Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Cardiopulmonary-related patient-reported outcomes in a randomized clinical trial of radiation therapy for breast cancer.

BACKGROUND: Long-term prospective patient-reported outcomes (PRO) after breast cancer adjuvant radiotherapy is scarce. TomoBreast compared conventional radiotherapy (CR) with tomotherapy (TT), on the hypothesis that TT might reduce lung-heart toxicity. METHODS: Among 123 women consenting to participate, 64 were randomized to CR, 59 to TT. CR delivered 50 Gy in 25 fractions/5 weeks to breast/chest wall and regional nodes if node-positive, with a sequential boost (16 Gy/8 fractions/1.6 weeks) after lumpectomy. TT delivered 42 Gy/15 fractions/3 weeks to breast/chest wall and regional nodes if node-positive, 51 Gy simultaneous-integrated-boost in patients with lumpectomy. PRO were assessed using the European Organization for Research and Treatment of Cancer questionnaire QLQ-C30. PRO scores were converted into a symptom-free scale, 100 indicating a fully symptom-free score, 0 indicating total loss of freedom from symptom. Changes of PRO over time were analyzed using the linear mixed-effect model. Survival analysis computed time to > 10% PRO-deterioration. A post-hoc cardiorespiratory outcome was defined as deterioration in any of dyspnea, fatigue, physical functioning, or pain. RESULTS: At 10.4 years median follow-up, patients returned on average 9 questionnaires/patient, providing a total of 1139 PRO records. Item completeness was 96.6%. Missingness did not differ between the randomization arms. The PRO at baseline were below the nominal 100% symptom-free score, notably the mean fatigue-free score was 64.8% vs. 69.6%, pain-free was 75.4% vs. 75.3%, and dyspnea-free was 84.8% vs. 88.5%, in the TT vs. CR arm, respectively, although the differences were not significant. By mixed-effect modeling on early ≤2 years assessment, all three scores deteriorated, significantly for fatigue, P ≤ 0.01, without effect of randomization arm. By modeling on late assessment beyond 2 years, TT versus CR was not significantly associated with changes of fatigue-free or pain-free scores but was associated with a significant 8.9% improvement of freedom from dyspnea, P = 0.035. By survival analysis of the time to PRO deterioration, TT improved 10-year survival free of cardiorespiratory deterioration from 66.9% with CR to 84.5% with TT, P = 0.029. CONCLUSION: Modern radiation therapy can significantly improve long-term PRO. TRIAL REGISTRATION: Trial registration number ClinicalTrials.gov NCT00459628 , April 12, 2007 prospectively.

Variability in lymph node irradiation in patients with breast cancer-results from a multi-center survey in German-speaking countries.

PURPOSE: Lymph node irradiation in breast cancer has gained complexity due to recently published studies and technical innovations which then led to changes in international guidelines. We sought to determine real-time variability in lymph node irradiation in clinical practice in German-speaking countries. METHODS: The Department of Radiation Oncology, Technical University of Munich (TUM), developed an online-based questionnaire focusing on the indication, target definition, and treatment technique of lymph node irradiation in patients with breast cancer. The invitation to participate in the survey was sent to members of the German Society of Radiation Oncology (DEGRO) by e­mail. The results of the survey were exported from the online platform into SPSS for a detailed analysis. RESULTS: In total, 100 physicians completed the questionnaire between 05/2019 and 06/2019. Despite the existence of several treatment and contouring guidelines, we observed large variability of lymph node irradiation: The guideline recommendation for internal mammary irradiation is not consistently implemented in clinical practice and irradiation of the axilla after positive SLNB (sentinel lymph node biopsy) or ALND (axillary lymph node dissection) is handled very differently. Furthermore, in most clinics, the ESTRO (European Society for Therapeutic Radiology and Oncology) contouring consensus is not used, and PTV (planning target volume) definitions and margins vary considerably. CONCLUSION: Further clinical studies should be performed with a particular focus on radiotherapy for lymphatic drainage to support and amend the existing guidelines. These studies should establish a more standardized treatment of the lymph node regions in clinical practice. Quality assurance should enforce broad implementation of consensus recommendations.

