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ObjectiveTo investigate whether neoadjuvant chemotherapy followed by interval debulking surgery is superior to primary debulking surgery in terms of perioperative complications and progression-free survival, in advanced epithelial ovarian, fallopian tube or primary peritoneal cancer patients with high tumor load.MethodsPatients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer (stage IIIC-IV) underwent laparoscopy. Patients with high tumor load assessed by a standardized laparoscopic predictive index were randomly assigned (1:1 ratio) to undergo either primary debulking surgery followed by adjuvant chemotherapy (arm A), or neoadjuvant chemotherapy followed by interval debulking surgery and adjuvant chemotherapy (arm B). Co-primary outcome measures were progression-free survival and post-operative complications; secondary outcomes were overall survival, and quality of life. Survival analyses were performed on an intention-to-treat population.Results171 patients were randomly assigned to primary debulking surgery (n=84) versus neoadjuvant chemotherapy (n=87). Rates of complete resection (R0) were different between the arms (47.6% in arm A vs 77.0% in arm B; p=0.001). 53 major postoperative complications were registered, mainly distributed in arm A compared with arm B (25.9% vs 7.6%; p=0.0001). All patients were included in the intent-to-treat analysis. With an overall median follow-up of 59 months (95% CI 53 to 64), 142 (83.0%) disease progressions/recurrences and 103 deaths (60.2%) occurred. Median progression-free and overall survival were 15 and 41 months for patients assigned to primary debulking surgery, compared with 14 and 43 months for patients assigned to neoadjuvant chemotherapy, respectively (HR 1.05, 95% CI 0.77 to 1.44, p=0.73; HR 1.12, 95% CI 0.76 to 1.65, p=0.56).ConclusionsNeoadjuvant chemotherapy and primary debulking surgery have the same efficacy when used at their maximal possibilities, but the toxicity profile is different.

Neoadjuvant checkpoint inhibition, in which the therapy is administered before surgery, is a promising new approach to managing bulky but resectable melanoma, and is also being explored in other cancers. This strategy has a high pathologic response rate, which correlates with survival outcomes. The fact that biopsies are routinely available provides a unique opportunity for understanding the responses to therapy and carrying out reverse translation in which these data are used to select therapies in the clinic or in trials that are more likely to improve patient outcomes. In this Perspective, we discuss the rationale for neoadjuvant immunotherapy in resectable solid tumors based on preclinical and human translational data, summarize the results of recent clinical trials and ongoing research, and focus on future directions for enhancing reverse translation. The emerging success of neoadjuvant therapy is creating opportunities for understanding successful immune responses and improving therapies using this unique pool of knowledge.

Background Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. Methods In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m 2 ) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. Results Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. Conclusions The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. Trial registration ClinicalTrials.gov, NCT03588091

BackgroundPrimary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection.Primary ObjectiveTo clarify the optimal timing of surgical therapy in advanced ovarian cancer.Study HypothesisPrimary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer.Trial DesignTRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB–IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB–IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations.Major Inclusion/Exclusion CriteriaMajor inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB–IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy.Primary EndpointOverall survival.Sample Size772 patients.Estimated Dates for Completing Accrual and Presenting ResultsAccrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024.Trial Registration NCT02828618.

Background Perioperative chemotherapy has become the standard of care for locally advanced gastric cancer. Total neoadjuvant therapy (TNT), including both chemotherapy and chemoradiation, is utilized in other gastrointestinal malignancies. We determined survival in a contemporary cohort of gastric cancer patients treated with TNT. Methods Using a prospective institutional database, patients diagnosed with cT2-4 or cN+ gastric adenocarcinoma (January 2012 to June 2022) who underwent staging laparoscopy, received TNT, and underwent gastrectomy were identified. Overall survival (OS) and disease-specific survival (DSS) were determined using standard statistical methods. Results The study included 203 patients. The most common TNT sequence was induction chemotherapy followed by chemoradiation ( n = 186 [91.6%]). A total of 195 (96.1%) patients completed planned neoadjuvant treatments. Surgery included total gastrectomy in 108 (53.2%), extended (D1+/D2) lymphadenectomy in 193 (95.1%), and adjacent organ resection in 19 (9.4%) patients. Pathologic complete response (pCR) was achieved in 32 (15.8%) patients. The 5-year OS rate was 65.2% (95% confidence interval [CI] 57.8–73.5%), and the 5-year DSS rate was 70.8% (95% CI 63.6–78.9%) in the study cohort. Among patients with pCR, the 5-year OS rate was 89.1% (95% CI 78.1–100.0%), and the 5-year DSS rate was 96.9% (95% CI 91–100%). Posttreatment pathologic N and M stages were the strongest prognostic indicators associated with both OS and DSS. Conclusions Total neoadjuvant therapy for resectable gastric cancer is associated with a high rate of treatment completion and promising survival outcomes. Prospective comparisons with perioperative treatment are needed to identify patients most likely to benefit from TNT.

