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The standard treatment regimen for esophageal cancer is chemoradiation followed by esophagectomy. However, the use of neoadjuvant chemoradiotherapy damages the surrounding tissue, which potentially increases the risk of postoperative complications, including anastomotic leakage. The impact of definitive chemoradiotherapy (dCRT, 50.4 Gy radiotherapy) compared to the standard neoadjuvant scheme (nCRT, 41.4 Gy radiotherapy) prior to surgery on the incidence of anastomotic leakage remains poorly understood. To study this, all patients who received dCRT between 2011 and 2021 followed by esophagectomy were included. For each patient, two patients who received nCRT were selected as matched controls. Outcomes included postoperative anastomotic leakage, pulmonary and other complications, anastomotic stenosis, pulmonary and other postoperative complications (Clavien Dindo Classification ≥1), and overall survival. One hundred and eight patients were included with a median follow-up of 28 months. The time between neoadjuvant treatment and surgery was longer in the dCRT group compared to the nCRT group (65 vs. 48 days, P < 0.001). Postoperatively, significantly more patients in the dCRT group suffered from anastomotic leakage (11% vs. 1%, P = 0.04) and anastomotic stenosis (42% vs. 17%, P < 0.01). No differences were found for other complications or overall survival between both groups. In conclusion, preoperative dCRT is associated with a higher risk of anastomotic leakage and stenosis. These complications, however, can be treated effectively. Therefore, esophagectomy after dCRT is considered to be an appropriate treatment strategy in a selected patient group., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of mature T-cell neoplasms with an unfavorable prognosis; presentation with stage I(E) disease is uncommon. In clinical practice, an abbreviated chemotherapy treatment regimen combined with radiotherapy (combined modality treatment [CMT]) is commonly used, although evidence from clinical trials is lacking. The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL. All newly diagnosed patients ≥18 years with stage I(E) anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma NOS (PTCL not otherise specified [NOS]) in 1989-2020 were identified in the Netherlands Cancer Registry. Patients were categorized according to treatment regimen, i.e., chemotherapy (CT), radiotherapy (RT), CMT, other therapy and no treatment. The primary endpoint was overall survival (OS). Patients with stage I(E) ALCL, AITL and PTCL NOS (n=576) were most commonly treated with CMT (28%) or CT (29%), 2% underwent SCT. RT only was given in 18%, and 8% received other therapy and 16% no treatment. Overall, the 5-year OS was 59%. According to subtype, 5-year OS was superior for ALCL as compared to PTCL NOS and AITL (68% vs. 55% and 52%, respectively; P=0.03). For patients treated with CMT, 5-year OS was significantly higher (72%) as compared to patients treated with either CT or RT alone (55% and 55%, respectively; P<0.01). In multivariable analysis, age per year increment (hazard ratio [HR] =1.06, 95% confidence interval [CI]: 1.05-1.07), male sex (HR=1.53, 95% CI: 1.23-1.90), and CT, or no treatment (HR=1.64, 95% CI: 1.21-2.21, and HR=1.55, 95% CI: 1.10-2.17, respectively) were associated with a higher risk of mortality. For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 59%, comparing favorably to historical outcome in advanced-stage disease. Superior outcome estimates were observed in patients treated with CMT.

Conditional relative survival (CRS) is useful for communicating prognosis to patients as it provides an estimate of the life expectancy after having survived a certain time after treatment. Our study estimates the 3-year relative survival conditional on having survived a certain period for patients with esophageal or gastric cancer. Patients with nonmetastatic esophageal or gastric cancer diagnosed between 2006 and 2020 treated with curative intent (resection with or without [neo]adjuvant therapy, or chemoradiotherapy) were selected from the Netherlands Cancer Registry. CRS was calculated since resection or last day of chemoradiotherapy. The probability of surviving an additional 3 years (ie, 3-year CRS), if the patients survived 1, 3 and 5 years after diagnosis was 62%, 79%, 87% and 69%, 84%, 90% for esophageal and gastric cancer, respectively. The 3-year CRS after having survived 3 years for patients with esophageal cancer who underwent a resection (n = 12 204) was 91%, 88%, 77% and 60% for pathological Stage 0, I, II and III, and for patients with esophageal cancer who received chemoradiotherapy (n = 4158) was 51% and 66% for clinical Stage II and III, respectively. The 3-year CRS after having survived 3 years for patients with gastric cancer who underwent a resection (n = 6531) was 99%, 90%, 73% and 59% for pathological Stage 0, I, II and III, respectively. Despite poor prognosis of patients with esophageal or gastric cancer, life expectancy increases substantially after patients have survived several years after treatment. Our study provides valuable information for communication of prognosis to patients during follow-up after treatment., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88 / CD79B and/or CDKN2A -loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A , MYC , and PIM1 . Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88 / CD79B and/or CDKN2A -loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients.

Objectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement., Methods: Physicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, nine-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision-making Effectiveness, and five-item Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later., Results: In total, 151 treatment decision-making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were>.60 for most items., Conclusions: The iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement., Practice Implications: Results from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To gain insight into the treatment outcomes for anal cancer a retrospective analysis was performed with a special emphasis on trends in outcome and toxicities over time and on treatment of elderly patients., Materials and Methods: Medical records of 98 consecutive patients with squamous cell carcinoma of the anus of all stages treated with curative intent between 01-01-2009 and 31-12-2018 were analyzed with follow up until 31-12-2020. Standard tumor and pathological lymph node dose were 59.4 Gy (median 59.4 Gy, range 59.4-70 Gy) or 60 Gy (no deviation from intended dose), elective nodal regions were treated with 45 Gy (no deviations). Radiotherapy techniques in this period evolved from 3D-conformal to IMRT and VMAT. In 23 patients electron beams were used., Results: Median age was 63 years (range 41-88), the majority of patients were female (60%). Twenty three patients were > 75 years old. The TNM stages were I, II, IIIA, and IIIB in 18%, 40%, 15% and 27%, 58% of patients had N0 status. Concurrent mitomycin C and 5-fluoruracil-based chemotherapy was given in 63 patients (64%). Five-year overall survival (OS), disease free survival (DFS), locoregional control (LRC) and colostomy free survival (CFS) were 71%, 80%, 82%, and 82% for the whole group. Results in patients > 75 years of age were not statistically different from those in younger patients. With the introduction of more conformal techniques DFS did not change and toxicities decreased., Conclusion: Real word treatment outcomes per disease stage were in line with what is reported in literature. Older patients should also be offered treatment with curative intent., (© 2022. The Author(s).)

