To our knowledge, this is the first population-based study on outcomes after a diagnosis of second primary GI cancers among HL survivors. The large cohort of HL patients (n = 18 671) enabled us to identify a substantial number of second GI cancers for comparison with the general US population, with all study subjects derived from the SEER program. After adjusting for age and calendar year at GI cancer diagnosis, socioeconomic status, and cancer treatment variables, we found that HL survivors with regional or distant stage colon cancer and localized stage stomach cancer had inferior OS than patients who developed de novo GI malignancies, with significant HRs of 1.46 and 3.46, respectively. HL survivors who developed localized esophageal cancer or regional or distant stage rectal cancer also experienced significantly increased risk of deaths, albeit based upon only 4 and 11 deaths, respectively.
risks of subsequent GI cancers
It is well established that HL survivors are at the increased risk of developing subsequent cancers in the GI system [5
]. Factors associated with increased risk of second GI cancers include alkylating agents [17
], radiotherapy [5
], and younger age at HL diagnosis [6
], while other pertinent factors such as heritable cancer syndromes or geographic area have not been analyzed in these retrospective studies. Use of larger radiation field including abdomen and pelvis was shown to be associated with the higher risk of second cancers [5
]. However, no prospective studies showed dose- and field-dependent association between abdominal radiation and second GI cancer risk. Hodgson et al. [6
] pointed out the need for early screening for colorectal cancer in selected HL survivors as the risk of colorectal cancer by age 40 of patients who were treated before age 25 was higher than the risk in 50-year olds in the general population. A prospective clinical trial that looks into the benefit of colonoscopy screening on young patients who received abdominal radiation more than 10 years ago is in progress.
Increased risk of second cancers among HL survivors translates into increased mortality. Studies by Aleman et al. [2
] and Ng et al. [18
] showed that mortality from second cancers after HL exceeds that due to HL 15–30 years after treatment.
Cancer mortality, however, is not only influenced by incidence, but also by disease characteristics such as clinical stage and tumor biology. Recent reports [11
] analyzed the characteristics and outcome of second breast cancer among HL survivors compared with those of first primary cancers in matched cohorts, and found that second cancers occur earlier and survival is worse. While the increased risk of second GI cancer among HL survivors is well established, our study is the first to report inferior outcome of second GI cancers compared with primary GI cancers.
survival after subsequent colon cancer
HL survivors developed colon cancer at a significantly younger age than patients with a first primary colon cancer. Though survival of HL patients who developed localized colon cancer was similar to that of the GI-1 group, age-matched OS of HL patients with regional or distant stage colon cancer was significantly reduced by almost 50%. Among colon cancer patients in the general population, younger age has been reported to be a poor prognostic factor, perhaps attributable to more aggressive disease in the young [20
]. However, O'Connell et al. [24
] reported that the inferior survival among young patients was attributed to a higher frequency of stage III-IV disease; the stage-specific survival of younger patients was similar or better compared with older patients. While the age-matched OS of HL patients with regional or distant stage colon cancer was worse, we could not appreciate inferior CSS or increased deaths due to other medical causes.
In our study, no significant difference in pathologic stage of colon cancer existed between HL-GI and GI-1 groups, when examined by age. In subgroup analyses, however, the frequency of more advanced stage disease in the transverse colon was greater in HL-GI patients, who also experienced a significantly reduced OS and CSS. While we were able to show that transverse segment of colon receives significantly higher dose of radiation in modeling of abdominal RT for HL, there was no significantly increased risk of second cancer in transverse segment after RT. Whether higher radiation doses result in the development of more aggressive colon cancers has not been studied to our knowledge and could not be answered from our study.
survival after subsequent stomach cancer
For early noninvasive stomach cancer in the general population, younger age is associated with improved survival [25
]. In contrast, we found that HL survivors developed localized stomach cancers at a younger age compared with the patients with primary localized stomach cancer and had a poorer outcome (HR = 3.46). However, it is important to note that a small number (n
= 8) of patients warrants cautious interpretation of this result. Also, we could not analyze the independent effect of age on survival. It is possible that radiation-induced stomach cancer has more aggressive tumor biology. While further research is needed to explain the inferior survival after localized stomach cancer among HL survivors, early diagnostic evaluation upon presentation of dyspectic symptoms in patients who have additional risk factors for stomach cancer, such as a history of infection with Helicobacter pylori
], and tobacco use [29
], may improve outcomes. In Japan, where the general population has an eightfold greater incidence of gastric cancer than in Western populations [30
], endoscopic screening results in diagnosis of gastric cancer at an earlier age, earlier nodal stage at diagnosis, and improved CSS [32
Overall, 51 of 147 deaths were due to other cancers or noncancer causes (data not shown). Because of the small number of deaths from these causes, we were not able to compare mortality from other cancers or noncancer causes between HL-GI and GI-1 subgroups, as we had done in a similar analysis of breast cancer patients [11
Through a large population-based analysis that minimized selection bias and improved generalizability, we report significantly inferior OS among HL survivors who developed subsequent advanced colorectal or localized stomach malignancies compared with patients presenting with similar de novo cancers. This finding along with the increased risk of developing second GI malignancies among HL survivors, which persists more than years, and the importance of lifelong vigilance in this vulnerable population. Strengths of the current study include the sizable number of patients (476 592 patients with de novo GI cancer and 209 patients with GI cancer after HL) identified in a large population-based setting. Substantial patient numbers allowed for analyses of outcomes according to GI site and stage. Known limitations of SEER data include a lack of detailed information with regard to radiotherapy and an absence of chemotherapy data. Further, lifestyle and social factors associated with the development of cancers in the GI tract are not recorded (i.e. diet and alcohol use). Future research should continue to address the relationship between the dose of chemotherapy or radiation to specific organs and the subsequent risk of GI cancers, as well as the interaction with other established risk factors. Improved understanding of treatment-related risk regarding second GI cancer will help in the consideration of screening guidelines for patients at highest risk.