Total Neoadjuvant Therapy Research Articles

Patterns of Care for Patients with Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy between 2016-2020: An NCDB Analysis

Treatment for locally advanced rectal cancer (LARC), defined as T3/4 or any T with N+ disease, typically requires multi-modality management consisting of radiation (RT), chemotherapy (CHT), and surgery. Despite emerging evidence that total neoadjuvant therapy (TNT) is the preferred treatment of LARC, it remains unknown what proportion of patients are receiving TNT in the United States. Our objective was to (1) determine the proportion of patients with LARC receiving TNT over time, (2) determine the most common method in which TNT is being delivered, and (3) determine what factors are associated with a lower likelihood of receiving TNT in the United States. Retrospective data was obtained from the National Cancer Database (NCDB) for patients diagnosed with rectal cancer between 2016-2020. Patients were excluded if they had M1 disease, T1-2 N0 disease, incomplete staging information, non-adenocarcinoma histology, received RT to a non-rectum site, or received a non-definitive RT dose. Patients were determined to have received TNT if they (1) received RT and multi-agent (MA)-CHT prior to surgery, (2) had an interval of >180 days from the onset of neoadjuvant therapy to surgery if they received long course (LC)-chemoradiation (CRT) (based on 35 days for LC-CRT + 112 days for 8 cycles of MA-CHT + 30 days to surgery), or (3) had an interval of >150 days from the onset of neoadjuvant therapy to surgery if they received short course (SC)-RT (based on 5 days for SC-RT + 112 days for 8 cycles of MA-CHT + 30 days to surgery). Data were analyzed using linear regression, Chi-square test, and binary logistic regression. Of the 26,375 patients included, the median age was 60 (range 21-90) years, with the majority of patients being <65 years old (65.6%), male (62.1%), and non-Hispanic white (77.0%). A total of 5,003 (19.0%) patients received TNT, and 21,372 (81.0%) patients received classical combined modality therapy (CMT). The proportion of patients receiving TNT increased significantly over time, from 6.1% in 2016, 9.0% in 2017, 15.3% in 2018, 25.8% in 2019, to 34.6% in 2020 (slope = 7.36, 95% CI 4.58-10.15, R2 = 0.96, p = 0.040). The most common TNT regimen was MA-CHT followed by LC-CRT (73.2% of cases from 2016-2020). The proportion of patients receiving SC-RT as part of TNT significantly increased from 2.8% in 2016, 1.7% in 2017, 4.6% in 2018, 7.3% in 2019, to 13.7% in 2020 (slope = 2.74, 95% CI 0.37-5.11, R2 = 0.82, p = 0.035). On multivariate analysis, factors associated with a lower likelihood of TNT use included age >65 (OR 0.66, 95% CI 0.61-0.71, p<0.001), female gender (OR 0.92, 95% CI 0.86-0.98, p = 0.014), Black race (OR 0.87, 95% CI 0.77-0.98, p = 0.024), and T3 N0 disease (OR 0.60, 95% CI 0.52-0.70, p<0.001). TNT utilization rates have significantly increased in recent years, from 6.1% in 2016 to 34.6% in 2020. The observed trend appears to be in line with the recent National Comprehensive Cancer Network (NCCN) guidelines recommending TNT as the preferred approach.

Timing of Surgery and Pathologic Complete Response (pCR) after Completing Total Neoadjuvant Therapy for Rectal Adenocarcinoma: A Retrospective Study of the National Cancer Database

