Survivors of Hodgkin lymphoma (HL) face lifelong risks of treatment-related late adverse effects, yet many lack adequate knowledge of these risks. This study examined sociodemographic, clinical, and care-related correlates of survivorship knowledge among adult HL survivors engaged in a national, risk-based survivorship program. Adult HL survivors participating in the Dutch INSIGHT study within the BETER survivorship-care infrastructure completed a multi‑domain survivorship knowledge questionnaire assessing awareness of endocrine, cardiovascular, oncologic, infectious, and symptom-related late effects. A 12-item sex-comparable knowledge index was constructed and scored using partial-credit rules. Missing data were handled using multiple imputation. Multiple linear regression models were used to estimate independent associations between sociodemographic characteristics, treatment exposures, survivorship-care utilization, and knowledge scores. Among 370 survivors (53

BACKGROUND:Hodgkin lymphoma (HL) survivors are at increased risk of late adverse events, eg, cardiovascular diseases (CVD), breast cancer (BC), hypothyroidism and severe infections. At Dutch BETER clinics, HL survivors are regularly screened for (risk factors for) these adverse events. The impact of survivorship care on the burden of disease from adverse outcomes has rarely been evaluated. METHODS:In a nationwide retrospective cohort study, we compared HL survivors invited for BETER care in 2013-2016 (intervention group) with matched survivors who were eligible for such care but were not invited until 2019-2024 (comparison group). Incidence and mortality rates for CVD, BC, hypothyroidism, and severe infections were collected from general practitioners and nationwide registries. Disability-adjusted life years (DALYs) attributable to late adverse events were compared using multivariable regression models. RESULTS:At study start, survivors in the intervention group (n = 491) and comparison group (n = 373) had a median age of 46 years; median time since HL diagnosis was 15-18 years. After 8.5 years (median), there were no significant differences in DALYs attributable to CVD, BC, hypothyroidism, and severe infections between the groups. In both groups, approximately one third of survivors acquired DALYs attributable to adverse events. Adherence to recommended screening diagnostics was high, but cardiovascular risk management and vaccination rates were suboptimal. CONCLUSION:After 8.5 years of follow-up, survivorship care for HL survivors was not associated with lower disease burden. Better care coordination, amendment of the cardiovascular risk management guidelines, and greater survivor involvement may improve long-term effectiveness of measures to prevent late adverse events.

BACKGROUND:Patients with Hodgkin lymphoma are at increased risk of developing lung cancer, especially after chest radiation therapy. No tools are currently available, however, to predict lung cancer risk for different Hodgkin lymphoma treatments. METHODS:In a cohort of 5370 individuals who had survived Hodgkin lymphoma for at least 5 years, were 15 to 50 years of age at the time of Hodgkin lymphoma diagnosis, and who were treated in the Netherlands between 1965 and 2012, we used radiation therapy fields and prescribed dose to estimate mean lung dose. The twinning method was used to divide the cohort into homogenous parts: 80% for model development and 20% for validation using inverse probability of censoring weighting area under the curve. Cox proportional hazards models allowing for time-dependent coefficients were used to model time from Hodgkin lymphoma diagnosis to lung cancer and lung cancer-free death as the competing event for predicting absolute lung cancer risk up to 30 years after Hodgkin lymphoma diagnosis. RESULTS:Treatment information consisted of supradiaphragmatic radiation therapy in 75.2% of patients with a mean lung dose of 15.8 Gy. During follow-up, 218 survivors developed lung cancer. Older age, male sex, smoking at the time of Hodgkin lymphoma diagnosis, and higher mean lung dose were associated with higher lung cancer risk. The median Inter Quartile Range (IQR) estimated 30-year absolute lung cancer risk in our cohort was 1.2% (0.8%-1.9%) in nonsmokers and 6.9% (4.6%-10.9%) in smokers at the time of Hodgkin lymphoma diagnosis. The 20-year and 30-year inverse probability of censoring weighting areas under the curve values were 0.79 (95% Confidence Interval (CI) = 0.73 to 0.85) and 0.75 (95% CI = 0.69 to 0.81), respectively. CONCLUSION:We developed a well-calibrated prediction tool that estimates long-term risk of lung cancer with good discrimination based on patient characteristics and mean lung dose, allowing application in Hodgkin lymphoma survivors and contemporary patients with Hodgkin lymphoma.

