Multiple primary lung cancer (MPLC) is a special type of lung cancer characterized by more than one cancerous lesions independent of each other and is becoming more common clinically. It may be widely accepted that surgery is the principal treatment for MPLC patients. For these multiple primary lesions, some applied radical resection for all while others used sublobar resection. As the surgical strategy for the treatment of MPLC is divergent, this study aimed to evaluate the difference between these two strategies in terms of prognosis. This study included 913 cases that went through resection of at least two lesions from ten independent researches. And the results suggested that sublobar resection was not an indicator for worse prognosis compared with complete standard resection for all lesions (HR: 1.07, 95%CI: 0.67-1.71). With medium heterogeneity, subgroup analysis based on different type (synchronous or metachronous), geographic origin and dominant sex was carried out, which showed no statistical difference. No publication bias was detected by either qualitative or quantitative methods.
As for single lesion, anatomic pulmonary resection is recommended for patients at early stages [7], which might be applicable to MPLC patients. Yet sublobar resection including segmentectomy and wedge resection is appropriate in selected patients. Indications include poor pulmonary reserve or other major comorbidities that contraindicate lobectomy, peripheral nodule less than 2 cm with at least one of the following: pure AIS, nodule has more than 50% ground-glass appearance on CT, or radiologic surveillance confirms a long doubling time (more than 400 days). Adenocarcinoma in situ (AIS) is defined as a small (≤3 cm) localized nodule with lepidic growth, mostly non-mucinous and multiple AIS tumors can occur synchronously [21]. Researches showed that for small size (less than 3 cm), low-risk and poor pulmonary function NSCLC patients, those taking sublobar resection had a comparable survival outcome compared with standard surgical approach [22]. A research by Fan et al [23] found that for stage I NSCLC patients, those undergoing lobectomy tended to have better survival than sublobar resection; but the difference was insignificant while comparing stage Ia patients with lesion size less than 2cm in diameter. Another research aiming at solid pulmonary nodules at stage Ia also indicated that these two surgical strategies had no significant difference in terms of patient survival [24]. Some researchers reckoned that for early stage NSCLC, sublobar resection, without improving peri-operative mortality, would increase the risk of non-R0 resection, decrease the number of lymph nodes dissected and thus influence the upstaging of N-stage, which would lead to worse prognosis and higher regional recurrence rate [25]. As for MPLC patients, anatomic lobectomy or even pneumonectomy may not be applied. For those with less pulmonary reserve, especially when multiple lesions locate in ipsilateral different lobes or contralateral lobes, standard operation is neither applicable nor safe. Most MPLC patients considering radical resection as main treatment strategy were considered to be at an early stage during pre-operative evaluation, especially when looking into the second large lesion independently. That is to say, it was possible that these lesions were of lower risk and suitable for sublobar resection. Hence no negative effects on patients’ prognosis were found applying the relatively conservative surgical strategy. This finding was in accordance with the impression during clinical practice in our center to treat MPLC patients surgically, as those taking sublobar resection strategy have not shown any tendency towards worse survival so far.
The result of the study showed medium heterogeneity, which limited the value of the combined HR. Though subgroup analysis had been applied, the sources of heterogeneity could not be disclosed completely. Besides, as all studies included were carried out retrospectively and randomization could not be obtained in observational studies, there could be selective bias. Therefore, the main limitation of this study was the relatively low quality of included literature. And the relatively strict inclusion and exclusion criteria led to a small number of included studies. Also, the publication language was limited to English for the improvement of literature quality, which inevitably increased publication bias.
Although TNM staging play a crucial role in the prediction of the prognosis of NSCLC patients, we were not able to apply it for analysis in this research due to different versions of staging system adopted in each literature. A few researchers found that the highest pT stage of MPLC was an independent prognostic factor [14, 20]. Some researches indicated that lymph node involvement was an indicator for prognosis [13, 19] while others found no significant correlation between the two [16, 17]. Overall, there tended to be a correlation between TNM stage situation of MPLC and postoperative survival. However, because of the lack of unanimity in the classification of multiple primary lung cancer [26], we could not draw any conclusion and further researches on this particular subject were needed.
A few researches suggested that stage I NSCLC patients with single lesion receiving segmentectomy tended to have better prognosis compared with wedge resection [27, 28]. As these ten researches did not compare the difference between these two approaches, no further analysis could be made here. A more specific and precise comparison of various sublobar resection approaches need to be further studied.
For synchronous MPLC lesions adopting sequential resection, De Leyn et al [18] preferred to have the larger lesion removed first, while Trousse et al [13] held that the smaller one should be dealt with first for safety and a better chance for second operation. Researchers believed that synchronous MPLC with ipsilateral sites should apply lung function preserving approaches, i.e. sublobar resection, while avoiding pneumonectomy; and those with contralateral sites should adopt staged operation [4]. Yet no evidence was given in terms of the sequence of resections.