Neuroendocrinology (DOI:10.1159/000381716)
(Accepted, unedited article not yet assigned to an issue)
© 2015 S. Karger AG, Basel www.karger.com/nen
Advanced Release: March 21, 2015
Received: January 8, 2015 Accepted after revision: March 16, 2015
Incidence of second primary malignancies in patients with neuroendocrine tumours
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
Ashley K Clift1, Panagiotis Drymousis2, Adil Al‐Nahhas3, Harpreet Wasan2, John Martin4, Sture Holm5 & Andrea Frilling2 1: School of Medicine, Imperial College London, UK 2: Department of Surgery and Cancer, Imperial College London, UK 3: Department of Nuclear Medicine, Imperial College London, UK 4: Department of Gastroenterology, Imperial College London, UK 5: Department of Mathematical Sciences, Chalmers and Göteborg University, Göteborg, Sweden Short title: Second cancers in neuroendocrine tumours Key words: neuroendocrine tumour, second primary cancer Corresponding Author and Mailing Address: Prof Andrea Frilling Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS Email: [email protected] Fax: 00442033133963 Phone: 0044 2033133210
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
2
Abstract: Background: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. Methods: Retrospective review of our institutional prospectively‐maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Results: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n=6), breast and renal carcinomas (both n=5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small‐ bowel NET patients were comparable (15.7% vs. 19.6%, p=0.78). A person‐year methodology was used to compare observed numbers of SPM against expected values generated from age‐ and sex‐ specific incidence tables, with standardised incidence ratios (SIRs) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous sub‐set (SIR 2.732, CI 1.177‐ 5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241‐0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044‐1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238‐30.474). Conclusions: Our data support the use of colonoscopy in the diagnostic work‐up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
3
Introduction Neuroendocrine tumour disease – most recently reclassified as neuroendocrine neoplasms (NEN) [1] ‐ represents a spectrum of individually uncommon malignancies originating from the body's neuroendocrine cell system, with most neuroendocrine tumours (NET) originating from the gastroenteropancreatic (GEP‐NET) and bronchopulmonary tracts. Historically termed “carcinoids” and regarded as relatively indolent tumours with a protracted natural history, NET have increased in incidence over the past 3 decades [2] with a suggested incidence of 1.3‐5.7 per 100,000 individuals per year [2,3]. Furthermore, a projected prevalence of 35/100,000 individuals was derived from analysis of the US Surveillance Epidemiology and End Results (SEER) database, rendering NET commoner than oesophageal and pancreatic cancers combined [3]. Whether these represent true increases in incidence, or are at least in part reflections of improved diagnostic techniques and imaging is debatable. With ever improving outcomes in oncology, that cancer survivorship may be complicated by developing second primary malignancies (SPM) is increasingly evident. Second primary cancers have been reported to occur in multiple cancer types [4–6] and are at least partly attributable to the treatment modalities utilised in cancer treatment, many of which themselves are mutagenic. Further aetiological factors may include overlapping risk factors and genetic susceptibilities common between disparate neoplasms. Indeed, 18% of all malignancies diagnosed in the US are of a second or higher order [7]. A number of reports have also demonstrated increased risk of additional malignancies occurring in the NET patient set [8–14], a factor which may add to the already challenging management of individuals with NET if co‐existent. With the aforementioned relatively prolonged natural history of this tumour type, this presents a pertinent clinical consideration. Although some studies report the incidence of additional malignancy in up to 55% of patients with NET, one review demonstrated that the rates of SPM in NET range between 12‐46%, with an average occurrence of 17% [15]. Here, we undertook a retrospective review of a NET patient cohort, aiming to assess our own centre’s experience with second cancers in these patients. Patients and Methods: We retrospectively reviewed our institutional database of NET patients, which has compiled patients between 2010 and 2014, with some patients diagnosed with NET prior to 2010. Imperial College
data regarding gender, age, type of NET diagnosed, diagnosis of any additional malignancy and the date of diagnoses extracted. Patients known to have any hereditary tumour predisposition