ABSTRACT Introduction Hodgkin lymphoma (HL) is a highly curable malignancy mainly affecting young adults, but survivors are at risk of serious late adverse effects, like cardiovascular disease and subsequent malignancies, which may impact health‐related quality of life (HRQoL). The Dutch BETER consortium introduced a nationwide survivorship care program offering tailored screening for late effects among HL survivors from 5 years after diagnosis onward. This study evaluates the association between BETER survivorship care and HRQoL, knowledge of late effects, and distress levels. Methods The INSIGHT study is a nationwide retrospective cohort study comparing HL survivors who received BETER care since 2013‐2016 to matched survivors who did not receive survivorship care until 2019–2024. HRQoL was cross‐sectionally assessed in 2021–2024 (median time since HL diagnosis ~25 years) using the SF‐36 and EQ‐5D‐5L questionnaires. Knowledge of late effects and distress levels were evaluated using a modified Cancer Worry Scale and a 15‐item knowledge questionnaire. Multivariable negative binomial regression analyses were performed to compare outcomes between groups. Results HRQoL outcomes showed no significant differences between survivors screened since 2013‐2016 (n = 251) and the comparison group (n = 119). Overall, HRQoL of HL survivors matched that of the general population in the Netherlands. Knowledge of late effects was suboptimal in both groups, and distress levels were similarly low. Eighty percent of survivors perceived BETER care as beneficial, with most individuals stating that increased knowledge outweighed potential worries. Conclusion BETER survivorship care was not associated with better HRQoL among long‐term HL survivors, but the care was perceived as beneficial by survivors. Future (qualitative) research could focus on survivors' preferences for education about their risk of late effects.

PURPOSE:Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages. METHODS:We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses. RESULTS:After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m2 doxorubicin (Ptrend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR]age <21 years, 1.5 [95% CI, 0.9 to 2.6]; HRage ≥21 years, 1.3 [95% CI, 0.9 to 1.9) or chest RT (HRwithout mantle/axillary field RT, 1.9 [95% CI, 1.06 to 3.3]; HRwith mantle/axillary field RT, 1.2 [95% CI, 0.8 to 1.8]). CONCLUSION:This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Table S1. Participating institutions for all patients (N=345) and patients presenting with anemia(N=54).

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.

Table S2. Eligibility criteria.

Table S3. Treatment delivery for all patients (N=345) and the patients presenting with anemia (N=54).

12074 Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Recently concern has been raised that anthracyclines may also increase BC risk, based on studies in childhood cancer survivors with/without a history of chest RT. So far, the association between anthracyclines and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Now that RT dose and volumes are decreasing, the potential contribution of anthracyclines to BC risk is an important issue. Methods: We assessed BC risk in a cohort of 2314 female 5-year HL survivors, treated at ages 15-50 years and diagnosed between 1965 and 2008 in 20 Dutch hospitals. Treatment factors were time-dependently included in the analysis, focusing on the effect of anthracycline exposure on BC risk. Results: After a median follow-up of 18.8 years, 258 women developed invasive BC or ductal carcinoma in situ as a subsequent malignancy. The 30-year cumulative incidence was 15.0% (95% Confidence Interval (CI) 12.8-17.4%). Mantle field RT (or other RT involving both axillae) was associated with increased risk of BC (Hazard ratio (HR) 1.9; 95% CI 1.2-2.8) compared to no supradiaphragmatic RT or RT to the neck only (Table 1). Gonadotoxic treatment (>4.2 g/m2 procarbazine or pelvic RT) significantly decreased this risk. In a multivariable analysis, anthracycline exposure was associated with increased BC risk (HR 1.8; 95% CI 1.3-2.5) in patients who received a cumulative dose of >200 mg/m2. Among patients exposed to gonadotoxic treatment, the HR of BC associated with >200mg/m2 anthracyclines was 3.8 (95% CI 2.0-7.2), with a trend for higher risk with higher anthracycline dose (HR 1.58 per 100mg/m2 anthracycline, p<0.001). Conclusions: Our results suggest an association of anthracyclines with BC risk in HL survivors. Also when accounting for the protective effect of gonadotoxic treatment on RT-associated BC risk, anthracyclines significantly contributed to a higher BC risk.[Table: see text]

The prognostic and predictive value of the proliferation marker Ki‐67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma.

