Postoperative chemoradiotherapy in patients with locally advanced gastric cancer with poor pathologic response to neoadjuvant chemotherapy.

PURPOSE: To evaluate the effect of postoperative chemoradiotherapy (CRT) in patients with locally advanced gastric cancer (LAGC) who respond poorly to neoadjuvant chemotherapy (ChT). MATERIALS AND METHODS: The database of a tertiary medical center (2009-2020) was retrospectively reviewed for patients with LAGC in whom the initial treatment strategy consisted of perioperative ChT and surgery. Those who were subsequently referred for postoperative CRT because of a poor pathologic primary-tumor response (ypT3-4, ypN2-3, R1 resection) were selected for the study. CRT consisted of 45 Gy in 25 fractions of 1.8 Gy combined with capecitabine 825 mg/m2 twice daily on radiotherapy days or continuous infusion of 5-fluorouracil 180 mg/m2/day. RESULTS: The cohort included 26 patients of median age 61 years with LAGC (clinical stage IIA-III) after surgery with D1-D2 lymphadenectomy. R0 resection was achieved in 15 (58%). The pathological stage was III in 69% (IIA-IVA). Treatment was well tolerated. During a median follow-up time of 39 months, recurrences were documented in 14 patients (54%): 11 distant and 3 locoregional. Median progression-free survival was 23 months, and median overall survival was 65 months. Estimated 5-year survival rates were 42 and 54%, respectively. CONCLUSIONS: This small retrospective study suggests that in patients with LAGC who show a poor pathologic response to neoadjuvant ChT, a good outcome relative to reference arms in randomized trials can still be achieved with the addition of postoperative CRT. Further studies of the benefit of a tailored adaptive treatment approach to LAGC based on the response to neoadjuvant ChT are warranted.

Inflammatory and Nutritional Biomarkers in Patients With Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemotherapy and Radiation Therapy.

OBJECTIVES: To investigate the relationship between pretreatment inflammatory and nutritional biomarkers in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemotherapy and radiation therapy (nCRT). SAMPLE & SETTING: 213 patients with newly diagnosed stage II-III ESCC who received nCRT at an academic hospital in Taiwan. METHODS & VARIABLES: Electronic health record data were used. Records on inflammatory and nutritional biomarkers and clinical outcomes were extracted. Logistic regression analysis was used to predict treatment-related adverse events, Cox regression was used for survival outcomes, and receiver operating characteristic curve analysis was used to determine optimal cutoff values. RESULTS: There was a significant association between low prognostic nutritional index (PNI) and nCRT toxicities and survival. Advanced cancer stage, high platelet-to-lymphocyte ratio, and occurrence of pneumonia/infection were linked to survival outcomes. IMPLICATIONS FOR NURSING: PNI shows promise in predicting prognosis, helps identify high-risk patients, and enables nurses to apply tailored interventions.

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial.

BACKGROUND: Upfront surgery followed by postoperative treatment is a commonly adopted treatment for resectable pancreatic ductal adenocarcinoma (rPDAC). However, the risk of positive surgical margins, the poor recovery that often impairs postoperative treatments, and the risk of recurrence might limit the outcome of this strategy. This study evaluated the safety and the activity of liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX) in the perioperative treatment of patients with rPDAC. METHODS: Eligible patients had a rPDAC with < 180° interface with major veins' wall. Patients received 3 cycles before and 3 cycles after resection with NALIRIFOX, days 1 and 15 of a 28-day cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. RESULTS: 107 patients began preoperative treatment. Nine patients discontinued the treatment because of related or unrelated adverse events. Disease-control rate was 92.9%. 87 patients underwent surgical exploration, 11 had intraoperative evidence of metastatic disease, and 1 died for surgical complications. R0 resection rate was 65.3%. 49 patients completed the three postoperative cycles. The most common grade ≥ 3 adverse events were diarrhea and neutropenia. Median overall survival (OS) of ITT patients was 32.3 months (95% CI 27.8-44.3). Median disease-free and OS from surgery of resected patients were 19.3 (95% CI 12.6-34.1) and 40.3 months (95% CI 29-NA), respectively. CONCLUSION: Perioperative NALIRIFOX was manageable and active, and deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Perioperative Chemotherapy and Chemoradiotherapy for Patients With Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.

Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.

INTRODUCTION: Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. METHODS: All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. RESULTS: Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. CONCLUSION: The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.

[Transanal Tumor Resection: Indication, Surgical Technique and Management of Complications]. / Transanale Tumorresektion: Indikation, Operationstechniken und Komplikationsmanagement.

Transanal resection procedures are special operations for the minimally invasive treatment of rectal tumours. Apart from benign tumours, this procedure is suitable for the excision of low-risk T1 rectal carcinomas, if these can be completely removed (R0 resection). With stringent patient selection, very good oncological results are achieved. Various international trials are currently evaluating whether local resection procedures are oncologically sufficient if there is a complete or near complete response after neoadjuvant radio-/chemotherapy. Numerous studies have shown that the functional results and the postoperative quality of life after local resection are excellent, especially considering the well-known functional deficits of alternative operations, such as low anterior or abdominoperineal resection.Severe complications are very rare. Most complications, such as urinary retention or subfebrile temperatures, are minor in nature. Suture line dehiscences are usually clinically unremarkable. Major complications comprise significant haemorrhage and the opening of the peritoneal cavity. The latter must be recognized intraoperatively and can usually be managed by primary suture. Infection, abscess formation, rectovaginal fistula, injury of the prostate or even urethra are extremely rare complications.

Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048).

PURPOSE: The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions. METHODS: PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N-, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL). RESULTS: From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point. CONCLUSION: For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.

Elevated Sera IL-6 and NK-T Cells Associated With Increased Pathological Complete Response in HER2-positive Breast Cancer With Carboplatin-based Neoadjuvant Therapy.

Context: Neoadjuvant therapy is the primary treatment for stage II to III breast cancer (BC). The heterogeneity of BC challenges the identification of effective neoadjuvant regimens and of the related sensitive populations. Objective: The study intended to explore the predictive role of inflammatory cytokines, immune-cell subsets, and tumor-infiltrating lymphocytes (TILs) for the accomplishment of the pathological complete response (pCR) after a neoadjuvant regimen. Design: The research team conducted a phase II, single-armed, open-label trial. Setting: The study took place at the Fourth Hospital of Hebei Medical University in Shijiazhuang, Hebei, China. Participants: Participants were 42 patients at the hospital receiving treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) between November 2018 and October 2021. Intervention: Participants received neoadjuvant therapy of six cycles of docetaxel, carboplatin, and trastuzumab (TCbH). Outcome Measures: The research team: (1) measured 13 cytokines and immune-cell populations in peripheral blood prior to neoadjuvant therapy administration; (2) measured TILs in tumor tissues; (3) analyzed correlations among biomarkers and pCR. Results: Of the 42 participants, 18 achieved pCR (42.9%) after the neoadjuvant therapy, with 37 having an overall response rate (ORR) of 88.1%. All participants experienced at least one short-term adverse event. The most common toxicity was leukopenia, with 33 participants (78.6%), while no cardiovascular dysfunction occurred. Compared with the non-pCR group, the pCR group had higher serum levels of tumor necrosis factor alpha (TNF-ɑ), with P = .013; interleukin 6 (IL-6), with P = .025; and IL-18, with P = .0004. Univariate analysis showed that IL-6 (OR, 3.429; 95% CI,1.838-6.396; P = .0001) had a significant correlation with pCR. Participants in the pCR group had a higher level of natural killer T (NK-T) cells (P = .009) and a lower ratio of cluster of differentiation 4 (CD4):CD8 (P = .0014) before neoadjuvant therapy. Univariate analysis linked a high population of NK-T cells (OR, 0.204; 95% CI,0.052-0.808; P = .018), a low CD4:CD8 ratio (OR, 10.500; 95% CI, 2.475-44.545; P = .001), and TILs expression (OR, 0.192; 95% CI, 0.051-0.731; P = .013) to pCR. Conclusions: Immunological factors, including IL-6, NK-T cells, CD4+ T versus CD8+ T ratio, and TILs expression were significant predictors for response to TCbH neoadjuvant therapy with carboplatin.

The Safety of Neoadjuvant Therapy with Polyethylene Glycol Liposome Adriamycin Combined with Docetaxel in Patients with Breast Cancer Complicated by Axillary Lymph Node Metastasis.

Objective: To evaluate the safety of the combination of pegylated liposomal doxorubicin and docetaxel in neoadjuvant therapy for breast cancer (BC) with axillary lymph nodes metastasis. Methods: In this single-arm study, 91 patients with clinical stage IIA-IIIc BC received 6 cycles of pegylated liposomal doxorubicin plus docetaxel as neoadjuvant chemotherapy (NAC). Trastuzumab was allowed in patients with human epidermal growth factor receptor 2-positive tumors. The effects of new anthracycline-polyethylene glycol liposomal doxorubicin on the patients' hearts were studied. The changes in left ventricular ejection fraction (LVEF) before and after treatment were evaluated by echocardiography, and the levels of cardiac-specific biomarker troponin I (cTnI) and N terminal B natriuretic peptide (NT-pro-BNP) were noted before and after treatment. Result: In our study, 88 patients completed 6 cycles of neoadjuvant chemotherapy. LVEF was within normal range; average LVEF was 67% at baseline, 66% after NAC. The difference was not statistically significant. However, LVEF decreased by more than 10% in 44.4% of patients. There was no significant difference in troponin I or NT-pro-BNP levels before or after treatment. No cardiac events with clinical symptoms were reported. Conclusion: The combination of polyethylene glycol liposome adriamycin and docetaxel in neoadjuvant chemotherapy in patients with early BC with axillary lymph node metastasis has certain cardiac safety. And in the human epidermal growth factor receptor-2 (HER-2) positive population, polyethylene glycol liposome adriamycin combined with docetaxel and trastuzumab also has certain cardiac safety.

A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.

BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS. METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression. RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS. CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

HIPEC after neoadjuvant chemotherapy is associated with acceptable toxicity and favorable quality of life in newly diagnosed advanced ovarian cancer patients.

OBJECTIVE: To evaluate toxicity, quality of life and PFS in patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by CRS and HIPEC with carboplatin. METHODS: Patients with stage IIIC or IVA epithelial ovarian cancer, who were not candidates for primary CRS, were enrolled in this phase two trial. Patients received 3-6 cycles of NAC with an IV carboplatin doublet followed by CRS with HIPEC (carboplatin 800 mg/m2 for 90 min). They were followed for at least 12 months to assess for adverse events, quality of life (QOL) and disease progression. QOL was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires prior to CRS and post-operatively at 6 weeks, 3 months, and 6 months after CRS. RESULTS: Twenty patients were enrolled. HIPEC was completed successfully in all twenty patients, and there was no peri-operative mortality. Twelve (70.6%) patients experienced a grade 3 or 4 toxicity; most commonly anemia (59%), thrombocytopenia (29%), and hypokalemia (24%). There was no significant change between the pre-operative and postoperative 6 weeks, 3 month, and 6 month FACT-O, NTX, and AD scores. Nine (45%) patients have experienced disease recurrence to date. The median progression free survival in this cohort is 11.2 months (2.5-23.7 months). CONCLUSION: The addition of HIPEC with carboplatin to interval CRS was well tolerated in patient population. Myelosuppression was the most common adverse event. CRS with HIPEC did not adversely impact these patients' QOL indices. The efficacy of this regimen should be further evaluated in a larger clinical trial.

A Randomized Controlled Phase 2 Study of Neoadjuvant Eribulin Versus Paclitaxel in Women with Operable Breast Cancer: The JONIE-3 Study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. METHODS: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. RESULTS: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. CONCLUSION: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

Quality of life in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer-INCAGI004.

BACKGROUND: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. OBJECTIVE: To prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens. METHODS: Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (group 1) or 5-Fu and leucovorin (group 2) concomitant to long-course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ-C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and 1 year after the end of treatment or stoma closure (T4). The Wexner scale was used for fecal incontinence evaluation at T4. A C30SummaryScore (Geisinger and cols.) was calculated to compare QOL results. RESULTS: Thirty-two patients were assigned to group 1 and 31 to group 2. Clinical downstaging occurred in 70.0% of group 1 and 53.3% of group 2 (p = 0.288), and sphincter preservation was 83.3% in group 1 and 80.0% in group 2 (p = 0.111). No significant difference in QOL was detected when comparing the two treatment groups after neoCRT using QLQ-C30. However, the CR38 module detected differences in micturition problems (15.3 points), gastrointestinal problems (15.3 points), defecation problems (11.8 points), and sexual satisfaction (13.3 points) favoring the capecitabine group. C30SummaryScore detected significant improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p = 0.025). The mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4. CONCLUSIONS: QOL was equivalent between groups after neoCRT except for micturition problems, gastrointestinal problems, defecation problems, and sexual satisfaction favoring the capecitabine arm after. The overall QOL using the C30SummaryScore was improved after neoCRT, but decreased following rectal resection, returning to basal levels at late evaluation. Fecal incontinence was high after sphincter preservation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03428529.

Neo-adjuvant FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Surgery and systemic therapy provide the best option for long-term cancer control in localized resectable pancreas cancer. The present study assessed the efficacy and safety of neoadjuvant treatment with FOLFIRINOX in patients with borderline resectable (BR) and locally advanced (LA) pancreas cancer (PDAC). METHODS: This was a prospective noninterventional observational trial of neoadjuvant FOLFIRINOX in BR and LA PDAC. The primary objective was the R0/R1 surgical resection rate. Secondary objectives included progression free survival (PFS) and overall survival (OS), tolerability, and toxicity. RESULTS: Forty-nine patients were enrolled between 2013 and 2019; the majority had LA disease (59.2%). Median age was 61 years, and median Ca 19-9 level pretreatment was 523.4 µmol/L. Following neoadjuvant FOLFIRINOX, 11 patients (22.5%) underwent surgical resection, the majority of which were BR at diagnosis (72.7%). Median OS and PFS for the entire group were 25 (95% CI: 17.2-32.8) and 12 months (95% CI: 9.7-13.3), respectively. Median PFS in BR patients was 14 (95% CI: 10.5-17.5) compared to 12 months (95% CI: 5.2-18.8) in patients with LA patients. Median OS and PFS were not reached in patients who underwent surgical resection as compared to 22 (95% CI: 18.6-25.4) and 9 months (95% CI: 4.2-13.9) in those who did not, respectively. Grade 3/4 neutropenia, leukopenia, neuropathy, nausea/vomiting, and diarrhea occurred in 6.3%, 2.1%, 10.4%, 4.2%, and 8.3%, respectively. CONCLUSION: Neoadjuvant FOLFIRINOX is an active regimen for patients with LA/BR PDAC with a resection rate of 22.5%. These results are in line with prior data.

Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.