Risk of male breast cancer after Hodgkin lymphoma.

Female survivors of Hodgkin lymphoma (HL) treated with chest radiotherapy have a strongly increased risk of breast cancer (BC), but the treatment-specific BC risk in male survivors of HL has not been evaluated. We assessed BC risk in a cohort of 3077 male survivors of 5-year HL treated at age ≤51 years in 20 Dutch hospitals between 1965 and 2013. We estimated standardized incidence ratios (SIRs), absolute excess risks per 10 000 person-years, and cumulative BC incidences. After a 20-year median follow-up, we observed 8 cases of male with BC. Male survivors of HL experienced a 23-fold (95% confidence interval [CI], 10.1-46.0) increased BC risk compared with the general population, representing 1.6 (95% CI, 0.7-3.3) excess BC incidences per 10 000 person-years. The 20- and 40-year cumulative BC incidences after HL treatment were 0.1% (95% CI, 0.02-0.3) and 0.7% (95% CI, 0.3-1.4), respectively. Treatment with chest radiotherapy without alkylating chemotherapy yielded a strongly increased SIR (20.7; 95% CI, 2.5-74.8), which was not significantly different for chest radiotherapy and alkylating chemotherapy (41.1; 95% CI, 13.4-96.0). Males treated with chest radiotherapy and anthracyclines had an SIR of 48.1 (95% CI, 13.1-123.1). Two patients died from BC (median follow-up, 4.7 years). To ensure early diagnosis and treatment, clinicians should be alert to BC symptoms in male survivors of HL.

Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma.

Importance: Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear. Objective: To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors. Design, Setting, and Participants: A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022. Exposures: Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets. Main Outcomes and Measures: Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored. Results: The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose. Conclusions and Relevance: This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.

Breast cancer and cardiovascular outcomes after breast cancer in survivors of Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. METHODS: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age- and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. RESULTS: Compared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2- to 4.5-fold). BC-HL patients with a screen-detected BC had a significantly reduced (61%) BC-specific mortality. One-third of BC-HL patients had CVD at BC-diagnosis, compared to <0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. CONCLUSIONS: BC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. LAY SUMMARY: Patients with breast cancer after Hodgkin lymphoma (BC-HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD). BC treatment considerations were reported for 71% of BC-HL patients. We examined whether BC-HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC-1). We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors.

Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy.

BACKGROUND: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. METHODS: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 µg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). RESULTS: Overall, the optimal surveillance strategy was annual FIT (47 µg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 µg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 µg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). CONCLUSIONS: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. IMPACT: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Clinicopathological features and risk factors for developing colorectal neoplasia in Hodgkin's lymphoma survivors.

BACKGROUND: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia. AIMS: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors. METHODS: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right-sided, were detected, as published previously. An average-risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy. RESULTS: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high-grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4-9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient. CONCLUSIONS: Colorectal neoplasia in HL survivors differ from average-risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow-up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors.

Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients.

BACKGROUND: Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients. METHODS: This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated. RESULTS: HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02). CONCLUSIONS: Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity.

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors.

BACKGROUND: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. METHODS: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis. RESULTS: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001). CONCLUSIONS: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered.

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors.

This corrects the article DOI: 10.1038/bjc.2017.85.

Comparison of 36 Gy, 20 Gy, or No Radiation Therapy After 6 Cycles of EBVP Chemotherapy and Complete Remission in Early-Stage Hodgkin Lymphoma Without Risk Factors: Results of the EORT-GELA H9-F Intergroup Randomized Trial.