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
London is an ENETS Centre of Excellence for NET. Individual patient case notes were obtained, with
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
4
syndrome, e.g. multiple endocrine neoplasia (MEN), Von Hippel Lindau and Cowden syndromes, were excluded from our analyses. SPM were categorised as one of the following three sub‐groups: ‘previous’ if diagnosed more than 6 months prior to, ‘synchronous’ if diagnosed within 6months prior to subsequent to, or ‘subsequent’ if diagnosed more than 6 months subsequent to NET diagnosis, respectively. Diagnoses of both neuroendocrine and second tumours were confirmed histologically. Person‐years at risk (PYAR) for previous SPM were calculated up until the aforementioned cut off. For synchronous tumours, PYAR were counted from the date of NET diagnosis up until 6 months afterwards and doubled to reflect the bidirectional remit of synchronicity. PYAR for metachronous SPM were calculated from 6‐months post‐NET diagnosis until death, SPM detection or date of final data review (11th November 2014). PYAR were stratified on the basis of gender and age. The expected incidence of SPM was calculated by multiplying the PYAR distributions of each sub‐group by age‐ and sex‐matched incidence data for all cancers obtained from Cancer Research UK (http://www.cancerresearchuk.org/cancer‐info/cancerstats/incidence). Standardised incidence ratios (SIR) were calculated by dividing the observed number of SPM (O) by the derived expected values (E) with 95% confidence intervals (CI) calculated using Poisson tables. Similar PYAR analyses were executed for the commonest SPM observed in each sub‐group, using tumour‐specific age‐ and sex‐matched incidence data, again from Cancer Research UK. Since there were several types of results treated in a common discussion, it was necessary to consider multiple inference problems. There were ten cases, each with two possible directions, i.e. 20 one‐sided tests handled. A refinement of the simple Bonferroni method [16] was used to calculated one‐sided p values for CI. For the comparison of categorical risk factors, χ2 tests were used, whilst the Welch’s t‐test was used in the comparison of means. All statistical analyses were executed with IBM SPSSTM version 22. Significance was set at p
(Accepted, unedited article not yet assigned to an issue)
© 2015 S. Karger AG, Basel www.karger.com/nen
Advanced Release: March 21, 2015
Received: January 8, 2015 Accepted after revision: March 16, 2015
Incidence of second primary malignancies in patients with neuroendocrine tumours
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
Ashley K Clift1, Panagiotis Drymousis2, Adil Al‐Nahhas3, Harpreet Wasan2, John Martin4, Sture Holm5 & Andrea Frilling2 1: School of Medicine, Imperial College London, UK 2: Department of Surgery and Cancer, Imperial College London, UK 3: Department of Nuclear Medicine, Imperial College London, UK 4: Department of Gastroenterology, Imperial College London, UK 5: Department of Mathematical Sciences, Chalmers and Göteborg University, Göteborg, Sweden Short title: Second cancers in neuroendocrine tumours Key words: neuroendocrine tumour, second primary cancer Corresponding Author and Mailing Address: Prof Andrea Frilling Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS Email: [email protected] Fax: 00442033133963 Phone: 0044 2033133210
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
2
Abstract: Background: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. Methods: Retrospective review of our institutional prospectively‐maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Results: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n=6), breast and renal carcinomas (both n=5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small‐ bowel NET patients were comparable (15.7% vs. 19.6%, p=0.78). A person‐year methodology was used to compare observed numbers of SPM against expected values generated from age‐ and sex‐ specific incidence tables, with standardised incidence ratios (SIRs) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous sub‐set (SIR 2.732, CI 1.177‐ 5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241‐0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044‐1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238‐30.474). Conclusions: Our data support the use of colonoscopy in the diagnostic work‐up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
3