Background and Objectives: Since the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary resectable nonmetastatic esophageal cancer (EC) has been implemented as standard curative treatment in the Netherlands. The purpose of this retrospective study is to evaluate the clinical outcomes of this treatment in daily practice in a large academic hospital., Methods: Medical records of patients treated for primary resectable nonmetastatic EC between May 2010 and December 2015 at our institution were reviewed. Treatment consisted of five weekly courses of carboplatin (area under the curve 2) and paclitaxel (50 mg/m2) with concurrent external beam radiotherapy (23 fractions of 1.8 Gy), followed by transthoracic or transhiatal resection. Data on survival, progression, acute and late toxicity were recorded., Results: A total of 145 patients were included. Median follow-up was 43 months. Median overall survival (OS) and progression-free survival (PFS) were 35 (95% confidence interval [CI] 29.8-40.2) and 30 (95% CI 19.7-40.3) months, respectively, with corresponding 3-year OS and PFS of 49.6% (95% CI 40.4-58.8) and 45.6% (95% CI 36.6-54.6). Acute toxicity grade ≥3 was observed in 25.5% of patients. Late adverse events grade ≥3 were seen in 24.8%, mostly esophageal stenosis., Conclusion: Neoadjuvant CRT followed by resection for primary resectable nonmetastatic EC in daily practice results in a 3-year OS of 49.6% (95% CI 40.4-58.8) and PFS of 45.6% (95% CI 36.6-54.6), compared with 58% (51-65%) and 51% (43-58%) within the CROSS-trial. The slightly poorer survival in our daily practice group might be due to the presence of less favorable patient and tumor characteristics in daily practice, as is to be expected in daily practice. Toxicity was comparable with that in the CROSS-trial and considered acceptable., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Purpose: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported., Methods: In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial., Results: Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer., Conclusion: Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer., Competing Interests: Marc G. BesselinkResearch Funding: Intuitive Surgical, Medtronic, Ethicon/Johnson & Johnson, Oncosil, Viatris Ronald M. van DamResearch Funding: Abbott Laboratories (Inst) Ferry A. L. M. EskensHonoraria: Servier, AstraZeneca/MerckConsulting or Advisory Role: Merck Serono, Roche, Eisai, IpsenTravel, Accommodations, Expenses: Pfizer, Ipsen Jan Willem B. de GrootConsulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier Bas Groot KoerkampResearch Funding: Tricumed (Inst) Ignace H. de HinghResearch Funding: Roche (Inst), QP&S/RanD (Inst) Marjolein Y. V. HomsTravel, Accommodations, Expenses: Servier Jeanin E. van HooftConsulting or Advisory Role: Boston Scientific, Cook Medical, Medtronic, Olympus Medical Systems Judith de Vos-GeelenConsulting or Advisory Role: Servier, MSD, AstraZeneca, Pierre Fabre, AmgenResearch Funding: Servier (Inst)Travel, Accommodations, Expenses: Servier Johanna W. WilminkConsulting or Advisory Role: Servier, Celgene, MerckSpeakers' Bureau: MedscapeResearch Funding: Servier, Celgene, Novartis, AstraZeneca (Inst), Pfizer/EMD Serono (Inst), Roche (Inst), Merck (Inst) Aeilko H. ZwindermanConsulting or Advisory Role: Torrent Pharmaceuticals Ltd Cornelis J. PuntConsulting or Advisory Role: Nordic Bioscience (Inst)No other potential conflicts of interest were reported.

Background: Patients with potentially curable esophageal cancer can be treated with neo-adjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy with curative intent. For frail older patients choosing the appropriate oncological treatment can be difficult, and data on geriatric deficits as determinants of treatment outcomes are not yet available., Objectives: To describe the prevalence of geriatric deficits and to study their association with treatment discontinuation and mortality in older patients with potentially curable esophageal cancer., Material and Methods: A cohort study was conducted in a Dutch tertiary care hospital including patients aged ≥70 years with primary stage I-IVA esophageal cancer. Geriatric screening and assessment data were collected. Outcomes were treatment discontinuation and one year all-cause mortality., Results: In total, 138 patients with curable esophageal cancer were included. Mean age was 76.1 years (standard deviation 4.7), 54% had clinical stage III and 24% stage IVA disease. Most patients received neo-adjuvant chemoradiotherapy and surgery (41%), 32% definitive chemoradiotherapy and 22% palliative radiotherapy. Overall, one year all-cause mortality was 36%. Geriatric screening and assessment was performed in 94 out of 138 patients, of which 60% was malnourished, 20% dependent in Instrumental Activities of Daily Living (IADL) and 52% was frail. Malnutrition was associated with higher mortality risk (Hazard Ratio, 3.2; 95% Confidence Interval, 1.3-7.7)) independent of age, sex and tumor stage. Seventy-six out of 94 patients were treated with chemoradiotherapy, of which 23% discontinued treatment. Patients with IADL dependency and Charlson Comorbidity Index ≥1 discontinued treatment more often., Conclusion: All-cause mortality within one year was high, irrespective of treatment modality. Treatment discontinuation rate was high, especially in patients treated with definitive chemoradiotherapy. Geriatric assessment associates with outcomes in older patients with esophageal cancer and may inform treatment decisions and optimization in future patients, but more research is needed to establish its predictive value. Trial registration: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Purpose: Total skin electron beam therapy (TSEBT) is used mostly in the treatment of cutaneous T cell lymphoma. In this study we describe the results of TSEBT applied in the Netherlands using two different schedules, a conventional dose schedule of 35 Gy and a low-dose schedule of 12 Gy. We aimed to evaluate the treatment results in and compare treatment outcomes between the two treatment groups and to further define indications for both doses., Methods: In the LUMC, Leiden, we performed a retrospective analysis of 51 patients treated with TSEBT between January 2008 and December 2018, with follow-up untill December 2019. Thirty one patients were treated with 35 Gy and twenty with 12 Gy. The dose was chosen based on the severity of skin involvement. Outcome measures were time to meaningful progression, survival, response rate and toxicity., Results: Time to meaningful progression was 5.1 months with no significant differences between dose groups (P = 0.77). Overall survival was 27.4 months. Both time to progression and survival were significantly better for T2 vs T3 stage. Overall response rate was 80.4 %. Both dose groups showed improvement of symptoms. Treatment was generally well tolerated., Conclusions: Both high-dose and low-dose TSEBT offer similar results for TMP and OS. It remains unclear which patients benefit most from a high-dose schedule. We propose to use the low-dose schedule as a standard for TSEBT and use supplementary boosts or escalation to high-dose treatment for patients unresponsive to the low-dose schedule., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Accumulating evidence of trials demonstrates that patient-reported health-related quality of life (HRQoL) at diagnosis is prognostic for overall survival (OS) in oesophagogastric cancer. However, real-world data are lacking. Moreover, differences in disease stages and tumour-specific symptoms are usually not taken into consideration. The aim of this population-based study was to assess the prognostic value of HRQoL, including tumour-specific scales, on OS in patients with potentially curable and advanced oesophagogastric cancer., Methods: Data were derived from the Netherlands Cancer Registry and the patient reported outcome registry (POCOP). Patients included in POCOP between 2016 and 2018 were stratified for potentially curable (cT1-4aNallM0) or advanced (cT4b or cM1) disease. HRQoL was measured with the EORTC QLQ-C30 and the tumour-specific OG25 module. Cox proportional hazards models assessed the impact of HRQoL, sociodemographic and clinical factors (including treatment) on OS., Results: In total, 924 patients were included. Median OS was 38.9 months in potentially curable patients (n = 795) and 10.6 months in patients with advanced disease (n = 129). Global Health Status was independently associated with OS in potentially curable patients (HR 0.89, 99%CI 0.82-0.97), together with several other HRQoL items: appetite loss, dysphagia, eating restrictions, odynophagia, and body image. In advanced disease, the Summary Score was the strongest independent prognostic factor (HR 0.75, 99%CI 0.59-0.94), followed by fatigue, pain, insomnia and role functioning., Conclusion: In a real-world setting, HRQoL was prognostic for OS in patients with potentially curable and advanced oesophagogastric cancer. Several HRQoL domains, including the Summary Score and several OG25 items, could be used to develop or update prognostic models., (© 2021. The Author(s).)

