Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study.

BACKGRUOUND: Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. METHODS: We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. RESULTS: A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05-1.24 and 1.17- 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. CONCLUSION: High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Risk factors for second primary malignancies following thyroid cancer: a nationwide cohort study.

Objective: Thyroid cancer survivors have a high risk of second primary malignancies (SPMs). We aimed to evaluate the site-specific incidence, prognosis, and risk factors for metachronous SPMs following thyroid cancer. Design: A nationwide cohort study. Methods: This study included data from the Korea National Health Insurance Service (between 2002 and 2018). Exposure to diagnostic radiation was defined by the number of computed tomography (CT) and positron emission tomography-CT scans after the index date. A cumulative radioactive iodine (RAI) dose >100 mCi was considered high-dose RAI. Results: During the median 6 years of follow-up, among 291 640 patients, 13 083 (4.5%) developed SPMs. Thyroid cancer survivors had a 26% increased risk of SPMs compared with the general population (standardized incidence ratio: 1.26; 95% CI: 1.22-1.29). Furthermore, those with SPMs had a significantly poorer survival rate than those without SPMs (hazard ratio: 11.85; 95% CI: 11.21-12.54; P < 0.001). Significantly elevated risks were observed in myeloid leukemia and 13 solid cancer sites: lip, salivary gland, small intestine, larynx, lung, mediastinum and pleura, mesothelium, breast, corpus uteri, ovary, prostate, kidney, and bladder. Frequent diagnostic medical radiation exposure and high-dose RAI therapy were independent risk factors for several SPMs, including the cancer of salivary gland, lung, mediastinum and pleura, breast, kidney, and bladder, as well as myeloid leukemia. Conclusions: Frequent diagnostic radiation exposure and high-dose RAI therapy are independent risk factors for SPM following thyroid cancer. Clinicians need to consider minimizing unnecessary diagnostic radiation exposure and administering a high dose RAI only when justified in patients with thyroid cancer.

[Impact of nutritional factors during and after cancer]. / Impact des facteurs nutritionnels pendant et après cancer.

Nutritional factors (diet, weight, alcohol, physical activity) are identified as factors having an impact on the onset of several cancer sites. Less abundant scientific data also underline their impact on the tumor progression. A review of the scientific literature was carried out by a group of experts established by the French National Cancer Institute (INCa) to better document the influence of nutritional factors during and after cancer on outcomes such as overall mortality, cancer specific mortality, recurrence, second primary cancers and quality of life. This analysis of the literature completes messages of reduction of alcohol consumption, prevention of undernutrition or excess weight and adherence to dietary recommendations, avoiding the use of dietary supplements, fasting or restrictive diets and strengthens messages promoting the practice of physical activity and the fight against sedentary lifestyle.

Radioactive Iodine Treatment for Children and Young Adults with Thyroid Cancer in South Korea: A Population-based Study.

PURPOSE: This study investigated radioactive iodine treatment (RAIT) patterns and the secondary cancer incidence among children and young adults receiving RAIT after thyroidectomy for thyroid cancer. METHODS: This population-based cohort study used the Health Insurance Review and Assessment database of South Korea to identify a total of 18 617 children and young adults (0-29 years) who underwent thyroidectomy for thyroid cancer between 2008 and 2018. We recorded age at surgery, sex, the interval from surgery to RAIT, the doses of RAI, the number of RAIT sessions, and secondary cancer incidence. RESULTS: A total of 9548 (51.3%) children and young adults underwent 1 or more RAIT sessions. The initial dose of RAIT was 4.35 ±â€…2.19 GBq. The overall RAIT frequency fell from 60.9% to 38.5%, and the frequency of high-dose RAIT (>3.7 GBq) fell from 64.2% to 36.5% during the observational period. A total of 124 cases of secondary cancer developed during 120 474 person-years of follow-up; 43 (0.5%) in the surgery cohort and 81 (0.8%) in the RAIT cohort. Thus, the RAIT cohort was at an increased risk of secondary cancer (adjusted hazard ratio 1.52 [95% confidence interval 1.03-2.24], P = 0.035). CONCLUSION: The proportion of children and young adults receiving RAIT, and the RAI dose, fell significantly over the observational period. RAIT was associated with secondary cancers. This is of major concern in the context of child and young adult thyroid cancer survivors.

Rationale for evaluating breast cancers of Lynch syndrome patients for mismatch repair gene expression.

