Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Risk of treatment-related esophageal cancer among breast cancer survivors.

BACKGROUND: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN: Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy.

BACKGROUND: It is unknown whether breast cancer (BC) characteristics among young women treated with radiotherapy (RT) for Hodgkin's lymphoma (HL) differ from sporadic BC. METHODS: Using population-based data, we calculated BC risk following HL according to clinicopathologic features. RESULTS: Compared with BC in the general population, risks of oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive and ER-negative/PR-negative BC in young, irradiated HL survivors were increased five-fold (95% confidence interval (CI)=3.81-6.35) and nine-fold (95% CI=6.93-12.25), respectively. Among 15-year survivors, relative risk of ER-negative/PR-negative BC exceeded by two-fold (P=0.002) than that of ER-positive/PR-positive BC. CONCLUSION: Radiotherapy may disproportionately contribute to the development of BC with adverse prognostic features among young HL survivors.

Second solid cancers after radiotherapy for breast cancer in SEER cancer registries.

BACKGROUND: Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. METHODS: We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. RESULTS: By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total. CONCLUSIONS: Most second solid cancers in breast cancer survivors are not related to radiotherapy.

Second cancers in patients with chronic lymphocytic leukemia.

BACKGROUND: Reports to date have provided widely divergent estimates of the risk of second malignant neoplasms in patients with chronic lymphocytic leukemia (CLL), ranging from cancer deficits to excesses of twofold to threefold. PURPOSE: Our purpose was to estimate the risk of second primary cancers following CLL, utilizing population-based tumor registries, and to determine whether site-specific excesses might be associated with type of initial treatment for CLL. METHODS: We analyzed data for 9456 patients diagnosed with CLL as a first primary cancer between 1973 and 1988, who were reported to one of nine tumor registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and who survived 2 or more months. SEER files were searched for invasive primary malignancies that developed at least 2 months after the initial CLL diagnosis. RESULTS: Compared with the general population, CLL patients demonstrated a significantly increased risk of developing all second cancers (840 observed; observed-to-expected ratio [O/E] = 1.28; 95% confidence interval [CI] = 1.19-1.37). Significant excesses were noted for cancers of the lung (O/E = 1.90), brain (O/E = 1.98), and eye (intraocular melanoma) (O/E = 3.97) as well as malignant melanoma (O/E = 2.79) and Hodgkin's disease (O/E = 7.69). Cancer risk, which did not vary according to initial treatment category, was also constant across all time intervals after CLL diagnosis. CONCLUSION: CLL patients are at a significantly increased risk of developing a second malignant neoplasm. The pattern of cancer excesses suggests a susceptibility state permitting the development of selected second malignancies in patients with CLL, perhaps because of shared etiologic factors, immunologic impairment, and/or other influences. Although our results do not suggest a strong treatment effect, more detailed studies of second tumors in CLL are needed to investigate the role of radiation therapy and chemotherapy.

Risk of leukemia associated with the first course of cancer treatment: an analysis of the Surveillance, Epidemiology, and End Results Program experience.

The risk of leukemia associated with the first course of cancer treatment was evaluated in over 440,000 patients diagnosed during 1973-80 (average follow-up = 1.91 yr) from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Although the reporting of the first course of therapy probably was incomplete, 34 acute nonlymphocytic leukemias (ANLL) developed compared with 7.6 expected among 70,674 patients known to receive initial chemotherapy [relative risk (RR) = 4.5, 95% confidence interval (Cl) = 3.1-6.3]. Significant ANLL excesses were observed following chemotherapy for breast cancer (RR = 8.1), ovarian cancer (RR = 22.2), and multiple myeloma (RR = 9.5). Patients initially treated with radiation (with no record of chemotherapy) also had a significantly increased ANLL risk; 45 leukemias occurred versus 17.9 expected (RR = 2.5, 95% Cl = 1.8-3.4). In this group, excess ANLL were found following irradiation for uterine corpus cancer (RR = 4.0). Kidney and renal pelvis cancer patients had a twofold leukemia risk (all types) that was unrelated to treatment (RR = 2.2).

