Long-term effects of neoadjuvant radiotherapy, adjuvant radiotherapy, and chemotherapy-only on survival of locally advanced non-small cell lung Cancer undergoing surgery: a propensity-matched analysis

Lung cancer is currently the leading cause of cancer death around the world [1]. American Cancer Society has estimated that there will be 222,500 new cases and 155,870 deaths caused by lung cancer in the United States in 2017 [2], of which non-small cell lung cancer (NSCLC) constitutes about 85% [3]. Approximately one-third of NSCLC patients are diagnosed with locally advanced (LA) disease (stage IIIA/IIIB) [4]. Since this is an extremely heterogeneous group, the optimal treatment remains controversial [5‐9]. Though many studies have compared the survival difference between adjuvant chemotherapy or radiotherapy (RT) and surgery alone [10‐13], and between neoadjuvant therapy and surgery alone [14‐17], few have investigated the difference between neoadjuvant RT and adjuvant RT, as well as the survival difference between RT plus chemotherapy and chemotherapy-only for LA NSCLC patients undergoing surgery. Although a combined modality approach of RT, chemotherapy, and surgery is routinely recommended for resectable LA patients, the optimal sequence is still under debate, and the prognosis remains poor with a high rate of distant metastasis and low five-year overall survival rate [4, 18].

The aims of neoadjuvant RT are to improve resectability through shrinking the tumor, downstage the nodal disease, sterilize micrometastases, and enhance local control by the removal of the residual tumor and nodal disease [8, 19, 20]. The disadvantages are also coexisting which show the negative impact of treatment on patients’ performance status, the technically challenging surgery after RT, and the increased rate of postoperative complications [21]. To date, no population-based evaluation of the long-term effects of neoadjuvant/adjuvant RT has been performed. Therefore, we designed a retrospective study with three propensity-score-matched groups: surgery + chemotherapy + neoadjuvant RT group (neoadjuvant RT group), surgery + chemotherapy + adjuvant RT group (adjuvant RT group), and surgery + chemotherapy-only group(chemotherapy-only group), to evaluate the effect of the sequence of RT with surgery on cancer-specific and overall survival among patients with LA NSCLC.

To our knowledge, the present study is the first to compare the effect of neoadjuvant RT, adjuvant RT, and chemotherapy-only on the long-term survival of LA NSCLC patients undergoing surgery using the large population-based SEER database and propensity score matching technique. The RT arms did not confer an additional cancer-specific or overall survival advantage beyond that achieved with surgery plus chemotherapy alone. However, for patients at T1/2 & N2/3, the chemotherapy-only group seems to be at a survival disadvantage compared with neoadjuvant or adjuvant RT groups. The risk factors for cancer-specific and overall mortality are mainly the tumor characteristics including the grade, the size, and the lymph node involvement.

A recent analysis based on the National Cancer Database [23] shows that both adjuvant and neoadjuvant chemotherapy provide superior survival outcomes compared to surgery alone, though no clear evidence is showing that neoadjuvant is superior to adjuvant in the treatment of resectable stage II and III NSCLC. In fact, whether RT can improve or not the outcomes of surgery and chemotherapy in LA NSCLC is still the subject of scientific debate, on which Robinson et al. conducted a study using large database analyses [24] and concluded that modern postoperative radiotherapy seems to confer an additional overall survival advantage beyond that achieved with adjuvant chemotherapy alone for patients with N2 NSCLC after complete resection. While a recently issued critical review by Tini et al., which discussed possible combination strategies aimed to improve the outcome of lung cancer patients, indicated the RT management of LA NSCLC is currently unsatisfactory [25]. Results from our study further confirmed that for patients with N2/3 and T1/2, all of whom received complete resection and chemotherapy, neoadjuvant and adjuvant RT confer an additional improvement in cancer-specific survival. However, such an advantage was not discovered among patients with other T and N stage.

Previous studies have shown that respectable survival can be achieved after neoadjuvant chemoradiation, followed by anatomic resection, in selected patients with clinically advanced NSCLC [26]. However, this study did not find a significant difference between neoadjuvant and adjuvant RT. There is some issue to discuss. Firstly, the patients in neoadjuvant RT group at least showed a good response, as the patients with the response evaluation of “PD” lose the opportunity to surgery, which may cause unbalance between the neoadjuvant and adjuvant RT groups. Secondly, for patients who received neoadjuvant RT, the primary tumors were harder to undergo surgery, which made the neoadjuvant RT necessary to come first and weakened the additional survival benefit of neoadjuvant RT compared to adjuvant RT. Thirdly, though not significantly different in multivariate analysis, the survival curves of neoadjuvant and adjuvant RT are much closer for patients with T1/2 & N2/3 than those of patients with T3/4 & N2/3 or T3/4 & N0/1. Besides, the survival rate of the neoadjuvant RT is a little higher than that of the adjuvant RT (combined with lobectomy/bilobectomy) for patients with T3/4 & N0/1, while the situation is reversed for patients with T3/4 & N2/3, which indicates the benefit of neoadjuvant or adjuvant RT may be linked to a proper selection of patients.

Results from our study also confirm the importance of well-established predictors of poorer outcome in patients with NSCLC, including older age and male sex [27, 28], although the absolute effect was small relative to other factors. We also demonstrated an independent effect of tumor size and higher tumor grade.

Unlike clinical trials, many factors involved in determining the course of treatment will not be captured in the registry data. Such factors include patient preferences, physician recommendations, comorbidities, and proximity to treatment providers. However, the potential selection bias originating from the retrospective design was minimized with the propensity score matching process and the subgroup analyses, and the sensitivity analyses also proved the validity and reliability of study results. Nevertheless, several limitations should be taken seriously when interpreting the results. Firstly, we chose to study the long-term effects of neoadjuvant RT, adjuvant RT, and chemotherapy-only on survival among patients who received radical surgery, but the sequence of chemotherapy with surgery and RT was unknown. Therefore, neither did we distinguish neoadjuvant or adjuvant chemotherapy in this study nor did we know whether the patient received concurrent or sequential chemoradiotherapy or the two treatment modalities were divided by surgery. Secondly, the detailed information of RT such as daily and total dose, volume of RT field, and the details of surgery such as pathologic resection margin status, lymphadenectomy, and surgical techniques of surgeons was not available thus could not be evaluated in this study. Thirdly, Other unmeasured and potential confounders included patients’ medical history and comorbidities. The simple classification of surgery according to the extent of resection may not fully reflect the details of the surgical procedures. In the future, with enough information of chemotherapy, studies on the effect of different combinations of treatment modalities as well as different sequences of RT or chemotherapy should be performed to learn more about their long-term effects.

Though with limitations, this study indicated that the RT did not confer an additional cancer-specific or overall survival advantage beyond that achieved with surgery plus chemotherapy alone for LA NSCLC patients. However, for patients at T1/2 & N2/3, the chemotherapy-only group seems to be at a survival disadvantage compared with neoadjuvant or adjuvant RT groups. The findings of this study suggest that the benefit of additional neoadjuvant or adjuvant RT to chemotherapy may be linked to a proper selection of LA NSCLC patients who undergo surgery. The timing of radiotherapy should be decided on the premise of fully considering patients’ condition and the quality of life after treatment.