Post-mastectomy immediate breast reconstruction and adjuvant radiotherapy: long term results of a mono institutional experience.

INTRODUCTION: The aim of this paper is to investigate the outcome of patients treated with mastectomy, immediate breast reconstruction (IBR) and post-mastectomy radiotherapy (PMRT) and the risk of late complications. MATERIAL AND METHOD: All patients had post-mastectomy, immediate reconstructive surgical procedure by using autologous abdominal implant; tissue expander (TE)/permanent prosthesis (PP); or even combined procedures. Adjuvant external beam radiotherapy treatment (EBRT) was delivered to the reconstructed chest wall and supraclavicular nodes, for a total dose of 50 Gy in 25 fractions. The Kaplan-Meyer analysis evaluates patients' rate of late side effects, Overall Survival (OS), Progression Free survival (PFS), Local-regional free survival (LRFS) and Metastasis Free Survival (MFS). The univariate analysis investigates the correlation between late toxicity and related factors. RESULTS: Between November 2003 and October 2016, 91 breast cancer patients were treated with IBR and PMRT. Twenty-three (25.3%) patients experimented late toxicity. Overall, 16 (17.6%) patients experienced late complications which required a surgical approach. The 1- 2- 5- years late toxicity rates were 96.6%, 87.1% and 77.9%, respectively. The type of reconstruction was not statistically related with late toxicity rate (P = 0.35). The median follow-up period was 59 months (range 6-142 months). Median OS was not reached, the 1- 2- 5-years OS rates were 100%, 95.4% and 81% respectively. CONCLUSION: This study underlines that the type of reconstruction does not influence late toxicity rate. Moreover, IBR followed by adjuvant radiotherapy, has showed acceptable late toxicity profile and no influence on OS.

Phase II feasibility study of preoperative concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil and elective lymph node irradiation for clinical stage II/III esophageal squamous cell carcinoma.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is a standard treatment for stage II/III esophageal cancer. Preoperative chemotherapy is also considered a standard treatment for stage II/III esophageal squamous cell carcinoma (ESCC) in patients who undergo radical lymph node dissection. We conducted a feasibility study of preoperative CRT with cisplatin plus 5-fluorouracil (CF) and elective lymph node irradiation followed by esophagectomy with radical lymph node dissection in patients with stage II/III ESCC. METHODS: Patients with clinical stage II/III, excluding T4, ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy comprised two courses of CF infusion repeated after 4-weeks. Radiation therapy was concurrently administered to the primary tumor, metastatic lymph nodes, and regional lymph nodes at a dose of 41.4 Gy. After the completion of CRT, transthoracic esophagectomy with 2-3 fields lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment with R0 resection. RESULTS: Thirty-one eligible patients were enrolled. During CRT, the most common grade 3 or 4 toxicities were leukopenia (65%), neutropenia (65%), anemia (13%), thrombocytopenia (13%), febrile neutropenia (13%), anorexia (16%), esophagitis (16%) and hyponatremia (16%). Thirty patients (96.8%) underwent surgery. One patient received palliative chemotherapy because of appearance of lung metastasis during CRT. The completion rate of protocol treatment was 93.5% (29/31). There was one treatment-related death after surgery. Pathological complete response was achieved in 42% (13/30). CONCLUSION: Preoperative CRT with CF and elective lymph node irradiation showed an acceptable toxicity and promising activity especially in ESCC.

Dosimetric comparison of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for left-sided chest wall and lymphatic irradiation.