A retrospective cohort analysis of second breast cancer risk for primary breast cancer patients with an assessment of the effect of radiation therapy.

Second breast cancer experience was examined for 27,175 primary breast cancer patients diagnosed in the State of Connecticut during 1935-75 with follow-up for second breast cancers through 1980. The overall ratio of observed to expected second breast cancers was 3.2. Relative risk was found to be inversely related to age at diagnosis and directly related to stage of the first breast cancer. The overall risk of second breast cancers was 711 per 100,000 person-years at risk. Risk of second breast cancers showed a similar relationship to age and stage as relative risk and was also directly related to calendar period of diagnosis of the first breast cancer. Some interactions were observed because patients less than 45 years old at diagnosis with positive nodes had elevated risks and relative risks in the early followup period, whereas less of an effect of stage on relative risk and risk was seen for older patients. The effect of the use of adjunctive radiation therapy on second breast cancer risk was also assessed by the ratio of the risk of second breast cancers for those patients who received both surgery and radiation to the risk of those patients who only received surgery being estimated for patients diagnosed during 1935-59 and for patients diagnosed during 1960-75. For both cohorts relative risks of 1.2-1.4 were found for the 5-year period immediately following diagnosis, likely resulting from the uncontrolled effect of stage in the analysis. Elevated long-term relative risks were not found for patients diagnosed during 1935-59. A long-term marginally statistically significant relative risk of 1.4 (greater than or equal to 10 yr after diagnosis) was found for patients diagnosed during 1960-75. The data do not indicate an overall pattern of relative risks consistent with an effect on long-term second breast cancer risk of radiation exposure to the opposite breast incurred during adjunctive radiation therapy for a first breast cancer.

Second cancers following radiotherapy for cervical cancer.

Incidence of second primary cancers was evaluated in 7,127 women with invasive cancer of the cervix uteri, diagnosed between 1935 and 1978, and followed up to 38 years (average, 8.9 yr) in Connecticut. Among 5,997 women treated with radiation, 449 developed second primary cancers compared with 313 expected (relative risk = 1.4) on the basis of rates from the Connecticut Tumor Registry. Excess incidence was noticeable 15 years or more after radiotherapy and attributed mostly to cancers of sites in or near the radiation field, especially the bladder, kidneys, rectum, corpus uteri, and ovaries. No excess was found for these sites among the 1,130 nonirradiated women. The ratio of observed to expected cancers for these sites did not vary appreciably by age at irradiation. The data suggested that high-dose pelvic irradiation was associated with increase in cancers of the bladder, kidneys, rectum, ovaries, corpus uteri, and non-Hodgkin's lymphoma but, apparently, not leukemia, Hodgkin's disease, breast cancer, or colon cancer.

Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma.

BACKGROUND: Cyclophosphamide is an established bladder carcinogen, but few studies have examined the relationship between dose and effect. The largest analysis to date included only seven cases of bladder cancer. No investigation has estimated the risk of kidney cancer. PURPOSE: The purpose of this study was to quantify the risk of bladder and kidney cancer following cyclophosphamide therapy. METHODS: Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy. Detailed information on chemotherapeutic drugs and cumulative dose received was collected for all subjects. Radiation dose to the target organ was estimated from individual radiotherapy records. Evaluations of the risk of second cancer as a result of treatment with cyclophosphamide alone, radiation alone, or both therapies were made relative to those patients who were exposed to neither treatment modality. RESULTS: A significant 4.5-fold risk of bladder cancer (95% confidence interval [CI] = 1.5-13.6) followed therapy with cyclophosphamide, and risk was dependent upon cumulative dose. Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold (95% CI = 1.3-29) and 14.5-fold (95% CI = 2.3-94) risks of bladder malignancy followed cumulative doses of 20-49 g and 50 g or more, respectively (P value for trend = .004). Radiotherapy given without cyclophosphamide was associated with a nonsignificant increased risk of bladder malignancy. Excess bladder cancer risk following treatment with both radiotherapy and cyclophosphamide was as expected if individual risks were summed. Neither radiotherapy nor cyclophosphamide was associated with excesses of kidney cancer. CONCLUSIONS: Cyclophosphamide-related bladder cancer is dose dependent. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up. At cumulative doses of 50 g or more, the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients. IMPLICATIONS: The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points. The risk of secondary bladder malignancy and other late sequelae of therapy must be carefully weighted against the curative gains provided by cyclophosphamide. Moreover, long-term side effects of therapy that might be acceptable in cancer treatment may need to be re-evaluated for patients with non-neoplastic disorders.

