Dataset Information

Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.

ABSTRACT:

Background

The question whether lymphocyte radiosensitivity is representative of patients' response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients' and RCT characteristics on cytogenetic damage, and tested for correlations with patients' outcome in terms of tumor response, survival and treatment-related toxicity.

Methods

The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3?Gy. RCT included 50.4?Gy of pelvic RT with 5-fluorouracil (5-FU) alone (n =?78) or 5-FU plus oxaliplatin (n =?56). The analyzed variables included patients' age, gender, RT characteristics (planning target volume size [PTV size], RT technique), and chemotherapy characteristics (5-FU plasma levels, addition of oxaliplatin). Outcome was analyzed as tumor regression, patient survival, and acute and late toxicity.

Results

Cytogenetic damage increased significantly with the radiation dose and varied substantially between individuals. Women were more sensitive than men; no significant age-dependent differences were observed. There was a significant correlation between the cytogenetic damage after in-vitro irradiation and in-vivo RCT. We found a significant effect of the PTV size on the yields of cytogenetic damage after RCT, while the RT technique had no effect. Neither the addition of oxaliplatin nor the 5-FU levels influenced cytogenetic damage. We found no correlation between patient outcome and the cytogenetic damage.

Conclusions

We found consistent cytogenetic damage in lymphocytes after in-vivo RCT and in-vitro irradiation. Gender was confirmed as a well-known, and the PTV size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation. A consistent level of cytogenetic damage after in-vivo and in-vitro irradiation may indicate the importance of genetic factors for individual radiosensitivity. However, we found no evidence that in-vivo or in-vitro irradiation-induced cytogenetic damage is an adequate biomarker for the response to RCT in rectal cancer patients.

SUBMITTER: Droge LH

PROVIDER: S-EPMC7931609 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.

Dröge Leif Hendrik LH Hennies Steffen S Lorenzen Stephan S Conradi Lena-Christin LC Quack Henriette H Liersch Torsten T Helms Christian C Frank Miriam Alice MA Schirmer Markus Anton MA Rave-Fränk Margret M Beißbarth Tim T Wolff Hendrik Andreas HA

BMC cancer 20210304 1

<h4>Background</h4>The question whether lymphocyte radiosensitivity is representative of patients' response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients' and RCT characteristics on cytogenetic ...[more]

PMID: 33663399

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Project description:Background:Neoadjuvant chemoradiation is currently standard of care in stage II-III rectal cancer, resulting in tumor downstaging for patients with treatment-responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients. Methods:The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II-III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two-sided. Results:A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI?=?110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI?=?110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI?=?106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI?=?110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI?=?97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI?=?1.10 to 1.41; HR of pT3 = 1.81, 95% CI?=?1.61 to 2.05; HR of pT4 = 2.72, 95% CI?=?2.28 to 3.25, all P ? .001 vs pT1; HR of pN1 = 1.50, 95% CI?=?1.41 to 1.59; HR of pN2 = 2.17, 95% CI?=?2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI?=?0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI?=?0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI?=?0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI?=?0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI?=?0.86 to 1.08, P = .48 vs cN0). Conclusions:Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients.

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Project description:BackgroundWe examined the predictive value of mismatch repair (MMR) status in relation to responses to neoadjuvant therapy and the prognosis of locally advanced rectal cancer patients.MethodsA total of 854 consecutive patients with locally advanced rectal cancer with MMR status who underwent neoadjuvant therapy followed by curative surgery between January 2013 and December 2018 were included this retrospective study. MMR status was determined by an analysis of MMR protein expression by immunohistochemistry (IHC). Propensity score matching was performed to reduce imbalances in baseline characteristics. The categorical variables were compared using the Chi-square test or Fisher's exact test. Local recurrence-free survival (LRFS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier method.ResultsDeficient MMR (dMMR) was detected in 63 of the 854 (7.4%) patients. Patients with dMMR had a lower proportion of tumor regression grade (TRG) of 0-1 compared with proficient MMR (pMMR) (28.6% vs. 43.7%; P=0.027). After propensity score matching at 1:4 for patients who received chemotherapy alone, proportion of TRG of 0-1 was observed to be significantly lower in dMMR than pMMR patients (9.1 vs. 30.3%%; P=0.013). For patients who received chemoradiation, after matching, no significant difference in the proportion of TRG 0-1 and the pathological complete response (pCR) rate was observed. The multivariable analysis revealed that patients whose tumors had dMMR had significantly longer DFS than those whose tumors had pMMR [hazards ratio (HR) =0.38, 95% confidence interval (CI): 0.18-0.81, P=0.013]. In the subgroup analysis, dMMR was only a statistically significant prognostic factor for DFS in patients with ypStage II/III (HR =0.38, 95% CI: 0.17-0.86; P=0.020).ConclusionsWe found that patients with dMMR responded worse to chemotherapy alone than patients with pMMR, in terms of TRG. Also, dMMR is a good prognostic marker for DFS in patients with ypStage II/III after neoadjuvant therapy.

Dataset Information

Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.

Background

Methods

Results

Conclusions

Publications

Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.

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