SPAR – a randomised, placebo-controlled phase II trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: an AGITG clinical trial

Abstract Background Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). Methods A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. Discussion When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. Trial registration ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

Download Full-text

CCTG CO.28 primary endpoint analysis: Neoadjuvant chemotherapy, excision and observation for early rectal cancer, the NEO trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3508 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3508-3508

Author(s):

Hagen Fritz Kennecke ◽

Carl J Brown ◽

Jonathan M. Loree ◽

Husein Moloo ◽

Derek J. Jonker ◽

...

Keyword(s):

Rectal Cancer ◽

High Risk ◽

Tumor Progression ◽

Primary Endpoint ◽

Organ Preservation ◽

Rectal Adenocarcinoma ◽

The United States ◽

High Rate ◽

Pelvic Mri ◽

Preservation Rate

3508 Background: CO.28 (NCT03259035) is a phase II study designed to determine if patients with cT1-T3a/bN0 rectal cancer can be treated with induction chemotherapy (FOLFOX/CAPOX) and organ-preserving surgery. Methods: Patients with MRI staged cT1-3a/bN0 tumors and no pathologic (p) high risk features received 6/4 cycles of FOLFOX/CAPOX, repeat sigmoidoscopy/pelvic MRI and subsequent Transanal Endoscopic Surgery (TES) in the absence of tumor progression. ypT0/T1N0 tumors were treated with observation while ypT2+ or ypN+ stage were recommended Total Mesorectal Excision (TME). The primary endpoint was protocol specified Organ Preservation Rate (psOPR = ypT0/T1N0, no p high risk features) and actual Organ Preservation Rate (aOPR = ypT0/T1N0 stage plus higher yp stage patients who declined TME surgery). The study would be considered negative with an psOPR of 50% or lower (H0) and as promising if it is 65% or higher (H1). Results: Between 08/2017 to 05/2020, 58 eligible patients were accrued in Canada and the United States, median age was 67 years, 71% male. All had well-moderately differentiated, non-mucinous rectal adenocarcinoma and median tumor height was 6 cm (range 0-18). Median follow-up was 15.4 months. Chemotherapy with FOLFOX (32) or CAPOX (26) was administered, 90% completed all planned cycles. A total of 56/58 (97%) proceeded to TES, while one patient was ineligible due to tumor progression (1.7%) and one declined. In the intention to treat analysis, the psOPR was 57% (95% CI 43-70%) while the aOPR was 79% (95% CI 67% to 89%) due to 13/23 declining recommended TME surgery. Of 10 patients who proceeded to recommended TME, a complete R0 TME was performed in 9/10, and no p residual carcinoma was found in 7/10. Crude loco-regional (LR) and distant recurrence rates were 3.5% (95% CI 0.4 to 12%) and 0%, respectively. A recurrence occurred in 1/13 patients who initially declined TME surgery. Conclusions: In select patients with early stage rectal cancer, three months of induction CAPOX/FOLFOX followed by TES resulted in a high OPR without the use of pelvic irradiation. The observed high rate of pathologic downstaging may point to high chemo-responsiveness in early rectal adenocarcinoma with no p high risk features. Further trials to evaluate this approach are justified and updated results will be presented. Clinical trial information: NCT03259035. [Table: see text]

Download Full-text

A single-institution phase II trial of five fractions of radiotherapy followed by four courses of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.553 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 553-553 ◽

Cited By ~ 7

Author(s):

Robert J. Myerson ◽

Parag J Parikh ◽

Benjamin Tan ◽

Steven Hunt ◽

James W Fleshman ◽

...

Keyword(s):