Relationship of leukemia risk to radiation dose following cancer of the uterine corpus.

BACKGROUND: Radiotherapy has been linked infrequently to secondary leukemia despite extensive exposure of the active bone marrow to ionizing radiation. Few studies include substantial numbers of elderly patients. PURPOSE: We evaluated women with cancer of the uterine corpus, the majority of whom were treated at older ages, to gain additional information on cancer risk following partial-body radiotherapy and to examine differences in risk between external-beam therapy and brachytherapy. METHODS: A cohort of 110,000 women with invasive cancer of the uterine corpus who survived at least 1 year following their initial cancer was assembled from nine population-based cancer registries. Cancer diagnoses occurred from 1935 through 1985, and most patients were diagnosed during the 1960s and 1970s. Radiation doses were computed to 17 sections of the active bone marrow for 218 women who developed leukemia and for 775 matched control subjects. RESULTS: Radiotherapy did not increase the risk of chronic lymphocytic leukemia (CLL) (relative risk [RR] = 0.90; 95% confidence interval [CI] = 0.4-1.9). However, for all leukemias except CLL, a significant risk was identified (RR = 1.92; 95% CI = 1.3-2.9). Overall, the pattern of risk in relation to dose was erratic and was most consistent with a constant increased risk across the entire dose range. The risk following continuous exposures from brachytherapy at comparatively low doses and low dose rates (RR = 1.80; 95% CI = 1.1-2.8; mean dose = 1.72 Gy) was similar to that after fractionated exposures at much higher doses and higher dose rates from external-beam treatment (RR = 2.29; 95% CI = 1.4-3.7; mean dose = 9.88 Gy), indicating a large difference in the estimated risk per unit dose. Risk did not vary by age at first exposure; increased risks were apparent for irradiated patients aged 65 years or older (RR = 1.77; 95% CI = 0.9-3.5). CONCLUSION: The leukemia risk associated with partial-body radiotherapy for uterine corpus cancer was small; about 14 excess leukemia cases were due to radiation per 10,000 women followed for 10 years. Women aged 65 years or older had a radiation risk comparable with that found in younger women. The relationship of leukemia risk to radiation dose was found to be complex due to the competing processes of cell killing, transformation, and repair. At very high doses delivered at high rates, destruction of cells likely dominates, and the risk per unit dose is low. In the low dose range, where dose was protracted and delivered at relatively low dose rates, the leukemia risk appears lower than that projected from risk estimates derived from the instantaneous whole-body exposures of atomic bomb survivors.

Second cancers among long-term survivors of non-Hodgkin's lymphoma.