PURPOSE: While patients with early-stage Hodgkin lymphoma (HL) have an excellent outcome with combined treatment, the radiation therapy (RT) dose and treatment with chemotherapy alone remain questionable. This noninferiority trial evaluates the feasibility of reducing the dose or omitting RT after chemotherapy. METHODS AND MATERIALS: Patients with untreated supradiaphragmatic HL without risk factors (age ≥ 50 years, 4 to 5 nodal areas involved, mediastinum-thoracic ratio ≥ 0.35, and erythrocyte sedimentation rate ≥ 50 mm in first hour without B symptoms or erythrocyte sedimentation rate ≥ 30 mm in first hour with B symptoms) were eligible for the trial. Patients in complete remission after chemotherapy were randomized to no RT, low-dose RT (20 Gy in 10 fractions), or standard-dose involved-field RT (36 Gy in 18 fractions). The limit of noninferiority was 10% for the difference between 5-year relapse-free survival (RFS) estimates. From September 1998 to May 2004, 783 patients received 6 cycles of epirubicin, bleomycin, vinblastine, and prednisone; 592 achieved complete remission or unconfirmed complete remission, of whom 578 were randomized to receive 36 Gy (n=239), 20 Gy of involved-field RT (n=209), or no RT (n=130). RESULTS: Randomization to the no-RT arm was prematurely stopped (≥20% rate of inacceptable events: toxicity, treatment modification, early relapse, or death). Results in the 20-Gy arm (5-year RFS, 84.2%) were not inferior to those in the 36-Gy arm (5-year RFS, 88.6%) (difference, 4.4%; 90% confidence interval [CI] -1.2% to 9.9%). A difference of 16.5% (90% CI 8.0%-25.0%) in 5-year RFS estimates was observed between the no-RT arm (69.8%) and the 36-Gy arm (86.3%); the hazard ratio was 2.55 (95% CI 1.44-4.53; P<.001). The 5-year overall survival estimates ranged from 97% to 99%. CONCLUSIONS: In adult patients with early-stage HL without risk factors in complete remission after epirubicin, bleomycin, vinblastine, and prednisone chemotherapy, the RT dose may be limited to 20 Gy without compromising disease control. Omitting RT in these patients may jeopardize the treatment outcome.

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk of therapy-related colorectal cancer: study design.

BACKGROUND: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. METHODS/DESIGN: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived ≥8 years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. DISCUSSION: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. TRIAL REGISTRATION: Registered at the Dutch Trial Registry (NTR): NTR4961 .

Intra-fraction uncertainties of MRI guided brachytherapy in patients with cervical cancer.

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention.

Risk of multiple primary malignancies following treatment of Hodgkin lymphoma.

We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged <25, 25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies.

Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: a single institution experience.

PURPOSE: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. METHOD: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. RESULTS: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. CONCLUSION: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity.

Parenthood in survivors of Hodgkin lymphoma: an EORTC-GELA general population case-control study.

PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.

Xerostomia: a day and night difference.

PURPOSE: To compare patient-reported xerostomia during daytime and during nighttime with objectively measured parotid and submandibular gland function in a cohort of head-and-neck cancer (HNC) patients treated with RT. MATERIALS AND METHODS: A cohort of 138 HNC patients underwent objective measurements of parotid (PF) and submandibular (SMF) gland function and completed a xerostomia questionnaire (XQ) before RT, at 6 weeks, 6 months and 1 year after RT. No attempt was made to spare the submandibular gland(s). The XQ contained specific questions concerning the sensation of dry mouth during day- (XD) and nighttime (XN), scored on a 5-point Likert scale. Patients with no or mild (grade 1-3) xerostomia and patients with more severe (grade 4-5) complaints were grouped together. RESULTS: Before RT, no association existed between dry mouth complaints and PF or SMF. At 6 weeks, 6 months and 1 year after RT; 37%, 51% and 36% had grade 4-5 XD and 65%, 64% and 56% had grade 4-5 XN, respectively. Patients with grade 4-5 XD and XN had significantly worse SMF at all time points after RT compared to patients with grade 1-3 XD and XN, while PF was significantly worse only at 6 weeks after RT. In multivariate analyses, SMF was consistently the most important factor related to XN after treatment. PF significantly influenced XD at 6 weeks and 1 year after RT. CONCLUSIONS: Differentiating between complaints during day- and nighttime in xerostomia research is necessary. Dry mouth at night is a frequent problem after (parotid-sparing) RT for HNC and is explained by submandibular gland dysfunction. Sparing of the contralateral submandibular gland, in addition to parotid gland sparing, may result in improved patient-reported xerostomia.

MUC5B levels in submandibular gland saliva of patients treated with radiotherapy for head-and-neck cancer: a pilot study.

