UIP and lung cancer
The incidence of lung cancer in UIP is well described; with up to 50% of patients with UIP developing some form concurrent pulmonary malignancy.16 The incidence was significantly higher than in the age-matched general population without UIP (48.2% vs 9.1%, p<0.001).17 This is not altogether surprising given that there are underlying molecular and genetic aberrations common to both disease processes.18 Yoo et al demonstrated that cumulative year on year risk for malignancy in UIP increased at a near exponential rate; 1 year for lung cancer was 1.1%, whereas at 10 years this was 31.1%.19 Male gender, current smoker at diagnosis and a rapid annual decline of more than 10% in forced vital capacity (FVC) were associated with increased risk of lung cancer.19
Postoperative outcomes in lung cancer and underlying UIP
Online supplemental table 2 illustrates the major studies20 ,21 ,35 ,23 ,24 ,25 ,26 which have explored the impact of underlying UIP for patients who undergo major lung resection for NSCLC. Despite having a variable prevalence, some groups reporting up to 13%,19 UIP is consistently recognised as a significant independent negative prognostic factor in terms of postoperative pulmonary complications, in-hospital mortality and overall survival (online supplemental table 2). The impact of UIP on disease-free interval must be interpreted cautiously, some groups have reported no difference27 whereas others have demonstrated a significantly worse disease free interval with underlying UIP.28 This must be stratified according to the type of surgical resection as lesser resections are often employed in UIP patients to protect against disease AE postoperatively. As we shall explore later, lesser resections do associate with higher rates of locoregional recurrence. Sato et al5 29 have presented the largest series of concomitant NSCLC and UIP (n=1763) to date and showed that death due to cancer was the main cause of mortality (50.2%), followed by respiratory failure (26.8%).
Our analysis has demonstrated that the rate of AE post lung cancer resection as 14.6% (random effects model, 95% CI 9.8 to 20.1, I2=74%) (figure 1), which is a significant proportion particularly when AE is a significant predictor of in-hospital mortality.5 16 29–34 Eight studies reported 5-year overall survival in this unique group of patients, 886 out of 2128 patients survived to 5 years post lung cancer resection with random effects testing yielding a 5-year survival rate of 47.4%. This again must be interpreted with caution as proper stratification according to stage of disease, degree of fibrosis, type of fibrosis and resection extent must be accounted for.
In the pretreatment decision-making phase, careful attention should be paid to the type of interstitial lung disease (ILD) present on the radiology, for example, non-specific interstitial pneumonia (NSIP) carries a much better prognosis and this should be radiologically classified making the distinction between fibrotic type NSIP and true UIP. The prognosis of NSIP is significantly better than that of UIP; 5-year survival of 43% among patients with UIP, compared with 90% in NSIP and this is similarly reflected in those patients undergoing major lung resections for cancer.2 3
Although we did not perform a robust risk factor analysis for AE in these patients (ie, duration of surgery, oxygenation levels, vent settings, FVC, severity of UIP, Karnofsky status and comorbidities of patients), this has already been well described by Hao et al35 who demonstrated a series of factors that confer higher risk in these patients. Of note, UIP pattern on CT conferred an OR of 1.52 for postoperative AE (95% CI 1.06 to 2.17, p=0.021)35; not all studies confirmed clear clinical or biopsy proven diagnoses of UIP, some studies reported a blend of ILD.5 29 These factors are critical to the prognostic algorithm in this group of patients.
The role of limited resection
Limited surgical resection in lung cancer has been increasingly adopted in recent years, for early stage solid and subsolid lesions, particularly in light of the findings from the recent JCOG0802 randomised controlled trial7 which assessed the 5-year outcomes following segmentectomy (sublobar) (n=552) or lobectomy (n=554) for stage Ia NSCLC less than or equal to 2 cm. Overall survival was 94.3% and 91.1%, respectively (p=0.0082), yet there was no significant difference in disease-free survival; 88% and 87.9%, respectively. The proportion of locoregional recurrence in the segmentectomy arm was significantly higher than the lobectomy arm, 10.5% vs 5.4% (p=0.0018), respectively. In this particular field, there is limited scope to delineate between segmentectomy and lobectomy hence the discussion will also compare sublobar (wedge resection and segmentectomy combined) to lobar resection, which is a reflection of the paucity of large-scale robust data.
