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Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation. We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181. Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group. APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women. National Cancer Institute, US Department of Health and Human Services.

Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5–15·0), 5 years (16·5%, 12·5–20·4), and 7 years (17·7%, 12·9–22·3). External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Locally advanced cervical cancer is treated with chemoradiotherapy (standard of care), but many patients still relapse and die from metastatic disease. We investigated chemoradiotherapy with or without induction chemotherapy to determine whether induction chemotherapy improves both progression-free survival and overall survival. The INTERLACE trial was a multicentre, randomised phase 3 trial done at 32 medical centres in Brazil, India, Italy, Mexico, and the UK. Adults (aged ≥18 years) with locally advanced cervical cancer (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, IIA, IIB, IIIB, or IVA disease) were randomly assigned (1:1), by minimisation, using a central electronic system, to standard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m2 for 5 weeks with 45·0–50·4 Gy external beam radiotherapy delivered in 20–28 fractions plus brachytherapy to achieve a minimum total 2 Gy equivalent dose of 78–86 Gy) alone or induction chemotherapy (once-a-week intravenous carboplatin area under the receiver operator curve 2 and paclitaxel 80 mg/m2 for 6 weeks) followed by standard cisplatin-based chemoradiotherapy. Stratification factors were recruiting site, stage, nodal status, three-dimensional conformal radiotherapy or intensity modulated radiotherapy, age, tumour size, and histology (squamous vs non-squamous). Primary endpoints were progression-free survival and overall survival within the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01566240, and EUDRACT, 2011-001300-35. Between Nov 8, 2012, and Nov 17, 2022, 500 eligible patients were enrolled and randomly assigned to the chemoradiotherapy alone group (n=250) or the induction chemotherapy with chemoradiotherapy group. Of 500 patients, 354 (70%) had stage IIB disease and 56 (11%) stage IIIB disease. Pelvic lymph nodes were positive in 215 (43%) patients. 230 (92%) patients who received induction chemotherapy had at least five cycles. Median interval between induction chemotherapy and chemoradiotherapy was 7 days. Four or more cycles of cisplatin were given to 212 (85%) participants in the induction chemotherapy with chemoradiotherapy group and to 224 (90%) of participants in the chemoradiotherapy alone group. 462 (92%) participants received external beam radiotherapy and brachytherapy with a median overall treatment time of 45 days. After a median follow-up of 67 months, 5-year progression-free survival rates were 72% in the induction chemotherapy with chemoradiotherapy group and 64% in the chemoradiotherapy alone group with a hazard ratio (HR) of 0·65 (95% CI 0·46–0·91, p=0·013). 5-year overall survival rates were 80% in the induction chemotherapy with chemoradiotherapy group and 72% in the chemoradiotherapy alone group, with an HR of 0·60 (95% CI 0·40–0·91, p=0·015). Grade 3 or greater adverse events were reported in 147 (59%) of 250 individuals in the induction chemotherapy with chemoradiotherapy group versus 120 (48%) of 250 individuals in the chemoradiotherapy alone group. Short-course induction chemotherapy followed by chemoradiotherapy significantly improves survival of patients with locally advanced cervical cancer. Cancer Research UK and University College London–University College London Hospitals Biomedical Research Centre.

In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1·44% (95% CI 0·51–2·38) with APBI and 0·92% (0·12–1·73) with whole-breast irradiation (difference 0·52%, 95% CI −0·72 to 1·75; p=0·42). No grade 4 late side-effects were reported. The 5-year risk of grade 2–3 late side-effects to the skin was 3·2% with APBI versus 5·7% with whole-breast irradiation (p=0·08), and 5-year risk of grade 2–3 subcutaneous tissue late side-effects was 7·6% versus 6·3% (p=0·53). The risk of severe (grade 3) fibrosis at 5 years was 0·2% with whole-breast irradiation and 0% with APBI (p=0·46). The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. German Cancer Aid.

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2–5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9–33·6) in the SIRT group and 28·1 months (20·0–35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7–9·9) in the SIRT group versus 9·9 months (8·7–11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94–1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. Sirtex Medical Inc.