INTRODUCTION: The aim of this study was to compare five different techniques for chest wall (CW) and lymphatic irradiation in patients with left-sided breast carcinoma. METHODS: Three-dimensional conformal radiotherapy (3DCRT), forward-planned intensity-modulated radiotherapy (FP-IMRT), inverse-planned IMRT (IP-IMRT; 7- or 9-field), and hybrid IP-/FP-IMRT were compared in 10 patients. Clinical target volume (CTV) included CW and internal mammary (IM), supraclavicular (SC), and axillary nodes. Planning target volumes (PTVs), CTVs, and organs at risks (OARs) doses were analyzed with dose-volume histograms (DVHs). RESULTS: No differences could be observed among the techniques for doses received by 95% of the volume (D95%) of lymphatics. However, the FP-IMRT resulted in a significantly lower D95% dose to the CW-PTV compared to other techniques (P = 0.002). The 9-field IP-IMRT achieved the lowest volumes receiving higher doses (hotspots). Both IP-IMRT techniques provided similar mean doses (Dmean) for the left lung which were smaller than the other techniques. There was no difference between the techniques for maximum dose (Dmax) of right breast. However, FP-IMRT resulted in lower Dmean and volume of right breast receiving at least 5 Gy doses compared to other techniques. CONCLUSION: The dose homogeneity in CW-CTV was better using IMRT techniques compared to 3DCRT. Especially 9-field IP-IMRT provided a more homogeneous dose distribution in IM and axillary CTVs. Moreover, the OARs volumes receiving low radiation doses were larger with IP-IMRT technique, while volumes receiving high radiation doses were larger with FP-IMRT technique. Hybrid IMRT plans were found to have the advantages of both FP- and IP-IMRT techniques.

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation.

Reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HCT) can reduce morbidity and mortality, but patients with advanced disease may require alternative approaches. In an initial report of RIC with fludarabine (FLU) and melphalan (MEL) with total marrow lymphoid irradiation (TMLI) in HCT for advanced hematologic malignancies in 33 patients, we found that the addition of TMLI to RIC was feasible and safe. Here we report long-term outcomes for these patients. This prospective study included 61 patients treated with TMLI to a dose of 12 Gy (1.5 Gy twice daily for 4 days), FLU (25 mg/m2/day for 5 days), and MEL (140 mg/m2/day for 1 day). Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were measured from the date of HCT. Survival outcomes were analyzed using Kaplan-Meier analysis. Patients were categorized as low/intermediate or high/very high risk using the Disease Risk Index. The median follow-up was 7.4 years. The majority of patients had acute leukemia (72%); 49% had high/very high-risk disease. The median patient age was 55 years (range, 9-70 years). Two-year OS, EFS, CIR, and NRM were 54% (95% confidence interval [CI], 41%-66%), 49% (95% CI, 36%-61%), 21% (95% CI, 13%-35%), and 30% (95% CI, 20%-43%), respectively. Five-year OS, EFS, CIR, and NRM were 42% (95% CI, 30%-54%), 41% (95% CI, 28%-53%), 26 (95% CI, 17%-40%), and 33% (95% CI, 23%-47%, respectively). Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 69% and 74% of patients, respectively. The most common toxicity was mucositis. The addition of TMLI to FLU/MEL conditioning was well tolerated, with favorable outcomes. Dosage escalation of TMLI or other modifications may be needed to improve disease control.

Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer : A systematic review.

PURPOSE: To review the evidence regarding post-mastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NACT) for breast cancer, with a special focus on individualization of adjuvant radiotherapy based on treatment response. METHODS: A systematic literature search using the PubMed/Medline database was performed. We included prospective and retrospective reports with a minimum of 10 patients that had been published since 1st January 2000, and provided clinical outcome data analyzed by treatment response and radiotherapy. RESULTS: Out of 763 articles identified via PubMed/Medline and hand search, 68 full text-articles were assessed for eligibility after screening of title and abstract. 13 studies were included in the systematic review, 9 for PMRT and 5 for RNI. All included studies were retrospective reports. CONCLUSIONS: There is a considerable lack of evidence regarding the role of adjuvant radiotherapy and its individualization based on treatment response after NACT. Results of prospective randomized trials such as NSABP B­51/RTOG 1304 and Alliance A11202 are eagerly awaited.

