Second malignant neoplasms after childhood non-central nervous system embryonal tumours in North America: A population-based study

BackgroundFew studies in North America have quantified the risks of second malignant neoplasms (SMNs) among survivors of childhood non-central nervous system (non-CNS) embryonal tumours due to their rarity. We aimed to investigate these risks by combining population-based data from the United States of America and Canada.MethodsWe evaluated patients with childhood non-CNS embryonal tumours reported to the Surveillance Epidemiology and End Results program and eight Canadian cancer registries from 1969 to 2010. Standardised incidence ratio (SIR) and cumulative incidence of SMNs were calculated. Subgroup analyses were conducted by the type of first primary cancer, age at first primary diagnosis and follow-up duration.FindingsOf the 13,107 survivors, 190 SMNs were reported over 134,548 person-years of follow-up. The SIR for all SMNs combined was 6.4 (95% confidence interval [CI]: 5.5–7.4). Most site-specific SIRs were significantly increased, ranging from 36 (95% CI: 26–49) for bone and joint cancer to 3.1 (95% CI: 1.5–5.2) for brain tumour. The risk for second malignancies declined as the time elapsed from the first primary diagnosis and was less prominent for patients first diagnosed at age 1–4 years. Notably, rhabdomyosarcoma survivors had a higher risk for SMNs than those with other first primaries. The overall cumulative incidence of SMNs was 1.0% at 10 years, increasing to 2.2% at 20 years and 4.1% at 30 years.InterpretationSurvivors with childhood non-CNS embryonal tumours faced an increased risk for SMNs compared to the general population. The risk variations observed in different patient categories may help target prevention strategies in high-risk subgroups.     

Risk of a second malignant neoplasm after cancer in childhood treated with radiotherapy: correlation with the integral dose restricted to the irradiated fields

PURPOSE: After successful treatment of cancers in childhood, the occurrence of second malignant neoplasm (SMN) came to the fore. Few studies have considered the relationship between the radiation dose received and the risk of developing an SMN. To take into account the heterogeneity of the dose distribution so as to evaluate the overall risk of an SMN after a childhood cancer, we therefore focused on the integral dose restricted to the irradiated fields. METHODS AND MATERIALS: The study was performed in a cohort of 4,401 patients who were 3-year survivors of all types of childhood cancer treated between 1947 and 1986 in France and Great Britain. For each patient, the integral dose was estimated for the volume inside the beam edges. RESULTS: We found a significant dose-response relationship between the overall risk of an SMN and the estimated integral dose. The excess relative risk for each incremental unit of the integral dose was only 0.008 in a linear model and 0.017 when a negative exponential term was considered, when adjusted for chemotherapy. The risk of SMN occurrence was 2.6 times higher in the case of irradiation. However among patients who had received radiotherapy, only those who had received the highest integral dose actually had a higher risk. CONCLUSIONS: The integral dose in our study cannot be considered as a good predictor of later risks. However other studies with the same study design are obviously needed to evaluate the use of the integral dose as a tool for decision making concerning different radiotherapy techniques.     

Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study

BACKGROUND: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNS: METHODS: A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNS: All statistical tests were two-sided. RESULTS: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P =.01, respectively), and exposure to alkylating agents (P for trend =.02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up. CONCLUSIONS: Success in treating children with cancer should not be overshadowed by the incidence of SMNS: However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.     

Concomitant chemo-radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: a case-control study

Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.     

The risk of second malignant tumors and its consequences for the overall survival of Hodgkin's disease patients and for the choice of their treatment at presentation: analysis of a series of 1524 cases consecutively treated at the Florence University Hospital

Purpose: To quantify the incidence of second malignant tumors (SMT) as a whole and that of second “solid” tumors (SST) and leukemia (L) in a large series of 1524 Hodgkin’s disease (HD) patients (pts) treated at the Florence University Hospital (UFH); to define the clinical and therapeutic features possibly related with SMT occurrence; to evaluate the consequences of SMT for the overall survival of the series studied and for the choice of the treatment of HD at presentation.

Methods and Materials: From 1960 to 1991, 1524 pts with HD, Clinical Stage (CS) I–IV have been treated at the UFH. Overall treatment consisted of radiation alone (RT, 36%), chemotherapy alone (CHT, 21%), or both (RT + CHT, 43%). The cumulative probability (CP) of SMT, SST, and L was calculated for the whole series and for the different clinical and therapeutic subgroups, and the results compared with uni- and multivariate analysis (“internal” comparison, IC). Standardized incidence ratios (SIR) for different SMT types (estimated on the basis of gender, age, period specific incidence rates of the general population) have been also calculated (“external” comparison, EC). The impact of the SMT-related mortality on the survival of the entire series has been estimated.

