The Risk of Secondary Malignancies Over 30 Years After the Treatment of Non-Hodgkin Lymphoma

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1 108 The of Secondary Malignancies Over 30 Years After the Treatment of Non-Hodgkin Lymphoma Jonathan D. Tward, MD, PhD 1 Merideth M. M. Wendland, MD 1 Dennis C. Shrieve, MD, PhD 1 Aniko Szabo, PhD 2 David K. Gaffney, MD, PhD 1 1 Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, Utah. 2 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. BACKGROUND. Survivors of non-hodgkin lymphoma (NHL) are at increased risk for developing secondary malignancies. For the current study, the authors quantitated this risk in a group of NHL survivors over 30 years of follow-up. METHODS. Standardized incidence ratios (observed-to-expected [] ratio) and absolute excess risk of secondary malignancies were assessed in 77,876 patients who were diagnosed with NHL between 1973 and 2001 from centers that participated in the National Cancer Institute s Surveillance, Epidemiology, and End Results Program. RESULTS. There were 5638 patients who developed secondary malignancies, significantly more than the endemic rate (, 1.14; P.001). Overall, irradiated patients had a similar risk of secondary malignancies compared with unirradiated patients (relative risk, 1.04; 95% confidence interval, ; P.21). Irradiated patients had excess risk for sarcomas, breast cancers, and mesothelioma compared with unirradiated survivors (P.05). Patients age 25 years at the time of their NHL diagnosis had the highest relative increased risk (no radiation:, 2.1; P.05; radiation:, 4.51; P.05). Overall, no statistical difference was observed for secondary cancer incidence between females and males (, 1.12 vs. 1.15, respectively). Female survivors of NHL were less likely to develop breast cancer than the general population (, 0.85; P.05), but women age 25 years at the time of their NHL diagnosis were more likely to develop breast cancer (no radiation:, 2.1; P.05; radiation:, 4.51; P.05). CONCLUSIONS. The overall risk of secondary malignancies was increased for NHL survivors and varied according to age at NHL diagnosis, gender, and treatment. Cancer 2006;107: American Cancer Society. KEYWORDS: absolute excess risk, observed-to-expected ratio, second malignancies, standardized incidence ratio, Surveillance, Epidemiology, and End Results Program. Dr. Jonathan D. Tward had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Address for reprints: Jonathan D. Tward, MD, PhD, Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Salt Lake City, UT ; Fax: (801) ; jonathan.tward@hci.utah.edu Received January 11, 2006; revision received February 16, 2006; accepted February 28, This year, an estimated 56,300 patients will be newly diagnosed with non-hodgkin lymphoma in the U.S., and it is estimated that there will be nearly 19,200 deaths from NHL. 1 The survivors of NHL have a significantly elevated risk for secondary cancers, especially lung cancer, brain cancer, renal cancer, bladder cancer, melanoma, Hodgkin lymphoma, and acute nonlymphocytic leukemia. 2 Chemotherapy, 3 7 high-dose chemotherapy, autologous stem cell transplantation, 8 11 and radiation therapy 2,12,13 all have been implicated as risk factors. Currently, patients with lymphoma receive various combinations of chemotherapy, radiation, radioimmunotherapy, and highdose chemotherapy with autologous stem cell transplantation. Therefore, it is important to understand how different patient characteristics and their therapies alter their future cancer risk profiles, so that appropriate follow-up and management may occur American Cancer Society DOI /cncr Published online 17 May 2006 in Wiley InterScience (

2 Secondary Cancers in NHL Survivors/Tward et al. 109 Accordingly, we evaluated the absolute excess risk (AER) and relative site-specific risks (standardized incidence ratio [SIR] or observed-to-expected [] events) among 77,823 patients who were treated for NHL between 1973 and 2001, taking into account age at diagnosis, gender, radiation therapy, and latency period, with regard to the development of secondary cancers. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results Program The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute collects and publishes cancer incidence and survival data from 14 population-based cancer registries and 3 supplemental registries that cover approximately 26% of the U.S. population. SEER began collecting data on January 1, 1973 and currently has information on 3 million patients with in situ and invasive cancer. The SEER Registries routinely collect data on patient demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and follow-up for vital status. Study Population The SEER Program statistical analysis software package (SEER*Stat, version 5.3.1) 14 was used to identify patients who were diagnosed with any stage of NHL