Simulated dosimetric impact of online replanning for stereotactic body radiation therapy of lymph node oligometastases on the 1.5T MR-linac.

PURPOSE: Online 1.5T MR imaging on the MR-linac gives better target visualization compared to CBCT and facilitates online adaptive treatment strategies including daily replanning. In this simulation study, the dosimetric impact of online replanning was investigated for SBRT of lymph node oligometastases as a method for correcting for inter-fraction anatomical changes. METHODS: Pre-treatment plans were created for 17 pelvic and para-aortic lymph nodes, with 3 and 8 mm PTV margins reflecting our clinical practice for lymph nodes with good and poor visibility on CBCT. The dose-volume parameters of the pre-treatment plans were evaluated on daily anatomy as visible on the repeated MRIs and compared to online replanning. RESULTS: With online MRI-based replanning significant dosimetric improvements are obtained for the rectum, bladder, bowel and sigmoid without compromising the target dose. The amount of unintended violations of the dose constraints for target and surrounding organs could be reduced by 75% for 8 mm and 66% for 3 mm PTV margins. CONCLUSION: The use of online replanning based on the actual anatomy as seen on repeated MRI compared to online position correction for lymph node oligometastases SBRT gives beneficial dosimetric outcomes and reduces the amount of unplanned violations of dose constraints.

Extended-field radiotherapy for locally advanced cervical cancer.

BACKGROUND: The para-aortic lymph nodes (located along the major vessels in the mid and upper abdomen) are a common place for disease recurrence after treatment for locally advanced cervical cancer. The para-aortic area is not covered by standard pelvic radiotherapy fields and so treatment to the pelvis alone is inadequate for women at a high risk of occult cancer within para-aortic lymph nodes. Extended-field radiotherapy (RT) widens the pelvic RT field to include the para-aortic lymph node area. Extended-field RT may improve outcomes in women with locally advanced cervical cancer by treating occult disease in para-aortic nodes not identified at pretreatment imaging. However, RT treatment of the para-aortic area can cause severe adverse effects, so may increase harms.Studies of pelvic chemoradiotherapy (CRT) demonstrated improved survival rates compared to pelvic RT alone. CRT is now the standard of care in the treatment of locally advanced cervical cancer. Studies comparing pelvic RT alone (without concurrent chemotherapy) with extended-field RT should therefore be viewed with caution, since they compare treatments against what is now substandard treatment (pelvic RT alone). This review should therefore be read with this in mind and comparisons with pelvic RT cannot be extrapolated to pelvic CRT. OBJECTIVES: To evaluate the effectiveness and toxicity of extended-field radiotherapy in women undergoing first-line treatment for locally advanced cervical cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 7), MEDLINE via Ovid (1946 to August week 4, 2018), and Embase via Ovid (1980 to 2018, week 35). We checked registers of clinical trials, grey literature, conference reports, and citation lists of included studies to August 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effectiveness and toxicity of extended-field RT for locally advanced cervical cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently selected potentially relevant RCTs, extracted data, assessed risk of bias, compared results, and made judgements on the quality and certainty of the evidence for each outcome. Any disagreements were resolved by discussion or consultation with a third review author. MAIN RESULTS: Five studies met the inclusion criteria. Three included studies compared extended-field RT versus pelvic RT, one included study compared extended-field RT with pelvic CRT, and one study compared extended-field CRT versus pelvic CRT.Extended-field radiotherapy versus pelvic radiotherapy aloneCompared to pelvic RT, extended-field RT probably reduces the risk of death (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.48 to 0.94; 1 study; 337 participants; moderate-certainty evidence) and para-aortic lymph node recurrence (risk ratio (RR) 0.36, 95% CI 0.18 to 0.70; 2 studies; 477 participants; moderate-certainty evidence), although there may or may not have been improvement in the risk of disease progression (HR 0.92, 95% CI 0.69 to 1.22; 1 study; 337 participants; moderate-certainty evidence) and severe adverse events (RR 1.05, 95% CI 0.79 to 1.41; 2 studies; 776 participants; moderate-certainty evidence).Extended-field radiotherapy versus pelvic chemoradiotherapyIn a comparison of extended-field RT versus pelvic CRT, women given pelvic CRT probably had a lower risk of death (HR 0.50, 95% CI 0.39 to 0.64; 1 study; 389 participants; moderate-certainty evidence) and disease progression (HR 0.52, 95% CI 0.37 to 0.72; 1 study; 389 participants; moderate-certainty evidence). Participants given extended-field RT may or may not have had a lower risk of para-aortic lymph node recurrence (HR 0.44, 95% CI 0.20 to 0.99; 1 study; 389 participants; low-certainty evidence) and acute severe adverse events (RR 0.05, 95% CI 0.02 to 0.11; 1 study; 388 participants; moderate-certainty evidence). There were no clear differences in terms of late severe adverse events among the comparison groups (RR 1.06, 95% CI 0.69 to 1.62; 1 study; 386 participants; moderate-certainty evidence).Extended-field chemoradiotherapy versus pelvic chemoradiotherapyVery low-certainty evidence obtained from one small study (74 participants) showed that, compared to pelvic CRT, extended-field CRT may or may not have reduced risk of death (HR 0.37, 95% CI 0.14 to 0.96) and disease progression (HR 0.25, 95% CI 0.07 to 0.87). There were no clear differences between the groups in the risks of para-aortic lymph node recurrence (RR 0.19, 95% CI 0.02 to 1.54; very low-certainty evidence) and severe adverse events (acute: RR 0.95, 95% CI 0.20 to 4.39; late: RR 0.95, 95% CI 0.06 to 14.59; very low-certainty evidence). AUTHORS' CONCLUSIONS: Moderate-certainty evidence shows that, compared with pelvic RT alone, extended-field RT probably improves overall survival and reduces risk of para-aortic lymph node recurrence. However, pelvic RT alone would now be considered substandard treatment, so this result cannot be extrapolated to modern standards of care. Low- to moderate-certainty evidence suggests that pelvic CRT may increase overall and progression-free survival compared to extended-field RT, although there may or may not be a higher rate of para-aortic recurrence and acute adverse events. Extended-field CRT versus pelvic CRT may improve overall or progression-free survival, but these findings should be interpreted with caution due to very low-certainty evidence.High-quality RCTs, comparing modern treatment techniques in CRT, are needed to more fully inform treatment for locally advanced cervical cancer without obvious para-aortic node involvement.