Results: A 14.9% 20-year CP of SMT was registered, along with a SIR of 2.04 (95% confidence interval [CI]: 1.2–2.5). Both IC and EC showed a statistically significant relationship between L incidence and treatment with CHT, alone or in combination with RT. A significant excess of breast cancers has been observed in RT-treated patients with longer follow-up (SIR, 2.9); an excess of other common SST (lung, non-Hodgkin’s lymphomas) is evident in pts treated with either RT, RT + CHT, or CHT. The actuarial long-term survival of the series would have been better of about 3%, in absence of the SMT mortality possibly due to HD treatment, which is almost equally divided between patients treated with RT alone, CHT alone, and RT + CHT.

Conclusions: SMT represent an important late event in HD long-term survivors. The relationship between L and treatment with CHT seems to be the most clearly defined. The effect of SMT on the survival of the entire series, although not negligible, does not seem to justify by itself substantial alterations in the current standards for the treatment of HD at presentation.     

Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study

PURPOSE: To assess long-term cause-specific mortality in breast cancer patients. PATIENTS AND METHODS: We studied mortality in 7425 patients treated for early breast cancer between 1970 and 1986. Follow-up was 94% complete until January 2000. Treatment-specific mortality was evaluated by calculating standardized mortality ratios (SMRs) based on comparison with general population rates and by using Cox proportional hazards regression. RESULTS: After a median follow-up of 13.8 years, 4160 deaths were observed, of which 76% were due to breast cancer. Second malignancies showed a slightly increased SMR of 1.2 (95% confidence interval [CI], 1.0-1.3). Radiotherapy (RT) as compared with surgery was associated with a 1.7-fold (95% CI, 1.2-2.5) increased mortality from cardiovascular disease (CVD). After postlumpectomy RT, no increased mortality from CVD was observed (hazard ratio, 1.0; 95% CI, 0.5-1.9). Postmastectomy RT administered before 1979 and between 1979 and 1986 was associated with a 2-fold (95% CI, 1.2-3.4) and 1.5-fold (95% CI, 0.9-2.7) increase, respectively. Patients treated before age 45 experienced a higher SMR (2.0) for both solid tumors (95% CI, 1.6-2.7) and CVD (95% CI, 1.3-3.1). CONCLUSION: Currently, a large population of breast cancer survivors is at increased risk of death from CVDs and second cancers, especially when treated with RT at a young age. Patients irradiated after 1979 experience low (postmastectomy RT) or no (postlumpectomy RT) excess mortality from CVD.     

Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up

PURPOSE: To report the incidence of second bladder and colorectal cancers after prostate brachytherapy. METHODS AND MATERIALS: This review included 125 patients treated with I-125 brachytherapy alone, and 223 patients who received supplemental external beam radiation therapy. Median follow-up was 10.5 years. Patients were followed for the development of lower genitourinary and colorectal cancers. Second malignancies arising five years after radiation therapy were defined as being potentially associated with treatment; observed rates were then compared with age-matched expected rates according to Surveillance, Epidemiology, and End Results data. RESULTS: Five years out of treatment, there were 15 patients with a second solid tumor, including bladder cancer (n = 11), colorectal cancer (n = 3), and prostatic urethra cancer (n = 1). The incidence of second malignancy was no different in patients treated with brachytherapy alone (1.6%) vs. those receiving external beam radiotherapy (5.8%, p = 0.0623). There were more observed bladder cancers compared with those expected (relative risk, 2.34, 95% confidence interval 0.96-3.72; absolute excess risk 35 cancers per 10,000 patients). Relative risk did not significantly change over increasing follow-up intervals up to 20 years after treatment. CONCLUSIONS: There may be an increased but small risk of developing a second malignancy after radiation therapy for prostate cancer. This outcome could be related to radiation carcinogenesis, but more vigilant screening and thorough workup as a result of radiation side effects and predisposing conditions (e.g., genetic and environmental factors) in many of the patients found to have second malignancies likely contributed to the higher number of observed malignancies than expected.     

Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain

In a population-based, retrospective cohort study of 16 541 3-year survivors of childhood cancer treated in Britain up to the end of 1987, 278 second malignant neoplasms (SMNs) were identified against 39.4 expected giving a standardised incidence ratio (SIR) of 6.2. The overall cumulative risk of an SMN by 25 years from 3-year survival from childhood cancer was 4.2%. Analysis of the cohort of nonretinoblastoma childhood cancers combined revealed a significant decline in SIR of SMN with increasing duration of follow-up. There was a greater risk of developing a SMN, particularly secondary acute myeloid leukaemia, in those diagnosed with childhood cancer from 1980 onwards. However, on multivariate modeling, this was not an independent risk factor. There was significant heterogeneity (P<0.001) in SIR of SMN across different treatment groups, the greatest risk observed in the group exposed to both radiotherapy and chemotherapy. The risks of SMN observed were comparable with those in other population-based studies. While the decline in SIR with duration of follow-up and the small excess numbers of cancers observed over later decades after diagnosis are reassuring, the high excess risk, particularly of leukaemia, associated with recent more intense therapy is of concern.     

Second neoplasms after oesophageal cancer

The authors considered the incidence of second neoplasms among 1,672 oesophageal cancers diagnosed between 1974 and 2004 in the Cancer Registries of the Swiss Cantons of Vaud and Neuchatel, and followed-up to 2004. A total of 141 second neoplasms were observed versus 38.5 expected, corresponding to a standardized incidence ratio (SIR) of 3.7 (95% confidence interval: 3.1-4.3). The SIRs were statistically significant for cancers of the oral cavity and pharynx (57.3), larynx (24.3), lung (6.6) and intestines (2.6). The SIRs were higher in subjects diagnosed below age 50 and in the first year after diagnosis. The SIR of upper digestive and respiratory tract neoplasms was higher for oesophageal cancers diagnosed in the upper (87.5) and middle (68.1), as compared with the lower third (19.4). There was no rise of second oral, pharyngeal and laryngeal cancer with advancing age, and their incidence tended indeed to decline from 100/1,000 at age 40-49 to 25/1,000 at age 70-79. There was no tendency to rise with age in the incidence of first oesophageal cancer in subjects who subsequently developed another upper digestive or respiratory tract neoplasm. The excess risks of upper digestive and respiratory tract neoplasms are attributable to increased diagnosis and registration of second neoplasms following a diagnosis of oesophageal cancer, as well as to heavy tobacco and alcohol consumption in oesophageal cancer cases. The absence of rise in incidence with age is also compatible with the existence of a subset of the population of susceptible individuals.     

Risk of second primary lung cancer in women after radiotherapy for breast cancer

Background

Several epidemiological studies have reported increased risks of second lung cancers after breast cancer irradiation. In this study we assessed the effects of the delivered radiation dose to the lung and the risk of second primary lung cancer.

Methods

We conducted a nested case–control study of second lung cancer in a population based cohort of 23,627 early breast cancer patients treated with post-operative radiotherapy from 1982 to 2007. The cohort included 151 cases diagnosed with second primary lung cancer and 443 controls. Individual dose-reconstructions were performed and the delivered dose to the center of the second lung tumor and the comparable location for the controls were estimated, based on the patient specific radiotherapy charts.

Results

The median age at breast cancer diagnosis was 54 years (range 34–74). The median time from breast cancer treatment to second lung cancer diagnosis was 12 years (range 1–26 years). 91% of the cases were categorized as ever smokers vs. 40% among the controls. For patients diagnosed with a second primary lung cancer five or more years after breast cancer treatment the rate of lung cancer increased linearly with 8.5% per Gray (95% confidence interval = 3.1–23.3%; p < 0.001). This rate was enhanced for ever smokers with an excess rate of 17.3% per Gray (95% CI = 4.5–54%; p < 0.005).

Conclusions

Second lung cancer after radiotherapy for early breast cancer is associated with the delivered dose to the lung. Although the absolute risk is relative low, the growing number of long-time survivors after breast cancer treatment highlights the need for advances in normal tissue sparing radiation techniques.     

