Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and ...autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study.
Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT.
Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL.
Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.
To elucidate the temporal relationship between detection of glaucomatous optic disc progression, as assessed by fundus photography, and visual field progression.
Prospective, randomized, longitudinal ...trial.
Three hundred six study eyes with manifest glaucoma with field loss and 192 fellow eyes without any field defect at the start of the trial, from a total of 249 subjects included in the Early Manifest Glaucoma Trial (EMGT), were assessed.
Evaluation of visual field progression and optic disc progression during an 8-year follow-up period. Three graders independently assessed optic disc progression in optic disc photographs. Visual field progression was assessed using glaucoma change probability maps and the EMGT progression criterion.
Time to detection of visual field progression and optic disc progression.
Among study eyes with manifest glaucoma, progression was detected in the visual field first in 163 eyes (52%) and in the optic disc first in 39 eyes (12%); in 1 eye (0%), it was found simultaneously with both methods. Among fellow eyes with normal fields, progression was detected in the visual field first in 28 eyes (15%) and in the optic disc first in 34 eyes (18%); in 1 eye (1%), it occurred simultaneously.
In eyes with manifest glaucoma, progression in the visual field was detected first more than 4 times as often as progression in the optic disc. Among fellow eyes without visual field loss at baseline, progression was detected first as frequently in the optic disc as in the visual field.
Studies have causally linked external thyroid radiation exposure in childhood with thyroid cancer. In 1995, investigators conducted relative risk analyses of pooled data from seven epidemiologic ...studies. Doses were mostly <10 Gy, although childhood cancer therapies can result in thyroid doses >50 Gy. We pooled data from 12 studies of thyroid cancer patients who were exposed to radiation in childhood (ages <20 years), more than doubling the data, including 1,070 (927 exposed) thyroid cancers and 5.3 million (3.4 million exposed) person-years. Relative risks increased supralinearly through 2–4 Gy, leveled off between 10–30 Gy and declined thereafter, remaining significantly elevated above 50 Gy. There was a significant relative risk trend for doses <0.10 Gy (P < 0.01), with no departure from linearity (P = 0.36). We observed radiogenic effects for both papillary and nonpapillary tumors. Estimates of excess relative risk per Gy (ERR/Gy) were homogeneous by sex (P = 0.35) and number of radiation treatments (P = 0.84) and increased with decreasing age at the time of exposure. The ERR/Gy estimate was significant within ten years of radiation exposure, 2.76 (95% CI, 0.94–4.98), based on 42 exposed cases, and remained elevated 50 years and more after exposure. Finally, exposure to chemotherapy was significantly associated with thyroid cancer, with results supporting a nonsynergistic (additive) association with radiation.
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Background The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. Methods We obtained a cohort of 47 697 children and adolescents aged 0–19 ...years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943–2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. Results A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60–69 years. For children treated in the prechemotherapy era (1943–1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975–2005). Conclusion Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.
