The ypT may better predict the efficacy of neoadjuvant chemoradiotherapy than tumor regression grade in locally advanced rectal cancer patients diagnosed ypT1-4N0 / El ypT puede predecir mejor la eficacia de la quimiorradioterapia neoadyuvante que el grado de regresión tumoral en pacientes con cáncer de recto localmente avanzado diagnosticados ypT1-4N0

Purpose: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). Methods: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan–Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. Results: The median follow‐up was 35.8 months (range 2.8–71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. Conclusions: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.(AU)

DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.

BACKGROUND: The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. METHODS: Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. RESULTS: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58 years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). CONCLUSION: Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

The Auxiliary Effects of Low-Molecular-Weight Fucoidan in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy Before Surgery: A Double-Blind, Randomized, Placebo-Controlled Study.

Patients with cancer use low-molecular-weight fucoidan (LMF) as a supplement to therapy. However, most studies of LMF are in vitro or conducted using animals. Concurrent chemoradiotherapy (CCRT) is the gold standard for locally advanced rectal cancer (LARC). This study investigated the quality of life (QoL) and clinical outcomes of patients with LARC taking LMF as a supplement to neoadjuvant CCRT. This was a double-blind, randomized, placebo-controlled study. The sample comprised 87 patients, of whom 44 were included in a fucoidan group and 43 were included in a placebo group. We compared their QoL scores and clinical outcomes before treatment, and at 1 month, 2 months, and 3 months posttreatment. Pretreatment and posttreatment gut microbiota differences were also compared. Although enhanced physical well-being (PWB) at 2 months and 3 months posttreatment in the fucoidan group were observed (both P < .0125), the improvements of the Functional Assessment of Cancer Therapy for Patients with Colorectal Cancer (FACT-C) were nonsignificant (all P > .0125). Skin rash and itching and fatigue were less common in the fucoidan group (both P < .05). Posttreatment, the genus Parabacteroides was significantly more common in the gut microbiota of the fucoidan group. LMF administration improved the QoL, skin rash and itching, fatigue, and gut microbiota composition of the patients with LARC receiving CCRT.Clinical Trial Registration: NCT04342949.

Predictive factors for survival in borderline resectable and locally advanced pancreatic cancer: are these really two different entities?

BACKGROUND: The treatment of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) has evolved with a wider application of neoadjuvant chemotherapy (NACHT). The aim of this study was to identify predictive factors for survival in BR and LA PDAC. METHODS: Clinicopathologic data of patients with BR and LA PDAC who underwent surgical exploration between January 2011 and June 2021 were retrospectively collected. Survival from the date of surgery was estimated using the Kaplan-Meier method. Simple and multiple Cox proportional hazards models were fitted to identify factors associated with survival. Surgical resection was analyzed in combination with the involvement of lymph nodes as this last was only known after a formal resection. RESULTS: Ninety patients were surgically explored (BR: 45, LA: 45), of which 51 (57%) were resected (BR: 31, LA: 20). NACHT was administered to 43 patients with FOLFIRINOX being the most frequent regimen applied (33/43, 77%). Major complications (Clavien-Dindo grade III and IV) occurred in 7.8% of patients and 90-day mortality rate was 3.3%. The median overall survival since surgery was 16 months (95% CI 12-20) in the group which underwent surgical resection and 10 months (95% CI 7-13) in the group with an unresectable tumor (p=0.001). Cox proportional hazards models showed significantly lower mortality hazard for surgical resection compared to no surgical resection, even after adjusting for National Comprehensive Cancer Network  (NCCN) classification and administration of NACHT [surgical resection with involved lymph nodes vs no surgical resection (cHR 0.49; 95% CI 0.29-0.82; p=0.007)]. There was no significant difference in survival between patients with BR and LA disease (cHR= 1.01; 95% CI 0.63-1.62; p=0.98). CONCLUSIONS: Surgical resection is the only predictor of survival in patients with BR and LA PDAC, regardless of their initial classification as BR or LA. Our results suggest that surgery should not be denied to patients with LA PDAC a priori. Prospective studies including patients from the moment of diagnosis are required to identify biologic and molecular markers which may allow a better selection of patients who will benefit from surgery.

A randomized phase II study comparing preoperative mFOLFOX6 versus FOLFOXIRI for locally advanced colon cancer: JCOG2006.

