Risk of second primary cancer among patients with head and neck cancers: A pooled analysis of 13 cancer registries Shu-Chun Chuang 1,2 , Ghislaine Scelo 1 , Jon M. Tonita 3 , Sharon Tamaro 4 , Jon G. Jonasson 5,6 , Erich V. Kliewer 7,8 , Kari Hemminki 9,10 , Elisabete Weiderpass 11,12,13 , Eero Pukkala 14 , Elizabeth Tracey 15 , Soren Friis 16 , Vera Pompe-Kirn 17 , David H. Brewster 18 , Carmen Martos 19 , Kee-Seng Chia 20,21 , Paolo Boffetta 1 , Paul Brennan 1 and Mia Hashibe 1 * 1 International Agency for Research on Cancer (IARC), Lyon, France 2 Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 3 Saskatchewan Cancer Agency, Regina, Saskatchewan, Canada 4 British Columbia Cancer Agency, Vancouver, British Columbia, Canada 5 Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland 6 Faculty of Medicine, University of Iceland, Reykjavik, Iceland 7 Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, Canada 8 Community Health Sciences, University of Manitoba, Winnipeg, Canada 9 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 10 Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden 11 The Cancer Registry of Norway, Oslo, Norway 12 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 13 Samfundet Folkhalsan, Department of Genetic Epidemiology, Helsinki, Finland 14 Finnish Cancer Registry, Institute for Statistical and Epidemiology Cancer Research, Helsinki, Finland 15 New South Wales Cancer Registry, Eveleigh, New South Wales, Australia 16 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark 17 Cancer Registry of Slovenia, Institute of Oncology, Ljubljana, Slovenia 18 Scottish Cancer Registry, Information Services, NHS National Services Scotland, Edinburgh, Scotland, United Kingdom 19 Cancer Registry of Zaragoza, Health Department of Aragon Government, Zaragoza, Spain 20 Center for Molecular Epidemiology, Singapore 21 Singapore Cancer Registry, Singapore The objective of the study was to assess the risk of second primary cancers (SPCs) following a primary head and neck cancer (oral cavity, pharynx and larynx) and the risk of head and neck cancer as a SPC. The present investigation is a multicenter study from 13 population-based cancer registries. The study population involved 99,257 patients with a first primary head and neck cancer and contributed 489,855 person-years of follow-up. To assess the excess risk of SPCs following head and neck cancers, we calcu- lated standardized incidence ratios (SIRs) by dividing the observed numbers of SPCs by the expected number of cancers cal- culated from accumulated person-years and the age-, sex- and cal- endar period-specific first primary cancer incidence rates in each of the cancer registries. During the observation period, there were 10,826 cases of SPCs after head and neck cancer. For all cancer sites combined, the SIR of SPCs was 1.86 (95% CI = 1.83–1.90) and the 20-year cumulative risk was 36%. Lung cancer contrib- uted to the highest proportion of the SPCs with a 20-year cumula- tive risk of 13%. Excess second head and neck cancer risk was observed 10 years after diagnosis with lymphohaematopoietic can- cers. The most common SPC following a first primary head and neck cancer was lung cancer. However, the highest excess of SPCs was in the head and neck region. These patterns were consistent with the notion that the pattern of cancer in survivors of head and neck cancer is dominated by the effect of tobacco smoking and alcohol drinking. ' 2008 Wiley-Liss, Inc. Key words: head and neck cancer; second cancer A significant improvement in locoregional control of head and neck squamous cell carcinoma has been seen over the last deca- des, due to the introduction of new surgical techniques, improved radiotherapy techniques and the use of chemotherapy. However, 5-year relative survival from head and neck cancer has not increased greatly over the period of 1985–1994. 1,2 One of the rea- sons for the lack of improvement in overall survival is the frequent development of second primary cancers (SPCs) that occur more often in head and neck cancer patients than in patients with can- cers of other sites 3 and lead to poor prognosis. 4–6 Head and neck cancers (oral cavity, pharynx and larynx) com- prise around 5% of all cancer cases worldwide and result in 6% of cancer deaths in men and 3% in women. 7 SPCs after head and neck cancers are mostly found in the aerodigestive tract, including the lung and esophagus, which leads to a significant decrease in survival. 5 In contrast to the overall 5-year survival rate for head and neck cancer patients of approximately 50%, the 5-year sur- vival rate in head and neck cancer patients who developed SPC was around 20% after the SPC was diagnosed. 4,5 The 5-year sur- vival rates after SPC diagnosis were above 30% if the SPC was also a head and neck cancer and decreased to 8% if the SPC was outside the head and neck area. 4 Multiple cancers within a person provide a unique clue to the understanding of cancer etiology and mechanisms. 8,9 Multiple cancers could be due to common risk factors or other predisposi- tions or treatment for the first cancer. If the risk increases over time with a special pattern, the association may be more likely due to the treatment for the first cancer. For example, with alkylating agent treatment, leukemia risk begins to increase and peaks at 5 to 10 years, whereas therapy-associated solid cancer risk increases typically after 10 years. 10 Otherwise, if both associations treating the index cancer as the primary cancer and as the SPC with a spe- cific cancer are observed, then common risk factors may be sug- gested for the association. The present investigation is a multicenter study including can- cer data from 13 population-based cancer registries in Europe, Canada, Australia and Singapore. The data were used to assess the Grant sponsor: National Cancer Institute of the US NIH; Grant number: R03 CA101442. *Correspondence to: International Agency for Research on Cancer, 150 Cours Albert Thomas, 69008 Lyon, France. Fax: 133-4-72-73-83-20. E-mail: hashibe@iarc.fr Received 7 December 2007; Accepted after revision 20 May 2008 DOI 10.1002/ijc.23798 Published online 26 August 2008 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 123, 2390–2396 (2008) ' 2008 Wiley-Liss, Inc. Publication of the International Union Against Cancer