Rectal Cancer ◽

Residual Disease ◽

Rectal Adenocarcinoma ◽

Standard Of Care ◽

Response Rates ◽

Cytotoxic Agents ◽

Preoperative Treatment ◽

Local Response ◽

Grade 3 ◽

Folfox Chemotherapy

553 Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the known benefits of preoperative RT on local response/control, (2) provide for preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT. Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for surgery, provided the response was sufficient. Preoperative treatment was 5 fractions RT (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of mFOLFOX6. Postoperative CT was at the discretion of the medical oncologist. The principal objectives are to demonstrate that this regimen can achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal to or better than historical controls. Results: Accrual opened late 2009, with 60 patients enrolled through 8/2011. Forty-six have had sufficient time to proceed to surgery with 4 having grade 3 preoperative GI morbidity. Two cases are inevaluable for response: one withdrew consent prior to CT and one received no surgery due to progression of cM1 disease (with local response). The 44 evaluable cases included 4 cT4 and 40 cT3; 32 (73%) cN+, 4 cM1. At surgery 33 (75%) had ypT0-2 residual disease including 13 (30%) ypT0, 14 (32%) were ypN+. Cases were sub-analyzed by whether disease was too advanced for the upcoming ACOSOG preoperative FOLFOX vs. 5FU-RT trial. By ACOSOG eligibility, response rates were (eligible first, ineligible second) ypT0: 10/22 (45%) vs. 3/22 (14%) (p = 0.05), ypT0-2: 19/22 (86%) vs. 14/22 (64%) (p = NS). Conclusions: This regimen achieves high response rates with acceptable morbidity. The response for ACOSOG eligible cases meets pre-determined stopping criteria for proceeding to a randomized trial. Our successor study will randomize to this regimen vs. FOLFOX alone for ACOSOG eligible cases, while initially continuing as a single arm trial for ACOSOG ineligible cases.

Download Full-text

Association of perineural invasion with outcomes after neodjuvant chemoradiation for locally advanced rectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.750 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 750-750

Author(s):

Priyanka Vinod Chablani ◽

Phuong Nguyen ◽

Charles Andrew Robinson ◽

Xueliang Jeff Pan ◽

Steve Andrew Walston ◽

...

Keyword(s):

Rectal Cancer ◽

Perineural Invasion ◽

Locally Advanced ◽

Prognostic Significance ◽

Rectal Adenocarcinoma ◽

Residual Tumor ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Resected Specimen ◽

Free Survival

750 Background: Perineural invasion (PNI) as a prognostic indicator has not been well studied in patients with rectal adenocarcinoma treated with neoadjuvant chemoradiation (nCRT). In this study, we investigated the incidence and prognostic significance of PNI in patients with stages II-III locally advanced rectal cancer treated with nCRT. Methods: We performed a retrospective study of 110 consecutive patients treated with nCRT for locally advanced rectal adenocarcinoma at a single institution from 2004 to 2011. 88 of these patients had residual tumor in the resected specimen after nCRT. We evaluated the association of PNI with clinical outcomes, including disease-free survival (DFS), distant-metastasis-free survival (DMFS), and overall survival (OS), using log-rank and Cox proportional hazard modeling. Results: Of the 88 patients with residual tumor at surgery, 14 patients (16%) had PNI and 74 patients (84%) did not. Baseline distribution of selected variables in the PNI+ and PNI- groups are shown in Table 1. Median follow-up was 27 months (range 0.9 to 84 months). The median DFS was 13.5 months for PNI+ patients and 39.8 months for PNI- patients (p<0.0001). The median DMFS was 13.5 months for PNI+ patients and median not reached (> 40 months) for PNI- patients (p<0.0001). We did not detect a significant association between the presence of PNI and worse OS, perhaps due to a high rate of censored patients in the OS analysis. In a multivariate model including pT stage, pN stage, tumor location, tumor size, type of surgery, and radial margin status, PNI remained a significant predictor of DFS (HR 16.8, 95% CI, 3.7–75.5, p<0.0002) and DMFS (HR 18.9, 95% CI, 4.4–81.9, p<0.0001). Conclusions: For patients with locally advanced rectal cancer treated with nCRT prior to surgical resection, PNI found at the time of surgery is significantly associated with worse DFS and DMFS. [Table: see text]

Download Full-text

Prognostic significance of tumour regression grade after neoadjuvant chemoradiotherapy for a cohort of patients with locally advanced rectal cancer: an 8-year retrospective single-institutional study

Colorectal Disease ◽

10.1111/codi.13757 ◽

2017 ◽

Vol 19 (7) ◽

pp. O263-O271 ◽

Cited By ~ 5

Author(s):

L. Xu ◽

S. Cai ◽

T. Xiao ◽

Y. Chen ◽

H. Qiu ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Prognostic Significance ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumour Regression ◽

Tumour Regression Grade ◽

Regression Grade

Download Full-text

Predictive factors and prognostic significance of tumor regression grade in rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.739 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 739-739

Author(s):

