Screening

Given the poor prognosis of second primary lung cancer in our series and others, it is clear that efforts should be focused on early detection in this high-risk cohort. Furthermore, retrospective data suggest that patients with resectable second primary lung cancer have a similar prognosis to lung cancer patients with no previous history of head and neck SCC.^{Reference Koppe, Zoetmulder, van Zandewijk, Hart and Rutgers12}

In patients who have undergone a previous total laryngectomy, the proximal tracheobronchial tree can be easily assessed at follow up by flexible endoscopy. A study of 30 such patients using white light and autofluorescence bronchoscopy detected pre-malignant lesions in 20 per cent of cases.^{Reference Cetinkaya, Veyseller, Yildirim, Aksoy, Ozgül and Gençoğlu13} Similar findings were reported in a study from the Netherlands, where autofluorescence bronchoscopy detected otherwise radiologically occult second primary lung cancers in 9 per cent of patients (5 out of 51) undergoing post-treatment surveillance of head and neck SCC.^{Reference Lee, de Bree, Brokx, Leemans, Postmus and Sutedja14}

In one large retrospective series of 1086 patients, there was a small (four months) but statistically insignificant difference in median survival between patients whose second primary lung cancer was detected by routine screening chest X-ray versus those in whom symptoms prompted investigation of the chest.^{Reference Shah and Applebaum15} This no doubt reflects the relative insensitivity of plain X-ray in the detection of early lung cancer compared to computed tomography (CT). While some smaller studies from Japan and the Netherlands did show a modest survival advantage with annual chest X-ray, this could of course be attributable to lead time bias.^{Reference Shimizu, Ando, Teramoto, Moritani and Nishii16,Reference Engelen, Stalpers, Manni, Ruijs and van Daal17}

Since 1993, the Early Lung Cancer Action Project has recruited more than 1000 asymptomatic smokers with at least 10 pack-years smoking history to assess the effectiveness of low-dose CT and plain chest X-ray as screening tools for lung cancer.^{Reference Henschke, McCauley, Yankelevitz, Naidich, McGuinness and Miettinen18} Lung cancer was detected on CT in 2.7 per cent of cases at initial screening, versus 0.4 per cent on plain X-ray. Stage I lung cancer was detected six times more frequently on low-dose CT when compared with plain X-ray, and was associated with a 10-year survival rate of 90 per cent.^{Reference Henschke, McCauley, Yankelevitz, Naidich, McGuinness and Miettinen18}

Another landmark study in this area was the 2011 National Lung Cancer Screening Trial, which randomised more than 53 000 patients to receive either annual low-dose CT or plain X-ray over a three-year period.^{Reference Aberle, Adams, Berg, Black and Clapp19} The inclusion criteria were patients between 55 and 74 years of age, with at least a 30 pack-year smoking history, including ex-smokers who had quit within 15 years of the enrolment date. Five-year outcomes showed a 20 per cent (95 per cent confidence interval = 6.8–26.7, p < 0.004) reduction in lung cancer specific mortality in the CT group compared with the plain X-ray group, as well as a 6.7 per cent reduction in all-cause mortality because of the improved detection of other incidental chest diseases.^{Reference Aberle, Adams, Berg, Black and Clapp19} As a result, recent guidance from the National Comprehensive Cancer Network has suggested a role for CT screening for early lung cancer in patients who fulfil these criteria.²⁰

Clearly, the potential exists for patients with laryngeal cancer to undergo some form of screening for second primary lung cancer. In Northern Ireland, follow-up assessment includes visualisation of the upper aerodigestive tract by flexible nasendoscopy; routine imaging of the chest is generally not carried out in asymptomatic patients. Our results showed that even in stage IVa laryngeal SCC, disease-specific and recurrence-free survival rates were 75 per cent and 76 per cent, respectively, at five years. There is a contrast therefore between the intensive surveillance of the primary site and the lack of routine attention paid to the chest, with its second primary lung cancer rate of 8 per cent and associated poor prognosis.

Diagnosis and prognosis

Any assessment of second primary lung cancer incidence will always incur some risk of misdiagnosing pulmonary metastatic disease as a true second primary lung cancer, and vice versa. Given that most laryngeal cancers are SCCs, the distinction is straightforward in cases where a different histological subtype is found in the chest (e.g. adenocarcinoma). In cases of a human papilloma virus (HPV)-positive oropharyngeal SCC, the detection of HPV DNA in any lung tumour may be of some value in making this distinction.^{Reference Bishop, Ogawa, Chang, Illei, Gabrielson and Pai21} However, there is some evidence to suggest that the surgical resection of limited pulmonary head and neck SCC metastases may confer some survival benefit. A small series of 36 patients from authors in the Netherlands compared outcomes following surgical resection in second primary lung cancer versus those with isolated pulmonary metastases from head and neck SCC. No significant difference was seen, with survival of roughly two years in both cohorts.^{Reference Geurts, Balm, van Velthuysen, van Tinteren, Burgers and van Zandwijk22}