Purpose: To analyze the effect of radiation dose escalation to the primary tumor on local tumor control in definitive chemoradiation (dCRT) for patients with esophageal cancer., Patients and Methods: Patients with medically inoperable and/or irresectable esophageal carcinoma, referred for dCRT, were randomly assigned between a standard dose (SD) of 50.4 Gy/1.8 Gy for 5.5 weeks to the tumor and regional lymph nodes and a high dose (HD) up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under the curve 2) and paclitaxel (50 mg/m 2 ) in both arms once a week for 6 weeks. The primary end point was local progression-free survival., Results: Between September 2012 and June 2018, 260 patients were included. Squamous cell carcinoma (SCC) was present in 61% of patients, and 39% had adenocarcinoma (AC). Radiation treatment was completed by 94%, and 85% had at least five courses of chemotherapy. The median follow-up time for all patients was 50 months. The 3-year local progression-free survival (LPFS) was 70% in the SD arm versus 73% in the HD arm (not significant). The LPFS for SCC and AC was 75% versus 79% and 61% versus 61% for SD and HD, respectively (not significant). The 3-year locoregional progression-free survival was 52% and 59% for the SD and HD arms, respectively ( P = .08). Overall, grade 4 and 5 common toxicity criteria were 12% and 5% in the SD arm versus 14% and 10% in the HD arm, respectively ( P = .15)., Conclusion: In dCRT for esophageal cancer, radiation dose escalation up to 61.6 Gy to the primary tumor did not result in a significant increase in local control over 50.4 Gy. The absence of a dose effect was observed in both AC and SCC., Competing Interests: Mark I. van Berge HenegouwenConsulting or Advisory Role: Medtronic, Johnson & Johnson, Mylan, Alesi SurgicalResearch Funding: Olympus, StrykerTravel, Accommodations, Expenses: Johnson & Johnson Jeanin E. van HooftConsulting or Advisory Role: Boston Scientific, Cook Medical, Medtronic, Olympus Medical Systems Hanneke W. M. van LaarhovenConsulting or Advisory Role: Lilly/ImClone, Nordic Group, Bristol Myers Squibb, ServierResearch Funding: Bristol Myers Squibb, Bayer Schering Pharma, Celgene, Janssen-Cilag, Lilly, Nordic Group, Philips Healthcare, Roche, Merck Sharp & Dohme, Servier, Merck KGaATravel, Accommodations, Expenses: AstraZenecaNo other potential conflicts of interest were reported.

Purpose: Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven., Patients and Methods: In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat., Results: Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% ( P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery ( P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = . 029). The proportion of patients who suffered serious adverse events was 52% versus 41% ( P = . 096)., Conclusion: Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.

Background and Purpose: Although external beam radiotherapy (EBRT) is frequently used for palliative treatment of patients with incurable esophageal cancer, the optimal schedule for symptom control is unknown. This retrospective study evaluated three EBRT schedules for symptom control and investigated possible prognostic factors associated with second intervention and overall survival (OS)., Material and Methods: Patients with esophageal cancer treated with EBRT with palliative intent between January 2009 and December 2015 were evaluated. Univariate and multivariate Cox regression models estimated the effect of treatment schedule (20 Gy in 5 fractions, 30 Gy in 10 fractions or 39 Gy in 13 fractions) on OS. To study the effect of prognostic factors on time to second intervention (repeat EBRT, intraluminal brachytherapy or stent placement) a competing risk model with death as competing event was used., Results: 205 patients received 20 Gy (31%), 30 Gy (38%) or 39 Gy (32%). Improvement of symptoms was observed in 72% with no differences between schedules. Median OS after 20 Gy, 30 Gy and 39 Gy was 4.6 months (95%CI 2.6-6.6), 5.2 months (95%CI 3.7-6.7) and 9.7 months (95%CI 6.9-12.5), respectively. Poor performance status (HR 2.25 (95%CI 1.53-3.29)), recurrent esophageal cancer (HR 1.69 (95%CI 1.15-2.47)) and distant metastasis (HR 1.73 (95%CI 1.27-2.35)) were significantly related to worse OS. Treatment with 30 Gy and 39 Gy was related to longer time to second intervention compared to 20 Gy (adjusted cause specific HR 0.50 (95%CI 0.25-0.99) and 0.27 (95%CI 0.13-0.56), respectively)., Conclusions: Palliative EBRT provides good symptom control in patients with symptomatic esophageal cancer. A higher dose schedule was related to a longer time to second intervention. Hence, selection based on life expectancy is vital to prevent unnecessary long treatment schedules in patients with expected short survival, and limit the chance of second intervention when life expectancy is longer.

Purpose: To determine the optimal radiation dose for treatment of primary cutaneous anaplastic large cell lymphoma (C-ALCL) with solitary or localized, multifocal or recurrent skin lesions., Methods and Materials: In this multicenter study, patients with C-ALCL who had been treated with radiation therapy (RT) between 1984 and 2016 were retrieved from the Dutch registry of cutaneous lymphomas. Distinction was made between patients first presenting with solitary or localized lesions (n=63), with multifocal skin lesions (n=6), and patients with a skin relapse (n=22). Radiation doses, treatment response, and follow-up were evaluated. Radiation doses were categorized as low-dose (≤20 Gy), intermediate-dose (21-39 Gy), and high-dose (≥40 Gy) RT., Results: Of 63 patients presenting with solitary or localized skin lesions, 61 (97%) showed a complete response (CR). There were no differences in CR between low-dose (16 of 17), intermediate-dose (15 of 15), and high-dose RT (30 of 31). After a median follow-up of 46 months, 30 of 63 patients (48%) had a relapse, but in-field relapses were never observed. Six of 6 patients (100%) initially presenting with multifocal skin lesions showed a CR (3 of 3 low-dose, 2 of 2 intermediate-dose, 1 of 1 high-dose RT). After a median follow-up of 27 months, 3 of 6 patients had a relapse. Treatment of 33 skin relapses in 22 patients showed no differences in CR between low-dose (18 of 19), intermediate-dose (6 of 6), and high-dose RT (8 of 8). In the last 10 years there has been a decrease in radiation dose used in the treatment of C-ALCL. Treatment of multifocal and recurrent lesions with a dose of 8 Gy (2 × 4 Gy) resulted in CR of 17 of 18 lesions., Conclusions: Our results show that a radiation dose of 20 Gy (8 × 2.5 Gy) is effective in patients presenting with solitary or localized skin lesions. For patients with multifocal skin lesions and patients with a skin relapse, a dose of 8 Gy (2 × 4 Gy) may be sufficient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: While the curative approach to gastric cancer includes perioperative regimens in several countries, a substantial proportion of patients may not receive treatment prior to surgery. This study examines the adjuvant provision of chemoradiotherapy (CRT) for non-pretreated patients with cancer of the stomach including the gastric cardia., Methods: All surgically treated patients with primary adenocarcinoma of the stomach and gastric cardia diagnosed between January 2004-December 2013 were selected from the Netherlands Cancer Registry. Patients who did not receive neoadjuvant treatment were included. Early gastric cancers (cT1), postoperative deaths within 90 days, patients with metastatic disease (M1), patients who received adjuvant chemotherapy and patients with macroscopic tumor after surgery (R2) were excluded., Results: Some 3277 patients underwent surgery, and 99 patients (3%) received adjuvant CRT. Treatment was more often administered in patients with a younger age (<65 years) and a high socioeconomic status (SES), in case of non-cardia cancer, positive lymph nodes, and positive resection margins (R1). Median survival time was 28 months (95% CI 17-39), compared to 35 months (95% CI 33-38) in CRT-naïve patients. After adjustment for confounders, a small net benefit for adjuvant CRT was found (hazard ratio, HR: 0.75, 95% CI 0.58-0.96). In subgroup analyses, benefit was most pronounced for patients with seven or more lymph metastases., Conclusions: Marginal survival benefit was observed for adjuvant CRT in gastric cancer patients who did not receive neoadjuvant treatment. Treatment could be considered for patients with disease involving nodal invasion and those left with microscopic residual disease after surgery.