BACKGROUND: Patients with non-Hodgkin's lymphoma (NHL) are at increased risk for second cancers. Few studies, however, include long-term survivors, and none report risk for second cancer among NHL patients surviving 15 or more years. PURPOSE: Our aim was to examine the pattern of second cancers among long-term survivors of NHL. METHODS: A cohort of 6171 patients diagnosed with NHL as a first primary cancer and who survived 2 or more years was identified within population-based tumor registries in Sweden, Ontario, and Iowa and within the affiliated tumor registry of The Netherlands Cancer Institute. Nearly 1000 NHL patients lived 15 or more years after diagnosis. Tumor registry files were searched for new invasive primary malignancies. RESULTS: Second cancers were reported in 541 subjects (observed-to-expected ratio [O/E] = 1.37; 95% confidence interval = 1.26-1.49), with significant excesses seen for all solid tumors (O/E = 1.28), acute nonlymphocytic leukemia (O/E = 4.83), melanoma (O/E = 2.38), Hodgkin's disease (O/E = 12.0), and cancers of the lung (O/E = 1.36), brain (O/E = 2.33), kidney (O/E = 2.07), and bladder (O/E = 1.77). Among 15-year survivors, significantly increased risks persisted for all second cancers (O/E = 1.45), solid tumors (O/E = 1.37), bladder cancer (O/E = 3.24), and Hodgkin's disease (O/E = 25.0). The actuarial risk of developing a second cancer 3-20 years after diagnosis of NHL was 21%, compared with a population expected cumulative risk of 15%. CONCLUSIONS: Patients with NHL continue to be at significantly elevated risk of second primary cancer for up to two decades following diagnosis. The pattern of risk suggests the influence of treatment as well as factors associated with the underlying disease. IMPLICATIONS: Quantitative studies of second cancer following NHL are needed to clarify the role of antecedent therapy, shared risk factors, host susceptibility, and other etiologic and diagnostic influences. Despite the generally advanced age of patients with NHL, the persistently elevated risk of second cancers should alert clinicians to the importance of continued medical surveillance.

Risk of leukemia following treatment for non-Hodgkin's lymphoma.

BACKGROUND: There have been few evaluations of the risk of acute nonlymphocytic leukemia (ANLL) following therapy for non-Hodgkin's lymphoma (NHL). Further, the relationship between cumulative dose of cytotoxic drug, radiation dose to active bone marrow, and the risk of ANLL following NHL have not been well described. PURPOSE: Our purpose was to examine the risk of ANLL in relationship to all prior treatment for NHL. METHODS: Within a cohort study of 11,386 2-year survivors of NHL, 35 case patients with secondary ANLL were identified and matched to 140 controls with NHL who did not develop ANLL. The primary eligibility criteria for the cohort included a diagnosis of NHL as a first primary cancer from January 1, 1965, through December 31, 1989; age 18 through 70 years at the time of initial diagnosis; and survival for 2 or more years without the development of a second invasive primary malignancy. Detailed information on chemotherapeutic drugs and radiotherapy was collected for all patients. Standard conditional logistic regression programs were used to estimate the relative risk (RR) of ANLL associated with specific therapies by comparing the exposure histories of case patients with individually matched controls. RESULTS: Significant excesses of ANLL followed therapy with either prednimustine (RR = 13.4; 95% confidence interval [CI] = 1.1-156; P trend for dose < .05) or regimens containing mechlorethamine and procarbazine (RR = 12.6; 95% CI = 2.0-79; P < .05). Elevated risks of leukemia following therapy with chlorambucil were restricted to patients given cumulative doses of 1300 mg or more (RR = 6.5; 95% CI = 1.6-26; P < .05). Cyclophosphamide regimens were associated with a small, nonsignificant increased risk of ANLL (RR = 1.8;95% CI = 0.7-4.9), with most patients receiving relatively low cumulative doses (< 20,000 mg). Radiotherapy given at higher doses without alkylating agents was linked to a nonsignificant threefold risk of ANLL compared with lower dose radiation or no radiotherapy. CONCLUSIONS: Our results suggest that prednimustine may be a human carcinogen, with a positive dose-response gradient evident for ANLL risk. The low, nonsignificant risk of leukemia associated with cyclophosphamide was reassuring because this drug is commonly used today. Despite the excesses of ANLL associated with specific therapies, secondary leukemia remains a rare occurrence following NHL. Of 10,000 NHL patients treated for 6 months with selected regimens including low cumulative doses of cyclophosphamide and followed for 10 years, an excess of four leukemias might be expected.

Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries.