The poor prognosis for second primary lung cancer has been shown in large-scale observational studies, with reported median survival of less than one year.^{Reference Chen, Huang, Chan, Chen and Lee23} The finding persists even in patients with histologically discordant head and neck and lung cancers, suggesting the limited prognosis cannot be ascribed to the misdiagnosis of pulmonary metastases as second primary cancers.^{Reference Jayaprakash, Cheng, Reid, Dexter, Nwogu and Hicks10} This underlines the need for improved head and neck SCC follow-up regimens, which will maximise the chance of early second primary lung cancer detection. Some small case series have suggested an increasingly favourable outcome in second primary lung cancer as the time interval from index head and neck SCC increases.^{Reference Dequanter, Shahla, Lardinois, Gilbert, Hanquet and Tragas24} A recent meta-analysis looked at 13 studies dealing with pulmonary metastasectomy in the context of head and neck SCC primary cancer. This showed an overall five-year survival rate of 29.1 per cent. Poor prognostic factors included oral cavity and node-positive index tumours.

Risk factors

In our series, supraglottic versus glottic laryngeal SCC was associated with a significantly increased risk of second primary lung cancer (hazard ratio = 4.14, p = 0.03). This finding has been reported in several other series to date.^{Reference Milano, Peterson, Zhang, Singh and Chen7,Reference Silvestri, Bussani, Cosatti and Bosatra25} Other reported risk factors for SPLC include hypopharyngeal subsite, black race and male sex.^{Reference Milano, Peterson, Zhang, Singh and Chen7}

The reasons for this increased second primary lung cancer risk in supraglottic SCC are unclear. The glottis and the lung are exposed almost exclusively to inhaled carcinogens in the form of tobacco smoke, whereas the supraglottis is to some degree also exposed to ingested carcinogens (e.g. alcohol). One might therefore expect a cohort of supraglottic cancer patients to have had relatively higher alcohol exposure than a similar cohort of glottic cancer patients, and conversely that a glottic cancer cohort would contain patients with relatively more tobacco but less alcohol exposure. If so, one might expect glottic cancers to present a higher risk of second primary lung cancer than other subsites. This is not borne out by current evidence, however. This may be explained by higher alcohol consumption being associated with corresponding higher tobacco exposure, and the known synergy of these two common carcinogens also clouds the picture somewhat.

Other evidence suggests that there may be a slight difference in patterns of second primary cancers with respect to index subsite, with more respiratory tract second primary cancer cases following laryngeal cancer and more digestive tract second primary cancer cases following hypopharyngeal cancer.^{Reference Lin, Patel, Chu, Matsuo, Singh and Wong26,Reference Chu, Chang, Huang and Tai27} This has obvious implications when considering follow-up strategies.

A Surveillance, Epidemiology, and End Results database study of more than 20 000 laryngeal cancer patients showed an overall second primary malignancy rate of 47 per cent at 20 years.^{Reference Gao, Fisher, Mohideen and Emami28} Among these second primary cancer cases, the lung was by far the most common anatomical site for synchronous or metachronous cancers (39 per cent). Interestingly, the study also suggested that the use of radiotherapy in laryngeal cancer treatment resulted in an 18 per cent increased relative risk of second primary lung cancer compared with the non-radiotherapy cohort. The extent to which one can infer a causal link, however, is limited as this study did not report on the use of chemotherapy, and conflicting findings have been reported by other, admittedly smaller, series.^{Reference Jones, Morar, Phillips, Field, Husbband and Helliwell29} There will of course be an association between radiotherapy and higher stage disease at presentation.

Study limitations

This study entailed a retrospective review of clinical records, and this invariably has the potential to adversely affect the quality and accuracy of the data. Unfortunately, during the time period in question, it was not our routine practice to record alcohol and smoking data routinely for all patients, and as such these potential variables could not be included in the analysis. These data are now included in the digital database for patients at first presentation to our regional head and neck multidisciplinary team, and we hope that this addition will improve the richness of data available for future studies in this and other areas.

The relatively low number of events (i.e. cases of second primary lung cancer) in this study (n = 16) must be taken into account when interpreting the multivariate analysis findings. The traditional rule of thumb is that 10 or more events per variable are required to ensure a robust multivariate logistical regression. Clearly, at our second primary lung tumour rate of 8 per cent (16 out of 209 cases) over five years, this would require an analysis of many thousands of cases of primary laryngeal cancer, many more than exist in our regional database covering a population of around 1.8 million people. Nonetheless, a recent study from authors in the Netherlands has concluded that the evidence base supporting the need for 10 events per variable is weak, and that this area requires some re-assessment and further study.^{Reference van Smeden, de Groot, Moons, Collins, Altman and Eijkemans30}