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group.

BACKGROUND AND PURPOSE: In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans. MATERIALS AND METHODS: Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans. RESULTS: The median CTV was 120 cm3 (IQR: 95-173 cm3) for Case 1, and 255 cm3 (IQR: 183-293 cm3) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans. CONCLUSIONS: We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites. This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Elective nodal irradiation is not necessary in chemoradiotherapy for postoperative loco-regional recurrent esophageal cancer.

PURPOSE: The purposes of the present study were to evaluate prognostic factors for patients with postoperative loco-regional recurrent esophageal cancer treated with chemoradiotherapy by multivariate analysis and to determine which irradiation is better, involved field irradiation or elective nodal irradiation, by matched-pair analysis. METHODS: We reviewed records for 80 patients with postoperative loco-regional recurrent esophageal cancer treated by chemoradiotherapy between 2000 and 2014. The median follow-up period was 62.0 months. Thirty-one cases were treated with elective nodal irradiation and were randomly matched by risk factors to 49 cases treated with involved field irradiation (1:1). RESULTS: Fifty-one patients had disease recurrence again, and irradiated-field failure was observed in 26 patients. The 5-year overall survival rate was 30.5% with a median survival period of 26.5 months. Grade 3 or higher late toxicity was observed in only one patient. In multivariate analysis, short disease-free interval and anastomotic recurrence were statistically significant unfavorable prognostic factors for overall survival (hazard ratios: 2.1 and 2.5, respectively). Matched-pair analysis including disease-free interval, pattern of recurrence and number of recurrent regions revealed that overall survival rate and irradiated-field control rate in patients treated with involved field irradiation were significantly better than those in patients treated with elective nodal irradiation (P = 0.016 and P = 0.014, respectively). CONCLUSIONS: Short disease-free interval and anastomotic recurrence are unfavorable factors and elective nodal irradiation is not necessary in chemoradiotherapy for patients with postoperative loco-regional recurrent esophageal cancer.