The numbers of second cancers among 182,040 women treated for cervical cancer that were reported to 15 cancer registries in 8 countries were compared to the numbers expected had the same risk prevailed as in the general population. A small 9% excess of second cancers (5,146 observed vs. 4,736 expected) occurred 1 or more years after treatment. Large radiation doses experienced by 82,616 women did not dramatically alter their risk of developing a second cancer; at most, about 162 of 3,324 second cancers (approximately equal to 5%) could be attributed to radiation. The relative risk (RR = 1.1) for developing cancer in organs close to the cervix that had received high radiation exposures--most notably, the bladder, rectum, uterine corpus, ovary, small intestine, bone, and connective tissue--and for developing multiple myeloma increased with time since treatment. No similar increase was seen for 99,424 women not treated with radiation. Only a slight excess of acute and non-lymphocytic leukemia was found among irradiated women (RR = 1.3), and substantially fewer cases were observed than expected on the basis of current radiation risk estimates. The small risk of leukemia may be associated with low doses of radiation absorbed by the bone marrow outside the pelvis, inasmuch as the marrow in the pelvis may have been destroyed or rendered inactive by very large radiotherapy exposures. There was little evidence of a radiation effect for cancers of the stomach, colon, liver, and gallbladder, for melanoma and other skin cancers, or for chronic lymphocytic leukemia despite substantial exposures. An excess of thyroid cancer possibly was related to the low dose received by this organ. Ovarian damage caused by radiation may have been responsible for a low breast cancer risk (RR = 0.7), which was evident even among postmenopausal women. A substantial excess of lung cancer (RR = 3.7) largely may be due to misclassification of metastases and the confounding influence of cigarette smoking. Women who were under 30 or over 50 years of age when irradiated were at greatest absolute risk for developing a second cancer. The RR, however, was higher among those under age 30 years at exposure (RR = 3.9) than among older women. The expression period for radiation-induced solid tumors appeared to continue to the end of life.

Treatment-associated leukemia following testicular cancer.

BACKGROUND: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer. METHODS: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided. RESULTS: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks. CONCLUSIONS: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.

Risk of second malignant neoplasms among long-term survivors of testicular cancer.

BACKGROUND: We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. METHODS: The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. RESULTS: Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. CONCLUSIONS: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Leukemia following chemotherapy for breast cancer.

Leukemia following chemotherapy for breast cancer was studied among patients diagnosed during 1973-1985 within the population-based tumor registries in the Surveillance, Epidemiology, and End Results Program. Among 13,734 women given initial chemotherapy, 24 developed acute nonlymphocytic leukemia (ANLL) compared to 2.1 expected based on general population rates (observed/expected = 11.5; 95% confidence interval = 7.4-17.1). Overall, 58 excess ANLL occurred per 100,000 women-years at risk for patients treated with chemotherapy. The cumulative incidence was 0.7% at 10 years. Risk remained high over all periods of observation up to 9 years after treatment. Among 7974 women treated only with surgery during 1973 and 1974, a period before the widespread use of adjuvant chemotherapy for breast cancer, ANLL was not significantly increased (observed = 7, expected = 5.1). A case-control study was then conducted in Connecticut to evaluate in more detail the risk associated with adjuvant chemotherapy in the general population. Among 20 cases (17 incident leukemias and 3 deaths due to preleukemia) and 60 matched controls, alkylating agents were linked to an 11.9-fold risk of ANLL and preleukemia (95% confidence interval = 2.6-55). Chemotherapy regimens including melphalan were related to a higher risk of leukemic conditions than those including cyclophosphamide. These data suggest that women in the general population treated with adjuvant chemotherapy for breast cancer are at an increased risk of leukemia, that the risk remains high among long-term survivors, and that risk differs by type of alkylating agent administered.

Second malignant neoplasms among long-term survivors of ovarian cancer.