Oluwabunmi Ogundimu ◽

Ravi Ramjeesingh ◽

Kevin Ren ◽

Melody Xuan Lu Qu ◽

David Hurlbut ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Tumour Size ◽

Prognostic Significance ◽

Scoring Systems ◽

Rank Test ◽

Tumor Regression Grade ◽

Tumour Regression ◽

Tumour Regression Grade ◽

Regression Grade

739 Background: Several systems describe tumour regression grade (TRG) after neo-adjuvant chemo-radiotherapy (nCRT) in rectal cancer; however, there is lack of literature on factors predicting TRG and its prognostic significance when comparing two TRG systems. Methods: Chart review of 187 patients (pts) diagnosed with rectal cancer managed at our institution identified clinical T3 or T4 and/ or node positive adenocarcinoma who completed nCRT between 2005-2011. Assessment of TRG post-nCRT in 104 pts was determined using College of American Pathologists (CAP) and Modified Rectal Cancer Regression Grade (mRCRG) scoring systems. Logistic regression model was used to identify factors associated with TRG. Overall survival (OS) was estimated using Kaplan-Meier method, log-rank test to compare groups and Cox proportional hazard model to estimate hazard ratio. Results: Median age of 103 eligible pts was 64 (range [r] 31-88) and 70% were male. Median pre-nCRT tumour size was 4 cm (r 0.5-12). 61% tumours were distal. Radiation dose (RD) was >54 Gy in 57%, 50.4 Gy in 40%, and 45 Gy in 3% patients. 71% received concomitant 5 FU; 12% capecitabine and 17% according to clinical trials prior to radical surgery. Median time between completion of nCRT and surgery was 49 days. CAP scoring was 0 (21%), 1 (7%), 2 (19%), and 3 (53%) whereas mRCRG scoring was 1 (31%), 2 (21%), and 3 (48%). With median follow up 5.04 years (yr), 5 yr OS was 65%. OS was 77% for CAP 0 and 1 vs. 59% for CAP 2 and 3 (p=0.0483, HR2.4); mRCRG 1 and 2 OS was 75% vs 54% for mRCRG 3 (p= 0.0060, HR2.6). >30% reduction in pre-nCRT tumour occurred in 63% of CAP 1, 2, and 3 cases. Age (≥65 yr), higher RD and higher pre-op CEA were associated with mRCRG grade 3 (p=0.0339, 0.0415, and 0.0760 respectively). Tumour size, location, grade, type of chemotherapy, or gender were not predictive of TRG. Conclusions: Favorable TRG post-nCRT is associated with a statistically significant OS advantage. Younger age and RD escalation are associated with favorable TRG. CAP and mRCRG scoring systems of TRG were comparable for prognosis. nCRT leads to a significant cytoreduction in 63% of non-complete responders. TRG may have a future role in decisions on surgery, organ sparing, adjuvant chemotherapy, surveillance and patient counseling.

Download Full-text

Prognostic significance of pathological grading of tumour regression in post neoadjuvant chemoradiotherapy rectal cancer- A 5 year experience from a tertiary centre in S. India

Annals of Oncology ◽

10.1093/annonc/mdx261.367 ◽

2017 ◽

Vol 28 ◽

pp. iii131

Author(s):

Paulose Roopa ◽

Menon Preethi ◽

Makuny Dinesh ◽

Bhaskaran Renjitha ◽

K. Sundaram

Keyword(s):

Rectal Cancer ◽

Prognostic Significance ◽

Neoadjuvant Chemoradiotherapy ◽

Tumour Regression ◽

Tertiary Centre

Download Full-text

The extent of lymphadenectomy and overall survival depend on the timing of radiotherapy for rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.540 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 540-540

Author(s):

M. N. Le ◽

B. A. Mailey ◽

W. Lee ◽

M. P. Duldulao ◽

J. Garcia-Aguilar ◽

...

Keyword(s):