as their first primary malignancy between 1973 and The SEER*Stat Multiple Primary-SIR tool was used to calculate SIRs and excess risk for secondary malignancies by comparing these patients subsequent cancer experience with the number of cancers that would be expected based on incidence rates for the general U.S. population. These analyses were adjusted for age, gender, race, and year of NHL diagnosis. Information regarding lymphoma staging, chemotherapy, radiation dose, and sites to which radiation therapy was directed is not available currently in the SEER publicuse data base. Individuals who developed a secondary malignancy within 2 months of their NHL diagnosis or whose NHL diagnosis was not their first primary cancer were excluded from the analysis. The time to development of secondary malignancies was calculated from the date patients were diagnosed with NHL. Statistical Analysis The risk of second cancers was estimated by compiling person-years (PYs) of observation according to age, gender, and calendar-year periods from 2 months after the date of NHL diagnosis to the date of death, the date of last follow-up evaluation, the date of diagnosis of second cancer, or the end of the study (December 31, 2001), whichever occurred first. Cancer incidence rates that were specific for 5-year age groups, gender, and calendar-year intervals were multiplied by the accumulated PYs at risk to estimate the number of cancer cases expected. The observed and expected numbers of second cancers were then summed, with the SIR expressed as the ratio of cases. The AER was determined by subtracting the expected number from the observed number of second cancers and then dividing the difference by the number of PYs at risk. The number of excess second cancers was expressed per 10,000 PYs. s of second cancers were stratified by gender, age group at NHL diagnosis, time since NHL diagnosis (latency), and treatment (radiotherapy vs. no radiotherapy). Statistical tests and 95% confidence intervals (95% CIs) were based on the assumption that the observed number of second cancers was distributed as a Poisson variable. Tests for heterogeneity and linear trend were conducted by using the methods of Breslow et al. 15 SIR and AER are 2 complimentary measures of the incidence of an event of interest (in this instance, secondary cancer) in a subpopulation compared with the entire population. Both are based on comparing the observed number of events in the subpopulation (O) with the number of events that would be expected (E) if the risk profile for the subpopulation was identical to that for the full population. Because, as an individual ages, his or her risk of an event typically changes (because of both attained age and attained calendar year), the calculation of the expected number of events is adjusted for these variables. In addition, fixed characteristics that affect event rates, such as gender and race, are incorporated into the calculation of the expected number of events. These adjustments make subpopulations of different structures comparable: for example, longer follow-up in a particular group. SIR and AER differ in the way they combine O and E: SIR measures the fold difference between the observed and expected number of events (SIR ), whereas AER measures the actual number of excess events normalized to the number of PYs observed (AER [O E]/PY). Therefore, SIR measures the relative risk of the event on an individual level, and it does not depend on the frequency of the event in the population; whereas AER measures the population impact, i.e., small increases in the relative risk of a common event affect more individuals than a large increase in a rare event. It should be noted that the length of follow-up does not affect either measure: the number of observed events (O) increases, but so do the number of expected events (E) and the number PYs (PY).

3 110 CANCER July 1, 2006 / Volume 107 / Number 1 TABLE 1 Patients with Non-Hodgkin Lymphoma at for Developing Secondary Malignancies All Patients External Beam No Radiation TABLE 2 Demographics of Patients Who Developed Secondary Malignancies All Patients External Beam No Radiation Variable No. % No. % No. % Characteristic No. % No. % No. % Total no. of patients with NHL 77,823 21,100 55,351 Males 41, , , Females 35, , No. who developed second malignancy Average age at NHL diagnosis, y Average age at first secondary, y years at risk 380, , ,073 Average months at risk Race American Indian/Alaska Native Asian or Pacific Islander Black Unknown White 68, NHL indicates non-hodgkin lymphoma. The effect of external-beam radiation therapy for the treatment of NHL on the development of secondary malignancies was analyzed for cohorts based on age at diagnosis of NHL, gender, and the latency period in decades. RESULTS There were 77,823 patients included in the current analysis. Patient