Second malignant neoplasms were evaluated among 32,251 women with ovarian cancer, including 4,402 10-year survivors, within the nine population-based registries of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (1973-1992) and the Connecticut Tumor Registry (1935-1972). Overall, 1,296 second cancers occurred against 1,014 expected [observed/expected (O/E), 1.28; 95% confidence interval (CI), 1.21-1.35]. Sites contributing 25 or more excess cancers included leukemia (O/E, 4.17; O, 111; 95% CI, 3.43-5.03) and malignancies of colon (O/E, 1.33; O, 188; 95% CI, 1.15-1.54), rectum (O/E, 1.43; O, 76; 95% CI, 1.13-1.79), breast (O/E, 1.18; O, 404; 95%, CI 1.07-1.30), and bladder (O/E, 2.07; O, 65; 95% CI, 1.59-2.63). Ocular melanoma (O/E, 4.45; O, 8; 95% CI, 1.92-8.77) was also significantly increased. Second cancer risk was high during all follow-up intervals, and cumulative risk at 20 years was 18.2%, compared with a population expected risk of 11.5%. Statistically significant relationships existed between serous adenocarcinoma of the ovary and breast cancer (O/E, 1.29; 95% CI, 1.06-1.56) and mucinous ovarian adenocarcinoma and rectal cancer (OE/E, 1.95; 95% CI, 1.09-3.22). Secondary leukemia appeared linked with antecedent chemotherapy, whereas radiotherapy was associated with cancers of connective tissue, bladder, and possibly pancreas. Genetic and reproductive factors predisposing to ovarian cancer may have contributed to the elevated risk of breast and colorectal neoplasms and possibly ocular melanoma. Thus, excess malignancies following ovarian cancer represent complications of curative therapies and/or underlying susceptibility states that have etiological and clinical ramifications.

Leukemia risk following radiotherapy for breast cancer.

To evaluate further the relationship between high-dose radiotherapy and leukemia incidence, a nested case-control study was conducted in a cohort of 22,753 women who were 18-month survivors of invasive breast cancer diagnosed from 1935 to 1972. Women treated for breast cancer after 1973 were excluded to minimize the possible confounding influence of treatment with chemotherapeutic agents. The cases had histologically confirmed leukemia reported to the Connecticut Tumor Registry (CTR) between 1935 and 1984. A total of 48 cases of leukemia following breast cancer were included in the study. Two controls were individually matched to each leukemia case on the basis of age, calendar year when diagnosed with breast cancer, and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. Local radiation doses to each of the 16 bone marrow components for each patient were reconstructed; the dose averaged over the entire body was 530 rad (5.3 Gy). Based on this dosage and assuming a linear relationship between dose and affect, a relative risk (RR) in excess of 10 would have been expected. However, there was little evidence that radiotherapy increased the overall risk of leukemia (RR = 1.16; 90% confidence interval [CI], 0.6 to 2.1). The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not significantly increased (RR = 1.8; n = 10); nor was the risk for all other forms of leukemia (RR = 1.0; n = 38). There was no indication that risk varied over categories of radiation dose. These data exclude an association between leukemia and radiotherapy for breast cancer of 2.2-fold with 90% confidence, and provide further evidence that cell death predominates over cell transformation when high radiation doses are delivered to limited volumes of tissue.

Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma.

PURPOSE: Low-dose total body irradiation (TBI) is used to treat non-Hodgkin's lymphoma (NHL) and several other malignancies. Large volumes of bone marrow and other tissue receive considerable exposure, but few studies have quantified late carcinogenic sequelae. PATIENTS AND METHODS: A cohort of 61 2-year survivors of NHL treated initially with low-dose TBI was monitored for second cancer occurrence. Data on primary and subsequent therapy were collected, and cumulative dose of radiation to active bone marrow (ABM) (median, 5.2 Gy) was reconstructed. RESULTS: Thirteen second primary cancers occurred. Four patients developed acute nonlymphocytic leukemia (ANLL), which represents a relative risk (RR) of 117 (95% confidence interval [CI], 31.5 to 300) compared with population rates. A fifth patient was diagnosed with myelodysplastic syndrome (MDS). All five patients with secondary hematologic malignancies subsequently received salvage treatment, with either alkylating agents alone (n = 1) or combined modality therapy (CMT) (n = 4). Overall, eight solid tumors were observed (RR = 2.0; 95% CI, 0.9 to 4.0). The 15-year cumulative risks of all second cancers and secondary ANLL were 37% and 17%, respectively. CONCLUSIONS: Despite the small number of subjects, a considerable risk of leukemia was observed among patients treated with low-dose TBI in combination with CMT including alkylating agents. Based on these results, approximately eight to nine excess ANLLs might be expected to occur among 100 NHL patients treated with low-dose TBI and salvage treatment and followed-up for 15 years.