Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Incidence and centralization of chordoma in the Netherlands: A nationwide study between 1991 and 2020.

INTRODUCTION: Chordomas are rare malignant bone tumors arising in the axial skeleton, with an incidence of 0.3-0.88 per million inhabitants. We studied the annual incidence rate and centralization of treatment for chordoma in the Netherlands. METHODS: We retrieved pathology excerpts from the PALGA nationwide Dutch Pathology Registry between 1991 and 2019 for patients with a chordoma to calculate incidence rates. From pathology reports we extracted patient age at diagnosis, sex, year of diagnosis, localization of primary tumor, histologic chordoma subtype (conventional including chondroid, poorly differentiated or dedifferentiated), center of diagnosis (bone tumor referral center (BTC) or other hospital), and partial identification of the BTCs. RESULTS: A total of 420 individual chordoma patients were identified in the given time period. The incidence of chordoma increased from 0.593 per million inhabitants between 1991-1995 to 1.111 from 2015-2019 (P = 0.001). Median age at diagnosis was 63 years (range 1-95), 252 patients (60%) were male. The proportion of samples analyzed in a BTC either primarily or secondary, as a consultation, revision or referral, increased significantly from 29.3% to 84.4% (P < 0.001). Most primary and secondary samples were analyzed at the Leiden University Medical Center (LUMC, 54.4% and 57% respectively). CONCLUSIONS: This study shows an increase in the standardized incidence of pathology proven chordoma in the Netherlands. We observed an increase in samples being analysed in the specialized BTCs as well, which is in line with current guidelines and will hopefully lead to more accurate diagnoses and optimal treatment plans for chordoma patients in specialized treatment centers.

Personalising sarcoma care using quantitative multimodality imaging for response assessment.

Over the last decades, technological developments in the field of radiology have resulted in a widespread use of imaging for personalising medicine in oncology, including patients with a sarcoma. New scanner hardware, imaging protocols, image reconstruction algorithms, radiotracers, and contrast media, enabled the assessment of the physical and biological properties of tumours associated with response to treatment. In this context, medical imaging has the potential to select sarcoma patients who do not benefit from (neo-)adjuvant treatment and facilitate treatment adaptation. Due to the biological heterogeneity in sarcomas, the challenge at hand is to acquire a practicable set of imaging features for specific sarcoma subtypes, allowing response assessment. This review provides a comprehensive overview of available clinical data on imaging-based response monitoring in sarcoma patients and future research directions. Eventually, it is expected that imaging-based response monitoring will help to achieve successful modification of (neo)adjuvant treatments and improve clinical care for these patients.

Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

The beneficial local and abscopal effect of splenic irradiation in frail patients with chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is a common haematological malignancy that mainly occurs in the elderly population. Patients frequently have comorbidities compromising the use of old and new systemic therapies. METHODS AND RESULTS: We report the prevalence of comorbidities in patients with CLL as present in the southern region of the Netherlands Cancer Registry. Comorbid conditions were present in 67% of the male and 63% of the female patients, and became more common with increasing age. Furthermore, we describe the beneficial local and abscopal effects of splenic irradiation in four patients with CLL who were not suitable for systemic chemoimmunotherapy because of severe comorbidities, or who were unwilling to undergo systemic therapy. CONCLUSION: Our results show that, although an old tool, splenic irradiation should not be forgotten as a potentially effective palliative treatment option in frail patients with symptomatic CLL.

Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors: phase II study of indication and acceptance†.

BACKGROUND: Cardiovascular diseases are the most common nonmalignant cause of death in Hodgkin lymphoma (HL) survivors, especially after mediastinal irradiation. We investigated the role of computed tomographic coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, and related CTA findings to exercise testing and subsequent interventions. PATIENTS AND METHODS: Patients were eligible for this phase II study if at least 10 years disease-free and treated with mediastinal radiotherapy. Screening consisted of electrocardiogram, exercise testing and CTA. Primary end point was significant CAD (stenosis >50%) on CTA. CTA screening was considered to be indicated for testing in a larger population if ≥6 of 50 CTA scanned patients (12%) would need revascularization. Screening was evaluated with a questionnaire before and after screening. RESULTS: Fifty-two patients were included, and 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. There were 45 evaluable scans. Significant CAD on CTA was found in 20% (N = 9), significantly increased compared with the 7% expected abnormalities (P = 0.01, 95% confidence interval 8.3% to 31.7%). In 11% (N = 5), significant stenosis was confirmed at coronary angiography, and revascularization was carried out. Additionally, two patients were treated with optimal medical therapy. Ninety percent of patients were content with screening, regardless whether the CTA showed abnormalities. CONCLUSIONS: Prevalence of significant CAD among HL survivors is high, while asymptomatic even in the presence of life-threatening CAD. This might justify screening by CTA in asymptomatic HL survivors who had mediastinal radiotherapy, but needs to be evaluated in a larger cohort. The trial protocol was approved by the Ethics Committee of the LUMC and registered with ClinicalTrials.gov, NCT01271127.

