Pre-operative chemoradiotherapy followed by mastectomy and breast reconstruction-A systematic review of clinical, oncological, reconstructive and aesthetic outcomes.

BACKGROUND: Pre-operative radiotherapy (PRT) and pre-operative chemoradiotherapy (PCRT) prior to mastectomy and immediate breast reconstruction for locally advanced breast cancer have the potential to reduce radiation late-effects and expedite oncologic treatment. Recent feasibility work indicates that PCRT is safe and technically possible. Here, we present a systematic review of currently available data on clinical, oncological, reconstructive and aesthetic outcomes. METHODS: A prospectively registered search of Medline (Ovid), EMBASE (Ovid), EMCARE (Ovid) and CINAHL (EBSCO) databases was performed in August 2023. Clinical, oncological, reconstructive and aesthetic outcomes were appraised with risk of bias (ROBINS-I) and methodological quality determined (STROBE checklist) for each study. RESULTS: Twenty-two published articles (19 journal articles and 3 abstracts) were identified reporting the outcomes of 1258 patients with median follow-up between 19.0-212.4 months. Patients received neoadjuvant chemotherapy in 20 studies. Rates of locoregional recurrence and overall survival ranged between 0-21.7% and 82.0%-98.3% respectively. Rates of flap loss or necrosis ranged from 0-7.6%. Rates of revisional procedures ranged between 1.9-35.3%. Patient-reported outcomes were reported in 7 studies and were mostly 'good' or 'excellent'. CONCLUSION: PRT and PCRT preceding mastectomy and breast reconstruction produce acceptable oncological outcomes with rates of surgical complication and reconstructive outcomes within normal limits, however, the majority of available studies are of low methodological quality and at high risk of bias. A pragmatic randomised trial comparing PRT versus PMRT in the setting of breast reconstruction is now urgently required to guide surgical practice.

Adjuvant chemotherapy improves long-term survival in pathologic stage III rectal mucinous adenocarcinoma after pre-operative chemoradiotherapy.

PURPOSE: The benefits of adjuvant chemotherapy remain debated rectal mucinous adenocarcinoma (MC). Our study aims to delve into the efficacy of adjuvant chemotherapy in pathologic stage III rectal MC by a large population-based database. METHODS: The Chi-square test was performed to examine the parameters between treatment groups. The overall survival (OS) and cancer-specific survival (CSS) of treatment groups were conducted by using the Kaplan-Meier method. The impact of factors on survival was assessed using Cox regression analyses. To balance the covariates and reduce the selection bias, we employed propensity score matching (PSM) to narrow the differences between treatment groups. RESULTS: The median follow-up time for overall patients was 80 months. In the pre-operative chemoradiotherapy (pre-CRT) group, patients who received adjuvant chemotherapy had significantly better 5-year OS and CSS. Multivariate analyses found that adjuvant chemotherapy was associated with better OS (p < 0.001, HR (95% CI): 0.66 (0.51-0.86)) and CSS (p = 0.012, HR (95% CI): 0.71 (0.54-0.93)). However, adjuvant chemotherapy was not an independent prognosis factor in both OS (p = 0.149, HR (95% CI): 0.76 (0.53-1.1); Supplement Table 1) and CSS (p = 0.183, HR (95% CI): 0.74 (0.48-1.15)) in patients who did not receive pre-CRT. After PSM, similar results were found in the pre-CRT and the no pre-CRT groups. CONCLUSION: In conclusion, our population-based retrospective cohort study indicates that the effects of adjuvant chemotherapy were associated with the pre-CRT status in patients with stage III rectal MC. In patients who underwent pre-CRT, the receipt of adjuvant chemotherapy was associated with better survival outcomes. Conversely, adjuvant chemotherapy does not seem to confer significant survival benefits to patients without pre-CRT.