Follow-up after childhood cancer: evaluation of a three-level model

IntroductionFollow-up for cancer survivors is recommended to detect recurrence; monitor late-effects; record toxicity and provide care and education. We describe our experience with a three-level model developed to guide decisions about intensity and frequency of follow-up [Wallace WHB, Blacklay A, Eiser C, et al. Developing strategies for the long term follow-up of survivors of childhood cancer. BMJ 2001;323:271–274].ProcedureOne hundred and ninety eight survivors (52% male) recruited over 12-months: (mean age = 23.8 years, range = 16–39 years; mean time since diagnosis = 16.2 years, range 2.4–32.7 years) reported their number of symptoms and late-effects. Information was taken from the medical records to assign each survivor to the appropriate levels by six clinic staff independently.ResultsThe survivors were assigned to level 1 (n = 8), level 2 (n = 97) and level 3 (n = 93). There were seven cases of disagreement. Level 3 survivors self-reported more symptoms and late-effects than level 2 survivors.ConclusionsCoding was relatively simple for experienced clinic staff, although there were some disagreements for the survivors of ALL. The relationship between assigned level and self-reported symptoms and late-effects provides some evidence for validity of the model. We conclude that it is important to maintain flexibility to allow movement between levels for individual patients and that the default should always be to the higher level.     

Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan

Objectives: The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. Methods: A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. Results: The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). Conclusions: The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity.     

URC测试对消化道恶性肿瘤根治术后复发监测的临意义

目的:探讨癌症尿液筛查监测试剂(URC)测试对消化道恶性肿瘤术后复发监测诊断的临床意义。方法:对100例消化道恶性肿瘤根治术后病人每月一次URC测试,与实际复发情况,进行阳性符合率、阴性符合率、灵敏度、假阳性率统计分析。结果:两家医院2年内100例患者共测480次,阳性146次(30.4%),阴性334例次(69.6%),其中真阳性124次(25.8%),真阴性310次(64.6%),阳性符合率84.9%,阴性符合率92.8%。,灵敏度83.8%,假阳性率(误诊率)6.6%。结论:URC测试对消化道恶性肿瘤根治术后复发监测有临床实用意义,能对复发早诊断提供线索,灵敏度高、误诊率低,无创简便易行,值得临床进一步研究推广。     

Second malignant neoplasms in patients with non Hodgkin's lymphoma

A retrospective review of the records of 3886 patients with non-Hodgkin's lymphoma registered at the Princess Margaret Hospital between 1970 and 1985 was undertaken to determine the incidence of second malignant tumours. Three thousand and twenty-one patients with a minimum documented follow-up of 6 months from referral were identified for analysis. The overall observed/expected ratio for all cancers in patients with malignant lymphoma was 1, suggesting no increased risk of developing a second malignant neoplasm compared to the general population. When the data were analyzed independently for each tumour site, statistically significant increased risk of developing acute non lymphocytic leukemia (ANLL) (p less than 0.001) and carcinoma of the tongue (p less than 0.05) were found. An increased risk of lung cancer following lymphoma was detected but was not statistically significant. Survival following diagnosis of ANLL and lung cancer was similar and significantly shorter than that following the diagnosis of other second malignancies. The risk of developing a second primary cancer was significantly related to increasing patient age.     

Second Primary Cancers Following Female Breast Cancer in Osaka, Japan--A Population-Based Cohort Study

Using the data accumulated in the Osaka Cancer Registry, a cohortstudy was conducted on the occurrence of second primary cancersfollowing the first breast cancer in females. Of the 9, 503breast cancer patients newly diagnosed in the period 1965–1982who were followed up until the end of 1983 (average follow-upperiod, 5.7 years), 344 developed second cancers, whereas theexpected number had been 211 (relative risk (RR) = 1.6; 95%confidence interval (CI) = 1.5–1.8). The increased riskwas observed throughout the observation period, and was higherin patients of less than 45 years of age at diagnosis than inolder women. Significant excess risks were found for secondcancers of the opposite breast (RR = 4.2; 95% CI = 3.4–5.2),buccal cavity (RR = 3.6; 95% CI = 1.6–7.2), stomach (RR= 1.4; 95% CI = 1.2–1.8), colon (RR = 1.8; 95% CI = 1.1–2.1)and thyroid gland (RR = 3.2; 95% CI % 1.5–6.1). The effectsof chemo- and radiotherapy administered for initial breast canceron the increased risk of the above mentioned second cancerswere also examined. These therapeutic measures were found notlikely to be related to the excess risks for cancers of thebuccal cavity, stomach and colon. For second cancer of the oppositebreast, however, both chemotherapy and radiotherapy remainedas possible risk factors. The effect of radiation was proposedas being a likely explanation for the excess risk of secondthyroid cancer.