BACKGROUND: The salivary mucin MUC5B, present in (sero)mucous secretions including submandibular gland (SMG) saliva, plays an important role in the lubrication of the oral mucosa and is thought to be related to the feeling of dry mouth. We investigated if MUC5B levels in SMG saliva could distinguish between the presence or absence of severe dry mouth complaints 12 months after radiotherapy (RT) for head-and-neck cancer (HNC). FINDINGS: Twenty-nine HNC patients with a residual stimulated SMG secretion rate of ≥ 0.2 ml/10 min at 12 months after RT were analyzed. MUC5B (in U; normalized to 1) and total protein levels (mg/ml) were measured in SMG saliva at baseline and 12 months after RT using ELISA and BCA protein assay, respectively. Overall, median MUC5B levels decreased after RT from 0.12 to 0.03 U (p = 0.47). Patients were dichotomized into none/mild xerostomia (n = 12) and severe xerostomia (n = 17) based on a questionnaire completed at 12 months. SMG and whole saliva flow rates decreased after RT but were comparable in both groups. The median MUC5B level was higher in patients with no or mild xerostomia compared to patients with severe xerostomia (0.14 vs 0.01 U, p = 0.22). Half of the patients with severe xerostomia had no detectable MUC5B at 12 months after RT. No differences in total protein levels were observed. CONCLUSIONS: Qualitative saliva parameters like MUC5B need further investigation in RT-induced xerostomia. This pilot study showed a trend towards lower MUC5B levels in the SMG saliva of patients with severe xerostomia 12 months after RT for HNC.

Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study.

PURPOSE: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. PATIENTS AND METHODS: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. RESULTS: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF. CONCLUSION: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.

Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer.

PURPOSE: The aims of this study were to investigate the benefit of the Utrecht interstitial CT/MR applicator for combined intracavitary/interstitial (IC/IS) approach, using magnetic resonance imaging-guided brachytherapy, over the intracavitary approach alone in patients with locally advanced cervical cancer and to analyze the clinical use of needles. METHODS AND MATERIALS: This study includes the first 20 patients treated with the new applicator. Brachytherapy consisted of two pulsed dose rate applications, and the second application was performed with the IC/IS approach. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the dose distribution and dosimetric shortcomings of the first application (IC alone). We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/IS(clinical)) with an additionally generated optimized plan without needle use (IC(study)). Furthermore, we studied the relation of the inserted needles and their source loading patterns with the high-risk clinical target volume (HR-CTV). RESULTS: A total of 54 needles (range, 1-6 per application) were applied with an average depth of 25 mm. The chosen needle positions corresponded with the location of the HR-CTV extensions. The total and individual needle treatment times per application were on average 19% (range, 4-35%) and 7% (range, 2-14%) of the implant treatment time, respectively. The total (external-beam radiotherapy + brachytherapy) D90 HR-CTV for the IC(study) and the IC/IS(clinical) were on average 79.5 (SD 7.4) Gy(α/ß10) and 83.9 (SD 6.7) Gy(α/ß10), respectively, with an average gain of 4.4 (SD 2.3) Gy(α/ß10) for the second application. CONCLUSIONS: Needle placement was feasible in all patients and resulted in a gain in dose and better coverage of HR-CTV. Defining the location of HR-CTV protrusions and analyzing the associated needles has given us deeper understanding of the possibilities in magnetic resonance imaging-guided (pre)treatment planning with the IC/IS Utrecht applicator.

MRI to quantify early radiation-induced changes in the salivary glands.

PURPOSE: We investigated radiation-induced changes in the salivary glands, 6 weeks after RT, using MRI. MATERIALS AND METHODS: Eighteen oropharyngeal cancer patients were treated with salivary gland sparing IMRT. All patients received a 3T MRI exam before and 6 weeks after the end of RT, including a T(1)-weighted (T(1)w), a T(2)-weighted (T(2)w), and a dynamic contrast-enhanced (DCE) MRI. For both time points separately, the parotid and submandibular glands were delineated on the MR images. Differences in median signal intensity and signal variation within the glands were tested for significance. Correlations were studied between the MR changes and the planned RT dose. RESULTS: The volume of the glands reduced significantly by 25%. The T(1)w signal decreased by 10% and the T(2)w signal increased by 23%. The k(ep) value decreased, while the v(e) increased. A correlation of the changes in T(2)w signal with the mean dose was found in both glands. CONCLUSIONS: Overall radiation-induced changes and volume loss were observed in the parotid and submandibular gland using MR. The observed differences indicated an increased water content such as found in oedema. The overall changes could be related to the mean dose, with a slightly greater impact in the high dose area.