characteristics for the entire cohort are shown in Table 1. Second cancers developed in 5638 patients. In some patients, 1 secondary cancer was diagnosed; therefore, 6188 additional malignancies were observed (Table 2). Overall, second malignancies occurred at a higher rate among the study population than what would be expected in the general population (, 1.14; 95%CI, ; AER, 20.12) (Table 3). There was a significantly increased risk for cancers of the head and neck, melanoma, lung cancer, colon cancer, bladder cancer, renal cancer, Hodgkin disease, leukemia, and Kaposi sarcoma compared with the general population. Significantly decreased risks of female breast cancer, prostate cancer, and myeloma also were observed. External-beam radiation did not alter the overall risk significantly for secondary cancers versus unirradiated patients with NHL (all sites:, 1.18 vs. 1.13, respectively; AER, vs , respectively) (Table Total no. of patients Males Females Age at NHL diagnosis, y Average Median years of follow-up 49,233 15,518 32,782 Follow-up, mo Average Median Race American Indian/Alaska Native Asian or Pacific Islander Black Unknown White NHL indicates non-hodgkin lymphoma. 4). However, when comparing specific cancer subtypes between the irradiated and nonirradiated cohorts, radiation therapy resulted in significantly more soft tissues cancers (sarcomas), female breast cancers, and mesotheliomas (P.05). Although the unirradiated patients had a significantly decreased risk of developing female breast cancer (, 0.79; AER, 3.57), the risk for the irradiated group was equivalent to the endemic rate (, 1.00; AER, 0.01). The prostate cancer risk also was significantly lower for unirradiated patients compared with the risk among the standard population (, 0.89; AER, 3.11). In general, the risk of all secondary cancers was similar in men and women (, 1.15 vs. 1.12, respectively; relative risk, 1.02; P.92). Lung cancer and mediastinal cancers accounted for the greatest AER in both men and women (6.36 and 7.19, respectively). The greatest decreases in risk were seen for breast cancer in women (AER, 5.05;, 0.85; P.05) and for prostate cancer in men (AER, 5.29;, 0.9; P.05). The risks of all secondary cancers and those for selected sites are listed in Table 5 according to age at diagnosis of NHL and treatment modality. The overall risk of secondary malignancies was highest for the youngest cohort and trended downward with increasing age. NHL diagnosed in patients age 75 years carried a relative risk of secondary malignancies similar to that for the general population and a decreased AER (all sites, with radiation:, 0.94; AER, 15.77;

4 Secondary Cancers in NHL Survivors/Tward et al. 111 TABLE 3 Standardized Incidence Ratios and Absolute for Second Cancers in Patients With Non-Hodgkin Lymphoma Malignancy/Tumor Site Patients (77,876) All Patients (381,257) Observed * 95% CI All sites 6, All sites excluding NHL 5, All solid tumors 5, Gynecologic malignancies Head and neck Melanoma Lung and mediastinum 1, Soft tissues Esophagus Stomach Colon excluding rectum Rectum and rectosigmoid junction Anus, anal canal, and anorectum Liver, gallbladder, and biliary Pancreas Breast Female breast Male breast Prostate Testis Penis Urinary bladder Kidney and renal pelvis Brain Thyroid Hodgkin lymphoma Myeloma Leukemia Mesothelioma Kaposi sarcoma Miscellaneous indicates observed to expected ratio; 95% CI, 95% confidence interval; NHL, non-hodgkin lymphoma. * risk indicates the number of patients per 10,000 person-years. P.05 for the standardized incidence ratio versus the general U.S. population. Excludes lymphohematopoietic disorders. For female-specific sites, the number of patients was 35,878 and the corresponding number of person-years was 185,505. all sites, without radiation:, 0.93; AER, 17.06). Patients age 25 years at the time of NHL diagnosis who had received therapy had a significantly elevated risk for leukemia, thyroid, and female breast cancer (: 16.21, 8.69, and 5.03, respectively). Women who did not receive radiation therapy had a decreased risk of breast cancer across all age cohorts. The relative risk of developing a secondary malignancy appeared to increase with increasing latency from diagnosis. However, after adjusting for age at diagnosis, the effect of latency disappeared: The adjusted SIR was 1.59, 1.55, and 1.65 for latencies 10 years, from 10 years to 20 years, and 20 years, respectively, for a test of equality with P.64. DISCUSSION Multiple studies 3,6,8,10,11,16,17 in the last decade have demonstrated that patients with NHL are at significantly greater risk for secondary cancers, despite earlier reports to the contrary Our current results update and expand on the 1993 findings of Travis et al. 2 and now represent the largest population-based study of NHL survivors. Greater than year survivors were included, allowing us to