The combination of stent insertion and single high-dose brachytherapy is a feasible and safe palliative treatment regimen in patients with unresectable oesophageal cancer. We aimed to further assess the efficacy of this treatment strategy compared to a conventional covered stent in patients with dysphagia caused by unresectable oesophageal cancer. In this multicentre, single-blind, randomised, phase 3 trial, we enrolled patients with unresectable oesophageal cancer from 16 hospitals in China. We included adult patients (aged ≥ 20 years) with progressive dysphagia, unresectable tumours due to extensive lesions, metastases, or poor medical condition, and with clear consciousness, cooperation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3. Eligible patients were randomly assigned (in 1:1 ratio, no stratification) to receive either a stent loaded with (125)iodine radioactive seeds (irradiation group) or a conventional oesophageal stent (control group). The primary endpoint was overall survival. Survival analyses were done in a modified intention-to-treat group. This study is registered with ClinicalTrials.gov, number NCT01054274. Between Nov 1, 2009, and Oct 31, 2012, 160 patients were randomly assigned to receive treatment with either an irradiation stent (n=80) or a conventional stent (n=80). During a median follow-up of 138 days (IQR 72-207), 148 stents (73 in the irradiation group and 75 in the control group) were successfully placed into the diseased oesophagus in 148 participants. Median overall survival was 177 days (95% CI 153-201) in the irradiation group versus 147 days (124-170) in the control group (p=0.0046). Major complications and side-effects of the treatment were severe chest pain (17 [23%] of 73 patients in the irradiation group vs 15 [20%] of 75 patents in the control group), fistula formation (six [8%] vs five [7%]), aspiration pneumonia (11 [15%] vs 14 [19%]), haemorrhage (five [7%] vs five [7%]), and recurrent dysphagia (21 [28%] vs 20 [27%]). In patients with unresectable oesophageal cancer, the insertion of an oesophageal stent loaded with (125)iodine seeds prolonged survival when compared with the insertion of a conventional covered self-expandable metallic stent.

Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer. Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40–46 Gy in 20–25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5). After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1·05 (95% CI 0·75–1·48; p=0·77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1·04; 95% CI 0·84–1·29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6·1%. Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity. Medical Research Council, National Cancer Research Network, National Cancer Institute of Canada, with funds from the Canadian Cancer Society.

Background The multicentre randomised SPARC trial evaluated the efficacy of a nurse-led sexual rehabilitation intervention on sexual functioning, distress, dilator use, and vaginal symptoms after radiotherapy for gynaecological cancers. Methods Eligible women were randomised to the rehabilitation intervention or care-as-usual. Four intervention sessions were scheduled over 12 months, with concurrent validated questionnaires and clinical assessments. Primary outcome was the Female Sexual Function Index (FSFI). A generalised-mixed-effects model compared groups over time. Results In total, 229 women were included ( n  = 112 intervention; n  = 117 care-as-usual). No differences in FSFI total scores were found between groups at any timepoint ( P  = 0.37), with 12-month scores of 22.57 (intervention) versus 21.76 (care-as-usual). The intervention did not significantly improve dilator use, reduce sexual distress or vaginal symptoms compared to care-as-usual. At 12 months, both groups had minimal physician-reported vaginal stenosis; 70% of women were sexually active and reported no or mild vaginal symptoms. After radiotherapy and brachytherapy, 85% (intervention) versus 75% (care-as-usual) of participants reported dilation twice weekly. Discussion Sexual rehabilitation for women treated with combined (chemo)radiotherapy and brachytherapy improved before and during the SPARC trial, which likely contributed to comparable study groups. Best practice involves a sexual rehabilitation appointment 1 month post-radiotherapy, including patient information, with dilator guidance, preferably by a trained nurse, and follow-up during the first year after treatment. Clinical trial registration NCT03611517.

To determine the safety and effectiveness of ultrasound-guided paracervical nerve blocks for the painless treatment of patients with cervical cancer post-implantation. Single-center randomized controlled trial. Fourth Hospital of Hebei Medical University (July 2023 to October 2023). ChiCTR2300071580 [https://clin.larvol.com/trial-detail/ChiCTR2300071580]. Eighty patients with cervical cancer underwent post-implantation treatment. Patients receiving and not receiving paracervical nerve blocks (Groups T and C, respectively) were randomly allocated. Primary measures included visual analog scale (VAS) scores and patient body movement scores at various stages, including vaginal speculum placement (T1), applicator/needle insertion (T2), treatment administration following connection of the treatment tube (T3), needle withdrawal and hemostasis (T4), and willingness to receive further treatment. The secondary observation indices in this study included the operation time, incidence of hypoxemia, occurrence of nausea and vomiting, adverse events related to the circulatory system, patient satisfaction score, operator satisfaction score, and operation duration required by patients with an Alderte score of ≥ 9. Forty patients each were randomly allocated into Groups T and C. The VAS scores did not differ significantly between the two groups at T1. However, at T3 and T4, the VAS scores of Group T was significantly lower than that of Group C. No significant difference was observed in the body movement scores between the two groups at T1 and T3. However, the body movement score of Group T was significantly lower than that of Group C (P < 0.001) at T2 and T4. Group T showed higher postoperative satisfaction and willingness to receive further treatment compared to that of Group C. Ultrasound-guided paracervical nerve block effectively reduced the pain scores in patients with cervical cancer undergoing post-implantation treatment and enhanced their inclination to undergo further treatment.

Background Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. Methods ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. Discussion ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. Trial registration NCT05230251 (ClinicalTrials.gov).