The Impact of Chemotherapy Completion on the Efficacy of Irinotecan in the Preoperative Chemoradiotherapy of Locally Advanced Rectal Cancer: An Expanded Analysis of the CinClare Phase III Trial

Wang, Jingwen; Fan, Jie; Li, Chao; Yang, Lifeng; Wan, Juefeng; Zhang, Hui; Zhang, Zhen

doi:10.1016/j.clcc.2020.01.004

Cited by 17 publications

(16 citation statements)

References 22 publications

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“…The combination of topoisomerase 1 inhibitor irinotecan with 5-fluorouracil has been proven effective for treating CRC [82]. Moreover, previous studies have demonstrated improved therapy efficacy combining irinotecan to the capecitabine or 5-fluorouracil chemoradiotherapy of locally advanced ReCa [83][84][85][86]. We found changes in the expression of the TOP1 gene in four ReCa signatures, while TOP1MT and TOP2A were altered in all six signatures.…”

Section: Discussionmentioning

confidence: 60%

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

Carvalho

Canto

Cury

et al. 2021

Cancers

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Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (TOP2A) gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.

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Section: Discussionmentioning

confidence: 60%

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

Carvalho

Canto

Cury

et al. 2021

Cancers

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“…In the last decade, most drugs tested concomitantly with radiotherapy plus fluoropyrimidines in the preoperative setting have not succeeded to become new treatment standards despite having previously shown efficacy in the metastatic colorectal cancer setting. These included oxaliplatin [15], irinotecan [16] and monoclonal antibodies (MoAb) such as BVZ and Cetuximab [17]. The most promising exploratory combinations involved oxaliplatin, that has been intensively studied in phase II trials, with increased ypCR rate up to 21-37% [18,19] but no benefit in long term survival outcomes [20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…Due to the discouraging results of irinotecan in the adjuvant colon cancer setting, this drug has not been extensively studied as neoadjuvant treatment. The ypCR rate communicated for Wang et al is in the rage of those reported with oxaliplatin combinations, although long term results have not been reported [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results

et al. 2020

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Background Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The “Tratamiento de Tumores Digestivos” group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. Methods Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). Results In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). Conclusions the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. Trial registration EudraCT number: 2009–010192-24. Clinicaltrials.gov number: NCT01043484.

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“…Irinotecan was also tested early as an adjunct to standard 5-FU based chemoradiation based on its known activity in metastatic colorectal cancer [ 37 ]. Several phase I-II trials and one phase III trial ([ 38 – 56 ], Table 2 ) evaluating different dose schedules have reported conflicting results with pCR rates of 10–38% (weighted average 24%). While the only phase III trial showed a significantly improved pCR rate at the cost of increased toxicity [ 55 ], the only randomized phase II trial failed to show any benefit of the addition of irinotecan to standard 5-FU based chemoradiation [ 51 , 52 ].…”

Section: Neoadjuvant Treatment Intensificationmentioning

confidence: 99%

Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review

et al. 2020

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The role of radiation therapy in the treatment of (colo)-rectal cancer has changed dramatically over the past decades. Introduced with the aim of reducing the high rates of local recurrences after conventional surgery, major developments in imaging, surgical technique, systemic therapy and radiation delivery have now created a much more complex environment leading to a more personalized approach. Functional aspects including reduction of acute or late treatment-related side effects, sphincter or even organ-preservation and the unsolved problem of still high distant failure rates have become more important while local recurrence rates can be kept low in the vast majority of patients. This review summarizes the actual role of radiation therapy in different subgroups of patients with rectal cancer, including the current standard approach in different subgroups as well as recent developments focusing on neoadjuvant treatment intensification and/or non-operative treatment approaches aiming at organ-preservation.

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The Impact of Chemotherapy Completion on the Efficacy of Irinotecan in the Preoperative Chemoradiotherapy of Locally Advanced Rectal Cancer: An Expanded Analysis of the CinClare Phase III Trial

Cited by 17 publications

References 22 publications

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results

Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review

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