Background Breast cancer patients under neoadjuvant chemotherapy includes a heterogeneous group of patients who eventually develop distal disease, not detectable by current methods. We propose the use of exosomal miRNAs and circulating tumor cells as diagnostic and predictive biomarkers in these patients. Methods Fifty-three breast cancer women initially diagnosed with localized breast cancer under neoadjuvant chemotherapy were prospectively enrolled in this study. However, six of them were later re-evaluated and diagnosed as metastatic breast cancer patients by PET-CT scan. Additionally, eight healthy donors were included. Circulating tumor cells and serum exosomal miRNAs were isolated from blood samples before and at the middle of neoadjuvant therapy and exosomal miRNA levels analyzed by qPCR. Results Before neoadjuvant therapy, exosomal miRNA-21 and 105 expression levels were higher in metastatic versus non-metastatic patients and healthy donors. Likewise, higher levels of miRNA-222 were observed in basal-like ( p  = 0.037) and in luminal B versus luminal A ( p  = 0.0145) tumor subtypes. Exosomal miRNA-222 levels correlated with clinical and pathological variables such as progesterone receptor status ( p  = 0.017) and Ki67 ( p  = 0.05). During neoadjuvant treatment, exosomal miRNA-21 expression levels directly correlated with tumor size ( p  = 0.039) and inversely with Ki67 expression ( p  = 0.031). Finally, higher levels of exosomal miRNA-21, miRNA-222, and miRNA-155 were significantly associated with the presence of circulating tumor cells. Conclusion Liquid biopsies based on exosomal miRNAs and circulating tumor cells can be a complementary clinical tool for improving breast cancer diagnosis and prognosis.

Purpose Evidence supporting the use of neoadjuvant chemotherapy (NAC) in early breast cancer is based on studies mainly including women, whereas the utilization and effectiveness of NAC in men is less studied. The present study aimed to investigate the utilization and effectiveness of NAC in men and women with early breast cancer. Methods Eligible patients were identified through the Swedish National Breast Cancer Quality Register, that includes all newly diagnosed breast cancer cases in Sweden from 2008 and onwards. For the treatment utilization analysis, all patients with stage I–III between 2008 and 2020 were included (n = 82,888), whereas for the effectiveness analysis the cohort was restricted to patients receiving NAC (n = 6487). For both analyses, multivariate logistic regression models were applied to investigate potential sex disparities in NAC utilization and effectiveness, adjusted for patient- and tumor characteristics. Results In the NAC utilization analysis, 487 men and 82,401 women with stage I–III were included. No statistically significant difference between sexes in terms of NAC utilization was observed (adjusted Odds Ratio (adjOR): 1.135; 95% Confidence Interval (CI) 0.606–2.128) with an overall utilization rate of 4.9% in men compared to 7.8% in women. Among the 24 men and 6463 women who received NAC, the pathologic complete response (pCR) rates were 16.7% and 21.2%, respectively (adjOR: 1.141; 95% CI 0.141–9.238). Conclusion The present study did not find any sex disparities in NAC utilization or effectiveness in terms of pCR. This supports the current recommendations of treating men with breast cancer with the same indications for NAC as women.

Among patients who received two 3-week cycles of neoadjuvant ipilimumab and nivolumab, the 12-month event-free survival was 83.7%, as compared with 57.2% among those who received only adjuvant therapy.

SummaryBackgroundSystemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. MethodsIn this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m 2 orally twice daily on days 1–14, oxaliplatin 130 mg/m 2 intravenously on day 1, and a chemotherapy-free interval between days 15–21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m 2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m 2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m 2 intravenously and fluorouracil 600 mg/m 2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3–14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m 2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FindingsBetween June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5–5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8–27·6) in the experimental group versus 30·4% (26·1–34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60–0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). InterpretationThe observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FundingDutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma 1 . We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate 2 . The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3–4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response ( P  = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial 1 , provide further confirmation of the efficacy and safety of this new immunotherapy regimen. Patients with resectable clinical stage III or oligometastatic stage IV melanoma were given neoadjuvant relatlimab and nivolumab combination immunotherapy, which induced a high pathologic complete response rate, indicating the efficacy and safety of this regimen.