Regional Control and Chemoradiotherapy Dose Response for Clinically Involved Lymph Nodes in Patients with Locally Advanced Endometrial Cancers Who are Not Candidates for Upfront Surgical Staging Extrafascial Hysterectomy.

AIMS: There are limited data in endometrial cancer for nodal control and appropriate treatment volume for non-surgically resected nodes treated with chemoradiotherapy (CRT) for patients who are not candidates for upfront extrafascial hysterectomy. MATERIALS AND METHODS: Patients (n = 105) with clinical stage ≥ II endometrial cancer who were not candidates for upfront extrafascial hysterectomy treated with preoperative CRT were retrospectively reviewed. CRT included pelvic nodes to the common iliac for node-negative disease and para-aortic nodes to the renal vessel for any node-positive disease. Involved nodes most commonly received a boost of 55 Gy in 25 fractions ± additional 4-6 Gy sequential boost for nodes >2 cm. RESULTS: Of the included 95 patients, 55 patients were node positive, with a total of 300 positive nodes. At a median follow-up of 25 months (interquartile range 9-46), the 3-year regional control was 91%. The 3-year involved nodal control rate was 96%. Involved nodal control was significantly higher in type I histology, nodes <2 cm and by radiation dose (75% for <55 Gy, 98% for 55 Gy in 25 fractions and 89% for >55 Gy, P = 0.03). The 3-year para-aortic failure rate for node negative patients treated with pelvis-only CRT was significantly higher with positron emission tomography/computed tomography (PET/CT) versus computed tomography (CT)-based staging (0% versus 20%). CONCLUSION: This is the largest study examining regional control rates of involved lymph nodes with CRT for patients who were not candidates for upfront extrafascial hysterectomy. Nodal failure was low following CRT and dose ≥55 Gy in 25 fractions seems to be adequate for involved nodes.

Patterns of recurrence in patients with curative resected rectal cancer according to different chemoradiotherapy strategies: Does preoperative chemoradiotherapy lower the risk of peritoneal recurrence?

The present study aimed to compare the pattern of distant recurrence between patients with non-metastatic rectal cancer treated with pre-operative (OP) and those treated with post-operative (post-OP) chemoradiotherapy (CRT). A total of 631 patients with newly diagnosed non-metastatic rectal cancer who had received pre-OP or post-OP CRT with curative intent surgery between August 2008 and April 2015 were identified. Inverse probability of treatment weighting (IPTW) was performed to account for baseline differences between the two arms. Overall, 449 and 182 patients were treated with pre-OP and post-OP CRT, respectively. Sex, tumor location, clinical tumor stage, CRT regimen and adjuvant chemotherapy regimen were significantly different between the two arms. The median follow-up duration was 55.4 months (range, 53.7-57.1). The 5-year distant recurrence-free survival (RFS) rates and 5-year overall survival (OS) rates were not significantly different between the pre-OP and post-OP CRT arms (RFS, 67.5 vs. 71.6%, P=0.595 and OS, 81.9 vs. 77.0%, P=0.449), and no difference was observed in the distant recurrence patterns. Following IPTW, there was still no difference in distant RFS (pre-OP vs. post-OP CRT; hazard ratio (HR)=0.62; P=0.911), but pre-OP CRT was significantly associated with lower peritoneal recurrence (pre-OP vs. post-OP CRT; HR, 0.13; P=0.032). In addition, there was no significant difference in OS between the two arms (pre-OP vs. post-OP CRT; HR, 0.85; P=0.665). In conclusion, although distant RFS was not significantly different between the two arms, pre-OP CRT was significantly associated with a lower risk of peritoneal recurrence than post-OP CRT in patients non-metastatic rectal cancer.

Is it Possible to Successfully Treat Locally Advanced Colon Cancer Using Pre-Operative Chemoradiotherapy?