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC: A direct comparison of PET-based treatment planning.

AIM: The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). METHODS: Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. RESULTS: IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D-CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). CONCLUSION: The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels.

Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine.

Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT.

Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.

BACKGROUND: Predicting outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is an area of uncertainty. It influences the decision-making for regional nodal irradiation (RNI). The aim of the NORA (NOdal RAdiotherapy) survey was to examine the patterns of RNI. METHODS: A web-questionnaire, including several clinical scenarios, was distributed to 88 EORTC-affiliated centers. Responses were received between July 2013 and January 2014. RESULTS: A total of 84 responses were analyzed. While three-dimensional (3D) radiotherapy (RT) planning is carried out in 81 (96%) centers, nodal areas are delineated in only 51 (61%) centers. Only 14 (17%) centers routinely link internal mammary chain (IMC) and supraclavicular node (SCN) RT indications. In patients undergoing total mastectomy (TM) with ALND, SCN-RT is recommend by 5 (6%), 53 (63%) and 51 (61%) centers for patients with pN0(i+), pN(mi) and pN1, respectively. Extra-capsular extension (ECE) is the main factor influencing decision-making RNI after breast conserving surgery (BCS) and TM. After primary systemic therapy (PST), 49 (58%) centers take into account nodal fibrotic changes in ypN0 patients for RNI indications. In ypN0 patients with inner/central tumors, 23 (27%) centers indicate SCN-RT and IMC-RT. In ypN1 patients, SCN-RT is delivered by less than half of the centers in patients with ypN(i+) and ypN(mi). Twenty-one (25%) of the centers recommend ALN-RT in patients with ypN(mi) or 1-2N+ after ALND. Seventy-five (90%) centers state that age is not considered a limiting factor for RNI. CONCLUSION: The NORA survey is unique in evaluating the impact of SLNB/ALND status on adjuvant RNI decision-making and volumes after BCS/TM with or without PST. ALN-RT is often indicated in pN1 patients, particularly in the case of ECE. Besides the ongoing NSABP-B51/RTOG and ALLIANCE trials, NORA could help to design future specific RNI trials in the SLNB era without ALND in patients receiving or not PST.

Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms.

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

Is elective nodal irradiation beneficial in patients with pathologically negative lymph nodes after neoadjuvant chemotherapy and breast-conserving surgery for clinical stage II-III breast cancer? A multicentre retrospective study (KROG 12-05).

BACKGROUND: To evaluate the effects of elective nodal irradiation (ENI) in clinical stage II-III breast cancer patients with pathologically negative lymph nodes (LNs) (ypN0) after neoadjuvant chemotherapy (NAC) followed by breast-conserving surgery (BCS) and radiotherapy (RT). METHODS: We retrospectively analysed 260 patients with ypN0 who received NAC followed by BCS and RT. Elective nodal irradiation was delivered to 136 (52.3%) patients. The effects of ENI on survival outcomes were evaluated. RESULTS: After a median follow-up period of 66.2 months (range, 15.6-127.4 months), 26 patients (10.0%) developed disease recurrence. The 5-year locoregional recurrence-free survival and disease-free survival (DFS) for all patients were 95.5% and 90.5%, respectively. Pathologic T classification (0-is vs 1 vs 2-4) and the number of LNs sampled (<13 vs ≥13) were associated with DFS (P=0.0086 and 0.0012, respectively). There was no significant difference in survival outcomes according to ENI. Elective nodal irradiation also did not affect survival outcomes in any of the subgroups according to pathologic T classification or the number of LNs sampled. CONCLUSIONS: ENI may be omitted in patients with ypN0 breast cancer after NAC and BCS. But until the results of the randomised trials are available, patients should be put on these trials.