The prognosis of locally advanced colon cancer (LACC) with surgical resection followed only by adjuvant chemotherapy is poor. Preoperative chemotherapy for LACC patients with risk factors such as cT4bN+ or cT3-4aN2-3 has attracted attention. Here, the authors describe the rationale and design of JCOG2006, a randomized phase II study comparing preoperative chemotherapy with mFOLFOX6 versus FOLFOXIRI for LACC. Their efficacy and safety are evaluated and a determination of which is the more promising treatment will be conducted in a subsequent phase III trial. A total of 86 patients will be accrued from 44 institutions over 2 years. The primary end point is the proportion of patients with a Tumor Regression Score of 0-2, and secondary end points include overall survival, response rate and adverse events. Clinical Trial Registration: jRCTs031210365 (https://jrct.niph.go.jp/).

Avelumab as First-Line Maintenance Treatment in Locally Advanced or Metastatic Urothelial Carcinoma.

This work provides a summary of guideline recommendations and an expert position on the use of maintenance avelumab therapy based on a review of current international clinical practice guidelines for locally advanced or metastatic urothelial carcinoma (UC). A PubMed literature search was conducted in March 2022 (updated in July 2023) to identify guidelines for locally advanced or metastatic UC. An expert panel (four oncologists and one urologist) reviewed the guidelines and clinical evidence, and discussed practical questions regarding the use of avelumab maintenance therapy in this clinical setting. The National Comprehensive Cancer Network, European Association of Urology and European Society for Medical Oncology guidelines recommend first-line cisplatin-containing chemotherapy for cisplatin-eligible patients, carboplatin-gemcitabine for cisplatin-ineligible patients who are fit for carboplatin, or immunotherapy with programmed death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) in platinum-ineligible patients. Maintenance avelumab is recommended in patients with response/stable disease following chemotherapy (regardless of PD-L1 status). In patients who relapse after/during chemotherapy, options include immunotherapy, erdafitinib [in those with fibroblast growth factor receptor (FGFR) mutations], enfortumab vedotin or further chemotherapy. The expert panel provided the following practical guidance: (1) consider maintenance avelumab in all eligible patients; (2) continue avelumab until disease progression/unacceptable toxicity; (3) ideally, administer six cycles of platinum-based chemotherapy prior to maintenance avelumab; (4) perform radiological evaluation after four chemotherapy cycles and prior to maintenance avelumab; (5) carboplatin-gemcitabine followed by maintenance avelumab is preferred in cisplatin-ineligible patients (regardless of PD-L1 expression), but consider first-line immunotherapy in PD-L1-positive patients and platinum-ineligible patients (regardless of PD-L1 status); and (6) for patients who relapse on avelumab, second-line options include enfortumab vedotin, FGFR inhibitors (in those with FGFR mutations) or clinical trial inclusion. In conclusion, avelumab maintenance therapy is recommended following platinum-based chemotherapy in all eligible patients with locally advanced or metastatic UC, continued until disease progression or unacceptable toxicity.

Meta-analysis of efficacy of Chinese medicine compound combined with concurrent radiotherapy and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma is a prevalent malignant tumor in clinical practice, with the highest incidence rate among otorhinolaryngological malignant tumors. OBJECTIVES: This study aims to comprehensively evaluate the clinical efficacy and safety of traditional Chinese medicine compound (CMC) combined with concurrent radiotherapy and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Relevant essays published before November 20, 2021, were retrieved from China National Knowledge Internet (CNKI), China Science and Technology Journal Database (CQVIP), Wanfang database, PubMed, and Web of Science databases. Randomized controlled trials regarding the clinical efficacy of CMC combined with concurrent radiotherapy and chemotherapy in the treatment of LA-NPC were included. RESULTS: A total of 15 publications involving 1324 patients were included in this study, including 665 in the experimental group and 659 in the control group. Meta-analyses revealed that compared with radiotherapy or chemotherapy only, CMC combined with concurrent radiotherapy and chemotherapy for LA-NPC significantly improved the efficacy [risk ratio (RR)=1.15, 95% confidence interval (95% CI) (1.09, 1.20), P<0.00001], the quality of life [RR=1.35, 95% CI (1.13, 1.62), P=0.0009], immune function indices CD4+ levels [RR=6.2, 95% CI (3.64, 8.76), P<0.00001], CD4+/CD8+ [RR=0.33, 95% CI (0.14, 0.53), P=0.0009], and alleviated the decrease in white blood cell counts [RR=0.67, 95% CI (0.52, 0.86), P=0.002]. CONCLUSION: CMC combined with concurrent radiotherapy and chemotherapy for the treatment of LA-NPC can significantly improve the efficacy and reduce severe adverse reactions caused by conventional radiotherapy and chemotherapy. However, due to limitations in the quantity and quality of the included studies, more high-quality, multi-center, and large sample-size studies are needed to provide high-level and high-quality medical evidence for systematic evaluation.

Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer.

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.

Determining the survival benefit of postoperative radiotherapy in patients with pT1-3N1M0 rectal cancer undergoing total mesorectal excision: a retrospective analysis.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend routine postoperative adjuvant radiotherapy and chemotherapy for patients with stage III rectal cancer who do not receive neoadjuvant therapy before surgery. The present study aimed to evaluate the value of postoperative radiotherapy in patients with low-risk disease (pT1-3N1M0) who did not receive neoadjuvant therapy prior to total mesorectal excision. METHODS: We used the Surveillance, Epidemiology, and End Results database (2004-2016) to retrospectively recruit patients with pT1-3N1M0 rectal cancer whose initial treatment was radical surgery with postoperative adjuvant chemotherapy. A propensity score model was used to balance the baseline covariates. RESULTS: Of the 2012 patients included in the present study, 1384 received adjuvant chemoradiotherapy (radio group), whereas the remaining 718 received chemotherapy alone (no-radio group). There was no significant difference in cancer-specific survival rate between the two groups (log-rank test χ2 = 2.372, P = 0.124) in the overall sample. Additionally, in the propensity score-matched cohort, adjuvant radiotherapy did not improve cancer-specific survival. Subgroup analysis showed that having three positive lymph nodes and a tumor > 50 mm, combined with postoperative adjuvant chemotherapy, could lead to an improved tumor-specific survival rate, while other cases did not benefit from postoperative radiotherapy. CONCLUSIONS: For patients with pT1-3N1M0 rectal cancer who did not receive neoadjuvant therapy before surgery, postoperative radiotherapy in addition to adjuvant chemotherapy did not significantly improve survival rates. The number of positive nodes (n = 3) and tumor size (> 50 mm) were found to be potential screening indicators for postoperative adjuvant radiotherapy.

Therapeutic Strategies for Resectable Stage-IIIA N2 Non-Small Cell Lung Cancer Patients: A Network Meta-Analysis.

Background: The National Comprehensive Cancer Network (NCCN) guidelines did not give an explicit comparison of the efficacy between surgery and radiotherapy in treating Stage-III N2 non-small cell lung cancer (NSCLC) patients, leaving a paucity for clinical reference. Through this study, we try to locate the optimum treatment strategy including surgical type for these patients. Methods: A systematic literature search was performed from PubMed, Cochrane Library, Embase, and Google Scholars. The endpoints were overall survival (OS), mean OS, and progression-free survival (PFS). The treatments comprised radiotherapy, lobectomy, and pneumonectomy. Network meta-analysis was carried out for calculating the odds ratio (OR) for binary variants. All the analyses implemented Stata 17.0 MP. Results: Eight clinical trials reporting 1756 patients met the inclusion criteria. Radiotherapy and surgery were equivalent in improving patients' OS (OR = 0.842, 95% confidence interval [CI]: [0.645, 1.099]). The mean OS of patients were similar in terms of radiotherapy, lobectomy, and pneumonectomy. Besides, radiotherapy and surgery had equivalent effects in improving PFS (OR = 0.896, 95% CI: [0.718, 1.117]). Conclusions: Since lobectomy and pneumonectomy following neoadjuvant treatments had equivalent efficacy in prolonging OS for patients with stage-IIIA N2 NSCLC compared with definitive radiotherapy, young patients with favorable performance status (0) should try surgery to pursue better prognosis while elderly patients with unfavorable PS or radiosensitive pathology types should accept definitive radiotherapy. More high-quality clinical trials are needed to support our findings.

Radiofrequency Hyperthermia Enhances Locally Delivered Oncolytic Immuno-Virotherapy for Pancreatic Adenocarcinoma.