Total neoadjuvant therapy (TNT) is a treatment strategy for rectal cancer that includes a course of multiagent chemotherapy and a separate course of radiation +/- concurrent chemotherapy 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. However, the influence of rest period from end of radiation to surgery after TNT is unclear. The objective of this study was to evaluate the relationship between rest period and pCR using data from the National Cancer Database. We hypothesized that longer duration of rest period before surgery will be positively associated with pCR. Patients aged 18 years and older diagnosed with primary rectal cancer between 2016 and 2020, who underwent an NCCN-recommended TNT regimen followed by definitive surgery at a Commission on Cancer-accredited facility were retrospectively analyzed in the current study. We included 5,997 patients who met the following inclusion criteria: clinical stage T2 and above, any N stage, M0, adenocarcinoma histology, and not receiving any adjuvant therapy. Logistic regression methods were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between duration of rest period and pCR. Restricted cubic splines were used to evaluate potential non-linear relationship between duration of rest period and pCR. The median age of the study sample was 57 years old (interquartile range: 49 - 65), with majority of them being males (62.3%) and reporting Non-Hispanic White race and ethnicity (75.5%). The overall pCR rate was 18.6%. The majority received long-course radiation (76.7%) and induction chemotherapy (86.3%). In multivariable adjusted models, there was a non-linear relationship between duration of rest period and pCR (p = 0.036). Rest periods of 8-24 weeks were significantly associated with elevated odds of pCR with the odds highest at 14 weeks (OR = 2.86, 95% CI: 1.20 - 6.84) when compared to rest periods of less than a week. There was no difference in pCR between long-course vs. short course radiation and no difference between those who received induction chemotherapy vs. consolidative chemotherapy. Although the rest period is inherently longer when radiation therapy precedes consolidative chemotherapy, the order of chemotherapy to radiation itself did not impact pCR but rather the duration of rest period. These data demonstrate an ideal window for surgery to achieve pCR in rectal cancer in the TNT era and the need for further prospective investigations of optimal rest period before surgery to achieve maximal pCR with homogenous TNT treatment regimens.

Patterns of Locoregional Pancreatic Cancer Recurrence after Total Neoadjuvant Therapy and Implications on Optimal Neoadjuvant Radiation Treatment Volumes

Neoadjuvant treatment for patients with localized pancreatic adenocarcinoma (PDAC) has improved survival duration. As survival increases, local disease control becomes even more important. We sought to understand the patterns of locoregional recurrence following total neoadjuvant therapy (TNT) and determine the impact of treatment volumes on recurrence. Patients with PDAC managed with neoadjuvant chemotherapy and chemoradiation (TNT) followed by surgery who developed an isolated locoregional or simultaneously locoregional and distant recurrence were identified. Locoregional recurrences were individually contoured utilizing commercially available software. When available, original neoadjuvant dose distributions were registered to the scans on which the locoregional recurrences were contoured. Recurrences where then classified as in-field (> 95% of prescription dose), marginal (50-95% of prescription dose), or out of field (< 50% of prescription dose). Target volumes were created using four commonly utilized PDAC contouring guidelines to characterize the relationship of the local recurrence to the RT dose distribution. Of 474 patients treated with TNT and surgery, 80 (17%) patients developed a locoregional recurrence with or without distant recurrence, visible on diagnostic imaging. Of the 80 patients, 56 (70%) had tumors in the pancreatic head; 46 (57.5%) were borderline resectable, 23 (28.8%) locally advanced, and 11 (13.6%) resectable. The most common initial neoadjuvant therapies were FOLFIRINOX (57.5%) and gemcitabine/nab-paclitaxel (18.8%). Chemoradiation included concurrent gemcitabine (47.5%) or 5-fluorouracil (26.3%). RT dose distributions were available for 38 patients; 22 (57.9%) had in-field failures, 9 (23.7%) marginal failures, and 7 (18.4%) out of field failures. Each published contouring atlas covered a relatively low percentage of recurrences, which are summarized in Table 1. Regions at particularly high likelihood of recurrence that were under covered on existing atlases included: aortic-diaphragmic junction, retro-pancreatic duodenal nodal basin, and the region to the right of the superior mesenteric artery (SMA). We present the largest series (to our knowledge) of mapped locoregional recurrences for patients being treated with TNT in PDAC. These recurrences differ substantially from established atlases and highlight anatomical regions of highest priority for RT coverage. A novel visual contouring volume highlighting these regions will be presented which will strive to advance the use of RT in the TNT setting.

A Novel CT-Based Radiomic Analysis for the Prediction of Overall Survival in Rectal Cancer Patients Treated with Short Course RT Total Neoadjuvant Therapy