Summary Background The pattern of endocrine disorders in long-term survivors of childhood cancer has not been investigated comprehensively. Here, we aimed to assess the lifetime risk of these ...disorders in Nordic survivors of childhood cancer. Methods From the national cancer registries of Denmark, Finland, Iceland, Norway, and Sweden, we identified 31 723 1-year survivors of childhood cancer, notified since the start of registration in the 1940s and 1950s. From the national population registries, we randomly selected a comparison cohort of people matched by age, sex, and country. Study participants were linked to the national hospital registries, and observed numbers of first-time hospital contacts for endocrine disorders in survivors of childhood cancer were compared with the expected numbers derived from the population comparison cohort. We calculated the absolute excess risks attributable to status as a childhood cancer survivor and standardised hospitalisation rate ratios (SHRRs). Findings Of the childhood cancer survivors, 3292 had contact with a hospital for an endocrine disorder, yielding a SHRR of 4·8 (95% CI 4·6–5·0); the highest risks were in survivors of leukaemia (SHRR 7·3 95% CI 6·7–7·9), CNS tumours (6·6 6·2–7·0), and Hodgkin's lymphoma (6·2 5·6–7·0). The absolute excess risk for endocrine disorders was roughly 1000 per 100 000 person-years before 20 years of age, and 400 per 100 000 person-years during the remaining lifetime. For children with cancer diagnosed at 5–9 years of age, the cumulative risk for endocrine disorders was highest, and reached 43% at the age of 60 years. Diagnoses of pituitary hypofunction (SHRR 88·0), hypothyroidism (9·9), and testicular and ovarian dysfunction (42·5 and 4·7, respectively) together constituted 61% (655 of 1078) of all excess disease-induced and treatment-induced endocrine disorders in survivors of childhood cancer. Interpretation A cumulative risk for endocrine disorders at 60 years of age of above 40% in survivors of childhood cancer emphasises the importance of minimisation of damaging treatment, intensification of secondary prevention, and targeting of survivor follow-up throughout life. Since most long-term childhood cancer survivors are not followed in a specialised late-effect clinic, they are a growing challenge for the primary care physician and medical specialists working outside the late-effect area. Funding The Danish Council for Strategic Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Childhood cancer five-year survival now exceeds 70–80%. Childhood exposure to radiation is a known thyroid carcinogen; however, data are limited for the evaluation of radiation dose-response at high ...doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. To address these issues, we pooled two cohort and two nested case-control studies of childhood cancer survivors including 16,757 patients, with 187 developing primary thyroid cancer. Relative risks (RR) with 95% confidence intervals (CI) for thyroid cancer by treatment with alkylating agents, anthracyclines or bleomycin were 3.25 (0.9–14.9), 4.5 (1.4–17.8) and 3.2 (0.8–10.4), respectively, in patients without radiotherapy, and declined with greater radiation dose (RR trends, P = 0.02, 0.12 and 0.01, respectively). Radiation dose-related RRs increased approximately linearly for <10 Gy, leveled off at 10–15-fold for 10–30 Gy and then declined, but remained elevated for doses >50 Gy. The fitted RR at 10 Gy was 13.7 (95% CI: 8.0–24.0). Dose-related excess RRs increased with decreasing age at exposure (P < 0.01), but did not vary with attained age or time-since-exposure, remaining elevated 25+ years after exposure. Gender and number of treatments did not modify radiation effects. Thyroid cancer risks remained elevated many decades following radiotherapy, highlighting the need for continued follow up of childhood cancer survivors.
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Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk ...factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer.
Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated.
The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO.
This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.
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We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
We used data from the Childhood Cancer Survivor ...Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk RR, 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve AUC, 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict ...guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response.
Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for α-fetoprotein (AFP) of ≤ 7 days and/or for β-human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2.
Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients.
With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.
Summary
Background
Liver cirrhosis is characterized by a silent phase until decompensation, which is defined by ascites, bleeding from esophageal varices or hepatic encephalopathy.
Aim
To compare the ...clinical course, patterns of survival and causes of death by etiology during long‐term follow‐up in a large population‐based cohort of patients with incident cirrhosis.
Methods
We used population‐based medical registries for a cohort study of patients with liver cirrhosis diagnosed January 2001 to December 2010, in the Scania region of Sweden. Medical records were reviewed. Patients were classified according to etiology and clinical parameters were registered. Patients were followed until December 2017.
Results
The cohort comprised 1317 patients, 631 were decompensated at diagnosis and 387 decompensated during follow‐up. The cumulative 10‐year incidence of decompensation, with death and transplantation as competing risks, was 89% in alcoholic cirrhosis, 58% in hepatitis C and 75% in cryptogenic cirrhosis. The lowest 10‐year transplantation‐free survival rates were found in cryptogenic cirrhosis (11%), alcohol‐related cirrhosis (18%) and alcohol combined with hepatitis C (12%). Autoimmune hepatitis cirrhosis showed the best 10‐year survival (53%) and hepatitis C, non‐alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis and other causes averaged 30%. Decompensation at diagnosis was an important predictor for death in all etiologies apart from alcoholic cirrhosis. 991 patients died and 91 were transplanted.
Conclusion
Our results show that the clinical course and survival in cirrhosis differ considerably by both etiology and state at diagnosis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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