PURPOSE: To investigate the effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immuno-virotherapy on in vitro pancreatic adenocarcinoma cell line and in vivo rat pancreatic cancer model. MATERIALS AND METHODS: Rat pancreatic adenocarcinoma cell line and 24 Lewis rats with orthotopic pancreatic adenocarcinomas underwent treatment with either (1) oncolytic virotherapy (talimogene laherparepvec [T-VEC]) plus RFH at 42 °C for 30 min; (2) oncolytic virotherapy-only; (3) RFH-only; or (4) saline (control). MTS assays and flow cytometry were used to analyze tumor cell viability and apoptosis levels 24 h after treatment. In the in vivo studies, bioluminescence optical/x-ray imaging and ultrasound imaging was used to assess tumor viability and size 7 and 14 days after treatment. Histopathologic analysis was performed after hematoxylin and eosin staining, TUNEL, Ki-67, and immunohistochemical staining with CD8 and ANK61. RESULTS: Combination therapy (T-VEC + RFH) induced decreased cell viability and increased cell apoptosis compared to T-VEC alone, RFH alone, or control. Optical/x-ray imaging and ultrasound imaging demonstrated decreased tumor bioluminescent signal and tumor volume relative to baseline after combination therapy compared to T-VEC alone, RFH alone, or control. Histopathology demonstrated decreased tumor volume and cell proliferation, increased CD8+ T cell and NK cell infiltration in tumors treated with the combination therapy compared to other three groups. CONCLUSION: RFH enhances locally delivered oncolytic immuno-virotherapy for pancreatic adenocarcinoma, with decreased cell viability and increased apoptosis observed after combination therapy in vitro, and decreased cell viability and tumor volume and increased immune cell infiltrate observed after combination therapy in vivo.

Neoadjuvant chemotherapy and radiotherapy for locally advanced breast cancer: Safety and efficacy of reverse sequence compared to standard technique?

BACKGROUND: The reverse sequence of neoadjuvant chemotherapy, preoperative radiotherapy, mastectomy then immediate breast reconstruction is currently proposed for selected patients with locally advanced breast cancer. Few studies have compared it to the standard sequence of neoadjuvant chemotherapy, mastectomy and radiotherapy with or without differed reconstruction. Our study compares overall (OS) and recurrence-free (RFS) survivals of breast cancer patients treated with reverse sequence compared to the standard technique. METHODS: In this retrospective, single center study at a Comprehensive Cancer Center in France, patients were included if: female, age <65y, had received neoadjuvant chemotherapy, mastectomy and radiotherapy, and were M0. Outcomes for patients treated by reverse sequence (RS) are compared to those for patients treated by standard sequence (ST). Data was collected from medical records. RESULTS: From January 2009 to April 2018, 222 eligible patients were treated, 46 by RS and 176 by ST. Mean follow-up was 61.7 months. Five-year OS and RFS did not differ between groups. 5-yr OS: 88.4% 95%CI [74.1-95.0] for RS and 81.5% 95%CI [74.0-87.0] for ST (P = 0.4412); 5-yr RFS: 78.3% 95%CI [61.9-88.3] for RS and 70.1% 95%CI [62.2-76.7] for ST (P = 0.3003). Overall treatment time was significantly shorter in the RS group, and the rate of severe surgical complications did not differ between groups. CONCLUSIONS: For locally advanced breast cancer patients with an indication for radiation therapy the reverse sequence offers similar safety and efficacy results as the standard treatment while allowing immediate breast reconstruction. However, careful patient selection is necessary, particularly with regard to preoperative lymph node invasion.

Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001).