Pre-operative chemoradiotherapy (CRT) is a preferable treatment option for patients with locally advanced rectal cancer. However, few data are available regarding pre-operative CRT for locally advanced colon cancer. Here, we describe two cases of successful treatment with pre-operative CRT and establish evidence supporting this treatment option in patients with locally advanced colon cancer. In the first case, a 65-year-old woman was diagnosed with ascending colon cancer with duodenal invasion. In the second case, a 63-year-old man was diagnosed with a colonic-duodenal fistula due to transverse colon cancer invasion. These case reports will help to establish a treatment consensus for pre-operative CRT in patients with locally advanced colon cancer.

Is it Possible to Successfully Treat Locally Advanced Colon Cancer Using Pre-Operative Chemoradiotherapy?

Pre-operative chemoradiotherapy (CRT) is a preferable treatment option for patients with locally advanced rectal cancer. However, few data are available regarding pre-operative CRT for locally advanced colon cancer. Here, we describe two cases of successful treatment with pre-operative CRT and establish evidence supporting this treatment option in patients with locally advanced colon cancer. In the first case, a 65-year-old woman was diagnosed with ascending colon cancer with duodenal invasion. In the second case, a 63-year-old man was diagnosed with a colonic-duodenal fistula due to transverse colon cancer invasion. These case reports will help to establish a treatment consensus for pre-operative CRT in patients with locally advanced colon cancer.

Oxaliplatin-containing adjuvant chemotherapy improves the survival of locally advanced rectal cancer patients with pathological complete response after pre-operative chemoradiotherapy.

BACKGROUND: The necessity for adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) patients who achieve pathological complete response (pCR) after pre-operative chemoradiotherapy (CRT) is still not identified. We aimed to investigate the therapeutic value of ACT in these patients. METHODS: Clinical data were retrospectively collected from 105 consecutive LARC patients who achieved pCR after pre-operative CRT and underwent radical tumor resection between December 2008 and April 2014 in a comprehensive cancer center. Perioperative chemotherapy (CT) was administered by combining oxaliplatin with capecitabine (XELOX regimen). Disease-free survival (DFS) and overall survival (OS) rates of patients with or without ACT were compared. RESULTS: Eighty-three (79.0%) patients received ACT and 22 (21.0%) did not. With a median follow-up of 49 months, the ACT group had a significantly higher 3-year DFS rate (92.8 vs 86.4%, p = 0.029) and 3-year OS rate (95.1 vs 86.1%, p = 0.026) than the non-ACT group. In multivariable analyses, the presence of ACT was an independent prognostic factor for DFS (hazard ratio [HR]: 0.271; 95% confidence interval (CI): 0.080-0.916; p = 0.036) but not for OS. This benefit was more obvious in patients younger than 60 years via subgroup analysis (adjusted HR: 0.106; 95% CI: 0.019-0.606; p = 0.012). CONCLUSIONS: Oxaliplatin-containing ACT may confer survival benefits to patients with pCR, particularly younger patients. However, the routine use of ACT in patients with pCR needs further validation.

Preoperative intensity-modulated radiotherapy with a simultaneous integrated boost combined with Capecitabine in locally advanced rectal cancer: short-term results of a multicentric study.

