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10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation. EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I–III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851. Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0–17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0–75·2) in the IM-MS irradiation group and 70·9% (68·6–72·9) in the control group (HR 0·95 [95% CI 0·84–1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5–26·6] vs 27·1% [25·1–29·2]; HR 0·87 [95% CI 0·77–0·98], p=0·024) and breast cancer mortality (16·0% [14·3–17·7] vs 19·8% [18·0–21·7]; 0·81 [0·70–0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4–63·2] vs 59·9% [57·5–62·2]; HR 0·93 [95% CI 0·84–1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7–72·2] vs 68·2% [65·9–70·3]; 0·93 [0·83–1·04], p=0·18). Causes of death between groups were similar. The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I–III breast cancer. However, this is not converted to improved overall survival. Ligue Nationale contre le Cancer and KWF Kankerbestrijding.

Various locoregional treatments exist for PET–CT-detected pelvic nodal oligorecurrences in patients with prostate cancer. We aimed to assess whether elective nodal radiotherapy (ENRT) to the pelvis would be superior to metastasis-directed therapy (MDT). PEACE V–STORM is a phase 2, open-label, randomised, controlled trial conducted in 21 hospitals in Australia, Belgium, Italy, Norway, Spain, and Switzerland. Eligible participants were aged 18 years or older, with WHO performance status 0–1 and a histologically confirmed initial diagnosis of adenocarcinoma of the prostate, with a PET-detected pelvic nodal oligorecurrence (up to five nodes) following radical local treatment. Patients were randomly assigned (1:1) to MDT or ENRT. Randomisation was done online by minimisation with randomisation factor 0·80 and was stratified by type of PET tracer (choline vs prostate-specific membrane antigen) and type of MDT used (salvage lymph node dissection vs stereotactic body radiotherapy or simultaneous integrated boost). Participants and researchers were not masked to treatment assignment. Patients in the MDT group had salvage lymph node dissection or stereotactic body radiotherapy (30 Gy in three fractions every other day), with 6 months of androgen deprivation therapy. Patients in the ENRT group received a 45 Gy dose in 25 fractions to the pelvis with a simultaneous integrated boost of 65 Gy to the PET-positive nodes or salvage lymph node dissection, with 6 months of androgen deprivation therapy. The primary endpoint was metastasis-free survival, defined as the time between randomisation and the appearance of a metastatic recurrence (any M1) on PET imaging or death due to any cause, and was analysed per modified intention to treat. This study is registered with ClinicalTrials.gov, NCT03569241, and the Swiss National Clinical Trials Portal, SNCTP000002947, and is active, not recruiting. Between June 11, 2018, and April 30, 2021, 198 patients were screened for eligibility, 196 of whom were randomly assigned to MDT (n=99) or ENRT (n=97), with 190 evaluable patients (MDT n=97 and ENRT n=93). All patients were male. Data on race and ethnicity were not collected. Median follow-up was 50 months (IQR 42–58). 4-year metastasis-free survival was 63% (80% CI 56–69) in the MDT group and 76% (69–81) in the ENRT group (HR 0·62 [80% CI 0·44–0·86]; p=0·063). The most common grade 3 adverse events were urinary incontinence (six [6%] of 97 in the MDT group vs nine [10%] in the ENRT group) and diarrhoea (one [1%] in the MDT group vs two [2%] in the ENRT group). No treatment-related deaths occurred. To our knowledge, this is the first randomised trial for metachronous PET-detected nodal recurrences comparing two local treatment approaches (MDT and ENRT) in combination with 6 months of androgen deprivation therapy. By showing an improved metastasis-free survival with ENRT, this trial establishes ENRT as a potential standard treatment approach, awaiting a phase 3 trial confirming these results. Movember Foundation, Kom Op Tegen Kanker, Stichting tegen Kanker.

The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear. We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence-free interval). Secondary end points included the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, and overall survival. Safety was also assessed. A total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P = 0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group. The addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy. (Funded by the National Institutes of Health; NSABP B-51-Radiation Therapy Oncology Group 1304 ClinicalTrials.gov number, NCT01872975.).

Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects. In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (≤3 vs >3), maximum involved node diameter (≤4 cm vs >4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196. Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61–91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0·52 [95% CI 0·31–0·88], p=0·023). Overall survival (HR 1·27 [95% CI 0·89–1·79], p=0·21) and relapse-free survival (0·89 [0·65–1·22], p=0·51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3–4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15·0%) compared with observation (7·7%; difference 7·3% [95% CI 1·5–13·1], p=0·014). No significant differences in upper limb volume were noted between groups. Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy. National Health and Medical Research Council of Australia, Cancer Council Australia, Melanoma Institute Australia, and the Cancer Council South Australia.

Background To report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC). Methods Patients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy. Results A total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively ( P  = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P  = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P  = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib. Conclusions Concurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC. Clinical trial registration Trial registration: NCT00686114.

