Increased incidence of oral and gastrointestinal secondary cancer after allogeneic hematopoietic stem cell transplantation

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With an increasing number of long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT), more attention has been paid to late complications, of which secondary cancer is particularly life-threatening.1, 2 The risk of developing solid tumors after allo-HSCT has been reported to be two- to fourfold higher than that in the general population, and the actual incidence of developing secondary solid cancers is 2–6% at 10 years after allo-HSCT.3, 4, 5 Risk factors include chronic GvHD,3, 5 use of radiation,5, 6 younger age,4, 6 male sex4, 5, 7 and immunosuppressive therapy.8 Atsuta et al.3 analyzed the risk of secondary cancer after allo-HSCT using the Japan transplant registry database of 17 545 patients, and showed a continuing increased risk of secondary cancers after allo-HSCT, with a standard incidence ratio (SIR) of 1.8 and a cumulative incidence of 1.7% at 10 years. They also indicated that the risks of developing esophageal and oral cancer were significantly increased after allo-HSCT in the Japanese population. To further clarify practical incidence rates and risk factors of secondary cancers, and to inform survivorship care protocols, we performed a retrospective, single-center study.

We evaluated data on patients who had a hematological disorder and received their first allo-HSCT at our center between 1982 and 2012. Data were extracted from a transplant registry database in which patient information including long-term complications, such as chronic GvHD and secondary cancer, are updated annually. A total of 1060 patients were included in the analysis. The probability of secondary cancers was estimated using the cumulative incidence method, and death without development of secondary cancers was treated as a competing risk. Gray’s method was used to evaluate the differences between groups. Patients who had relapse of underlying hematological malignancy after HSCT were censored at the date of relapse. SIRs of secondary cancers were calculated to evaluate the difference between the present cohort and the general population in terms of the incidence of secondary cancers after receiving allo-HSCT. The age-adjusted incidence of secondary cancers was based on the data from Cancer Information Service NCC, Japan Cancer Registry and Statistics.9 The exact Poisson distribution was used to calculate 95% confidence intervals (CI). In patients who developed multiple metachronous secondary cancers, the date that the first cancer developed was used in calculations of cumulative incidence and SIR. Multivariate analysis was performed using a competing risk regression by the method of Fine and Gray. Statistical analyses were performed with EZR version 1.27. This study was approved by the institutional review board of the National Cancer Center Hospital.

The median age at transplant was 46 years and the median follow-up among surviving patients was 50 months (1–306, Table 1). The cumulative incidence of grade II–IV acute GvHD was 38.1% (95% CI: 35.2–41.0%) at 100 days, and that of chronic GvHD was 44.1% (95% CI: 41.0–47.2%) at 2 years. The cumulative incidences of oral and gastrointestinal chronic GvHD were 24.8% (95% CI: 22.2–27.5%) and 3.3% (95% CI: 2.3–4.6%) at 2 years, respectively. The median onset date of chronic GvHD was 139 days after HSCT. The observation period was 3710 person-years. Overall, 42 patients developed 48 secondary cancers at a median of 4.7 years after allo-HSCT (0.1–25.8 years) (Table 2). The median age at the time of secondary cancer development was 59 years (29–69 years). The cumulative incidence rates of developing any secondary cancer at 5, 10 and 15 years after allo-HSCT were 2.5% (95% CI: 1.6–3.8%), 5.9% (95% CI: 4.1–8.3%) and 8.5% (95% CI: 5.6–12.1%), respectively.

Table 1 Patient characteristics
Table 2 Standardized incidence ratios and observed numbers of secondary cancers

The SIR for developing secondary cancers compared with the Japanese general population was 3.4 (95% CI: 2.4–4.6, Table 2). SIRs were significantly higher for esophageal (SIR=23.4, 95% CI: 10.1–46.2) and oral (SIR=15.3, 95% CI: 4.2–39.2) cancers. The risk of developing esophageal cancer began increasing during the 1–5-year period after HSCT, and was particularly elevated from 5–10 years (SIR=74.0) and 10 years or after HSCT (SIR=24.0). The risk of developing oral cancer was elevated during the 5–10-year period (SIR=46.6) and at 10 years or after (SIR=30.2).

In a univariate analysis, patients aged 50 years or older (P<0.001), those with CML/MPD (P=0.009) or malignant lymphoma (P=0.006), those who received reduced-intensity conditioning (P=0.048) and those who developed chronic GvHD (P<0.001) had a significantly higher risk of developing secondary cancer. The risk was not significantly different between limited and extensive chronic GvHD (P=0.351). Multivariate analysis showed that age of 50 years or older (2.66, 95% CI: 1.07–6.62, P=0.036), CML/MPD (3.46, 95% CI: 1.56–7.70, P=0.002), and chronic GvHD (3.29, 95% CI: 1.59–6.82, P=0.001) were independently associated with the development of secondary cancers. The incidence of secondary cancers in older patients was significantly higher in those who developed chronic GvHD than in those who did not (P<0.001, 3.9% vs 0.6% at 2 years), while in younger patients, the incidences were comparable between those with and without chronic GvHD (P=0.208, 0.4% vs 0.6%).