Abstract Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345–54. ©2014 AACR.

BACKGROUND AND PURPOSE:In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON (accelerated radiotherapy with carbogen breathing and nicotinamide) to accelerated radiotherapy alone (AR) the prognostic and predictive value of CAIX, a hypoxia-associated protein, was investigated.MATERIAL AND METHODS:261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX. CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival.RESULTS:Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR. Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR (RC 97% vs 71%, p < 0.01 and MFS 92% vs 69%, p = 0.06). Patients with a perinecrotic CAIX staining pattern had a significantly worse local control, metastasis-free and overall survival compared to patients with a diffuse pattern (65% vs 84%, p = 0.01, 70% vs 96%, p < 0.01 and 42% vs 71%, p < 0.01 respectively), and this could not be improved with ARCON. After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival.CONCLUSIONS:ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression. The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value.

Background. Hypoxia, metabolism, and growth factor signaling are important prognostic features in most solid tumors. The purpose of this study was to determine whether head and neck squamous cell carcinoma (HNSCC) xenografts show similar biological and molecular characteristics as the primary tumor they originate from.Methods. Eighteen HNSCC primary tumor-xenograft pairs were immunofluorescently stained for pimonidazole (hypoxia), carbonic anhydrase IX (CAIX), glucose transporter-1 (GLUT-1), monocarboxylate transporter-1 (MCT-1), monocarboxylate transporter-4 (MCT-4), epidermal growth factor receptor (EGFR), and phosphorylated protein kinase B (pAKT).Results. Although no correlation was found for the amount of hypoxia, significant correlations between primary tumors and xenografts were observed for both the percentage of cells positive for expression and the hypoxia-related expression pattern of CAIX, GLUT-1, and MCT-1. For EGFR and MCT-4, the intensity of expression was correlated. No correlation was observed for pAKT.Conclusion. Xenografts did not always resemble the primary tumor they originate from, but the xenografts did represent the variability in expression levels and patterns observed in the primary tumors. (C) 2013 Wiley Periodicals, Inc.

PURPOSE To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

Background Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. Methods GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n = 41) and squamous cell carcinomas (n = 34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. Results Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p = 0.032). Conclusion Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

BACKGROUND:The cellular response of malignant tumors to hypoxia is diverse. Several important endogenous metabolic markers are upregulated under hypoxic conditions. We examined the staining patterns and co-expression of HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4 with the exogenous hypoxic cell marker pimonidazole and the association of marker expression with clinicopathological characteristics.METHODS:20 biopsies of advanced head and neck carcinomas were immunohistochemically stained and analyzed. All patients were given the hypoxia marker pimonidazole intravenously 2 h prior to biopsy taking. The tumor area positive for each marker, the colocalization of the different markers and the distribution of the markers in relation to the blood vessels were assessed by semiautomatic quantitative analysis.RESULTS:MCT1 staining was present in hypoxic (pimonidazole stained) as well as non-hypoxic areas in almost equal amounts. MCT1 expression showed a significant overall correlation (r = 0.75, p < 0.001) and strong spatial relationship with CAIX. LDH-5 showed the strongest correlation with pimonidazole (r = 0.66, p = 0.002). MCT4 and GLUT-1 demonstrated a typical diffusion-limited hypoxic pattern and showed a high degree of colocalization. Both MCT4 and CAIX showed a higher expression in the primary tumor in node positive patients (p = 0.09 both).CONCLUSIONS:Colocalization and staining patterns of metabolic and hypoxia-related proteins provides valuable additional information over single protein analyses and can improve the understanding of their functions and environmental influences.

Automated analysis of immunohistochemically stained tissue sections is of great importance in cancer research to detect tumor-specific prognostic markers and make therapy decisions. Here, an automated quantitative analysis is presented to assess the colocalization of CAIX, a membrane-bound hypoxic marker and Ki-67, a nuclear proliferation marker.