BACKGROUND: Preoperative radiotherapy (RT) in combination with fluoropyrimidine-based chemotherapy (CT) is the standard of care in patients with locally advanced, T3-T4 N0-2, rectal cancer (LARC). Given the correlation between RT dose-tumor response and the prognostic role of the tumor regression grade (TRG), treatment intensification represents an area of active investigation. The aim of the study was to analyze the role of RT dose-intensification in the preoperative treatment of LARC in terms of feasibility, efficacy and toxicity. METHODS: We retrospectively analyzed patients with LARC treated with intensity-modulated radiotherapy (IMRT) and simultaneous integrated boost (SIB) at five Italian radiation oncology centers. Concurrent Capecitabine was administered. Treatment response was evaluated in terms of disease down-staging and TRG. Acute toxicity was evaluated according to the CTC-AE 4.0 scale. RESULTS: A total of 76 patients were identified for this analysis. A dose of 45 Gy was prescribed to the entire mesorectum and pelvic lymph nodes with a median SIB dose of 54 Gy (range 52.5-57.5) to the tumor and corresponding mesorectum. Overall, 74/76 (97.4%) patients completed the planned RT, whereas 64/76 (84.2%) patients completed the prescribed CT. Eight (10.5%) patients developed grade 3-4 acute toxicity. Overall, 72/76 patients underwent surgery. The tumor and nodal down-staging was documented in 51 (70.8%) and 43 (67%) patients, respectively. Twenty (27.8%) patients obtained a pathologic complete response. Surgical morbidity was reported in 13/72 patients (18.1%). CONCLUSIONS: Although retrospective in design, this study indicates that IMRT-SIB with a dose range of 52.5-57.5 Gy (median 54 Gy) and concomitant Capecitabine appears feasible, well tolerated and effective in terms of disease down-staging and pathological complete response. Long-term toxicity and the impact on disease control and patient survival will be evaluated with a longer follow-up time. TRIAL REGISTRATION: NA.

Pre-operative chemoradiotherapy using capecitabine and cetuximab followed by definitive surgery in patients with operable rectal cancer.

BACKGROUND: Achieving a high rate of complete pathological response with pre-operative chemoradiotherapy in rectal cancer is an unmet need. We evaluated the efficacy and toxicity of the combination of cetuximab, capecitabine and radiation therapy in the pre-operative setting of localized rectal cancer. PATIENTS AND METHODS: Patients with clinically staged T3, T4 or nodepositive rectal cancer were treated with concurrent capecitabine and radiotherapy with weekly cetuximab starting one week before the start of radiation. This was followed by total mesorectal excision within 6-8 weeks. All patients achieving R0 resection received adjuvant capecitabine for 6 cycles. RESULTS: Fifteen patients were treated and all underwent surgery. Sphincter preservation was achieved in 11 patients (73.3%) and pathological complete response in two. With a median follow up of 48 months (range 8.4-57.5), 12 patients were relapse-free and 14 were alive with 4-year relapse free survival of 80%. Overall survival was 93%. Significant grade 3 and 4 toxicity was mainly cetuximab-induced skin reactions (33%), radiation-induced skin toxicity (13%) and diarrhea (20%). CONCLUSIONS: Adding cetuximab to pre-operative concurrent capecitabine and radiotherapy provides modest efficacy with manageable toxicity.

Serum miR-125b is a non-invasive predictive biomarker of the pre-operative chemoradiotherapy responsiveness in patients with rectal adenocarcinoma.

BACKGROUND: Therapeutic management of Locally Advanced Rectal Cancer (LARC) involves pre-operative chemoradiotherapy (pCRT) followed by surgery. However, after pCRT the complete pathological response is approximately 20%, whereas in 20 to 40% of patients the response is poor or absent. METHODS: Cancer biopsy specimens (n= 38) and serum samples (n= 34) obtained before pCRT from 38 LARC patients were included in the study. Patients were classified in responders (R, tumor regression grade [TRG] 1-2; n= 16) and non-responders (NR, TRG 3-5; n= 22) according to the pathological response observed upon surgery. We performed miRNA microarrays analysis on biopsy specimens, and validated the selected candidates both by qRT-PCR (tissue and serum) and by in situ hybridization (tissue, miR-125b) analyses. RESULTS: Eleven miRNAs were significantly different between R and NR (miR-154, miR-409-3p, miR-127-3p, miR-214*, miR-299-5p and miR-125b overexpressed in NR; miR-33a, miR-30e, miR-338-3p, miR-200a and miR-378 decreased). In particular, miR-125b resulted to be the best candidate to discriminate the two groups (AUC of 0.9026; 95% CI, 0.7618-1.043). Additionally, miR-125b serum levels were significantly overexpressed in NR patients compared to R (p-value=0.0087), with an excellent discriminating power (AUC of 0.782; 95% CI, 0.6123-0.9518). CONCLUSIONS: The obtained results further support the clinical impact of miRNA analysis. High miR-125b expression in tissue and serum were associated with a poor treatment response in LARC patients, therefore miR-125b could be considered as a possible novel non-invasive biomarker of response in LARC treatment.