Radiomics is a method based on the extraction of features from medical images, enriching the construction of predictive models for aiding patient management. The purpose of this study is to develop a model based on radiomic features for the overall survival (OS) in rectal cancer patients treated with total neoadjuvant therapy (TNT). Prediction of neoadjuvant rectal (NAR) score was also preliminarily evaluated. A retrospective cohort including patients treated with TNT at a single center between 2017-2021 was identified. TNT consisted of short course pelvic radiotherapy (25 Gy in 5 fractions) followed by FOLFOX or XELOX. A single CTV included mesorectum and nodal regions. Two endpoints were used: OS at 3 years (from the start of RT) and NAR score binary classification. A cut-off of 8.4 was used for NAR based on a previous local study. CTV radiomic features were extracted from simulation CTs using Pyradiomics v3. Features were extracted from the unfiltered images as well as from a set of eight filtered images. Radiomic features consist of 7 classes: shape, first order statistics, glcm, gldm, glrlm, glszm and ngtdm. 1967 initial features were extracted. Features with 0 standard deviation were removed as well as highly correlated ones (0.99 Pearson Coefficient). Dimension reduction using PCA was applied to each feature class, preserving 95% of the explained variance. Supervised algorithms were evaluated using a 10-fold cross-validation technique. Demographic and clinical features were also considered (age, sex, cT stage and N positivity) RESULTS: Eighty-two patients were included (37 females). Median age was 61.5 years (IQR 53-70). Clinical staging was comprised of 5 cT2 patients, 57 cT3 and 20 cT4, with 69 cN+. 3y-OS was 72%, with a median follow-up of 43.7 months (IQR 35.3-48.6). For the 3y-OS endpoint two prediction models were developed. First, a reference model (KNN classifying algorithm) based on demographic and clinical features only resulting in an AUC of 0.659 (SD 0.029). The second model (CART classifying algorithm) included demographic, clinical and radiomic features resulting in an AUC of 0.744 (SD 0.032). For the binary NAR classification model, a subset of 77 patients was used. Twenty-three presented a NAR<8.4 and 54 a NAR≥8.4. The CART algorithm presented the best performance with an AUC of 0.808 (SD 0.037) considering demographic, clinical and radiomic features. Radiomic models were developed for 3y-OS prediction and binary NAR classification. The addition of radiomic features to clinical and demographic information improved the predictive capability of the 3y-OS model. Radiomic prediction of NAR makes it a promising tool for the identification of potential short course RT TNT responders.

Outcomes of Watch and Wait Following Total Neoadjuvant Therapy for Rectal Cancer

To evaluate the outcomes of patients with locally advanced rectal cancer who achieved a clinical complete response (cCR) after total neoadjuvant therapy and enrolled in a prospective watch and wait (WW) database. Consecutive patients with locally advanced rectal cancer who achieved cCR following total neoadjuvant therapy (long-course chemoradiotherapy plus systemic chemotherapy) and were enrolled in our institutional WW surveillance protocol from 2014 through 2022 with the intention of organ preservation. Patients with lack of follow up according to our institutional protocol were excluded. Primary outcomes included local tumor regrowth and distant metastatic disease recurrence. Thirty-three consecutive patients (48% male; median age 61 [33-77] years) with the diagnosis of locally advanced rectal adenocarcinoma were managed by a multidisciplinary team. All patients had Eastern Cooperative Oncology Group Performance Status score of 0 or 1 at time of rectal cancer diagnosis. Location of tumor included upper rectum (18%), middle rectum (40%), and lower rectum (42%). On initial staging magnetic resonance imaging, 4 (12%) patients had evidence of extramural venous invasion, 6 (18%) had a threatened mesorectal margin, and 4 (12%) had anal sphincter or levator ani tumor involvement. A majority (61%) received chemotherapy followed by long-course chemoradiotherapy. Only one patient had an unplanned break during radiotherapy. Local tumor regrowth was diagnosed in 4 (12%) patients and all underwent successful salvage surgery without additional local failures at a median follow-up of 19 [12-48] months. Two of these four patients remain disease-free at a median follow-up time of 12.5 months. Mean time to local tumor regrowth as first site of cancer recurrence was 33.5 [18-46] months. Distant metastatic disease as the first site of recurrence occurred two patients (6%). Mean time to distant metastatic disease as first site of recurrence was 27 months. Only one mortality occurred in the entire group at a median follow-up of 49 [8-102] months. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer yields excellent outcomes with low local and distant relapse rates. Structured surveillance protocols and multidisciplinary care are essential for success.

Investigation of ATR Inhibitor VX970 as a Radiosensitizer in Colorectal Cancer Cells

Colorectal cancer (CRC) is the second leading cause of combined cancer-related mortality in males and females in the U.S. Traditional treatment of locally advanced rectal cancer consists of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Emerging data suggests that higher response rates can be achieved with total neoadjuvant therapy (TNT) where delivery of all chemotherapy and radiation therapy (RT) occurs prior to surgery. In addition, for patients with a complete response to TNT, non-operative management (NOM) can be considered. However, despite the use of TNT, pathologic complete response rates remain below 40% and NOM is only achieved in approximately 50% of rectal cancer patients. A strong need remains for more active anti-cancer therapies in rectal cancer to both reduce pelvic recurrence and facilitate NOM. Here, we tested the hypothesis that inhibition of the ataxia telangiectasia and Rad3-related protein kinase (ATR), a critical regulator of cellular DNA damage response, could increase the sensitivity of CRC to RT. VX970, a highly potent and selective ATR inhibitor, was investigated as a radiosensitizer in SW48 and LoVo CRC cell models. In vitro, IC50 of VX970 was assessed by alamarBlue cytotoxicity assay, while radiosensitivity was revealed by radiation clonogenic assays (0, 2, 4, 6, 8 Gy). ATR activity was determined by p-Chk1 using immunoblotting, and cell cycle distribution was analyzed by propidium iodide flow cytometry. CRC xenografts were generated using both LoVo and SW48 cells injected in the left flanks of athymic nude mice to explore the radiosensitizing effects of VX970 in vivo. Tumors were allowed to grow to 100-150 mm3, and the mice were randomized into multiple groups [vehicle alone, RT alone (10 Gy/5 fractions), VX970 alone, and VX970+RT]. Mouse weights and tumor size were measured three times weekly. Comparison of treatment groups was performed using the log-rank test with P<0.05 considered significant. The IC50 concentrations of VX970 on SW48 and LoVo cells were about 500 and 100 nM, respectively. VX970 at doses of 3 nM did not alter the viability of CRC cells, but significantly sensitized CRC cells to radiotherapy (P<0.05), with DER of 1.43 and 1.59, respectively, in SW48 and LoVo cells. VX970 efficiently attenuated p-Chk1 expression and significantly abrogated radiation induced G2/M cell cycle arrest (P<0.05). In addition, VX970 in combination with radiotherapy significantly prolonged tumor growth delay of CRC xenografts compared to radiation alone (P<0.05), with minimal toxicity observed. Inhibition of the ATR-Chk1 pathway by targeting ATR kinase with VX970 sensitizes CRC to radiotherapy in vitro and in vivo. Our findings support that ATR inhibition by VX970 is a promising new approach to improve the therapeutic ratio of radiotherapy for patients with CRC and warrants further clinical testing.

Prognostic Role and Time Varying Failure Hazard of Neoadjuvant Rectal (NAR) Scores in the Stellar Randomized Phase 3 Trial

This study examined the prognostic role of the neoadjuvant rectal (NAR) score on disease-free survival (DFS) in the STELLAR phase III trial and assessed time-varying failure hazard. The study included patients from the STELLAR trial who underwent total mesorecta excision and had calculable NAR scores. Chi-square tests were used to analyze the distribution of demographic information, treatment information, and NAR scores. Kaplan-Meier and Cox regression analyses assessed DFS, while smoothed hazard plots evaluated hazard variations. Of 461 patients, 231 received total neoadjuvant therapy (TNT) and 229 received concurrent chemoradiotherapy (CRT). With a median follow-up of 37 months, 3-year DFS rates for low, intermediate, and high NAR scores were 86.2%, 72.671.8%, and 53.153.6%, respectively (P <0.001). In the TNT group, rates for the corresponding NAR score groups were 87.3%, 67.6%, and 52.4% while in the CRT group, rates were 84.7%, 76.0%, and 53.4% (both P <0.001). Multivariate analysis showed NAR scores as independent prognostic factors for DFS (intermediate vs. low, hazard ratio (HR) = 2.452.55, 95% confidence interval (CI): 1.347 - 4.4675, P <0.003; high vs. low, HR = 4.2668, 95% CI: 2.5133 - 8.727.79, P <0.001). The DFS hazardrisk rates for different NAR score groups initially increased and then decreased, peaking in the second year with rates of 5.04.6%, 11.62%, and 21.52% for low, intermediate, and high NAR scores, respectively. After the fourth year, the high NAR score still had a higher failure hazardrisk (12.5%), while the intermediate and low NAR score had a lower relapse hazardrisk (<3%). The NAR score was a strong prognostic factor for DFS in the STELLAR trial, irrespective of TNT or CRT modalities. Hazard variations at different NAR score levels offer insights for personalized monitoring and warrant further investigation in clinical trials using NAR scores as endpoints. (NCT02533271).

Short Course Radiotherapy (SCRT) with Simultaneous Integrated Boost (SIB) in the Treatment of Rectal Cancer: Feasibility and Early Toxicities

To report the feasibility and early toxicities of dose-escalated SCRT in rectal cancer patients receiving total neoadjuvant therapy (TNT). This retrospective cohort study included 13 patients treated via a TNT approach (guided by RAPIDO trial) for locally advanced rectal cancer. The planned radiation was a standard dose of 25 Gy in 5 fractions to the primary tumor and at-risk lymphatics (PTV_Low). The dose-escalation was achieved via SIB delivering 30 Gy to the primary tumor (PTV_Mid) and 40 Gy (PTV_High) to inoperable lateral pelvic lymph nodes (LN), when present, over 5 fractions. A 5 mm margin was added to the rectal tumor and lateral pelvic LN to create the SIB targets. All patients were planned for intensity modulated radiation therapy via Varian EclipseTM (Palo Alto, CA) treatment planning system. Prior to treatment patients underwent kV and cone beam CT (CBCT) imaging for image guidance. Shifts were not performed solely to accommodate the boost target volume if it was felt to compromise the coverage of at-risk lymphatics. Normal tissue constraints were prioritized over boost coverage. Early toxicities were assessed for 30 days following treatment and graded using the Common Terminology Criteria for Adverse Events version 5.0. Offline image review was performed to determine the frequency at which the gross tumor volume (GTV) was captured within the 5 mm planning target volume (PTV_Mid) margin on daily CBCT scans. If a misalignment (tumor crossing outside of PTV_High) was discovered, the direction of misalignment (lateral/anterior/posterior) and location (superior/inferior) in relation to the superior border of the pubic symphysis was documented. An additional 5 mm margin from the PTV_Mid was created to determine if this would have captured the target. Twelve of the 13 patients were ≥ 30 days from treatment completion and were included in the toxicity analysis. The most common grade 1-2 toxicities were proctitis and diarrhea, which occurred in 42% and 25% of patients, respectively. Other toxicities were new onset rectal bleeding (17%), rectal pain (17%) and radiation dermatitis (8%). No grade 3+ toxicities were observed. Given five fractions for each of the 13 patients, a total of 65 CBCTs were reviewed and compared to the planning CT obtained at simulation. A total of 14/65 (22%) misalignments were discovered across six patients. All occurred above the superior edge of the pubic symphysis. Four misalignments were multi-directional. Nine were anterior, 6 were lateral, and 1 was posterior. Twelve of the 14 (86%) would have been covered within the additional 5 mm expansion volume. In this cohort of patients who received dose-escalated SCRT, the composite rate of acute toxicity was expectedly low. Feasibility of treatment delivery was established but could be improved upon with an addition 5 mm expansion, specifically in locations cranial to the superior edge of the pubic symphysis.

Anal Canal Adenocarcinomas: Prognostic Factors and Outcomes at a Single Institution

Adenocarcinomas of the anal canal (AAC) represent a rarity among cancers of the digestive tract. Data guiding management is limited to retrospective studies and optimal treatment paradigms of AAC are still evolving. Here, we aim to investigate their prognostic factors and outcomes. We reviewed anorectal adenocarcinoma patients who underwent curative-intent neo/adjuvant therapy +/- surgery at a single institution from 2015-2019. AAC were defined as tumor epicenters ≤ 2 cm from the dentate line. Our primary outcome was 5-year overall survival (OS). We also analyzed 5-year local recurrence, distant metastasis, and disease-free survival (DFS), defined as the interval after treatment completion to the first occurrence of local, regional, distant recurrence, or death. All tumors were staged according to the Rectal Cancer paradigm per AJCC 7th Staging. Kaplan-Meier and Cox-Proportional Hazards Model were used for survival analyses. In our cohort, 57 patients met inclusion criteria. Median follow-up time was 54 months. The median age was 64 years; 35% of the cohort was female. The majority of tumors were adenocarcinomas (77%), with a minority of mucinous (12%) and signet ring cell (11%) histologies. The median tumor size was 4 cm, located 1 cm from the anal verge. Most tumors (63%) were grade 2, 77% had T3 disease, and 53% had clinical nodal involvement. Most patients completed neoadjuvant chemoradiation, total mesorectal excision, and adjuvant chemotherapy (54%). Fifty-four percent underwent abdominopelvic resection. Of those who received neoadjuvant therapy, 11% achieved a pathologic complete response. Seventy percent of patients completed chemotherapy, either in the neoadjuvant or adjuvant setting. At 5 years, local recurrence was 9%, regional pelvic recurrence was 12%, inguinal nodal recurrence was 2%, and distant recurrence was 25%. Five-year DFS was 63% and 5-year OS was 70%. Multivariate analysis demonstrated age, female gender, CEA, grade 3 disease, mucinous histology, and nodal involvement to be prognostic of lower OS. Receipt of neo/adjuvant chemotherapy was found to be prognostic of higher OS (HR 0.13, p<0.05). In this cohort, the majority of whom received surgical management, we show numerically similar or higher overall survival in comparison with prior studies. This study is limited by its retrospective nature and sample sizes of an exceedingly rare entity. Receipt of neo/adjuvant chemotherapy appears to have an impact on survival. Further investigation is needed to explore the role of total neoadjuvant therapy in improving outcomes in this patient population.

Cost-Effectiveness of Short-Course Radiotherapy Based Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer in China

The phase III STELLAR (NCT02533271) trial demonstrated that four cycles of chemotherapy after short-course radiotherapy (SCRT-TNT) were not inferior to the standard care of long-course concurrent radiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). This study assessed the cost-effectiveness of SCRT-TNT versus LCRT in locally advanced rectal cancer in China on the basis of the STELLAR trial. A Markov model was used to synthesize the healthcare costs and benefits of LARC patients based on results from the STELLAR trial. The model assumes that LARC who meet the inclusion criteria of the STELLAR trial experience four possible states: No Evidence of Disease (NED), locally recurrence, distant metastases, or any death from rectal cancer or other unrelated causes, where local recurrence continues to be classified as resectable and unresectable. The transition status period is 3 month, and 5 years is used to calculate direct medical costs and health benefits. The probabilities of states transition after SCRT-TNT or LCRT were derived from the results of the STELLAR trial and previous published article (Table.1). Costs were evaluated from the Chinese payer's perspective reported in early 2022 US dollars (US$1 = 6.78 Chinese Yuan). Sensitivity analyses were performed for key variables. Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Willingness-to-pay (WTP) threshold was set at $43500/QALY. Data were collected from October 3, 2020, to September 20, 2021, and analyzed from November 15, 2020, to October 25, 2021. During the 5-year horizon, for the base case scenario, SCRT-TNT incurred a lower total cost and higher QALYs compared with LCCRT. The total cost was $65767 and QALYs were 1.77 for SCRT-TNT; for LCCRT, the total cost was $72802 and QALYs were 1.64. This resulted in an ICER of -$ 55470.69 per QALY. Therefore, SCRT-TNT was a cost-saving and dominating treatment strategy compared with LCRT. Sensitivity analysis showed that ICERs were most sensitive to the parameters of distant metastases risk after treatment. SCRT-TNT in locally advanced rectal cancer can be a cost-effective alternative to LCRT in China, and should be considered in appropriately selected patients.

Outcomes Following Recent and Distant Neoadjuvant Radiation in Rectal Cancer: An Institutional Retrospective Review and Analysis of NSQIP

BackgroundNeoadjuvant chemoradiotherapy (nCRT) is the standard of care in locally advanced rectal cancer (LARC). However, radiation therapy is thought to increase operative difficulty due to induction of fibrosis. Total neoadjuvant therapy (TNT) protocols increase the time between completion of radiation and surgical resection which may lead to increased operative difficulty and complications. MethodsA single institution retrospective review of patients ≥18 years with LARC undergoing nCRT from 2015 to 2022. Patients were dichotomized in 2 cohorts: <90 days from radiation to surgery (recent radiation), and ≥90 days from radiation to surgery (distant radiation). Institutional data was compared to National Surgical Quality Improvement Program (NSQIP) rectal cancer data from 2016 to 2020. Outcomes included intraoperative complications, 30-day morbidity, and oncologic outcomes. ResultsOne hundred forty-six institutional patients included, 120 had recent radiation, 26 had distant radiation. Thirty-day morbidity and intraoperative complications did not differ. There was greater radial margin positivity (7% vs. 24%), fewer lymph nodes harvested (17 ± 5 vs. 15 ± 6), and a lower rate of complete mesorectal dissection (88% vs. 65%,) in distant radiation patients 3059 patients were included in NSQIP analysis, 2029 completed radiation <90 days before surgery and 1030 without radiation 90 days before surgery. Patients without radiation 90 days preoperatively had more radial margin positivity (9.2% vs. 4.6%), organ space infection (8.6% vs. 6.4%), and pneumonia (2.2% vs. 0.9%). ConclusionThe present study suggests that increased time between radiation and surgery results in more challenging dissection with less complete mesorectal dissection and increased radial margin positivity without increasing technical complications.

Multimodal assessment after total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer accurately predicts complete responders.

This study aimed to compare local regrowth rates after total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy (SNCRT) in locally advanced rectal cancer (LARC) patients that were strictly selected and assessed with a multimodal approach. Secondary outcomes were 4-year disease-free (DFS) and overall survival (OS) rates. Locally advanced rectal cancer patients without distant metastases treated at Koç Healthcare Group between January 2014 and January 2021 were included. Patients were assessed for complete response with a combination of digital rectal exam, endoscopy, and magnetic resonance imaging with a dedicated rectum protocol. The systemic evaluation was performed with an upper abdomen MRI using intravenous hepatobiliary contrast agent and a thorax CT. Of the 270 patients with LARC, 182 fulfilled the inclusion criteria. Ninety-seven (53.3%) underwent TNT, while 85 (46.7%) underwent SNCRT. A cumulative combination of pathological and sustained clinical complete response was significantly higher in the TNT group than in the SNCRT (45.4% vs. 20.0%, p < 0.0001). After a median follow-up of 48months, seven patients in the W&W group had regrowth [TNT: 4 (10.8%) vs. SNCRT: 3 (23.1%), p = 0.357]. Based on pathological examination, complete/near complete mesorectum rates (p = 1.000) and circumferential resection margin positivity rates (p = 1.000) were similar between the groups. The 4-year DFS and OS rates were comparable. The patients with clinical or pathological complete response had significantly longer overall survival (p = 0.017) regardless of the type of neoadjuvant treatment. Multimodal assessment after TNT effectively detects complete responders, resulting in low local recurrence and increased cumulative complete response rates. However, these outcomes did not translate into a survival advantage.

Surveillance after Total Neoadjuvant Therapy: What to do for Near-Complete Responders.

A proportion of patients who undergo total neoadjuvant therapy for rectal cancer will achieve what is classified as a near-complete response. Significant debate exists as to the optimal management strategy for these patients with large heterogeneity in management. This article will examine the therapeutic and surveillance options for these patients as well as the relevant outcomes data.

Total neoadjuvant therapy for rectal cancer: evidence and challenge.

Recent advances in the management of rectal cancer have dramatically changed the clinical practice of colorectal surgeons because the main focus of rectal cancer treatment has changed from sphincter-saving to an organ-preserving strategies. Modifying the delivery of systemic chemotherapy to improve patients' survival is another progress in colorectal cancer management, known as total neoadjuvant therapy (TNT). TNT is a new strategy used by colorectal surgeons to improve the quality of life and survival of patients after treatment. TNT poses limitations or obstacles, such as overtreatment issues in patients with stage I rectal cancer. However, considering the quality-of-life issues in patients with low-lying rectal cancer necessitating a permanent colostomy, the indication for TNT will be expanded. This review summarizes the recently conducted clinical trials and foresees future perspectives on TNT.

Radiotherapy for Rectal Cancer: How Much is Enough?

Though resection has been the mainstay of treatment for nonmetastatic rectal cancer over the past century, radiation has become an increasingly integral component of care for locally advanced disease. Today, two predominant radiotherapy approaches-hyperfractionated chemoradiotherapy and "short-course" radiation-are widely utilized to reduce local recurrence and, in some cases, cure disease. Both have been incorporated into total neoadjuvant therapy (TNT) regimens and achieved excellent local control and superior complete response rates compared to chemoradiation alone. Additionally, initial results of "watch and wait" protocols utilizing either radiation modality have been promising. Yet, differences do exist; though short course is cheaper and more convenient for patients, recently published data may show superior complete response and local recurrence rates with chemoradiation. Ultimately, direct comparisons of short-course radiotherapy against chemoradiation within the TNT framework are needed to identify optimal radiation regimens in the treatment of locally advanced rectal cancer.

Chemoradiation, Consolidation Chemotherapy, and Watch and Wait for Early Rectal Cancer.

As watch and wait has become an attractive management alternative among patients with rectal cancer who achieve a clinical complete response to neoadjuvant chemoradiation, the focus of organ preservation has now shifted toward the use of this approach in patients with early rectal cancer. These patients would otherwise be treated without the use of neoadjuvant therapy for oncological reasons. The sole purpose of any neoadjuvant treatment here would be the achievement of a complete clinical response in an attempt to avoid total mesorectal excision. This has become particularly interesting after the incorporation of total neoadjuvant therapy regimens. These regimens have resulted in significantly higher rates of complete tumor regression and therefore become an interesting alternative among early rectal cancer patients where organ preservation is desired. The present review provides an overview of the currently available evidence and the preliminary experience with this rather controversial approach.

Total neoadjuvant therapy improves survival of patients with borderline resectable pancreatic cancer with arterial involvement.

This study aimed to evaluate the prognostic impact of total neoadjuvant therapy (TNT) for borderline resectable pancreatic cancer with arterial involvement (BR-A) pancreatic cancer. We analyzed 81 patients initially diagnosed as BR-A who received initial treatments between 2007 and 2021. Among them, 18 patients who received upfront surgery were classified as the UFS group, while 30 patients who were treated with neoadjuvant chemoradiotherapy were classified as the NACRT group. Furthermore, 33 patients who planned to receive a combination treatment of over 6 months of systemic chemotherapies followed by chemoradiotherapy before surgery were classified as the TNT group. There were no significant differences in the patients' backgrounds between the three groups at the time of initial treatment. The resection rates of the UFS, NACRT, and TNT groups were 89%, 77%, and 67%, respectively. NACRT had no impact on the prognosis compared to upfront surgery. In sharp contrast, the TNT group had a significantly better prognosis compared to the other groups, especially after pancreatic resection. Multivariate analysis demonstrated that TNT and resection were independent prognostic factors for the patients of BR-A. TNT can be a promising therapeutic strategy for patients with BR-A.

Influence of proton pump inhibitors on the pathological response of rectal cancer: a multicentre study.

The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial

BackgroundFor locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC.MethodsThis is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2–4 weeks in the TNT group and 6–10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate.DiscussionThe TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients.Trial registrationCris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Compliance and Toxicity of Total Neoadjuvant Therapy for Rectal Cancer: A Secondary Analysis of the OPRA Trial

Patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) may achieve organ preservation without a compromise to oncologic outcomes. However, reports on patient compliance with TNT and with treatment-related toxicities are limited. The OPRA trial assessed organ preservation rates and oncologic outcomes in patients with clinical stage II/III rectal adenocarcinoma randomized to induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Systemic chemotherapy consisted of 8 cycles (16 weeks) of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or 5 cycles (15 weeks) of capecitabine and oxaliplatin (CAPEOX). Patients received >4500 cGy of radiation with sensitizing capecitabine or fluorouracil. In this report, we compare compliance and treatment-related toxicity in patients receiving INCT-CRT versus CRT-CNCT. Additionally, we evaluate the association of compliance to chemotherapy, compliance to chemoradiation, and toxicity with organ preservation and disease-free survival (DFS). Of the 324 patients randomized, fewer patients started chemoradiation in the INCT-CRT group compared with the CRT-CNCT group (93% vs 98%, P=.03), and fewer patients started systemic chemotherapy in the CRT-CNCT group compared with the INCT-CRT group (94% vs 99%, P=.04). Order of TNT did not affect the ability to complete all intended cycles of FOLFOX (86% INCT-CRT vs 83% CRT-CNCT, P=.60) or CAPEOX (74% INCT-CRT vs 77% CRT-CNCT, P=.80). A total of 97% of INCT and 98% of CRT-CNCT patients received >4500 cGy radiation (P=.93). Sixty-four patients (41%) treated with INCT-CRT and 57 CRT-CNCT patients (34%) experienced a grade 3+ adverse event (P=.30). Compliance and toxicity were not associated with organ preservation or DFS. We identified only minor differences in treatment compliance between patients treated with INCT-CRT and CRT-CNCT. No difference in adverse events was observed between groups. Treatment compliance and toxicity did not correlate with organ preservation rates or DFS.