BACKGROUND: Lynch Syndrome (LS) patients harbor germline mutations in one of several mismatch repair (MMR) genes and are predisposed to the development of colon and endometrial cancers and multiple other cancers types as well. Tumors related to LS are characterized by deficient protein expression of one or more MMR genes (dMMR) and/or demonstrate high microsatellite instability (MSI-H) (Win et al. in Breast Cancer Res 15(2):R27, 2013). The National Comprehensive Cancer Network (NCCN) Guideline states that there have been "suggestions" of increased risk of breast cancer in diagnosed LS patients, but does not endorse "increased screening above-average-risk breast cancer screening recommendations" for patients with LS (Provenzale et al. in J Natl Compr Cancer Netw 14(8):1010-1030, 2019). RESULTS: This report describes a molecularly diagnosed LS patient who developed a dMMR breast cancer. CONCLUSIONS: Sporadic dMMR breast cancers are extremely rare (Davies et al. in Cancer Res 77:4755-4762, 2017). It seems reasonable to conclude that identifying a dMMR breast cancer in a patient with known LS strongly suggests that her LS is breast cancer-predisposing. LS patients with dMMR breast cancers might therefore be considered for above-average breast cancer screening for the development of additional breast cancers. Also, the FDA recently granted approval of checkpoint inhibitor therapy for all metastatic dMMR solid malignancies (Lemery et al. in N Engl J Med 377:1409-1412, 2017). MMR expression assays in metastatic breast cancers of LS patients would represent a more focused approach to identifying patients with breast cancers who are potentially eligible for checkpoint inhibitor therapy than would be universal MMR testing of all metastatic breast cancers.

Risk of skin cancer in psoriasis patients receiving long-term narrowband ultraviolet phototherapy: Results from a Taiwanese population-based cohort study.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) phototherapy is a widely used treatment for various dermatoses. The risk of skin cancer following long-term NB-UVB phototherapy has rarely been explored in skin phototypes III-V. METHODS: We conducted a nationwide-matched cohort study and identified a total of 22 891 psoriasis patients starting NB-UVB phototherapy from the Taiwan National Health Insurance Database during the period 2000-2013. Cumulative incidences of skin cancers were compared between subjects receiving less than 90 UVB treatments (S-cohort, N = 13 260) and age- as well as propensity score-matched subjects receiving more than or equal to 90 UVB treatments (L-cohort, N = 3315). RESULTS: There were no significant differences in the overall cumulative incidences of skin cancers between the two cohorts (log-rank t test, P = 0.691) during the follow-up periods. The S-cohort had a significantly lower prevalence of actinic keratosis when compared with the L-cohort (0.54% vs 1.00%, P = 0.005). CONCLUSION: Long-term NB-UVB phototherapy does not increase skin cancer risk compared with short-term NB-UVB phototherapy in psoriasis patients with skin phototypes III-V.

[Risk factors for early castration-resistant prostate cancer after androgen deprivation therapy for bone-metastatic prostate cancer].

OBJECTIVE: To investigate the risk factors for early castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) in patients primarily diagnosed with bone-metastatic prostate cancer (BMPC). METHODS: We retrospectively analyzed the clinical data on 97 cases of primarily diagnosed BMPC treated in our hospital between January 2010 and May 2016. We included the patients without CRPC in group A and those with CRPC found within 12 months after ADT in group B. We obtained clinical data from the two groups of patients, including preoperative levels of hemoglobin, C-reactive protein and serum prostate-specific antigen (PSA), prostate volume, incidence rates of hypertension and diabetes mellitus, long-term use of aspirin or metformin, methods of biopsy and castration, Gleason scores, anti-androgen drugs, and radiotherapy with 89SrCl2, which were subjected to uni- or multivariate logistic regression analysis. RESULTS: CRPC developed in 48 (49.48%) of the 97 patients within 12 months after ADT. Univariate analysis showed the preoperative hemoglobin level, Gleason scores and biopsy by transurethral plasmakinetic resection of the prostate (TUPKRP) to be the risk factors for early CRPC, and multivariate logistic regression analysis identified two independent risk factors for it, which were the Gleason score (P = 0.010) and TUPKRP (P = 0.002). CONCLUSIONS: The incidence rate of early CRPC is high in BMPC patients within 12 months after ADT, for which the independent risk factors include biopsy by TUPKRP and Gleason scores.

Radiation Therapy as an Alternative Treatment for Desmoid Fibromatosis.