Chronic fatigue in Hodgkin lymphoma survivors and associations with anxiety, depression and comorbidity.

BACKGROUND: Fatigue is a frequent and persistent problem among Hodgkin lymphoma (HL) survivors. We investigated the prevalence of clinically relevant fatigue in HL survivors and the relation between fatigue and anxiety and depression. METHODS: Fatigue was measured through the generic European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and Fatigue Assessment Scale (FAS). Anxiety and depression were measured with the Hospital Anxiety and Depression Scale. Questionnaires were mailed to 267 HL survivors. Results were compared with a Dutch age-matched normative population. RESULTS: Response rate was 68% (median age 46 years, mean time since diagnosis 4.6 years). Prevalence of fatigue was significantly higher among HL survivors than in the norm population (FAS 41% vs 23%, QLQ-C30 43% vs 28%), as were fatigue levels. There was a significant association between fatigue, anxiety and depression. Of the HL survivors with high symptom levels of depression, 97% also reported fatigue. In multivariate analysis, depression was strongly associated with high levels of fatigue and, to a lesser extent, anxiety and comorbidity. CONCLUSIONS: Prevalence rates of fatigue are significantly higher in HL survivors than in the general population and differences are clinically relevant. Depression and anxiety were strongly associated with high levels of fatigue. Reducing fatigue levels by treatment of depression and anxiety should be further explored.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

[Long-term complications following treatment of testicular cancer and Hodgkin lymphoma]. / Langetermijncomplicaties na behandeling voor zaadbalkanker en hodgkinlymfoom.

Patients who were treated in the past with radiotherapy or chemotherapy for testicular cancer or Hodgkin lymphoma are at risk of new malignancies and cardiovascular disease on the long run. Two patient groups who were diagnosed in various hospitals in the Netherlands as having testicular cancer and Hodgkin lymphoma in the period 1965-1995 have survived for a mean period of almost 20 years by now. Both patient groups have higher risks of a new malignancy or cardiovascular disease following radiotherapy and/or chemotherapy than the general population or patients treated without or with less intensive radiotherapy or chemotherapy. As recovery of Hodgkin lymphoma is only achieved by a more intensive treatment approach than the treatment approach for testicular cancer, the risks of a new malignancy or cardiovascular disease are considerably higher among survivors of Hodgkin lymphoma than among survivors of testicular cancer. In both patient groups the long-term risks of new malignancies and cardiovascular disease are still raised in both patient groups up to 25 years after treatment. Because of the relatively high risks of late treatment complications, recommendations for follow-up for survivors of testicular cancer and Hodgkin lymphoma are necessary.

Non-Hodgkin's lymphoma in the Netherlands: results from a population-based registry.

The Comprehensive Cancer Centre West (CCCW) population based non-Hodgkin's lymphoma (NHL) registry contains information on all newly diagnosed NHL patients living in the region covered by the CCCW. Patients were entered from June 1st 1981 to December 31st 1989. Follow-up is still ongoing, median follow-up is 113 months (1-191 months) for patients alive. In this study, patient and tumor characteristics, data on patterns of care, response and (relative) survival are described. As follicular lymphomas and diffuse large B-cell lymphomas are the most frequently occurring NHL subtypes in the database, a separate analysis is performed to characterize the clinical picture of these disease entities in the CCCW population. Our data illustrate that NHL patients in the general population are substantially older than patients included in trials and hospital based series. Due to older age, treatment is withheld or adapted for a substantial number of patients. The resulting survival and relative survival rates are a reflection of these choices.

Primary extranodal non-Hodgkin's lymphoma (NHL): the impact of alternative definitions tested in the Comprehensive Cancer Centre West population-based NHL registry.

BACKGROUND: The definition of primary extranodal non-Hodgkin's lymphoma (NHL) is a controversial issue, especially in patients where both nodal and extranodal sites are involved. PATIENTS AND METHODS: The impact of different definitions of primary extranodal NHL on incidence and prognosis is explored using data from a population-based NHL registry. RESULTS: Using liberal criteria, 389 (34%) cases were classified as primary extranodal NHL. Overall survival (OS) rates of nodal and extranodal NHL patients defined this way were comparable; however, extranodal NHL patients had a better disease-free survival (DFS). When strict criteria were applied, 231 cases (20%) were classified as primary extranodal NHL. OS and DFS rates of extranodal NHL patients defined this way were superior to nodal NHL patients; however, the difference in OS was reversed after correction for differences in International Prognostic Index and malignancy grade. CONCLUSION: This study illustrates the selection bias that is introduced when a strict definition of primary extranodal NHL, that excludes cases with disseminated disease, is used. Patients with primary extranodal NHL were found to have a superior DFS, irrespective of which definition of primary extranodal NHL was used.