Dataset Information

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

ABSTRACT:

Background and purpose

An early tumor regression index (ERI_TCP) was previously introduced and found to predict pathological response after neo-adjuvant radio-chemotherapy of rectal cancer. ERI_TCP was tested as a potential biomarker in predicting long-term disease-free survival.

Materials and methods

Data of 65 patients treated with an early regression-guided adaptive boosting technique (ART) were available. Overall, loco-regional relapse-free and distant metastasis-free survival (OS, LRFS, DMFS) were considered. Patients received 41.4?Gy in 18 fractions (2.3?Gy/fr), including ART concomitant boost on the residual GTV during the last 6 fractions (3?Gy/fr, D_mean: 45.6?Gy). Chemotherapy included oxaliplatin and 5-fluorouracil (5-FU). T2-weighted MRI taken before (MRI_pre) and at half therapy (MRI_half) were available and GTVs were contoured (V_pre, V_half). The parameter ERI_TCP?=?-ln[(1?-?(V_half/V_pre))^Vpre] was calculated for all patients. Cox regression models were assessed considering several clinical and histological variables. Cox models not including/including ERI_TCP (CONV_model and REGR_model respectively) were assessed and their discriminative power compared.

Results

At a median follow-up of 47?months, OS, LRFS and DMFS were 94%, 95% and 78%. Due to too few events, multivariable analyses focused on DMFS: the resulting CONV_model included pathological complete remission or clinical complete remission followed by surgery refusal (HR: 0.15, p?=?0.07) and 5-FU dose >90% (HR: 0.29, p?=?0.03) as best predictors, with AUC?=?0.75. REGR_model included ERI_TCP (HR: 1.019, p?90% (HR: 0.18, p?=?0.005); AUC was 0.86, significantly higher than CONV_model (p?=?0.05). Stratifying patients according to the best cut-off value for ERI_TCP and to 5-FU dose (> vs <90%) resulted in 47-month DMFS equal to 100%/69%/0% for patients with two/one/zero positive factors respectively (p?=?0.0002). ERI_TCP was also the only variable significantly associated to OS (p?=?0.01) and LRFS (p?=?0.03).

Conclusion

ERI_TCP predicts long-term DMFS after radio-chemotherapy for rectal cancer: an independent impact of the 5-FU dose was also found. This result represents a first step toward application of ERI_TCP in treatment personalization: additional confirmation on independent cohorts is warranted.

SUBMITTER: Fiorino C

PROVIDER: S-EPMC6617292 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

Fiorino Claudio C Passoni Paolo P Palmisano Anna A Gumina Calogero C Cattaneo Giovanni M GM Broggi Sara S Di Chiara Alessandra A Esposito Antonio A Mori Martina M Ronzoni Monica M Rosati Riccardo R Slim Najla N De Cobelli Francesco F Calandrino Riccardo R Di Muzio Nadia G NG

Clinical and translational radiation oncology 20190703

<h4>Background and purpose</h4>An early tumor regression index (ERI<sub>TCP</sub>) was previously introduced and found to predict pathological response after neo-adjuvant radio-chemotherapy of rectal cancer. ERI<sub>TCP</sub> was tested as a potential biomarker in predicting long-term disease-free survival.<h4>Materials and methods</h4>Data of 65 patients treated with an early regression-guided adaptive boosting technique (ART) were available. Overall, loco-regional relapse-free and distant meta ...[more]

PMID: 31334366

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Project description:Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase, DPYD). The clinical impact of testing DPYD*2A, DPYD*13, c.2846A > T and c.1236G > A-HapB3 before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes are TYMS (Thymidylate Synthase) and MTHFR (Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of a TYMS polymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, as BRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS (Kirsten Rat Sarcoma viral oncogene homolog), NRAS (Neuroblastoma RAS viral (v-ras) oncogene homolog), PIK3CA (Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well as TP53 (Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations in KRAS and TP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy.

Dataset Information

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

Background and purpose

Materials and methods

Results

Conclusion

Publications

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

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