Helical intensity-modulated radiotherapy of the pelvic lymph nodes with integrated boost to the prostate bed - initial results of the PLATIN 3 Trial.

BACKGROUND: Adjuvant and salvage radiotherapy of the prostate bed are established treatment options for prostate cancer. While the benefit of an additional radiotherapy of the pelvic lymph nodes is still under debate, the PLATIN 3 prospective phase II clinical trial was initiated to substantiate toxicity data on postoperative IMRT of the pelvic lymph nodes and the prostate bed. METHODS: From 2009 to 2011, 40 patients with high-risk prostate cancer after prostatectomy with pT3 R0/1 M0 or pT2 R1 M0 or a PSA recurrence and either > 20% risk of lymph node involvement and inadequate lymphadenectomy or pN + were enrolled. Patients received two months of antihormonal treatment (AT) before radiotherapy. AT continuation was mandatory during radiotherapy and was recommended for another two years. IMRT of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated boost to the prostate bed (68.0 Gy) was performed in 34 fractions. PSA level, prostate-related symptoms and quality of life were assessed at regular intervals for 24 months. RESULTS: Of the 40 patients enrolled, 39 finished treatment as planned. Overall acute toxicity rates were low and no acute grade 3/4 toxicity occurred. Only 22.5% of patients experienced acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. During follow-up, 10.0% late grade 2 GI and 5.0% late grade 2 GU toxicity occurred, and one patient developed late grade 3 proctitis and enteritis. After a median observation time of 24 months the PLATIN 3 trial has shown in 97.5% of all patients sufficient safety and thus met its prospectively defined aims. After a median of 24 months, 34/38 patients were free of a PSA recurrence. CONCLUSIONS: Postoperative whole-pelvis IMRT with an integrated boost to the prostate bed can be performed safely and without excessive toxicity.

CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects.

BACKGROUND: The DBCG-IMN is a nationwide population-based cohort study on the effect of internal mammary node radiotherapy (IMN-RT) in patients with node positive early breast cancer. Due to the risk of RT-induced heart disease, only patients with right-sided breast cancer received IMN-RT, whereas patients with left-sided breast cancer did not. At seven-year median follow-up, a 3% gain in overall survival with IMN-RT has been reported. This study estimates IMN doses and doses to organs at risk (OAR) in patients from the DBCG-IMN. Numbers needed to harm (NNH) if patients with left-sided breast cancer had received IMN-RT are compared to the number needed to treat (NNT). MATERIAL AND METHODS: Ten percent of CT-guided treatment plans from the DBCG-IMN patients were selected randomly. IMNs and OAR were contoured in 68 planning CT scans. Dose distributions were re-calculated. IMNs and OAR dose estimates were compared in right-sided versus left-sided breast cancer patients. In six left-sided patients, IMN-RT was simulated, and OAR doses were compared to those in the original plan. The NNH resulting from the change in mean heart dose (MHD) was calculated using a published model for risk of RT-related ischemic heart death. RESULTS: In original plans, the absolute difference between right- and left-sided V90% to the IMNs was 38.0% [95% confidence interval (5.5%; 70.5%), p < 0.05]. Heart doses were higher in left-sided plans. With IMN-RT simulation without regard to OAR constraints, MHD increased 4.8 Gy (0.9 Gy; 8.7 Gy), p < 0.05. Resulting NNHs from ischemic heart death were consistently larger than the NNT with IMN-RT. CONCLUSION: Refraining from IMN-RT on the left side may have spared some ischemic heart deaths. Assuming left-sided patients benefit as much from IMN-RT as right-sided patients, the benefits from IMN-RT outweigh the costs in terms of ischemic heart death.

Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.

UNLABELLED: Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. MATERIAL AND METHODS: All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non-adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. RESULTS: Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). CONCLUSION: Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity.