Total Neoadjuvant Therapy Research Articles

Total neoadjuvant oxaliplatin-based therapy (TNT) before (induction) and after (consolidation) chemoradiation for advanced rectal cancer: MRI correlation on complete response and outcome.

165 Background: Preoperative chemoradiation with fluoropyrimidine, followed by total mesorectal excision (TME) and adjuvant chemotherapy is the standard care for locally advanced rectal cancer (LARC). Studies have shown the potential benefit of oxaliplatin based TNT approach. The benefits of using of both induction and consolidation chemotherapy with chemoradiation prior of TME is not well studied. We investigate whether the use of oxaliplatin based before (induction) and after (consolidation) neoadjuvant chemoradiation will increase the pCR and clinical Complete response (cCR), improve survival and MRI correlation. Methods: Patients treated with curative intent surgery for LARC who received oxaliplatin based induction and consolidation chemotherapy with neoadjuvant capecitabine chemoradiation were identified. Demographics and clinicopathologic data were analyzed. Multiparametric MRI was used for initial staging and restaging before surgery. The primary endpoint will be the complete response (pathological and clinical), recurrent-free survival (RFS), and overall survival (OS). Results: A total of 21 patients have been identified, all patient has T3/T4 and positive nodes N1/N2 on initial MRI staging, 2 (10%) patients had Stage IV disease with abdominal para-aortic nodes. Median age was 63 (range: 26-76); 14 (67%) male. As for the induction regimen, 9 (43%) had CAPOX/FOLFOX, 7 (33%) had short-course capecitabine, 5 (24%) had FOLFIRINOX. All patient received neoadjuvant chemoradiation with capecitabine. As for consolidation, 19 (90%) had CAPOX/FOLFOX, 1 (5%) had capecitabine and 1 (5%) had FOLFIRINOX. Median time for induction and consolidation chemotherapy was 8.5 weeks (range: 1-24) and 8 weeks (range: 2-16) respectively. Median time from starting induction chemotherapy to surgery was 6.8 months (range: 3.2-11). Eight (38%) patients had cCR and pCR. Post-treatment restaging MRI prior of resection has 100% concordant rate with pCR. All (100%) pateints had tumor downstaged after treated with TNT and chemoradiation. The sensitivity of MRI in detecting the residual lymph node post TNT/neoadjuvant chemoradiation was 55% (95% CI: 26-81%), and the negative predictive value was 75% (51-90%); the specificity was 100% (76-100%) and the positive predictive value was 100% (57-100%). There is no death and one patient had recurrence after recurrence free for 2 years. Median RFS and OS are not meet. Median follow up time is 25.7 months (range: 9.1-76.8). Conclusions: Neoadjuvant oxaliplatin based therapy before and after chemoradiation for rectal cancer potentially improves CR rate, and accurately predicted by post-treatment MRI. The use of MRI can potentially help to select candidates who desire organ preservation.

High risk poorly differentiated locally advanced rectal cancers in young : Incorporating Total neoadjuvant therapy and tailoring the cancer treatment

High risk poorly differentiated locally advanced rectal cancers in young : Incorporating Total neoadjuvant therapy and tailoring the cancer treatment

Assessment of immunoscore and MRI tumor regression grade to predict complete pathologic response in patients with locally advanced rectal cancer: Data from phase II Averectal study.

212 Background: In patients with locally advanced rectal cancer (LARC), magnetic resonance imaging is the most accurate non-invasive staging tool, enabling response assessment to total neoadjuvant therapy. Wang et al had reported that 46.6% of patients with Magnetic Resonance Tumor Regression Grade 1 (mrTRG=1; complete radiologic response) achieved pathologic complete response (pCR; no residual tumor cells). We reported previously in a Phase II Averectal study the correlation between pre-treatment biopsy Immunoscore (IS) and pCR probability (68% ± 22 SD in patients with a high IS as opposed to 52% ± 22 SD in patients with a low IS; P=0.036). This study explores the value of combining IS and mrTRG to predict pCR among LARC patients. Methods: This is an open-label, single-arm multicenter stage-2 phase II study investigating the efficacy and safety of 5 fractions of short course radiotherapy, followed by 6 cycles of mFOLFOX-6 plus avelumab, followed by Total Mesorectal Excision (TME), in patients with LARC. Mean density percentiles of CD3 and CD8 positive T cells infiltrating the tumor and the invasive margin in baseline tissue samples were used to calculate IS (62% is considered the cutoff between high and low IS). Baseline and post treatment MRI were reviewed by two independent radiologists to measure mrTRG and other variables. Results: Between July 2018 and October 2020, 44 patients were accrued, out of which 40 (90%) completed at least 1 cycle of mFOLFOX/Avelumab and underwent TME. Of the 40, 36 (90%) had baseline IS, mrTRG (pre-post treatment) and pTRG (pathologic Tumor Regression Grade) assessed. Out of 36, 15 (41.6%) achieved pCR, 24 (66.7%) had mrTRG=1 and 22 (61%) had high IS. Of the high IS (n=22) patients, 10 (45.45%) achieved pCR. Also, out of 24 patients with mrTRG=1, 11 (45.8%) attained pCR. Most importantly, of the patients with combined high IS and mrTRG=1 (n=14), 11 (78.6%) achieved pCR. In patients with both mrTRG=1 and high IS, pCR rate was 78.6% (11/14). This result is significantly different from pCR rate for patients with either high IS (10/22, 45.45%) or mrTRG=1 (11/24, 45.8%) with P=0.0247 and P=0.0243 respectively. Conclusions: Combining both IS and mrTRG achieved a promising predictive value for pCR in LARC and therefore upon further validation may be potentially used for patient selection in non-operative management strategies. Clinical trial information: NCT03503630 .

Application of short-course radiotherapy with total neoadjuvant therapy in the treatment of middle and low rectal cancer

Objective: To compare the efficacy and safety of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) and neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced middle and low rectal cancer. Methods: A retrospective cohort study was carried out. A of 126 patients with locally advanced middle and low rectal cancer who were treated in the Department of Gastrointestinal Cancer Surgery of Fujian Cancer Hospital from September 2016 to March 2020 were enrolled, including 73 males and 53 females, with a mean age of (56.5±9.8) (23-77) years. Based on neoadjuvant regimen (nCRT treatment was performed before December 2018 and SCRT-TNT treatment was carried out after January 2019), patients were divided into nCRT group (n=68) and SCRT-TNT group (n=58). There were no statistically significant differences in age, sex, distance from tumor to anal verge, Eastern Cooperative Oncology Group (ECOG) performance status and clinical TNM stage between the two groups (all P>0.05). Patients in both groups received pelvic intensity-modulated radiotherapy (IMRT). The radiotherapy dose of nCRT group was 50Gy/25 times/5 weeks. Patients in nCRT group received oral capecitabine chemotherapy during radiotherapy and underwent surgery 6-8 weeks after chemoradiation. However, patients in SCRT-TNT group received CapeOX regimen (oxaliplatin+capecitabine) for 2 cycles of induction chemotherapy, followed by short-course radiotherapy (25Gy/5 times/5 days), then underwent a radical surgery two weeks after completion of consolidation chemotherapy (4 cycles). The adverse reactions, perioperative safety and efficacy of neoadjuvant therapy were compared and analyzed between the two groups. Results: Both groups completed neoadjuvant therapy as planned. Patients in nCRT group and SCRT-TNT group had similar incidence of adverse reactions to radiotherapy and chemotherapy, however, there were no statistically significant differences in the incidence of surgical complications, operation time, intraoperative blood loss and postoperative length of hospital stay (all P>0.05). A total of 119 patients underwent total mesenterectomy (TME), including 64 patients in the nCRT group and 55 patients in the SCRT-TNT group, all with R0 resection. The pathological complete response (pCR) rate was 10.9% (7/64) in the nCRT group and 25.5% (14/55) in the SCRT-TNT group, respectively, with a statistically significant difference (P=0.038). Two years after surgery, there was no statistically significant difference in local recurrence rate and overall survival rate between the two groups (both P>0.05). However, the clinical metastasis rate of SCRT-TNT group was significantly lower than that of nCRT group (20.3% vs 9.1%), with a statistically significant difference (P<0. 05). Conclusion: SCRT-TNT do not increase the adverse reactions of radio chemotherapy and perioperative risks in the treatment of locally advanced middle and low rectal cancer, and the tumor regression effect is good, which is worthy of clinical promotion.

Emerging trends in the prediction of pathological tumour response in rectal cancer following neoadjuvant therapy.

The treatment landscape of locally advanced rectal cancer (LARC) is moving towards total neoadjuvant therapy and potential organ preservation. Multimodality neoadjuvant therapy (NAT) and surgery remain the standard-of-care for LARC, with consideration for adjuvant chemotherapy. Neoadjuvant chemotherapy alone is another emerging strategy.1 Due to variation in multimodality treatment choice, biomarkers to predict response to NAT could personalize treatment plans for patients.2 Of particular interest are predictors of pathologic complete response (pCR) to guide selection for a watch and wait approach, or identify those who would benefit from surgery due to poor response to NAT or a higher risk of disease relapse. Tumour response to NAT is a complex interplay between variables including tumour biology, patient factors, and the sequencing and timing of the selected NAT approach. Presently available modalities (MRI and endoscopy) can aid assessment but do not predict for tumour response. There are currently no clinically actionable biomarkers to predict NAT response, however several promising contenders are emerging.2 Circulating tumour DNA (ctDNA) has been shown as a risk-stratification tool to guide adjuvant therapy choice in patients following colon cancer resection.3 The presence of ctDNA following long course chemoradiation and surgery is an adverse prognostic factor.4 Evidence for ctDNA in the neoadjuvant setting for LARC is also evolving. As a marker for minimal residual disease, studies have demonstrated that detectable ctDNA predicts for poorer response to NAT and potentially identifies patients that should proceed to surgery rather than a watch and wait strategy.5, 6 Other biochemical markers such as microRNA and tumour-infiltrating lymphocytes are also being evaluated.7, 8 The gut microbiome has a role in the carcinogenesis of colorectal cancer, and potentially predicts response to anticancer therapy through the effect of certain bacteria on pharmacokinetics, pharmacodynamics and immune response.9 However, questions remain regarding the specific microbiome biomarkers that can predict LARC response to NAT and its utility in clinical practice is currently limited.9 Immunogenomics is becoming increasingly relevant to the management of LARC, with immune checkpoint inhibitors exhibiting high response rates in mismatch repair deficient (dMMR) tumours and 100% clinical complete response in dMMR LARC.10 Initiatives such as the Cancer Genome Atlas Program are genomically sequencing colorectal cancers to identify genomic alterations beyond microsatellite instability that may predict responsiveness to immunotherapy and the likelihood of a pCR.11 Radiomics is a process whereby disease features, or ‘radiological biomarkers’ are extracted from standard patient imaging, constructing an algorithm which can then aid in predicting treatment response.12 T2 weighted MRI-based software for LARC successfully predicts pCR and nodal status post-NAT.13 Combined radiomics with both multi-parameter MRI (T1/T2/Contrast enhanced) and functional PET-CT may provide better predictive value for pCR.14 Currently, the widespread adoption of radiomics has been hindered by the technological and cost burden, limited reproducibility of data, and time-intensive manual data extraction.13 Larger prospective trials are required to validate its use in LARC management.13, 15 With the adoption of Artificial Intelligence (AI) and deep learning, data extraction will become increasingly accessible and construct reproducible algorithms,13 making clinical application feasible. Body composition measurement based on standard CT-staging is another ‘radiological biomarker’.16 Body composition is more accurate than body surface area for systemic therapy dosing, and predicting poor tolerance to chemotherapy in colorectal cancer.17 Recent evidence has suggested that skeletal muscle area pre-NAT can predict tumour response and survival outcomes for LARC, presenting a promising area for future studies.16 In summary, multiple promising biomarkers are emerging to identify the optimal individualized treatment paradigm for patients with LARC. It is hoped that further research and increasing validation of new technologies such as AI, will tailor future personalized decision making for patients with LARC. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. Matthew Y. Wei: Writing – original draft; writing – review and editing. Yasser Arafat: Validation; writing – review and editing. Margaret Lee: Validation; writing – review and editing. Suzanne Kosmider: Validation; writing – review and editing. Matthew Loft: Validation; writing – review and editing. Ian Faragher: Validation; writing – review and editing. Peter Gibbs: Conceptualization; validation; writing – review and editing. Justin Yeung: Conceptualization; supervision; writing – review and editing.

Clinical feasibility of the therapeutic strategies total neoadjuvant therapy and "watch and wait" in the treatment of rectal cancer patients with recurrence after clinical complete response.

In recent years, total neoadjuvant therapy (TNT) has emerged as a new therapeutic strategy against advanced rectal cancer (RC). After administration of TNT, some patients show complete clinical response (cCR) to treatment however, disputes about the effects of TNT and the alternative treatment plans in case of recurrence after cCR still exist. A total of 100 patients were included in this paper. CR and non-CR was observed when these patients were administered with TNT at the First Affiliated Hospital of Dalian Medical University, China from May 2015 to June 2021. These patients received different chemotherapeutic regimens, with close monitoring and watch and wait (W&W) strategy being applied by a multidisciplinary team (MDT). According to treatment results, patients were divided into a cCR group and a non-cCR group; according to the recurrence during W&W, they were divided into a recurrence group and a no-local-recurrence group. This study analyzed the factors that may affect the prognosis, and summarized the surgery and treatment after recurrence. The TNT strategy was effective, and 85% of patients achieved local remission. However, W&W did not affect the survival time of CR patients, nor did it cause new distant metastasis due to local recurrence during the observation period (P > 0.05). However, for patients with positive CRM, we do not recommend W&W as the first choice of treatment (P < 0.05). (1) Whole-course neoadjuvant therapy was an effective treatment scheme for advanced mid-term rectal cancer. The total local reduction rate of this group of cases was 85.00%, meaning that 25 patients achieved CR. (2) W&W was safe and reliable, and CR patients could receive it as the preferred treatment. (3) CRM was an independent risk factor for local recurrence in CR patients. We do not recommend W&W as the preferred treatment for CR patients with positive CRM.

MicroRNAs combined to radiomic features as a predictor of complete clinical response after neoadjuvant radio-chemotherapy for locally advanced rectal cancer: a preliminary study.

To define a predictive Artificial Intelligence (AI) algorithm based on the integration of a set of biopsy-based microRNAs expression data and radiomic features to understand their potential impact in predicting clinical response (CR) to neoadjuvant radio-chemotherapy (nRCT). The identification of patients who would truly benefit from nRCT for Locally Advanced Rectal Cancer (LARC) could be crucial for an improvement in a tailored therapy. Forty patients with LARC were retrospectively analyzed. An MRI of the pelvis before and after nRCT was performed. In the diagnostic biopsy, the expression levels of 7 miRNAs were measured and correlated with the tumor response rate (TRG), assessed on the surgical sample. The accuracy of complete CR (cCR) prediction was compared for i) clinical predictors; ii) radiomic features; iii) miRNAs levels; and iv) combination of radiomics and miRNAs. Clinical predictors showed the lowest accuracy. The best performing model was based on the integration of radiomic features with miR-145 expression level (AUC-ROC = 0.90). AI algorithm, based on radiomics features and the overexpression of miR-145, showed an association with the TRG class and demonstrated a significant impact on the outcome. The pre-treatment identification of responders/NON-responders to nRCT could address patients to a personalized strategy, such as total neoadjuvant therapy (TNT) for responders and upfront surgery for non-responders. The combination of radiomic features and miRNAs expression data from images and biopsy obtained through standard of care has the potential to accelerate the discovery of a noninvasive multimodal approach to predict the cCR after nRCT for LARC.

Rectal Sparing Approaches after Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-Analysis Comparing Local Excision and Watch and Wait.

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

Radiomics Approaches for the Prediction of Pathological Complete Response after Neoadjuvant Treatment in Locally Advanced Rectal Cancer: Ready for Prime Time?

In recent years, neoadjuvant therapy of locally advanced rectal cancer has seen tremendous modifications. Adding neoadjuvant chemotherapy before or after chemoradiotherapy significantly increases loco-regional disease-free survival, negative surgical margin rates, and complete response rates. The higher complete rate is particularly clinically meaningful given the possibility of organ preservation in this specific sub-population, without compromising overall survival. However, all locally advanced rectal cancer most likely does not benefit from total neoadjuvant therapy (TNT), but experiences higher toxicity rates. Diagnosis of complete response after neoadjuvant therapy is a real challenge, with a risk of false negatives and possible under-treatment. These new therapeutic approaches thus raise the need for better selection tools, enabling a personalized therapeutic approach for each patient. These tools mostly focus on the prediction of the pathological complete response given the clinical impact. In this article, we review the place of different biomarkers (clinical, biological, genomics, transcriptomics, proteomics, and radiomics) as well as their clinical implementation and discuss the most recent trends for future steps in prediction modeling in patients with locally advanced rectal cancer.

Distant Metastasis is the Dominant Cause of Treatment Failure after Lateral Lymph Node Dissection in Patients with Lateral Lymph Node Metastasis: Results of the Large Multicenter Lateral Node Study in China.

Background: Lateral lymph node (LLN) metastases (LLNM) are often associated with poor prognosis. This study aimed to investigate the prognostic significance and postoperative recurrence pattern in rectal cancer patients with LLNM after LLN dissection (LLND). Materials and Methods: This is a multicenter retrospective case-control study where propensity score-matched (PSM) analysis was introduced. From January 2012 to December 2019, 259 patients with clinical suspicion of LLNM who underwent LLND without neoadjuvant therapy were included in the study. They were divided into the negative (n = 197) and positive (n = 62) LLN groups. Primary endpoints were 3-year recurrence-free survival (RFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Results: After PSM, the DMFS rate in the positive LLN group was significantly worse (67.9 vs. 52.5%, P = 0.012). Pathological LLNM (HR, 3.07; 95% CI, 1.55-6.05; P = 0.001) were independent prognostic factors for DMFS. Patients in the positive LLN group had a higher proportion of distant metastases in all recurrence patterns (92.3% vs 82.6%). Among patients with LLN metastasis, metastases to the common iliac and external iliac arteries were the independent prognostic factor for DMFS (HR: 2.85; 95% CI, 1.31-4.67; P = 0.042). No significant different was observed for prognosis between patients with metastases to the obturator or internal iliac vessels and patients with a N2b stage. Conclusion: Distant metastasis is the main cause of treatment failure after LLND in patients with LLNM. Because of the low completion rate of adjuvant chemotherapy, preoperative chemotherapy or total neoadjuvant therapy may be considered before LLND. In addition, patients with metastasis to external iliac and common iliac vessels have an extremely poor prognosis, and systemic chemotherapy instead of LLND should be recommended.

Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in?

The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.

Total neoadjuvant therapy for pancreatic cancer: Just what are we talking about?

Background: Neoadjuvant therapy (NT) has increasingly gained popularity over upfront surgery for pancreatic adenocarcinoma (PDAC). Within this conceptual framework, administration of the complete chemotherapy course prior to surgery is considered optimal. This notion of “total” application of anti-oncologic therapy – so far referred to as Total Neoadjuvant Therapy (TNT) – appears to be, hitherto, an amalgam of different definitions, regimens and timing uniquely ascribed and executed by individual institutions. This review critically examines TNT’s reported efficacy for pancreatic cancer with an aim towards improving standardization of its nomenclature and clinical application.

Long-term outcomes in a retrospective cohort of patients with rectal cancer with complete response after total neoadjuvant therapy: a propensity-score weighted analysis.

The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery. The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis with log-rank test was used to compare survival outcomes. We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively (p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119). Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.

Total Neoadjuvant Therapy Using Short Course Radiotherapy Followed by Chemotherapy in Locally Advanced Rectal Cancer

Total Neoadjuvant Therapy Using Short Course Radiotherapy Followed by Chemotherapy in Locally Advanced Rectal Cancer

Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration

Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration

Abstract P021: Association of social determinants of health and healthcare-related factors with delayed total neoadjuvant therapy among rectal cancer patients from the national cancer database

Abstract Total neoadjuvant therapy (TNT) is a treatment strategy for rectal cancer that includes a course of chemotherapy and a separate course of chemoradiation before definitive surgery. The use of TNT has increased in recent years and carries the potential for improved sphincter preservation and a significant risk reduction of locoregional recurrence. One criterion of the National Accreditation Program for Rectal Cancer is to begin definitive treatment within 60 days of a patient’s diagnosis of rectal cancer. The objective of this study was to evaluate the association of social determinants of health and healthcare-related factors with starting TNT 60 days or more after diagnosis using data from the National Cancer Database (NCDB). Patients aged 18 years and older diagnosed with primary rectal cancer between 2016 and 2019, who underwent NCCN recommended TNT regimen followed by definitive surgery at a Commission on Cancer (CoC)-accredited facility and did not die before receiving surgery were eligible for the current study. We included 3,210 patients in the analytic sample who did not have the following conditions: clinical stage IV, clinical stage T1N0 or lower, non-adenocarcinoma histology, and adjuvant therapy use. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for factors potentially associated with starting TNT more than 60 days after a cancer diagnosis. The median age of patients included in the study was 57 years old, with a majority of them starting TNT within 60 days (87.5%), were males (62.3%), and reported as Non-Hispanic White race and ethnicity (76.7%). Furthermore, 35.0% had a median household income of $63,333 or more, 57.7% had private insurance/managed care, 65.0% traveled within 30 miles to their treatment facility, and 49.1% lived in a zip code where less than 10.9% of adults age 25 or older did not graduate from high school. In multivariable models, factors positively associated with starting TNT after 60 days or more were uninsured status (OR 2.93, CI: 1.84, 4.67), living in a zip code with more than 10.8% of adults age 25 or older not graduating from high school (OR 1.66, CI: 1.22, 2.25), traveling more than 30 miles to the treatment facility (OR 1.63, CI: 1.20, 2.20), treatment with an academic/research program (OR 1.51, CI: 1.13, 2.02), Medicaid as primary insurance (OR 1.50, CI: 1.03, 2.19), Hispanic ethnicity (OR 1.44, CI: 1.00, 2.07), male (OR 1.28, CI: 1.00, 1.65) and age (1.02, CI: 1.01, 1.04). In conclusion, results from this study show that social determinants of health and other healthcare-related factors are significantly associated with those who started TNT more than 60 days after a rectal cancer diagnosis. Further investigation is ongoing to understand the impact of delays in TNT and other treatment regimens for rectal cancer. Citation Format: Megan T. Mai, Zheng Shi, Duke Appiah. Association of social determinants of health and healthcare-related factors with delayed total neoadjuvant therapy among rectal cancer patients from the national cancer database. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P021.

Association of Systemic Chemotherapy Approaches With Outcomes in Appendiceal Peritoneal Metastases

IntroductionMany patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for appendiceal adenocarcinoma peritoneal metastases (APM) undergo preoperative systemic chemotherapy. The primary aim of this study is to evaluate differences in oncologic outcomes among two popular chemotherapy approaches in patients with APM undergoing CRS-HIPEC. MethodsWe performed a multicenter retrospective review of patients who underwent CRS-HIPEC for APM due to high or intermediate grade disease between 2013 and 2019. Patients in the total neoadjuvant therapy group (TNT) received 12 cycles of preoperative chemotherapy. Patients in the “sandwich” chemotherapy group (SAND) received six cycles of preoperative chemotherapy with a maximum of six cycles of postoperative chemotherapy. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS) defined as months from date of first treatment or surgery, respectively. ResultsA total of 39 patients were included in this analysis, with 25 (64%) patients in the TNT group and 14 (36%) patients in the SAND group. Patients in the TNT group had a median OS of 62 mo, while median OS in the SAND group was 45 mo (P = 0.01). In addition, patients in the TNT group had significantly longer RFS compared to the SAND group (35 versus 12 mo, P = 0.03). In a multivariable analysis, TNT approach was independently associated with improved OS and RFS. ConclusionsIn this multicenter retrospective analysis, a TNT approach was associated with improved overall and recurrence-free survival compared to a sandwiched chemotherapy approach in patients undergoing CRS-HIPEC for high or intermediate grade APM.

Associations between Response to Commonly Used Neo-Adjuvant Schedules in Rectal Cancer and Routinely Collected Clinical and Imaging Parameters.

Complete pathological response (pCR) is achieved in 10-20% of rectal cancers when treated with short-course radiotherapy (scRT) or long-course chemoradiotherapy (CRT) and in 28% with total neoadjuvant therapy (scRT/CRT + CTX). pCR is associated with better outcomes and a "watch-and-wait" strategy (W&W). The aim of this study was to identify baseline clinical or imaging factors predicting pCR. All patients with preoperative treatment and delays to surgery in Uppsala-Dalarna (n = 359) and Stockholm (n = 635) were included. Comparison of pCR versus non-pCR was performed with binary logistic regression models. Receiver operating characteristics (ROC) models for predicting pCR were built using factors with p &lt; 0.10 in multivariate analyses. A pCR was achieved in 12% of the 994 patients (scRT 8% [33/435], CRT 13% [48/358], scRT/CRT + CTX 21% [43/201]). In univariate and multivariate analyses, choice of CRT (OR 2.62; 95%CI 1.34-5.14, scRT reference) or scRT/CRT + CTX (4.70; 2.23-9.93), cT1-2 (3.37; 1.30-8.78; cT4 reference), tumour length ≤ 3.5 cm (2.27; 1.24-4.18), and CEA ≤ 5 µg/L (1.73; 1.04-2.90) demonstrated significant associations with achievement of pCR. Age &lt; 70 years, time from radiotherapy to surgery &gt; 11 weeks, leucocytes ≤ 109/L, and thrombocytes ≤ 4009/L were significant only in univariate analyses. The associations were not fundamentally different between treatments. A model including T-stage, tumour length, CEA, and leucocytes (with scores of 0, 0.5, or 1 for each factor, maximum 4 points) showed an area under the curve (AUC) of 0.66 (95%CI 0.60-0.71) for all patients, and 0.65-0.73 for the three treatments separately. The choice of neoadjuvant treatment in combination with low CEA, short tumour length, low cT-stage, and normal leucocytes provide support in predicting pCR and, thus, could offer guidance for selecting patients for organ preservation.

Short-course radiotherapy as part of total neoadjuvant therapy for locally advanced rectal cancer – a new standard?

Selection of optimal perioperative treatment for rectal cancer remains a subject of controversy. Recently established new rationales for the use of short-course preoperative radiotherapy (SCRT – 25 Gy in 5 fractions), instead of standard long-course preoperative radio-chemotherapy (LCRT-CT), are presented and discussed in the present review. New data suggest that short-course radiotherapy combined with 6 cycles of CAPOX, or 9 of FOLFOX4, at present may be considered the best option for perioperative treatment of high-risk rectal cancer. However, there is a clear need to further optimize preoperative treatment using rapidly evolving markers of treatment response, including microsatellite instability and targetable or predictive tumour mutations.

How We Treat Localized Rectal Cancer-An Institutional Paradigm for Total Neoadjuvant Therapy.

Total neoadjuvant therapy (TNT)-the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery-may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. Furthermore, increased response rates may allow organ-sparing strategies in a growing number of patients with low rectal cancer and upfront immunotherapy has shown very promising early results in patients with microsatellite instability (MSI)-high/mismatch-repair-deficient (dMMR) tumors. Despite the lack of a generally accepted treatment standard, we strongly believe that existing data is sufficient to adopt the concept of TNT and immunotherapy in clinical practice. The treatment algorithm presented in the following is based on our interpretation of the current data and should serve as a practical guide for treating physicians-without any claim to general validity.