Introduction Neuroendocrine tumour disease – most recently reclassified as neuroendocrine neoplasms (NEN) [1] ‐ represents a spectrum of individually uncommon malignancies originating from the body's neuroendocrine cell system, with most neuroendocrine tumours (NET) originating from the gastroenteropancreatic (GEP‐NET) and bronchopulmonary tracts. Historically termed “carcinoids” and regarded as relatively indolent tumours with a protracted natural history, NET have increased in incidence over the past 3 decades [2] with a suggested incidence of 1.3‐5.7 per 100,000 individuals per year [2,3]. Furthermore, a projected prevalence of 35/100,000 individuals was derived from analysis of the US Surveillance Epidemiology and End Results (SEER) database, rendering NET commoner than oesophageal and pancreatic cancers combined [3]. Whether these represent true increases in incidence, or are at least in part reflections of improved diagnostic techniques and imaging is debatable. With ever improving outcomes in oncology, that cancer survivorship may be complicated by developing second primary malignancies (SPM) is increasingly evident. Second primary cancers have been reported to occur in multiple cancer types [4–6] and are at least partly attributable to the treatment modalities utilised in cancer treatment, many of which themselves are mutagenic. Further aetiological factors may include overlapping risk factors and genetic susceptibilities common between disparate neoplasms. Indeed, 18% of all malignancies diagnosed in the US are of a second or higher order [7]. A number of reports have also demonstrated increased risk of additional malignancies occurring in the NET patient set [8–14], a factor which may add to the already challenging management of individuals with NET if co‐existent. With the aforementioned relatively prolonged natural history of this tumour type, this presents a pertinent clinical consideration. Although some studies report the incidence of additional malignancy in up to 55% of patients with NET, one review demonstrated that the rates of SPM in NET range between 12‐46%, with an average occurrence of 17% [15]. Here, we undertook a retrospective review of a NET patient cohort, aiming to assess our own centre’s experience with second cancers in these patients. Patients and Methods: We retrospectively reviewed our institutional database of NET patients, which has compiled patients between 2010 and 2014, with some patients diagnosed with NET prior to 2010. Imperial College
data regarding gender, age, type of NET diagnosed, diagnosis of any additional malignancy and the date of diagnoses extracted. Patients known to have any hereditary tumour predisposition
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 2:52:58 AM
London is an ENETS Centre of Excellence for NET. Individual patient case notes were obtained, with
Neuroendocrinology (DOI:10.1159/000381716)
© 2015 S. Karger AG, Basel
4
syndrome, e.g. multiple endocrine neoplasia (MEN), Von Hippel Lindau and Cowden syndromes, were excluded from our analyses. SPM were categorised as one of the following three sub‐groups: ‘previous’ if diagnosed more than 6 months prior to, ‘synchronous’ if diagnosed within 6months prior to subsequent to, or ‘subsequent’ if diagnosed more than 6 months subsequent to NET diagnosis, respectively. Diagnoses of both neuroendocrine and second tumours were confirmed histologically. Person‐years at risk (PYAR) for previous SPM were calculated up until the aforementioned cut off. For synchronous tumours, PYAR were counted from the date of NET diagnosis up until 6 months afterwards and doubled to reflect the bidirectional remit of synchronicity. PYAR for metachronous SPM were calculated from 6‐months post‐NET diagnosis until death, SPM detection or date of final data review (11th November 2014). PYAR were stratified on the basis of gender and age. The expected incidence of SPM was calculated by multiplying the PYAR distributions of each sub‐group by age‐ and sex‐matched incidence data for all cancers obtained from Cancer Research UK (http://www.cancerresearchuk.org/cancer‐info/cancerstats/incidence). Standardised incidence ratios (SIR) were calculated by dividing the observed number of SPM (O) by the derived expected values (E) with 95% confidence intervals (CI) calculated using Poisson tables. Similar PYAR analyses were executed for the commonest SPM observed in each sub‐group, using tumour‐specific age‐ and sex‐matched incidence data, again from Cancer Research UK. Since there were several types of results treated in a common discussion, it was necessary to consider multiple inference problems. There were ten cases, each with two possible directions, i.e. 20 one‐sided tests handled. A refinement of the simple Bonferroni method [16] was used to calculated one‐sided p values for CI. For the comparison of categorical risk factors, χ2 tests were used, whilst the Welch’s t‐test was used in the comparison of means. All statistical analyses were executed with IBM SPSSTM version 22. Significance was set at p