As for the site of chronic GvHD, patients who developed oral or gastrointestinal chronic GvHD had a significantly higher incidence of secondary cancers compared with those who had chronic GvHD of other sites (oral: P=0.018, 2.9% vs 1.0% at 2 years; gastrointestinal: P=0.014, 6.1% vs 1.7%). There were no significant differences in the incidences of secondary cancers between patients with and without skin, eye, lung, liver, joint and hair chronic GvHD. As for other risk factors, 23 (55%) of 42 patients who developed a secondary cancer had a history of smoking, including 4 of 4 patients who developed oral cancer, 4 of 8 with esophageal, 3 of 5 with gastric, 3 of 4 with lung and 2 of 4 with colon cancer.

The overall survival rate of 42 patients who developed secondary cancers was 62% at 3 years after diagnosis, with a median follow-up of 35 months (1–159). Twenty-seven patients (64%) were diagnosed with secondary cancer at our center, and 15 patients (36%) at other institutions. In 19 patients, cancers were detected by routine medical checkups or yearly screenings at outpatient clinics, and 16 (84%) of them were diagnosed in earlier stages. In 18 patients, diagnoses were made by examinations performed after the development of clinical symptoms, and excluding those with brain and hematological malignancies, 6 of 13 (46%) were in earlier stages. All but 6 patients with secondary cancers were treated: 26 underwent tumor resection, 13 received chemotherapy and 8 received radiotherapy. Eight received chemotherapy combined with surgery and/or radiotherapy, and one received surgery and radiotherapy. Fifteen patients died, and the cause of death was identified in 13 of them: progression of the secondary cancer in 10, treatment-related mortality after chemo-radiotherapy for esophageal cancer in 1 and recurrence of primary hematological disease in 2. Death occurred in 5 of 19 patients whose cancer was detected by screenings, and only 3 of them, all who had lung cancer, died of secondary malignancies.

Chronic GvHD is one of the most frequently reported risk factors for developing secondary cancer.4, 5, 8, 10 In many prior reports, chronic GvHD was shown to be associated with the development of squamous cell carcinoma, including esophageal and oral cancers.8 Although an increased incidence of oral cancer has been consistently identified in many of the studies of secondary cancers after allo-HSCT,3, 4, 11 the reported risk of developing esophageal cancer has been higher in studies in Japan, including our own.3, 11, 12 A Japanese multicenter study showed that extensive chronic GvHD was a significant risk factor for each of oral cancer and esophageal cancer.3 In our evaluation whether sites of chronic GvHD were related to the development of secondary cancer, chronic GvHD of mouth or gastrointestinal tract was associated with a higher risk of secondary cancer than other chronic GvHD sites. The mechanisms by which chronic GvHD increases the risk of secondary cancer are thought to involve chronic inflammation or immunosuppression due to GvHD treatment, the latter of which may lead to deterioration of antitumor immunity.8

We found a higher cumulative incidence and SIR of developing secondary cancers after allo-HSCT compared with previous nationwide reports (cumulative incidence: 5.9% vs 1–2.2% at 10 years; SIR: 3.4 vs 1.8–2.1).3, 4, 5 One explanation for that might be that most patients make annual visits to our long-term follow-up clinic. These regular checkups may increase the opportunities for patients to report new episodes or symptoms, which would then trigger further screenings. As delayed diagnosis of solid cancers is often associated with worse prognosis, early detection is beneficial, especially in those at risk. Considering that multiple Japanese studies, including ours, revealed significantly elevated risks of oral and esophageal cancers, screening of secondary cancers of these sites, which may consist of self-examination, evaluation by a dentist, and ideally a scheduled endoscopy, should be recommended after allo-HSCT in the Japanese population.3, 11, 12 Although patients with risk factors, older age and oral or gastrointestinal chronic GvHD should certainly undergo screening, all survivors of allo-HSCT should be informed of the risks of secondary malignancies and encouraged to routinely receive health examinations.

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Acknowledgements

This work was supported by grants from the National Cancer Research and Development Fund (26-A-26). We thank the medical, nursing, data-processing, laboratory and clinical staff at the National Cancer Center Hospital, Tokyo, Japan, for their important contributions to this study and their dedicated patient care.

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Correspondence to S Kurosawa.

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Tanaka, Y., Kurosawa, S., Tajima, K. et al. Increased incidence of oral and gastrointestinal secondary cancer after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52, 789–791 (2017) doi:10.1038/bmt.2017.4

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