Rectal Cancer ◽

Overall Survival ◽

Los Angeles ◽

Adjuvant Radiotherapy ◽

Prognostic Significance ◽

Rectal Adenocarcinoma ◽

Cancer Surveillance ◽

Optimal Cutoff ◽

Survival Difference ◽

The Impact

540 Background: Accurate staging and local disease control depend on the extent of lymphadenectomy (LAD) in rectal cancer. Previous studies suggest that lymph node (LN) number varies with neoadjuvant therapies. Our objectives were to measure the impact of timing of radiotherapy on extent of LAD and to determine the prognostic role of LN number in rectal cancer. Methods: Patients undergoing curative-intent surgery for rectal adenocarcinoma (1988-2006) in Los Angeles County were identified from the Cancer Surveillance Program. Patients were grouped according to radiotherapy timing (neoadjuvant, adjuvant, or none). To measure prognostic significance, an optimal cutoff was assessed for patients with N0 disease by dichotomizing LN numbers from 3-7. Results: Query of the registry identified 6,358 patients. Of these, 20% (n = 1,280), 25% (n = 1,573), and 55% (n = 3,545) received neoadjuvant, adjuvant, and no radiotherapy, respectively. There was no difference in LN number in patients with and without radiotherapy (7 vs. 8 LNs, p = NS). However, within the radiotherapy cohort, there was significantly lower LNs in the neoadjuvant group (5 vs. 9 LNs, respectively; p < 0.001). Survival differences favored the groups with higher LN number. The optimal LN cutoff with no survival difference was 7 in the adjuvant radiotherapy group; there was no optimal cutoff for neoadjuvant therapy patients. Conclusions: From our population-based cohort, we observed that patients receiving neoadjuvant radiotherapy had decreased LN retrieval and that LN number was non-prognostic. In contrast, the extent of LAD is a prognostic factor for overall survival in patients receiving adjuvant radiotherapy. [Table: see text] No significant financial relationships to disclose.

Download Full-text

Phase II trial of induction mFOLFOX6 plus bevacizumab followed by neoadjuvant S-1-based chemoradiation for MRI-defined poor-risk rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.700 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 700-700 ◽

Cited By ~ 1

Author(s):

Tsuyoshi Konishi ◽

Eiji Shinozaki ◽

Keiko Murofushi ◽

Masashi Ueno ◽

Yosuke Fukunaga ◽

...

Keyword(s):

Rectal Cancer ◽

Induction Chemotherapy ◽

Phase Ii ◽

Surgical Complications ◽

Phase Ii Trial ◽

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Phase Iii ◽

Preoperative Treatment ◽

Poor Risk

700 Background: Induction chemotherapy has been explored as a novel treatment option to improve oncological outcomes in poor-risk locally advanced rectal cancer (LARC). Although previous studies have suggested high pCR rate with a favorable toxicity profile in S-1-based neoadjuvant chemoradiation, no study has evaluated induction chemotherapy added with this regimen. The present study is designed to evaluate the safety and efficacy of induction chemotherapy with bevacizumab followed by neoadjuvant S-1 based chemoradiation in MRI-defined poor-risk LARC. Methods: This was a single-center phase II trial at a high-volume cancer center. Eligible patients had low rectal adenocarcinoma with MRI-defined poor-risk features. Patients received 12-week (6 course) mFOLFOX plus bevacizumab (5 mg/kg every 2 weeks) followed by concomitant oral S-1 (80mg/m2/day on days 1-5, 8-12, 22-27, and 29-33) plus radiotherapy (50.4Gy). Surgery was scheduled for 6-10 weeks after chemoradiation. Pathological complete response (pCR) was the primary endpoint. Results: A total of 43 eligible patients were enrolled. Forty-two patients (98%) completed induction chemotherapy. Forty-two patients (98%) completed planned radiation dose. One patient with cCR after completion of preoperative treatment declined surgery, but all the other 42 patients (98%) underwent R0 resection thorough a laparoscopic approach. A pCR was achieved in 16 patients (37%; 95% confidence interval 24.4%-52.1%). CTCAE grade 3 adverse events (AEs) occurred in 4 patients (9.3%) during induction chemotherapy and 5 patients (12%) during chemoradiation. There were no grade 4 AEs. Clavien-Dindo Classification grade III-IV surgical complications occurred in 6 patients (14%), including 1 grade IVa delirium, 1 grade IIIb anastomotic leakage, 1 grade IIIb bleeding, 2 grade IIIa pelvic abscess and 1 grade IIIa urethral fistula. There was no mortality. Conclusions: Induction FOLFOX plus bevacizumab followed by S-1-based chemoradiation achieved a high pCR rate with favorable toxicity and tolerable surgical complications in poor-risk LARC. Phase III trial is needed for further evaluation. Clinical trial information: UMIN000011457.

Download Full-text

A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3510 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3510-3510 ◽

Cited By ~ 3

Author(s):

Zhen Zhang ◽

Xinchen Sun ◽

Anwen Liu ◽

Yuan Zhu ◽

Yaqun Zhu ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Phase Iii ◽

Preoperative Treatment ◽

Pelvic Radiation ◽

Irinotecan Dose ◽

Ugt1a1 Genotype

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.

Download Full-text