time of diagnosis and 2.1 cm before surgery). However, according to the RECIST v1.1 criteria, the partial response rate was higher in the pCR group (p=0.02). The sizes of the tumors decreased to a greater extent in the pCR group (32.5±21.6% vs. 19.2±18.8%, respectively; p=0.002).

There was no statistically significant difference between the groups in terms of the T or N factor of clinical staging (Table 3). Neoadjuvant pre- and post-treatment N factors significantly regressed in both pCR and non-pCR groups (p=0.008 and p<0.001, respectively), indicating a statistically significant difference between the groups (p=0.563).

Table 3: Comparison of the patients with pT0 and non-pT0 according to clinical staging

A logistic regression analysis revealed that radiological tumor size shrinkage independently predicted the pCR apart from T and N factors (Table 4). For a cut-off value of 22.4% of tumor shrinkage after neoadjuvant therapy, the possibility of pCR increased with 75% sensitivity and 63% specificity (the area under the curve value for tumor size was 0.676; p=0.004) (Figure 2).

Table 4: Logistic regression analysis results

Figure 2: ROC curve for tumor shrinkage.
ROC: Receiver operating characteristic.

The mean follow-up was 38±3 (range, 1 to 132) months. During follow-up, 15 patients (13%) had a recurrence and 15 patients (13%) had a distant organ metastasis. Six patients (5%) patients died within the first postoperative 30 days in the non-pCR group, while no mortality was observed within the initial postoperative 30 days in the pCR group. During follow-up, 62 patients (55%) died. The median survival was longer in the pCR group (75±9 vs. 30±4 months, respectively; p<0.001) (Figure 3). Recurrence was observed in only one patient (3%) in the pCR group, while 29 patients (35%) had recurrence or metastasis in the non-pCR group.

Figure 3: Survival curve for pCR and non-pCR patients.
pCR: Pathological complete response.

Discussion

In the present study, more than one-fourth of the NSCLC patients who received preoperative cancer treatment were found to have pCR. In the pCR group, after neoadjuvant treatment, a marked decrease in the tumor size was observed radiologically, and this appears to be the first reported demonstration of this relationship. In addition, the disease-free survival of these patients was better and the length of time until recurrence was longer.

It has been reported that pCR patients who receive preoperative treatment have a longer survival time, compared to patients with early-stage NSCLC.[11,12] Katakami et al.[13] reported a five-year survival rate of 79% for NSCLC patients who had a complete response after neoadjuvant treatment. Similarly, Mouillet et al.[11] found a statistically significant higher five-year survival rate (80%) and Melek et al.[14] reported this figure as 72%. In a study conducted by Betticher et al.,[12] the rate of distant metastasis and recurrence was lower in pCR patients who underwent surgery after three cycles of neoadjuvant chemotherapy. Other studies also demonstrated that the rate of recurrence or metastasis was lower in patients with established pCR.[23,24] In line with the literature, the present study found that survival time was significantly longer in the pCR group and that the rate of recurrence or metastasis was lower than that of the non-pCR group. Thus, identifying these patients beforehand is of great importance for clinicians, as the achievement of pCR strongly predicts a favorable prognosis.

The rates of pCR differ among the conducted studies in the literature, ranging from 0 to 34% (Table 5).[14,25,26] Betticher et al.[12] reported pCR in 14 (19%) of 75 patients; however, they included tumors containing necrosis and fibrosis at a rate of ?95%. Cerfolio et al.[25] also reported pCR in 19 (34%) of 56 patients, but defined pCR as the presence of viable tumor cells in ?1% of the entire field of pathological examination. In the present study, the absence of any viable tumor cells in the pathological examination was defined as pCR, and a similar pCR rate was found.

Table 5: Rate of patients with pCR in the literature

To the best of our knowledge, there is no study examining the link between lymph node involvement or pancoast tumors and pCR. Albain et al.[6] found pCR in 14% of the patients who received neoadjuvant treatment only due to their N2 status. In another study including 574 N2 patients, pCR was detected in 13% of the cases.[27] In previous studies where pancoast tumors are considered an indication for neoadjuvant therapy, Rusch et al.[28] and Kunitoh et al.[29] detected pCR in 26% and 21% of their cases, respectively. In another study involving only cases with a pancoast tumor, the pCR rate was found to be 32%.[30] In our study, we found no statistically significant correlation between N2 and neoadjuvant treatment, although the ratio of patients who received neoadjuvant treatment for an N2 tumor was relatively higher. The pCR rate in cases with pancoast tumors was found to be closer to the rate reported in the literature.[30]

According to the histological type of tumors, variable results have been reported in the literature. Pisters et al.[15] found a statistically significantly higher rate of pCR in patients with adenocarcinoma. Mouillet et al.[11] reported squamous cell carcinoma as the sole predictor of pCR. Similarly, some other authors found higher rates of pCR in patients with squamous cell carcinoma.[10,31] A recent study concluded that squamous cell carcinoma responded better to neoadjuvant chemotherapy and that major pathological response criteria for adenocarcinoma and squamous cell carcinoma should be different.[16] In the present study, the pCR rate was higher in the patients with squamous cell carcinoma, but without a statistical significance. This may be due to the effect of genetic factors or molecular markers, rather than due to the tumor histology. Further researches would improve our understanding of this issue.

The results of the previous studies are in favor of an increased respectability of platinum-based regimens.[5] In the present study, chemotherapy regimen showed no significant effect on PCR rates. Cisplatin-docetaxel combination regimen had a slightly higher PCR rates, although the difference was not significant. Future studies may shed light into the therapeutic effect of immunotherapy and be helpful to identify the most effective chemotherapy combination. The addition of radiotherapy to neoadjuvant chemotherapy was also reported to increase the rate of pCR; however, the pathological response did not increase overall survival.[32,33] In our study, the patients with neoadjuvant chemoradiotherapy had a higher rate of pCR, while no statistically significant correlation was observed. Although the form of treatment is often not statistically significant, it may be helpful to better identify the molecular markers and determine the most appropriate individualized treatment modality.

The present study indicated a greater shrinkage in tumor size in the pCR group. To the best of our knowledge, there are two studies investigating this relationship before. Pisters et al.[15] in a series of 21 patients, and Cerfolio et al.[25] in a series of 36 patients found no significant relationship between change in the tumor size and pCR. Of note, in both studies, the sample size was lower than in our study. The rate of reduction in tumor size may be an indicator of response to neoadjuvant treatment. However, further studies are needed in this area.

The main limitations of the present study are its single-center and retrospective design. The main strengths of the study include close follow-up of the patients in the tertiary referral setting and the availability of complete, detailed documentation of the patients.

In conclusion, pathological complete response can be achieved in a significant number of nonsmall cell lung cancer patients undergoing surgical resection after neoadjuvant treatment. Patients with a pathological complete response have significantly better survival. The rate of shrinkage in tumor size following neoadjuvant treatment may be helpful in predicting pathological complete responses.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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