The guidance suggests that there is a role for surgery in the setting of high-risk patients with UIP36 although with a significantly lower 5-year survival rate (54.2%–61.6% for stage I NSCLC) and late death from respiratory failure.30 31 37 Retrospective data suggest that limited sublobar resection (wedge or segmentectomy) is better tolerated in this group given that there is a reduced incidence of AE, shorter postoperative hospital stay and reduced rate of air leak.16 29 34 Across 14 studies analysing 2472 patients, sublobar resection was significantly associated with a reduced odds of postoperative AE (OR 0.521 (fixed effects model), 95% CI 0.339 to 0.803, p=0.0031, I2=0%) (figure 2). This could be due to a number of different factors, reduced operative time, less handling of the lung and less lung tissue resected. We must bear in mind, however, that without level I evidence, this cannot be formally accepted as experienced centres performing segmentectomy do report that this operation is associated with more tissue handling and longer operating times particularly if performed minimally invasively. Moreover, the air leak rate following segmentectomy can be higher than a lobectomy, as the fibrotic lungs of patients with clinically significant IPF are typically very difficult to staple across the parenchyma for a sublobar resection. Two studies3 29 did stratify postoperative AE of UIP according to segmental and wedge resection; segmental resection was associated with higher odds of postoperative AE (OR 1.874) when compared with wedge resection, although this was not significant.
Wedge resection also associated with lower mortality from respiratory failure compared with lobectomy but conferred a poorer long-term prognosis (5-year survival of 33.2% compared with 68.4% with lobectomy).29 Small cohort retrospective data have shown significantly higher disease free survival following lobar resection compared with sublobar resection for early-stage lung cancer in patients with underlying UIP.15 However, we must bear in the mind recent robust randomised data from JCOG0802,7 which demonstrated a 5-year relapse-free survival rate of 88.0% (95% CI 85.0% to 90.4%) for segmentectomy and 87.9% (95% CI 84.8% to 90.3%) for lobectomy (HR 0.998; 95% CI 0.753 to 1.323; p=0.9889) for early-stage lung cancer, despite higher local recurrence in the segmentectomy group. Moreover, data from CALGB-140503 has shown comparable 5-year disease-free survival between sublobar and lobar resection groups (63.6% vs 64.1%, p=0.018 for non-inferiority), with 59% of the sublobar resection cases being wedge resections. The use of wedge resection therefore could be of fundamental importance to patients with concurrent UIP both in terms of short and long-term cancer-specific survival.
Our analysis did not demonstrate a significantly reduced long-term survival with sublobar resection (HR 0.978 (random effects model), 95% CI 0.521 to 1.833, p=0.9351, I2=71%) (figure 5). However, further meta-regression has suggested that in super-selected cases with early-stage small tumours that have gone through a proper risk stratification and counselling process may have comparable long-term survival to patients undergoing lobectomy. As there was no survival difference, it is highly likely that most sublobar resections were wedge resections and survival cannot be reliably controlled for the stage of disease and extent of resection given the paucity of reported data.
A delicate balance must be struck in order to ensure these patients have a long disease-free interval without local recurrence at the cost of significant postoperative mortality from IPF AE. Patient selection is key and opting for limited resection in patients with FVC<80% and low DLco are factors that can guide management. Furthermore intraoperative measures such as reducing the time on single-lung ventilation, avoiding fluid overload and hyperoxic time are also measures to be considered.33 Groups have described minimally invasive operative techniques as a means of mitigating the risk of postoperative AE.38 The role of limited resection in this setting and its association with a lower rate of AE must be correlated with the poorer oncological outcomes and is indeed the focus of an ongoing randomised study.39