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignant tumors. Esophageal cancer (EC) is a malignant tumor with a high incidence worldwide, and over 50% of EC cases occur in China. Under the National Comprehensive Cancer Network (NCCN) guidelines, concurrent chemoradiotherapy is the only standard neoadjuvant treatment for locally advanced ESCC. In the first-line treatment of advanced ESCC, the efficacy of immune checkpoint inhibitors (ICIs) combined with systemic chemotherapy is significantly better than that of chemotherapy alone. Paclitaxel and cisplatin (TP), as one of the neoadjuvant chemotherapy regimens for locally advanced ESCC, have been widely used in China in recent years. ICIs combined with TP as neoadjuvant therapy seems promising. Methods: This is an open-label, single-arm, single-center, phase-II trial. Locally advanced resectable (stage III) ESCC patients who have not undergone previous systemic treatments will be enrolled in this study. All the subjects will intravenously receive 3 cycles of pembrolizumab (200 mg) on day 1, paclitaxel (135 mg/m2) on day 2, and cisplatin (20 mg/m2) on days 2-4, every 3 weeks. After an efficacy evaluation, the subjects will undergo Da Vinci robot-assisted radical resection. If the postoperative pathologic results do not reveal a complete response, pembrolizumab will be administrated for at least 6 cycles as an adjuvant therapy with the same usage as before. The primary endpoints are the major pathological response and safety. The secondary endpoints include the objective response rate (ORR), overall survival (OS), disease-free survival (DFS), the R0 resection rate, and perioperative complications. The exploratory endpoint is to examine the correlation between related biomarkers and tumor responses to this neoadjuvant treatment regimen. Discussion: This trial is the first enrolled study to evaluate the safety and efficacy of pembrolizumab combined with TP as neoadjuvant therapy for locally advanced ESCC. Currently, under the NCCN guidelines, neoadjuvant chemoradiotherapy (nCRT) is the only recommended treatment for locally advanced ESCC. This phase-II study will provide preliminary evidence of the efficacy of pembrolizumab combined with TP as novel neoadjuvant therapy for patients with locally advanced ESCC. Trial Registration: Clinicaltrials.gov (Identifier: NCT04389177).

Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

Deep regional hyperthermia combined with modern concurrent chemoradiotherapy increases T-downstaging rate in locally advanced rectal cancer.

BACKGROUND: Deep regional hyperthermia might have an additional effect on radiotherapy in treating locally advanced rectal cancer (LARC). This study aimed to investigate the role of hyperthermia combined with modern preoperative concurrent chemoradiotherapy (CRT) for LARC. METHODS AND MATERIALS: From 2012 to 2018, 152 consecutive patients with LARC treated with neoadjuvant chemoradiation were enrolled and analyzed retrospectively. Pelvic radiotherapy (45-50 Gy) was delivered as volumetric modulated arc therapy (VMAT), concurrently with capecitabine chemotherapy. Fifty patients received hyperthermia combined with CRT (HCRT group) twice a week. Treatment response and outcomes were compared between the two groups. Furthermore, the relationships between peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) in response to hyperthermia were analyzed. RESULTS: Patients treated with hyperthermia had a significantly higher T-downstaging rate than those without hyperthermia (82.0 vs. 62.7%; p = .016). Hyperthermia was an independent favorable predictor of T-downstaging (odds ratio [OR] = 2.473; 95% confidence interval [CI] 1.050-5.826; p = .038). In the HCRT group, a pre-therapeutic elevated NLR (≥3) was associated with a higher T-downstaging rate (100.0 vs. 73.5%, p = .043). However, NLR was not associated with the T-downstaging rate in the CRT group. Five-year rates of locoregional recurrence-free survival (96.8 vs. 94.7%, p = .959), disease-free survival (DFS; 61.4 vs. 79.3%, p = .242), and overall survival (OS; 92.7 vs. 89.8%, p = .831) were not statistically different between the CRT and HCRT groups. CONCLUSIONS: Hyperthermia can improve preoperative treatment response in LARC. Pretreatment NLR may be a predictive factor for hyperthermia.

Immune checkpoint blockade for locally advanced or recurrent/metastatic cervical cancer: An update on clinical data.

Immunotherapy has shown great promise in the field of oncology, and recent clinical trials have illustrated that immune checkpoint blockade (ICB) is safe and effective at treating a range of tumor types. Cervical cancer (CC) is the fourth most common malignancy in women. However, first-line treatments for locally advanced cervical cancer (LACC) and recurrent/metastatic (R/M) CC have limited efficacy. Thus, it is necessary to explore new treatment approaches. The National Comprehensive Cancer Network (NCCN) currently recommends pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, as a first line therapy for individuals with R/M CC. This study reviews the progress of ICB therapy for LACC and R/M CC and describes the current status of the combination of ICB therapy and other therapeutic modalities, including radiotherapy, chemotherapy, targeted therapy, and other immunotherapies. The focus is placed on studies published since 2018 with the aim of highlighting novel CC-specific immunotherapeutic approaches and treatment targets.