evaluate cancer risk over 30 years. Our report validates more recent reports that NHL survivors are at a significantly increased risk for secondary cancers and that both the risk and AER increase with the length of survival. Men and women NHL survivors have an overall equivalent risk for developing secondary malignancies. The 1993 report by Travis et al. indicated that men had a relative risk of 1.25 for all secondary cancers compared with 1.08 for women. Our update showed that the relative risk was 1.15 in men and 1.12 in women. The current study demonstrated an risk for prostate cancer of 0.9 (95% CI, ; P.05). This translated to a decrease in AER of 5.3. This may be a significant underestimate of the effect, because the incidence of prostate cancer has risen sharply secondary to prostate-specific antigen screening. 23 Several hypotheses may explain the reduced risk for prostate cancer in NHL survivors. Modern treatment for NHL may eradicate or delay the clinically detectable progression of occult prostate cancers. 24,25 Alternatively, men who have been diagnosed with a prior malignancy like NHL may be more conscientious of their health, resulting in lifestyle changes that have an impact on their risk of prostate cancer In 1993, the risk of a secondary lung cancer in men was 1.61 times that of the reference population; whereas, in the current analysis, this risk had decreased to Cancer survivors are less likely to smoke than the general population, 29,30 which may explain this lung cancer risk decrease; however, in women, we observed a relative risk of 1.45 for lung cancer development, identical to the 1993 observation. When we excluded gender-specific malignancies, we discovered that women had a relative risk of 1.29 for secondary cancers over the general population. Female breast cancer accounted for the greatest number of observed secondary malignancies (548 patients)

5 112 CANCER July 1, 2006 / Volume 107 / Number 1 TABLE 4 Comparison of Standardized Incidence Ratios and Absolute for Patients by Treatment Modality No Radiation Radiation* Patients (55,392) (261,545) Patients (21,111) (112,281) Malignancy/Tumor Site Observed 95% CI Observed 95% CI All sites All sites excluding NHL All solid tumors Gynecologic malignancies Head and neck Melanoma Lung and mediastinum Soft tissues Esophagus Stomach Colon excluding rectum Rectum and rectosigmoid junction Anus, anal canal, and anorectum Liver, gallbladder, and biliary Pancreas Breast Female breast Male breast Prostate Testis Penis Urinary bladder Kidney and renal pelvis Brain Thyroid Hodgkin lymphoma Myeloma Leukemia Mesothelioma Kaposi sarcoma Miscellaneous indicates observed to expected ratio; 95% CI, 95% confidence interval; NHL, non-hodgkin lymphoma. * Includes patients whose radiotherapy was encoded as external beam only. risk indicates the number of patients per 10,000 person-years. P.05 for the standardized incidence ratio (SIR) versus the general U.S. population. Excludes lymphohematopoietic disorders. P.05 for differences in the SIR between the no radiation and radiation cohorts. P.01 for differences in the SIR between patients with NHL who did or did not receive radiotherapy. For female-specific sites, the number of patients in the no radiation group was 25,460, and the corresponding number of person-years was 127,398, The number of patients in the external beam radiation group was 9734, and the corresponding number of person-years was 54,249. in women, yet NHL survivors are protected from this malignancy compared with the general population (Table 3). It is conceivable that lowered estrogen levels from the ablation of ovarian function from chemotherapy may explain this decline. In patients with Hodgkin disease who receive ovarian-ablative therapy with either chemotherapy or radiotherapy, a decrease in breast cancer has been observed. 31,32 Radiation therapy did not increase the overall, solid tumor, or hematologic cancer risk of secondary malignancies significantly compared with the unirradiated cohort (Table 4). The only significant differences that were observed among irradiated patients versus unirradiated patients were in the development of soft tissue malignancies (sarcomas), female breast cancer, and mesothelioma. An increased risk of sarcoma development in irradiated patients has been reported for other malignancies Although the risk