AIM: To determine the outcome after radiation therapy for desmoid fibromatosis. MATERIALS AND METHODS: A retrospective review of 50 patients treated between 1988 and 2016 in a specialised bone and soft tissue tumour clinic. RESULTS: The median age at the time of radiation therapy was 36.8 years (range 15.1-69.0) and the median follow-up time was 51 months. Forty-three patients underwent radiation therapy as the definitive treatment with a median dose of 56 Gy (range 30-58.8 Gy). The median dose for the seven patients treated with postoperative radiation therapy was 50.4 Gy (range 48-56 Gy). Eleven patients (22%) developed progressive disease after radiation therapy at a median time of 41 months (range 12-113 months). The recurrences were within the radiation therapy field in four patients and outside the field in seven patients. One patient developed a radiation-induced malignancy 20 years after treatment. CONCLUSIONS: Radiation therapy is an alternative treatment in the management of desmoid fibromatosis. It should be considered in patients for whom surgical resection is not feasible, or as adjuvant therapy after surgery with involved margins where any further recurrences would cause significant morbidity.

Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review.

Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.

Resection of Locally Advanced Pancreatic Cancer without Regression of Arterial Encasement After Modern-Era Neoadjuvant Therapy.

INTRODUCTION: Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy. METHODS: Sixty-one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database. RESULTS: Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety-day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27-32.33) and 8.5 months (95%CI 6.0-15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0-79.7) and 39.0% (95%CI 23.7-53.8), respectively. CONCLUSION: With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging.

Potential strategies to ameliorate risk of radiotherapy-induced second malignant neoplasms.

This review is aimed at the issue of radiation-induced second malignant neoplasms (SMN), which has become an important problem with the increasing success of modern cancer radiotherapy (RT). It is imperative to avoid compromising the therapeutic ratio while addressing the challenge of SMN. The dilemma is illustrated by the role of reactive oxygen species in both the mechanisms of tumor cell kill and of radiation-induced carcinogenesis. We explore the literature focusing on three potential routes of amelioration to address this challenge. An obvious approach to avoiding compromise of the tumor response is the use of radioprotectors or mitigators that are selective for normal tissues. We also explore the opportunities to avoid protection of the tumor by topical/regional radioprotection of normal tissues, although this strategy limits the scope of protection. Finally, we explore the role of the bystander/abscopal phenomenon in radiation carcinogenesis, in association with the inflammatory response. Targeted and non-targeted effects of radiation are both linked to SMN through induction of DNA damage, genome instability and mutagenesis, but differences in the mechanisms and kinetics between targeted and non-targeted effects may provide opportunities to lessen SMN. The agents that could be employed to pursue each of these strategies are briefly reviewed. In many cases, the same agent has potential utility for more than one strategy. Although the parallel problem of chemotherapy-induced SMN shares common features, this review focuses on RT associated SMN. Also, we avoid the burgeoning literature on the endeavor to suppress cancer incidence by use of antioxidants and vitamins either as dietary strategies or supplementation.

Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission.

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

Joint and independent effect of alcohol and tobacco use on the risk of subsequent cancer incidence among cancer survivors: A cohort study using cancer registries.

Drinking alcohol and smoking tobacco are major modifiable risk factors for cancer. However, little is known about whether these modifiable factors of cancer survivors are associated with subsequent primary cancer (SPC) incidence, regardless of the first cancer sites. 27,762 eligible cancer survivors diagnosed between 1985 and 2007 were investigated for SPC until the end of 2008, using hospital-based and population-based cancer registries. The association between drinking, smoking and combined drinking and smoking (interaction) at the time of the first cancer diagnosis and incidence of SPCs (i.e., all SPCs, alcohol-related, smoking-related and specific SPCs) was estimated by Poisson regression. Compared with never-drinker/never-smoker, the categories ever-drinker/ever-smoker, current-drinker/current-smoker and heavy-drinker/heavy-smoker had 43-108%, 51-126% and 167-299% higher risk for all, alcohol-related and tobacco-related SPCs, respectively. The interaction of drinking and smoking had significantly high incidence rate ratios (IRRs) for SPCs among ever-drinker/ever-smoker and current-drinker/current-smoker, although ever drinking did not show a significant risk. Ever-drinker/ever-smoker had also significantly higher IRRs for esophageal and lung SPCs than never-drinker/never-smoker. Among comprehensive cancer survivors, ever and current drinkers only had a SPC risk when combined with smoking, while ever and current smokers had a SPC risk regardless of drinking status. Heavy drinking and heavy smoking were considered to be independent additive SPC risk factors. To reduce SPC incidence, it may be necessary (i) to reduce or stop alcohol use, (ii) to stop tobacco smoking and (iii) dual users, especially heavy users, should be treated as a high-risk population for behavioral-change intervention.

Metabolic syndrome and outcomes following early-stage breast cancer.