ObjectiveTangential field irradiation in breast cancer potentially treats residual tumor cells in the axilla after sentinel lymph node biopsy (SLNB). In recent years, hypofractionated radiotherapy has gained importance and currently represents the recommended standard in adjuvant breast cancer treatment for many patients. So far, the impact of hypofractionation on the effect of incidental lymph node irradiation has not be addressed.Materials and methodsBiological effective dose (BED) and tumor control probability (TCP) were estimated for four different hypofractionated radiation schemes (42.50 Gy in 16 fractions [Fx]; 40.05 Gy in 15 Fx; 27 Gy in 5 Fx; and 26 in 5 Fx) and compared to conventional fractionation (50 Gy in 25 Fx). For calculation of BED and TCP, a previously published radiobiological model with an α/β ratio of 4 Gy was used. The theoretical BED and TCP for incidental irradiation between 0 and 100% of the prescribed dose were evaluated. Subsequently, we assessed BED and TCP in 431 axillary lymph node metastases.ResultsThe extent of incidental lymph node irradiation and the fractionation scheme have a direct impact on BED and TCP. The estimated mean TCP in the axillary nodes ranged from 1.5 ± 6.4% to 57.5 ± 22.9%, depending on the patient’s anatomy and the fractionation scheme. Hypofractionation led to a significant reduction of mean TCP of lymph node metastases for all schedules.ConclusionOur data indicate that hypofractionation might affect the effectiveness of incidental radiotherapy in the axilla. This is particularly relevant for patients with positive sentinel lymph nodes who receive SLNB only.

Aim: The study aimed to evaluate the effect of concurrent computed tomography (CT)-guided percutaneous interstitial implantation of iodine-125 (125I) seeds and chemotherapy on cervical lymph nodes metastasis. Methods: The prospective randomized study included 82 cases with cervical lymph nodes metastasis who were admitted to our hospital from January 2010 to June 2012. All the subjects were randomly divided into the concurrent 125I implantation and chemotherapy group (n = 48) and chemotherapy-only group (n = 34) according to the treatment strategy. The concurrent 125I implantation and chemotherapy group was treated with CT-guided 125I seeds implantation and routine chemotherapy. The routine chemotherapy included paclitaxel and cisplatin. Patients were followed up for 6 months. Results: In the concurrent 125I implantation and chemotherapy group, overall response rate (complete response [CR] + partial response [PR]) was 82.61% and 85.51% at 2 and 6 months posttreatment, respectively. The longest diameter of CR and PR lymph nodes was markedly decreased after treatment (P < 0.05). In the chemotherapy-only group, overall response rate was 22.45% and 10.20% at 2 and 6 months posttreatment, respectively. The number of patients with moderate to severe pain was much less in concurrent 125I implantation and chemotherapy group than that of chemotherapy-only group (4.17% vs. 17.64%; P < 0.05) at 6-month posttreatment. No treatment-related death or severe complication was reported in the two groups. Conclusion: Concurrent CT-guided 125I seeds implantation and chemotherapy is superior to routine chemotherapy in efficacy, safety, and pain relief in patients with cervical lymph nodes metastasis.

Background and Purpose: Radiotherapy of Hodgkin’s lymphoma has evolved from extended-field to involved-field (IF) radiotherapy reducing toxicity whilst maintaining high cure rates. Recent publications recommend further reduction in the radiation field to involved-node (IN) radiotherapy; however, this concept has never been tested in a randomized trial. The German Hodgkin Study Group aims to compare it with standard IF radiotherapy in their future HD17 trial. Patients and Methods: All patients must be examined by the radiation oncologist before the start of chemotherapy. At that time, patients must have complete staging CT scans. For patients with IN radiotherapy, a radiation planning CT before and after chemotherapy with patients in the treatment position is recommended. Fusion techniques, allowing the overlapping of the pre- and postchemotherapy CT scans, should be used. Usage of PET-CT scans with patients in the treatment position is recommended, whenever possible. Results: The clinical target volume encompasses the initial volume of the lymph node(s) before chemotherapy and incorporates the initial location and extent of the disease taking the displacement of the normal tissues into account. The margin of the planning target volume should be 2 cm in axial and 3 cm in craniocaudal direction. If necessary, it can be reduced to 1–1.5 cm. To minimize lung and cardiac toxicity, the target definition in the mediastinum is different. Conclusion: The concept of IN radiotherapy has been proposed as a means to further improve the therapeutic ratio by reducing the risk of radiation-induced toxicity, including second malignancies. Field sizes will further decrease compared to IF radiotherapy.

Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy to overcome immune evasion and to improve treatment response. However, clinical benefits of radiotherapy-immunotherapy combinations have been modest. Routine concomitant tumor-draining lymph node irradiation (DLN IR) might be the culprit. As crucial sites for generating anti-tumor immunity, DLNs are indispensable for the in situ vaccination effect of radiotherapy. Simultaneously, DLN sparing is often not feasible due to metastatic spread. Using murine models of metastatic disease in female mice, here we demonstrate that delayed (adjuvant), but not neoadjuvant, DLN IR overcomes the detrimental effect of concomitant DLN IR on the efficacy of radio-immunotherapy. Moreover, we identify IR-induced disruption of the CCR7-CCL19/CCL21 homing axis as a key mechanism for the detrimental effect of DLN IR. Our study proposes delayed DLN IR as a strategy to maximize the efficacy of radio-immunotherapy across different tumor types and disease stages. Despite the described immunostimulatory properties of irradiation, the clinical benefit of radiotherapy-immunotherapy combinations has been modest so far. Here, in murine models of metastatic disease, the authors show that concomitant draining lymph node irradiation (DLN IR) abrogates the beneficial effect of combining radiotherapy with immune checkpoint inhibitors, while adjuvant DLN IR improves regional and distant disease control.