Background: Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin-directed therapies (SDTs). Recent studies distinguished indolent (early-stage FMF) and more aggressive (advanced-stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined., Objectives: To evaluate initial treatment results in patients with early- and advanced-stage FMF., Methods: A study was undertaken of 203 patients (84 early-stage, 102 advanced-stage, 17 extracutaneous FMF) included in the Dutch Cutaneous Lymphoma Registry between 1985 and 2014. Type and results of initial treatment were retrieved from the Dutch Registry. Main outcomes were complete remission (CR); sustained complete remission; partial remission (PR), > 50% improvement; and overall response (OR; CR + PR)., Results: Patients with early-stage FMF were treated with nonaggressive SDTs in 67 of 84 cases resulting, respectively, in CR and OR of 28% and 83% for monotherapy topical steroids, 0% and 83% for ultraviolet B (UVB), and 30% and 88% for psoralen plus ultraviolet A (PUVA). In patients with advanced-stage FMF these SDTs were less effective (combined CR and OR 10% and 52%, respectively). In patients with advanced-stage FMF local radiotherapy (CR 63%; OR 100%), total skin electron beam irradiation (CR 59%; OR 100%) and PUVA combined with local radiotherapy (CR 5%, OR 75%) were most effective., Conclusions: The results of the present study demonstrate that not all patients with FMF should be treated aggressively. Patients with early-stage FMF may benefit very well from standard SDTs also used in early-stage classic MF and have an excellent prognosis., (© 2017 British Association of Dermatologists.)

Patients with nonmetastatic esophageal cancer not suitable for surgery can be treated with definitive chemoradiotherapy with curative intent. The purpose of this retrospective study is to evaluate the clinical outcomes of definitive chemoradiotherapy using carboplatin and paclitaxel. Medical records were reviewed of patients treated for nonmetastatic squamous cell or adenocarcinoma of the esophagus between January 2009 and December 2013 in two collaborating institutes. Treatment consisted of external beam radiotherapy (28 fractions of 1.8 Gy) and 6 weekly courses of carboplatin (AUC = 2) and paclitaxel (50 mg/m2). Data on survival, progression, toxicity, and effect on dysphagia were recorded. Sixty-six patients were included. Median overall survival (OS) was 13.1 months (95% CI 4.7-21.5 months) and a 2-year OS was 30% (95% CI 18%-42%). At 2 years, 26% of patients developed local progression (95% CI 15%-37%) and 49% developed distant metastases (95% CI 36%-64%). Acute toxicity grade ≥3 was observed in 47% of patients. Late adverse events grade ≥3 were seen in 20%, mostly esophageal stenoses. Of patients with available data 3 months after treatment, 70% had relief of dysphagia. Definitive chemoradiotherapy led to a median OS of 13 months. Toxicity was common, mostly due to hematological toxicity. Given the relatively short median survival, an adequate selection of patients for this intensive treatment is required., (© The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The delineation of pancreatic tumors on CT is challenging. In this study, we quantified the interobserver variation for pancreatic tumor delineation on 3DCT as well as on 4DCT., Methods: Eight observers (radiation oncologists) from six institutions delineated pancreatic tumors of four patients with (borderline) resectable pancreatic cancer. The study consisted of two stages. In the 3DCT-stage, the gross tumor volume (GTV) was delineated on a contrast-enhanced scan. In the 4DCT-stage, the internal GTV (iGTV) was delineated, accounting for the respiratory motion. We calculated the volumes of the (i)GTV, the overlap of the delineated volumes (expressed as generalized conformity index: CI gen ), the local observer variation (local standard deviation: SD) and the overall observer variation (overall SD). We compared these results between GTVs and iGTVs. Additionally, observers were asked to fill out a questionnaire concerning the difficulty of the delineation and their experience in delineating pancreatic tumors., Results: The ratios of the largest to the smallest delineated GTV and iGTV within the same patient were 6.8 and 16.5, respectively. As the iGTV incorporates the GTV during all respiratory phases, the mean volumes of the iGTV (40.07 cm 3 ) were larger than those of the GTV (29.91 cm 3 ). For all patients, CI gen was larger for the iGTV than for the GTV. The mean overall observer variation (root-mean-square of all local SDs over four patients) was 0.63 cm and 0.80 cm for GTV and iGTV, respectively. The largest local observer variations were seen close to biliary stents and suspicious pathological enlarged lymph nodes, as some observers included them and some did not. This variation was more pronounced for the iGTV than for the GTV. The observers rated the 3DCT-stage and 4DCT-stage equally difficult and treated on average three to four pancreatic cancer patients per year., Conclusions: A considerable interobserver variation in delineation of pancreatic tumors was observed. This variation was larger for 4D than for 3D delineation. The largest local observer variation was found around biliary stents and suspicious pathological enlarged lymph nodes.

Background: For shared decision making to be successful, patients should receive sufficient information on possible benefits and harms of treatment options. The aim of this study was to evaluate what information radiation oncologists provide during the decision consultation about preoperative radiotherapy with rectal cancer patients., Methods: Decision consultations of 17 radiation oncologists with 81 consecutive primary rectal cancer patients, eligible for short-course radiotherapy followed by a low-anterior resection, were audio taped. Tapes were transcribed and analysed using the ACEPP (Assessing Communication about Evidence and Patient Preferences) coding scheme., Results: A median of seven benefits/harms were addressed per consultation (range, 2-13). This number ranged within and between oncologists and was not clearly associated with the patient's characteristics. A total of 30 different treatment outcomes were addressed. The effect of radiotherapy on local control was addressed in all consultations, the effect on survival in 16%. The most important adverse effects are bowel and sexual dysfunction. These were addressed in 82% and 85% of consultations, respectively; the latter significantly less often in female than in male patients. Four out of five patients did not initiate discussion on any benefits/harms., Conclusions: Our results showed considerable inconsistency between and within oncologists in information provision, which could not be explained by patient characteristics. This variation indicates a lack of clarity on which benefits/harms of radiotherapy should be discussed with newly-diagnosed patients. This suboptimal patient information hampers the process of shared decision making, in which the decision is based on each individual patients' weighing of benefits and harms.

Objective: To investigate the information provision concerning possible benefits and harms of short-course preoperative radiotherapy (PRT) at pre-treatment consultations between radiation oncologists and rectal cancer patients., Design: Observational study., Method: We audiotaped the consultations between 17 radiation oncologists and 81 patients with primary rectal cancer who were eligible for PRT. The recordings were transcribed and analysed descriptively., Results: A median of seven benefits/harms of PRT were addressed at each consultation (range, 2-13). This number differed both in and between individual oncologists and was not consistently associated with the patient's characteristics. A total of 30 different treatment outcomes was addressed. The effect of PRT on local control was addressed in all consultations, and the effect on survival in 16%. The most important adverse effects according to the literature are bowel dysfunction and sexual dysfunction. These were addressed in 82% and 85% of consultations, respectively; sexual problems were discussed significantly more often with male than female patients. Four out of five patients did not initiate discussion on potential benefits/harms., Conclusion: There was a considerable variation in the number and nature of benefits and harms of PRT that were discussed prior to treatment. This variation indicates a lack of clarity concerning which benefits/harms of radiotherapy should be discussed with newly-diagnosed patients. This suboptimal provision of information to patients hampers the process of shared decision making, in which the decision is based on each individual patient's weighing of benefits and harms. We do not believe our findings to be specific for PRT, but expect to find similar variation in provision of information with regard to other treatment decisions.

Objective: Since the Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) published recommendations for 3D MRI-based image-guided adaptive brachytherapy (IGBT) in the treatment of cervical cancer, many institutions have implemented this technique and favourable results were documented. We investigated if introduction of IGBT in our centre indeed improved treatment outcomes and reduced toxicity compared to conventional brachytherapy (CBT)., Methods: A retrospective analysis was done of outcomes of patients with stage IB-IVA cervical cancer treated with primary radiation therapy with curative intent between 2000 and 2012. Outcome measures were overall and disease-free survival, pelvic control, distant metastasis and treatment related adverse events (AE)., Results: 126 patients were analysed; 43 had been treated with CBT between 2000-2007, and 83 with IGBT between 2007-2012. External beam radiation (mean; 46.6Gy) was combined with concurrent weekly cisplatin (51.6%), or hyperthermia (24.6%); radiation alone was used in 23.8%. Median follow-up was 121.8months for CBT patients, vs. 42.3months for IGBT. Complete remission was achieved in 83.7% of patients in the CBT group and in 98.8% of IGBT patients (p<0.01). Overall survival at 3years was 51% and 86%, respectively (p=0.001). Pelvic recurrence was found in 32% vs. 7% (p<0.001). Most patients had low grade adverse events. High grade (3-4) AE occurred in 15.4% vs. 8.4% at 3years (p=0.06)., Conclusion: Introduction of IGBT for cervical cancer has led to significantly increased 3-year locoregional control and survival rates, whilst reducing late morbidity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Pituitary insufficiency after radiotherapy in the hypothalamic pituitary region is a well-known complication. However, endocrine assessments are not incorporated in the follow-up after cranial irradiation for head and neck tumours., Aim of the Study: To evaluate pituitary function in patients cranially irradiated for non-pituitary tumours., Patients and Methods: Evaluation of pituitary function in all available patients treated at our centre with cranial radiotherapy for head and neck tumours., Results: We included 80 patients. Forty patients were treated for cerebral tumours, 15 for nasopharyngeal tumours, and 25 for different tumours like meningioma or cerebral metastasis. Mean age was 47.5 (18.6-89.7)years. Mean radiation dose delivered at the pituitary region was 56.27 Gy (40.0-70.0). Pituitary insufficiency was present in 16 patients within 2 years after irradiation 23/49 patients (47%) after 5 years and 27/45 (60%) after 10 years and 31/35 patients (89%) after 15 years., Conclusion: Pituitary insufficiency is highly prevalent in adult patients treated with cranial radiotherapy for head and nasopharyngeal tumours. These prevalence rates are comparable to those observed after radiotherapy for pituitary tumours. Because hormone replacement of endocrine deficits improves quality of life and prevents potential severe complications, such as Addisonian crises, periodical evaluation of pituitary function is advocated., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this study was to measure and improve the quality of target volume delineation by means of national consensus on target volume definition in early-stage rectal cancer., Methods and Materials: The CTV's for eight patients were delineated by 11 radiation oncologists in 10 institutes according to local guidelines (phase 1). After observer variation analysis a workshop was organized to establish delineation guidelines and a digital atlas, with which the same observers re-delineated the dataset (phase 2). Variation in volume, most caudal and cranial slice and local surface distance variation were analyzed., Results: The average delineated CTV volume decreased from 620 to 460 cc (p<0.001) in phase 2. Variation in the caudal CTV border was reduced significantly from 1.8 to 1.2 cm SD (p=0.01), while it remained 0.7 cm SD for the cranial border. The local surface distance variation (cm SD) reduced from 1.02 to 0.74 for anterior, 0.63 to 0.54 for lateral, 0.33 to 0.25 for posterior and 1.22 to 0.46 for the sphincter region, respectively., Conclusions: The large variation in target volume delineation could significantly be reduced by use of consensus guidelines and a digital delineation atlas. Despite the significant reduction there is still a need for further improvement., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Context: Cranial radiotherapy is an important cause of hypopituitarism. The prevalence of hypopituitarism varies considerably between studies., Objective: We conducted a systematic review and meta-analysis of reported prevalences of hypopituitarism in adults radiated for nonpituitary tumors., Data Sources: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library to identify potentially relevant studies., Study Selection: Studies were eligible for inclusion with the following criteria: 1) cranial radiotherapy for nonpituitary tumors and/or total body irradiation for hematological malignancies; 2) adult population (>18 yr old); and 3) report on endocrine evaluation., Data Extraction: Data review was done by two independent reviewers. Besides extraction of baseline and treatment characteristics, also endocrine tests, definitions, and cutoff values used to define pituitary insufficiency were extracted., Results: Eighteen studies with a total of 813 patients were included. These included 608 patients treated for nasopharyngeal cancer (75%) and 205 for intracerebral tumors. The total radiation dose ranged from 14 to 83 and 40 to 97 Gy for nasopharyngeal and intracerebral tumors, respectively. The point prevalence of any degree of hypopituitarism was 0.66 [95% confidence interval (CI), 0.55-0.76]. The prevalence of GH deficiency was 0.45 (95% CI, 0.33-0.57); of LH and FSH, 0.3 (95% CI, 0.23-0.37); of TSH, 0.25 (95% CI, 0.16-0.37); and of ACTH, 0.22 (95% CI, 0.15-0.3), respectively. The prevalence of hyperprolactinemia was 0.34 (95% CI, 0.15-0.6). There were no differences between the effects of radiotherapy for nasopharyngeal vs. for intracerebral tumors., Conclusion: Hypopituitarism is prevalent in adult patients after cranial radiotherapy for nonpituitary tumors. Therefore, all patients treated by cranial radiotherapy should have structured periodical assessment of pituitary functions.

Purpose: To determine the efficacy of low-dose palliative radiotherapy for both low-grade malignant cutaneous B-cell lymphomas (CBCLs) and cutaneous T-cell lymphomas (mycosis fungoides)., Methods and Materials: A total of 18 patients with low-grade CBCL (10 primary cutaneous marginal zone B-cell and 8 primary cutaneous follicle center lymphomas) with 44 symptomatic plaques and tumors underwent low-dose (4 Gy in two fractions) local radiotherapy. A total of 31 patients with mycosis fungoides were treated at 82 symptomatic sites, initially with 4 Gy and later with 8 Gy in two fractions., Results: The complete response rate for CBCL lesions was 72%. Of the 44 B-cell lymphoma lesions, 13 were re-treated to the same site after a median of 6.3 months because of persistent (n = 8) or recurrent (n = 5) symptomatic disease. Of the mycosis fungoides patients treated with 4 Gy in two fractions (17 lesions), 70% failed to respond. Increasing the dose to 8 Gy in two fractions yielded a complete response rate of 92% (60 of 65 lesions). The patients in whom low-dose radiotherapy failed were retreated with 20 Gy in eight fractions., Conclusion: Our results have demonstrated that low-dose involved-field radiotherapy induces a high response rate in both CBCL and cutaneous T-cell lymphoma lesions without any toxicity. Therefore, this treatment is now our standard palliative treatment. At progression, it is safe and feasible to apply greater radiation doses.

Objective: To evaluate the long-term outcome of transsphenoidal resection of pituitary adenomas at the Leiden University Medical Center (LUMC), The Netherlands., Design: Retrospective, descriptive., Method: 416 consecutive patients undergoing surgery for pituitary adenoma at the LUMC between 1978 and 2004 were included; 174 patients with non-functioning macroadenomas (NFMA), 164 patients with acromegaly and 78 patients with Cushing's disease., Results: Biochemical remission was achieved in 66% of patients with acromegaly, and 72% of patients with Cushing's disease; incidence of pituitary failure was low in these patients (5% and 18% respectively). In 82% of the patients with NFMA visual function improved whereas the percentage with any degree of pituitary failure increased from 85% (preoperatively) to 95% (postoperatively). During follow-up of 10-15 years, the recurrence rate for acromegaly and Cushing's disease was 9% and for NFMA it was 15%., Conclusion: Transsphenoidal resection is an effective treatment in most, but not all, patients with pituitary adenomas. The surgical results at the LUMC are comparable with those obtained in important international centres. All patients cured by surgery need lifelong follow-up, because of the real risk of recurrent disease.

*Nonfunctioning pituitary adenomas are benign tumours characterised by the absence of hormone overproduction. *Clinical symptoms are caused by the mass effects of the tumour. The main symptoms are pituitary insufficiency, visual field defects, vision impairment and headache. *Treatment is unnecessary for tumours less than 1 cm, and an expectative approach can be used for some patients with larger tumours but no visual field defects. *Transsphenoidal surgery is indicated for patients with visual field defects. *Because nonfunctioning adenomas can recur, lifelong follow-up after treatment is necessary. *Poor quality of life has been reported in treated patients with nonfunctioning pituitary adenomas, which may be due to the intrinsic imperfections of hormonal replacement therapy.

Objective: To evaluate the results of radiotherapy in patients with primary cutaneous B-cell lymphoma (CBCL) classified according to the criteria of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification., Design: Multicenter, 20-year, retrospective, cohort analysis., Setting: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group., Patients: From 1985 until 2005, a total of 153 patients with CBCL were initially treated with radiotherapy with curative intent. These cases were classified according to the WHO-EORTC classification and consisted of 25 primary cutaneous marginal zone lymphomas (PCMZLs), 101 primary cutaneous follicle center lymphomas (PCFCLs), and 27 primary cutaneous large B-cell lymphomas, leg type (PCLBCLs, LT). Interventions Local radiotherapy with a median dose of 40 Gy (range, 20-46 Gy) applied to all visible skin lesions., Main Outcome Measures: Complete remission rate, relapse rate, 5-year relapse-free survival, 5-year overall survival, and 5-year disease-specific survival., Results: Complete remission was reached in 151 of 153 patients (99%). Relapse rates for PCMZL, PCFCL, and PCLBCL, LT were 60%, 29%, and 64%, and the 5-year disease-specific survival was 95%, 97%, and 59%, respectively. The PCFCLs presenting on the legs had a higher relapse rate (63%) and a much lower 5-year disease-specific survival (44%) than PCFCLs at other sites (relapse rate, 25%; 5-year disease-specific survival, 99%)., Conclusions: Radiotherapy is a suitable treatment for a large group of patients with CBCL. However, patients with PCFCL presenting with lesions on the leg and patients with PCLBCL, LT display a more unfavorable clinical course and should therefore be treated with more aggressive treatment modalities.

Objective: Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas (NFMA). In this study we evaluated the long-term effects of a treatment strategy in which postoperative radiotherapy was not routinely applied to patients with NFMA., Design: This was a retrospective follow-up study., Patients: We included 109 consecutive patients (age 56 +/- 13 yr) operated for NFMA between 1992 and 2004., Results: Radiological imaging revealed a macroadenoma in all patients, with suprasellar extension in 96% and parasellar/infrasellar extension in 36% of cases. Visual field defects were present in 87% of the patients and improved in 84% of these patients after surgery. Only six patients received postoperative radiotherapy. Ten patients died during the follow-up period. Ninety-seven patients could be assessed for tumor regrowth or tumor recurrence after a mean follow-up period of 6.0 +/- 3.7 yr. In nine patients there was evidence for tumor regrowth, and in one patient tumor recurrence was observed. The mean time to tumor growth/recurrence after initial therapy was 6.9 (range 3-12) yr. Follow-up duration was found to be an independent predictor for tumor regrowth., Conclusion: Transsphenoidal surgery without postoperative radiotherapy is an effective and safe treatment strategy for NFMA, without evidence for tumor regrowth in 90% of all patients, at least for the duration of follow-up presented in this study. Additional studies are required to exclude higher regrowth and recurrence rates during prolongation of the duration of follow-up.

Active acromegaly can be treated effectively by transsphenoidal surgery, radiotherapy and medical treatment in the form of somatostatin analogs and growth hormone receptor antagonists. Many patients will require a combination of treatment modalities to normalize growth hormone excess and associated increased mortality, and to improve comorbidity. Following postoperative radiotherapy, growth hormone and insulin-like growth factor-I levels gradually decrease and normalization of growth hormone and insulin-like growth factor-I is achieved in 50% of patients after 5 years and 75% after 10 years. Disadvantages of radiotherapy include the long interval until hormone levels have sufficiently decreased and the high incidence of radiation-induced hypopituitarism. Radiotherapy was associated with increased mortality in some but not other studies. Limitations in the design and confounding factors, such as years spent with active disease and changing treatment strategies, make it impossible to draw conclusions on this topic. Gamma knife radiosurgery may combine faster decline of growth hormone excess with a lower incidence of hypopituitarism in eligible cases, but long-term results of this radiation technique are lacking. At present, patients will preferentially be treated by primary surgery and/or somatostatin analog treatment, followed, if necessary, by growth hormone receptor antagonist treatment, while radiotherapy is reserved for selected cases only. The indications for radiotherapy and radiosurgery need to be revisited in the near future, when longer follow-up results for medical treatment and radiosurgery have become available. This review summarizes the recent literature on efficacy and side effects of radiotherapy and radiosurgery in acromegaly and discusses the place of radiation treatment in the treatment algorithm of acromegaly.

This placebo-controlled study evaluated the efficacy of Flt-3 ligand (FL) combined with TPO in myelosuppressed rhesus monkeys. The monkeys were subjected to 5 Gy total body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either 5 microg/kg of rhesus TPO i.v. on d 1 (n = 4) and 100 microg/kg/d s.c. human FL (n = 4) or FL alone (n = 4) for 14 consecutive days and were compared with results from a concomitant study involving the administration of TPO alone (n = 4) or placebo (carrier; n = 4). The TPO/FL combination was considerably less effective than TPO alone, with a more profound nadir and a slower recovery to thrombocyte counts > 100 x 109/l, approaching recovery patterns of placebo controls. Leucocyte regeneration was similar in all animals. Monkeys treated with FL alone displayed a regeneration of reticulocytes and thrombocytes in the lower range of those of the placebo controls. Recovery of bone marrow (BM) cellularity was slightly accelerated in the TPO/FL-treated monkeys, but was not reflected by an increase in progenitor cells, in contrast to TPO alone. Monkeys treated with FL alone showed a BM reconstitution similar to placebo-treated controls. FL by itself was not effective as a therapeutic agent in this model for myelosuppression. As FL also suppressed BM CD34+ cell reconstitution, we concluded that FL competed with TPO at the level of immature cell differentiation.

Objective: If administered in a sufficiently high dose to overcome receptor-mediated clearance and in a well-scheduled manner, thrombopoietin (TPO) prominently stimulates hematopoietic reconstitution following myelosuppressive treatment and potentiates the efficacy of both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). However, TPO alone is not effective after bone marrow transplantation. Based on results of GM-CSF and TPO treatment after myelosuppression that resulted in augmented thrombocyte, reticulocyte, and leukocyte regeneration, we evaluated TPO/GM-CSF treatment after lethal irradiation followed by autologous bone marrow transplantation., Materials and Methods: Young adult Rhesus monkeys were subjected to 8-Gy total body irradiation (TBI) (x-rays) followed by transplantation of 10(7)/kg unfractionated bone marrow cells. TPO 5 microg/kg was administered intravenously at day 0 to obtain rapidly high levels. Animals then were treated with 5 microg/kg Rhesus TPO and 25 microg/kg GM-CSF given SC on days 1 to 14 after TBI., Results: The grafts shortened the profound pancytopenia induced by 8-Gy TBI from 5-6 weeks to 3 weeks. The combination of TPO and GM-CSF did not significantly influence the recovery patterns of thrombocytes (p = 0.39), reticulocytes (p = 0.08), white blood cells (p = 0.08), or bone marrow progenitors compared to TPO alone., Conclusions: The present study demonstrates that, after high-dose TBI and transplantation of a limited number of unfractionated bone marrow cells, simultaneous administration of TPO and GM-CSF after TBI is ineffective in preventing pancytopenia. This result contrasts sharply with the prominent stimulation observed in a 5-Gy TBI myelosuppression model, despite a similar level of pancytopenia in the 8-Gy model of the present study. The discordant results of this growth factor combination in these two models may imply codependence of the hematopoietic response to TPO and/or GM-CSF on other factors or cytokines.

Purpose: To investigate the long-term effects of X-irradiation on different aspects of gastrointestinal function in the non-human primate (Macaca mulatta)., Materials and Methods: Animals were exposed to X-radiation (5 or 6 Gy) or not (sham) and gastrointestinal function was investigated 4-6 years after exposure. Basal and agonist-stimulated short circuit current (Isc) responses were measured in isolated jejunum. Intestinal tissue was taken for histological analysis as well as for determination of mucosal marker enzyme activities and gastrointestinal regulatory peptide levels. Vasoactive intestinal peptide receptor characteristics were determined as well as VIP-stimulated Isc responses. GI peptides were also measured in plasma., Results: Few differences were seen in basal electrical parameters or tissue morphology but there was a tendency for reduced basolateral membrane enzyme activity. VIP-stimulated Isc responses were reduced in irradiated animals as were VIP-stimulated adenylate cyclase responses. Plasma and tissue (ileal and colonic muscle layers) gastrin releasing peptide levels were increased in irradiated animals. In contrast circulating gastrin levels were lower., Conclusions: Late effects of total-body irradiation on GI function in monkeys showed altered circulating and tissue levels of some GI peptides. In addition the biological effects of vasoactive intestinal peptide were modified.

Thrombopoietin (TPO) has been used in preclinical myelosuppression models to evaluate the effect on hematopoietic reconstitution. Here we report the importance of dose and dose scheduling for multilineage reconstitution after myelosuppressive total body irradiation (TBI) in mice. After 6 Gy TBI, a dose of 0.3 microgram TPO/mouse (12 microgram/kg) intraperitoneally (IP), 0 to 4 hours after TBI, prevented the severe thrombopenia observed in control mice, and in addition stimulated red and white blood cell regeneration. Time course studies showed a gradual decline in efficacy after an optimum within the first hours after TBI, accompanied by a replacement of the multilineage effects by lineage dominant thrombopoietic stimulation. Pharmacokinetic data showed that IP injection resulted in maximum plasma levels 2 hours after administration. On the basis of the data, we inferred that a substantial level of TPO was required at a critical time interval after TBI to induce multilineage stimulation of residual bone marrow cells. A more precise estimate of the effect of dose and dose timing was provided by intravenous administration of TPO, which showed an optimum immediately after TBI and a sharp decline in efficacy between a dose of 0.1 microgram/mouse (4 microgram/kg; plasma level 60 ng/mL), which was fully effective, and a dose of 0.03 microgram/mouse (1.2 microgram/kg; plasma level 20 ng/mL), which was largely ineffective. This is consistent with a threshold level of TPO required to overcome initial c-mpl-mediated clearance and to reach sufficient plasma levels for a maximum hematopoietic response. In mice exposed to fractionated TBI (3 x 3 Gy, 24 hours apart), IP administration of 0. 3 microgram TPO 2 hours after each fraction completely prevented the severe thrombopenia and anemia that occurred in control mice. Using short-term transplantation assays, ie, colony-forming unit-spleen (CFU-S) day 13 (CFU-S-13) and the more immature cells with marrow repopulating ability (MRA), it could be shown that TPO promoted CFU-S-13 and transiently depleted MRA. The initial depletion of MRA in response to TPO was replenished during long-term reconstitution followed for a period of 3 months. Apart from demonstrating again that MRA cells and CFU-S-13 are separate functional entities, the data thus showed that TPO promotes short-term multilineage repopulating cells at the expense of more immature ancestral cells, thereby preventing pancytopenia. The short time interval available after TBI to exert these effects shows that TPO is able to intervene in mechanisms that result in functional depletion of its multilineage target cells shortly after TBI and emphasizes the requirement of dose scheduling of TPO in keeping with these mechanisms to obtain optimal clinical efficacy., (Copyright 1998 by The American Society of Hematology.)

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys to study thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the midlethal dose of 5-Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow (BM) cells and potentiated the response to growth factors such as GM-CSF and G-CSF. The accelerated reconstitution of BM CD34+ cells appeared to be reflected by a similar rise in peripheral blood CD34+ cells, both being augmented by concomitant GM-CSF. However, TPO was ineffective following transplantation of limited numbers of autologous BM or highly purified stem cells in monkeys conditioned with 8-Gy TBI. In the 5-Gy model, a single dose of TPO 24 h after TBI was effective in preventing thrombocytopenia and was augmented by GM-CSF. The strong erythropoietic stimulation may result in iron depletion and TPO treatment should be accompanied by monitoring of iron status. In mice, similar observations were made and the importance of dose and dose schedule for stimulation of multilineage repopulating cells versus the lineage-dominant thrombopoietic response studied in detail.

Under conditions of steady-state hemopoiesis, a small fraction of immature hemopoietic cells, including stem cells, circulates in peripheral blood (PB). In rhesus monkeys, a median number of 1.2 x 10(7)/l CD34+ cells was observed as opposed to a median number of 1.5 x 10(9)/l in aspirated bone marrow (BM). The concentration of circulating CD34+ cells is therefore approximately two logs less than that in BM. Since a 4-kg rhesus monkey has an estimated number of 3 x 10(10) BM cells and approximately 300 ml of blood, the fraction of CD34+ cells that circulates can be estimated at approximately 0.4% of the total pool of CD34+ cells. During hemopoietic reconstitution following a cytotoxic insult such as results from a midlethal dose of TBI, PB CD34+ cell numbers appeared to be correlated to those of BM, suggesting that PB CD34+ cells may reflect reconstitution of BM CD34+ cells. Reconstitution of BM immature cells can be accelerated by treatment with pharmacological doses of growth factors, resulting in largely expanded immature cell populations within a few weeks after TBI. Growth factors observed to exert such an effect included, notably, thrombopoietin. Such an acceleration can be monitored by daily assessment of circulating CD34+ cells. Expansion of immature circulating cells indicates expansion of similar cells in the bone marrow rather than growth factor-induced selective mobilization of immature cells.

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed.

Thrombopoietin (TPO) was evaluated for efficacy in a placebo-controlled study in rhesus monkeys with concurrent administration of either granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF, (G-CSF). Rhesus monkeys were subjected to 5 Gy total-body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either TPO 5 microg/kg intravenously (I.V.) at day 1 (n = 4), GM-CSF 25 microg/kg subcutaneously (S.C.) for 14 days (n = 4), TPO and GM-CSF (n = 4), G-CSF 10 microg/kg/d S.C. for 14 days (n = 3), TPO and G-CSF (n = 4), or placebo (carrier, n = 4; historical controls, n = 8). Single-dose I.V. treatment with TPO 1 day after TBI effectively counteracted the need for thrombocyte transfusions (provided whenever thrombocyte levels were <40 x 10(9)/L) and accelerated platelet reconstitution to normal levels 2 weeks earlier than placebo controls. TPO/GM-CSF was more effective than single-dose TPO alone in stimulating thrombocyte regeneration, with a less profound nadir and a further accelerated recovery to normal thrombocyte counts, as well as a slight overshoot to supranormal levels of thrombocytes. Monkeys treated with TPO/GM-CSF uniformly did not require thrombocyte transfusions, whereas those treated with GM-CSF alone needed two to three transfusions, similar to the placebo-treated monkeys, which required, on average, three transfusions. Also, reticulocyte production was stimulated by TPO and further augmented in monkeys treated with TPO/GM-CSF. TPO alone did not stimulate neutrophil regeneration, whereas GM-CSF shortened the period of neutrophil counts less than 0.5 x 10(9)/L by approximately 1 week; TPO/GM-CSF treatment elevated the neutrophil nadir, but did not further accelerate recovery to normal values. TPO also augemented the neturophil response to G-CSF, resulting in similar patterns of reconstitution following TPO/G-CSF and TPO/GM-CSF treatment. TPO/GM-CSF resulted in significantly increased reconstitution of CD34+ bone marrow cells and progenitor cells such as GM-CFU and BFU-E. Adverse effects of combining TPO with the CSFs were not observed. It is concluded that (1) a single I.V. administration of TPO is sufficient to prevent severe thrombocytopenia following myelosuppression, (2) TPO/G-CSF and TPO/GM-CSF treatment result in distinct response patterns, with TPO/GM-CSF being superior to TPO/G-CSF in stimulating thrombocyte and erythrocyte recovery while being equivalent in stimulating neutrophil recovery; and (3) TPO significantly improves the performance of CSFs in alleviating severe neutropenia.

The efficacy of recombinant human thrombopoietin (TPO) and recombinant human granulocyte colony stimulating factor (G-CSF) in stimulating platelet and neutrophil recovery was evaluated in a placebo-controlled study involving transplantation of limited numbers (1-3 x 10(4)/kg) of highly purified autologous stem cells (CD34++/RhLA-DR[dull]) into rhesus monkeys after the animals were subjected to 8 Gy of total body irradiation (TBI) (x-rays). The grafts shortened profound TBI-induced pancytopenia from 5 to 6 weeks to 3 weeks. Daily subcutaneous (sc) injection of TPO (10 microg/kg/day, days 1-21 after TBI) did not stimulate platelet regeneration after transplantation either alone or in combination with G-CSF (5 microg/kg/day sc, days 1-21 after TBI). G-CSF treatment failed to prevent neutropenia in the monkeys and did not stimulate recovery to normal neutrophil levels. Simultaneous administration of TPO and G-CSF did not influence the observed recovery patterns. To test the hypothesis that the limited number of cells transplanted or the subset chosen was responsible for the lack of effectiveness of TPO, three additional monkeys were transplanted with 10(7)/kg unfractionated autologous bone marrow cells. Two of these animals received TPO and the other served as a control. In this setting, as well, TPO treatment did not prevent thrombocytopenia. This study demonstrates that treatment with TPO does not accelerate platelet reconstitution from transplanted stem cells after high-dose TBI. These findings contrast with the rapid TPO-stimulated platelet recovery in myelosuppression induced by 5 Gy of TBI in rhesus monkeys; we conclude from this that the clinical effectiveness of the TPO response depends on the availability of TPO target cells in the first week after TBI, that is, before endogenous TPO levels reach the saturation point. In addition, protracted isolated thrombocytopenia was observed in two G-CSF-treated monkeys, one of which also received TPO. Furthermore, TPO treatment for 7 days in the 6th week after TBI during severe thrombocytopenia in one monkey produced prompt clinical improvement and an increase in platelet counts.

Simultaneous treatment with human thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) was evaluated in a placebo-controlled rhesus monkey study using 5 Gy total body irradiation (TBI) to induce 3 weeks of pancytopenia. Daily administration of TPO (10 microg/kg/day injected subcutaneously [sc] days 1-21 after TBI) promoted platelet and reticulocyte recovery, resulting in less profound nadirs and a rapid recovery to normal levels. Platelet transfusions were not required in these animals, in contrast to controls, and hemoglobin levels stabilized rapidly. TPO treatment did not influence neutrophil counts. G-CSF (5 microg/kg/day sc days 1-21) stimulated neutrophil regeneration and had no effect on platelet levels. Simultaneous treatment with TPO and G-CSF was as effective as treatment with TPO alone in preventing thrombocytopenia, although with the former regimen platelet levels did not rise to the supranormal levels seen with the latter. Neutrophil recovery was greatly augmented compared with G-CSF treatment alone, resulting in a less profound nadir and a recovery that started much earlier, as did monocyte, CD11b+, CD16+, and CD56+ cell reconstitution. In addition, TPO strongly promoted the recovery of bone marrow cellularity and granulocyte/macrophage and erythroid progenitor cells: The number of bone marrow CD34+ cells was greater by two orders of magnitude in TPO-treated animals than in controls in the second week of treatment, whereas G-CSF by itself had no influence. In the third week after TBI an elevation of LDH1 values was observed in TPO-treated monkeys concurrent with normoblastosis; both of these findings were attributed to rapid erythropoiesis. TPO had no effect on hemostasis parameters. Adverse TPO and/or G-CSF effects were not observed. This study demonstrates that simultaneous TPO and G-CSF treatment after cytoreductive treatment prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells. The effect on CD34+ GM progenitor cells may explain the augmented G-CSF responses in TPO-treated monkeys; it also suggests that TPO may become a key growth factor in the design of treatment regimens to accelerate both immature bone marrow and mature blood cell reconstitution after cytoreductive therapy.

The effectiveness of thrombopoietin (TPO) in alleviating thrombocytopenia was evaluated in a placebo-controlled study involving rhesus monkeys exposed to 5 Gy total-body irradiation (TBI) (300-kV x-rays) to result in 3 weeks of pancytopenia. Supraoptimal treatment with human recombinant TPO (10 microg/kg/d subcutaneously, days 1 to 21 after TBI) was highly effective in preventing thrombocytopenia, with nadirs for thrombocytes, on average, far higher than 100 x 10(9)/L, a greatly accelerated recovery to normal values, and no need for thrombocyte transfusions. TPO appeared to act selectively in that neutrophil regeneration was not influenced but red blood cell lineage recovery was prominently stimulated, with reticulocyte regeneration being initiated 10 days earlier than in placebo-treated animals. The reticulocytosis was followed by a normoblastosis that occurred earlier and was more pronounced than in placebo-treated monkeys. The effect of TPO on the red blood cell lineage was also reflected in a less profound nadir for hemoglobin (Hb) and hematocrit values than in placebo controls. However, this effect was not followed by a rapid recovery to normal values, due to development of a microcytic hypochromic anemia. Iron depletion was demonstrated by measurements of total serum iron and total iron-binding capacity (TIBC) and could be prevented by prophylactic intramuscular (IM) iron before TBI or corrected by IM iron after TPO treatment. Rechallenging with TPO in week 8 after TBI demonstrated a homogenous thrombocyte response similar in magnitude to the initial response, but a greatly diminished reticulocyte response. This demonstrated that the erythropoietic response to TPO administration depends on the hemopoietic state of the animal and may reflect multiple TPO target cells. It is postulated that the extremely rapid erythropoiesis due to TPO treatment in the initial regeneration phase following myelosuppression results in iron depletion by a mechanism similar to that seen following erythropoietin treatment in patients with end-stage renal failure. It is concluded that protracted TPO therapy to counteract thrombocytopenic states may result in iron depletion and that the iron status should be monitored before, during, and after TPO treatment.