Less than 12 lymph nodes in the surgical specimen after neoadjuvant chemo-radiotherapy: an indicator of tumor regression in locally advanced rectal cancer?

BACKGROUND: The number of lymph node retrieved in the surgical specimen is important for tumor staging and has paramount impact on prognosis in colorectal cancer and imitates the adequacy of lymph node surgical clearance. The paucity of lymph node yields in patients undergoing resection after preoperative chemo radiotherapy (CRT) in rectal cancer has seen. Lower total number of lymph nodes in the total mesoractal excision (TME) specimen after CRT, could a marker of better tumor response. METHODS: We retrospectively reviewed the prospectively managed data of patients underwent excision for rectal cancer, who treated by neoadjuvant radiotherapy with or without chemotherapy in locally advanced rectal cancer. From 2010 to 2014, 364 patients underwent rectal cancer surgery, of which ninety-one treated with neoadjuvant treatment. Standard surgical and pathological protocols were followed. Patients were categorized into two groups based on the number of total harvested lymph nodes with group 1, having 12 or more nodes harvested, and group 2 including patients who had <12 lymph nodes harvested. The total number of lymph nodes retrieved from the surgical specimen was correlated with grade of tumor regression with neoadjuvant treatment. RESULTS: Out of 91 patients, 38 patients (42%) had less than 12 lymph nodes examined in specimen. The difference in median number of lymph nodes was observed significantly as 9 (range, 2-11) versus 16 (range, 12-32), in group 2 and 1, respectively (P<0.01). Patients with fewer lymph node group were comparable with respect to age, BMI, pre-operative staging, neoadjuvant treatment. Pathological complete response in tumor pCR was seen with significantly higher rate (40% vs. 26%, P<0.05) in group 2. As per Mandard criteria, there was significant difference in tumor regression grade (TRG) between both the groups (P<0.05). Among patients with metastatic lymph nodes, median LNR was lower in <12 lymph nodes group at 0.167 (range, 0.09-0.45) versus 0.187 (range, 0.05-0.54), difference was not statistically significant (P=0.81). CONCLUSIONS: Retrieval of fewer than 12 lymph nodes in surgical specimen of rectal cancer who had received neo-adjuvant radiotherapy with or without chemotherapy should be considered as a good indicator of tumor response with better local disease control, and a good prognostic factor, rather than as a pointer of poor diligence of the surgical and pathological assessment.

Feasibility of pre-operative chemoradiotherapy with gemcitabine to treat pancreatic cancer in patients with impaired renal function.

OBJECTIVE: Although pre-operative chemoradiotherapy appears to be a promising treatment for patients with pancreatic ductal adenocarcinoma, there have been no reports of the feasibility of pre-operative chemoradiotherapy in pancreatic ductal adenocarcinoma patients with renal impairment. The aim of this study was to evaluate retrospectively the feasibility of pre-operative chemoradiotherapy in pancreatic ductal adenocarcinoma patients with renal impairment. METHODS: Twelve patients with resectable pancreatic ductal adenocarcinoma and a creatinine clearance of <60 ml/min were enrolled in this study. Gemcitabine-based pre-operative chemoradiotherapy was performed, followed by surgery. The feasibility of the treatment was evaluated in terms of clinical outcome and adverse events in the patients. RESULTS: All 12 patients completed gemcitabine-based pre-operative chemoradiotherapy without worsening of renal function. Restaging after the therapy revealed radiologically unresectable disease in two patients. Among the remaining 10 patients who underwent laparotomy, curative resection was performed in eight patients. After curative resection, five patients out of the eight completed post-operative adjuvant therapy. The 1- and 3-year survival rates after the start of chemoradiotherapy in the 12 patients were 80.8 and 36.9%, respectively. CONCLUSIONS: Our findings suggest that gemcitabine-based pre-operative chemoradiotherapy may be a safe and effective treatment for pancreatic ductal adenocarcinoma in patients with renal impairment.

