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Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

ABSTRACT: Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.

SUBMITTER: Ramzan Z

PROVIDER: S-EPMC4092337 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

Ramzan Zeeshan Z Nassri Ammar B AB Huerta Sergio S

World journal of gastrointestinal oncology 20140701 7

Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, ...[more]

PMID: 25024812

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Project description:PurposeThe standard of care in locally advanced rectal cancer is preoperative treatment with fluoropyrimidine-based chemoradiotherapy. Sorafenib works synergistically with radiation and inhibits Ras/Raf, PDFGR, and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-fluorouracil (5-FU) and radiation in patients with locally advanced rectal cancer.Methods and materialsPatients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level, with an expansion cohort at the maximum tolerated dose. A 3+3 dose escalation design was used. Radiation was given in 28 fractions at 1.8 Gy (50.4 Gy) day 1-5 at all dose levels. Initial dose of sorafenib was 200mg qd and titrated up to 400mg BID to determine the MTD. Standard dose of infusional 5-FU was used (225 mg/m(2)/24h). Patients underwent surgery 6-10 weeks after neoadjuvant therapy.ResultsBetween August 2011 and August 2014, 17 patients (median age of 54 years) were enrolled. After toxicities requiring dose interruptions were observed in cohort 1 (2 patients with grade 2 (G2) and grade 3 (G3) hand foot skin reaction and 1 patient with G2 mucositis), the protocol was amended, changing administration of chemotherapy and sorafenib from daily to days 1-5 only. With the amended protocol, the primary G3 toxicity was hypertension in 2 patients at the 200-mg adjusted dose level (day1-5) and 1 patient at the 400-mg twice daily dose level. One patient had G3 ALT elevation at 400mg, and no grade IV toxicities were observed. G1 and G2 toxicities included hand-foot skin reaction, diarrhea, mucositis, nausea, fatigue, and proctitis. No perioperative complications were seen. Two patients refused to undergo surgery. The pathological complete remission (pCR) rate was 33%, and downstaging was observed in 85.7% of patients. Median neoadjuvant rectal cancer score was 8.7.ConclusionsWith the changed dosing schedule, this regimen was very well tolerated. The tumor pCR and downstaging rates are encouraging and support further clinical investigation of this regimen.

Project description:BACKGROUND:Treatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT). METHODS/DESIGN:This study follows the 'cohort multiple randomized controlled trial' (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients-histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ?10 cm from the anorectal transition who provided consent for experimental intervention offers-form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed. sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3-4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat. DISCUSSION:The boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability. TRIAL REGISTRATION:The Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521 . Registered 18 September 2013.

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Dataset Information

Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

Publications

Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

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