The prevalence of risk factors contributing to metabolic syndrome (MetS) is increasing, and numerous components of MetS are associated with increased primary breast cancer (BC) risk. However, less is known about the relationship of MetS to BC outcomes. The aim of this study was to evaluate whether MetS, characterized by increased weight, hypertension, low HDL-cholesterol, high triglycerides, and diabetes or impaired glucose tolerance, is associated with risk of second breast cancer events (SBCE) and BC-specific mortality. Retrospective cohort study of women diagnosed with incident early-stage (I-II) BC between 1990 and 2008, enrolled in an integrated health plan. Outcomes of interest were SBCE, defined as recurrence or second primary BC, and BC-specific mortality. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for time-varying exposure to MetS components while accounting for potential confounders and competing risks. Among 4,216 women in the cohort, 26% had ≥3 MetS components and 13% developed SBCE during median follow-up of 6.3 years. Compared to women with no MetS components, presence of MetS (≥3 components) was associated with increased risk of SBCE (HR = 1.50, 95% CI 1.08-2.07) and BC-specific mortality (HR = 1.65, 95% CI 1.02-2.69). Of the individual components, only increased weight was associated with increased risk of SBCE (HR = 1.26, 95% CI 1.06-1.49). MetS is associated with modestly increased risk of SBCE and BC-specific mortality. Given the growing population of BC survivors, further research in larger and more diverse populations is warranted.

[Long term follow-up after chilhood cancer]. / Malgré la guérison, un risque accru de problèmes de santé â l'âge adulte. Suivi à long terme après un cancer chez l'enfant.

Five year survival rates among childhood cancer rose to 80%. Relapses are rare after five years of remission. Long term follow-up should also detect treatment related late adverse effects. Repeated cardiac evaluations are necessary, due to cumulative dose dependent cardiotoxicity of anthracycline. Endocrinological disorders and problems of fertility are mainly related to radiotherapy or high dose chemotherapy. Bone mineral density can be altered. Cognitive function, academic level and social outcome of irradiated patients and patients treated for cerebral tumors should be closely assessed and helped. Second neoplasms related to previous treatments may occur. One of the major on going treatment objective is to preserve the quality of life of cured patients, and to improve their information in the framework of a shared-care model involving the general practionner, the adult medicine specialists and the oncologic pediatric centre.

Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy.

BACKGROUND: American Thyroid Association guidelines currently recommend the selective use of radioactive iodine (RAI) therapy in patients with well differentiated thyroid cancer (WDTC). Despite these guidelines, RAI ablation has been used routinely in all but the very lowest risk patients with thyroid cancer over the last 30 years. The objective of this study was to evaluate patterns of RAI use and elevated risk of secondary primary malignancies (SPM) in patients with low-risk (T1N0) WDTC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to analyze trends in RAI use over time in the United States. To determine the excess risk of SPM, the standardized incidence ratio (SIR) and excess absolute risk (EAR) of various cancers were calculated in the 2 cohorts. Between 1973 and 2007, 37,176 patients with WDTC were followed in the SEER Program, equating to 408,750 person-years at risk (PYR). In total, 14,589 patients received RAI, and SPMs were observed in 3223 patients. RESULTS: During the study period, the rate of RAI use in patients with low-risk (T1N0) WDTC increased from 3.3% to 38.1%. For low-risk patients, the SIR of SPM was 1.21 (95% confidence interval [CI], 0.93-1.54), and the EAR was 4.6 excess cases per 10,000 PYR. SPM with significantly elevated risk because of RAI were salivary gland malignancies (SIR = 11.13; 95% CI, 1.35-40.2) and leukemia (SIR = 5.68; 95% CI, 2.09-12.37). The excess risk of leukemia was significantly greater in patients aged <45 years (SIR = 5.32; 95% CI, 2.75-9.30) compared with the excess risk in older patients (SIR = 2.26; 95% CI, 1.43-3.39). CONCLUSIONS: The increased risk of a SPM in patients with low-risk (T1N0) WDTC, along with a lack of data demonstrating improved survival outcomes with adjuvant RAI, provide a compelling argument in favor of rationing the use of RAI in this patient population.

Complications of radioactive iodine treatment of thyroid carcinoma.

Radioactive iodine (RAI) in the form of (131)I has been used to treat thyroid cancer since 1946. RAI is used after thyroidectomy to ablate the residual normal thyroid remnant, as adjuvant therapy, and to treat thyroid cancer metastases. Although the benefits of using RAI in low-risk patients with thyroid cancer are debated, it is frequently used in most patients with thyroid cancer and is clearly associated with acute and long-term risks and side effects. Acute risks associated with RAI therapy include nausea and vomiting, ageusia (loss of taste), salivary gland swelling, and pain. Longer-term complications include recurrent sialoadenitis associated with xerostomia, mouth pain, dental caries, pulmonary fibrosis, nasolacrimal outflow obstruction, and second primary malignancies. This article summarizes the common complications of RAI and methods to prevent and manage these complications.

Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma.

BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.