Early prediction of response by ¹8F-FDG PET/CT during preoperative therapy in locally advanced rectal cancer: a systematic review.

AIM: To assess the predictive value of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in early assessing response during neo-adjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. MATERIALS AND METHODS: A systematic review was performed by search of MEDLINE Library for the following terms: "rectal carcinoma OR rectal cancer", "predictive OR prediction OR response assessment OR response OR assessment", "early OR ad interim", "therapy", "FDG OR (18)F-FDG", "PET OR PET/CT". Articles performed by the use of stand-alone PET scanners were excluded. RESULTS: 10 studies met the inclusion criteria, including 302 patients. PET/CT demonstrated a good early predictive value in the global cohort (mean sensitivity = 79%; mean specificity = 78%). SUV and its percentage decrease (response index = RI) were calculated in all studies. A higher accuracy was demonstrated for RI (mean sensitivity = 82%; pooled specificity = 85%) with a mean cut-off of 42%. The mean time point to perform PET scan during CRT resulted to be at 1.85 weeks. Some PET parameters resulted to be both predictive and not statistical predictive of response, maybe due to the small population and few studies bias. CONCLUSION: PET showed high accuracy in early prediction response during preoperative CRT, increased with the use of RI as parameter. In the era of tailored treatment, the precocious assessment of non-responder patients allows modification of the subsequent strategy especially the timing and the type of surgical approach.

Operable gastro-oesophageal junctional adenocarcinoma: Where to next?

Oesophageal junctional adenocarcinoma is a challenging and increasingly common disease. Optimisation of pre-operative staging and consolidation of surgery in large volume centres have improved outcomes, however the preferred adjunctive treatment approach remains a matter of debate. This review examines the benefits of neoadjuvant, peri-operative, and post-operative chemotherapy and chemoradiotherapy in this setting in an attempt to reach an evidence based conclusion. Recent findings relating to the molecular characterisation of oesophagogastric cancer and their impact on therapeutics are explored, in addition to the potential benefits of fluoro-deoxyglucose positron emission tomography (FDG-PET) directed therapy. Finally, efforts to decrease the incidence of junctional adenocarcinoma using early intervention in Barrett's oesophagus are discussed, including the roles of screening, endoscopic mucosal resection, ablative therapies and chemoprevention.

Long-term survival without surgery following a complete response to pre-operative chemoradiotherapy for rectal cancer: A case series.

Pre-operative chemoradiotherapy (CRT) for rectal cancer yields a complete tumor response in 10-30% of patients. There is an argument for omitting surgery in these patients, but this remains highly controversial and the supporting evidence based on long-term follow-up is lacking. The present study analyzed the long-term outcomes of five patients with cT3 or cT4 rectal cancer who showed a clinical complete response (ycCR) following pre-operative CRT and underwent no surgery. The ycCR status was determined 7-12 weeks after the completion of CRT using clinical, endoscopic and radiological studies, including magnetic resonance imaging and biopsy. The follow-up period was 54-101 months. Three patients had no tumor recurrence and were alive with no evidence of disease at 101, 100 and 93 months, respectively. One patient developed local recurrence at 59 months and another developed lung metastasis at 32 months. The two patients with tumor recurrence remained disease-free 42 and 22 months after salvage pelvic and thoracic surgery, respectively. Despite being a small series, the long-term survival outcomes of the present study indicate that a non-operative approach may be feasible for a proportion of rectal cancer patients who reveal a ycCR following pre-operative CRT.