6 Secondary Cancers in NHL Survivors/Tward et al. 113 TABLE 5 The Age at Diagnosis of Non-Hodgkin Lymphoma Alters the Profile for Secondary Malignancies No Radiation Radiation* Age <25 Years Ages Years Ages Years Age >75 Years Age <25 Years Ages Years Ages Years Age >75 Years Patients (1752) Patients (12,288) (11,061) Patients (65,442) (29,549) Patients (148,890) (12,989) Patients (34,453) (1041) Person Patients (5104) Patients (31,744) (10,737) Patients (59,811) (4218) (11,624) Malignancy/Disease Site All sites All sites excluding NHL All solid tumors Gynecologic malignancies Head and neck Melanoma Lung and Mediastinum Soft tissues Esophagus Stomach Colon excluding rectum Rectum and rectosigmoid junction Anus, anal canal, and anorectum Liver, gallbladder, bile ducts Pancreas Breast Female breast Male breast Prostate Testis Penis Urinary bladder Kidney and renal pelvis Brain Thyroid Hodgkin lymphoma Myeloma Leukemia Mesothelioma Kaposi sarcoma Miscellaneous indicates observed to expected ratio; NHL, non-hodgkin lymphoma. * Includes patients whose radiotherapy was encoded as external beam only. risk indicates the number of patients per 10,000 person-years. P.05 for the standardized incidence ratio versus the general U.S. population. Excludes lymphohematopoietic disorders. For female-specific sites, the numbers of patients in the no radiation group ages 25 years, years, years, and 75 years were 592, 3944, 13,587, and 7337 patients, respectively, and the corresponding numbers of person-years were 4294, 27843, 74,561, and 20,701 person-years, respectively. For female-specific sites, the numbers of patients in the external beam radiation group ages 25 years, years, years, and 75 years were 328, 1778, 5046, and 2582 patients, respectively, and the corresponding numbers of person-years were 3105, 13,444, 30,255, and 7445 person-years, respectively.

7 114 CANCER July 1, 2006 / Volume 107 / Number 1 of a secondary breast cancer is greater for irradiated NHL survivors versus unirradiated women, the risk of a secondary breast cancer overall in irradiated women is not different from that in the general population (, 1.00; 95% CI, ). Additional analysis revealed that, for the irradiated women, age younger than 25 years at NHL diagnosis translated into a 5-fold risk increase for breast cancer, indicating the deleterious effect of radiotherapy in young patients. To the best of our knowledge, increased mesothelioma risk after irradiation has not been described in other population-based studies. The aggregate AER for soft tissue malignancies, female breast cancer, and mesothelioma in irradiated patients was 1.57 cases per 10,000 PYs. The risk of secondary cancers is greatest for the youngest cohort, whereas the AER for secondary cancers peaks among patients ages 25 to 49 years at the time of their initial NHL diagnosis, and then declines with advancing age (Table 5). This held true for both the irradiated and unirradiated patient cohorts. These data highlight the importance of the judicious use of radiotherapy in young patients, and particularly in growing children. Further studies with more complete data bases that can match cohorts with additional prognostic variables are needed to define these risks further. We also considered whether latency affects the incidence of secondary cancers; that is, whether the risk relative to the general population changes as the time since NHL diagnosis increases. At first glance, it appeared that, with increased latency, the SIR increased: For all cancers, the SIRs were 1.12, 1.21, and 1.50 for latencies 10 years, from 10 to 20 years, and 20 years, respectively, for a test of linear trend with P However, such an analysis is misleading, because age at diagnosis affects both the risk of secondary cancers and the probability of surviving for 10 or 20 years after diagnosis. The latter effect is a combination of higher cause-specific survival among younger patients and a lower rate of death from other causes. Consequently, among the patients who have a latency 10 years, 71% are age 50 years at diagnosis; whereas, among the patients with a latency 20 years, the proportion declines to 40%. After adjusting for age at diagnosis, the effect of latency disappears: The adjusted SIRs were 1.59, 1.55, and 1.65 for latencies 10 years, from 10 to 20 years, and 20 years, respectively, for a test of equality with P.64. We performed similar evaluations for all the cancer sites (data not shown) and found no evidence of latency-related changes in the risk of a secondary cancer after adjusting for age at diagnosis. The number of patients in the latency period beyond 240 months was comparatively smaller than the number in other latency periods; therefore, conclusions must be interpreted cautiously. Some clinical and pathologic data with known prognostic significance are not available in the SEER data base. Specifically lacking is information regarding lymphoma staging, details about types or amounts of chemotherapy, whether patients underwent bone marrow transplantation, the proportion of individuals who had the human immunodeficiency virus or who were otherwise immunocompromised, or the specifics of radiotherapy dose, treatment fields, and fractionation schemes. 37 In addition, the SEER data base does not record history of treatment failure or time of recurrence. 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