Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer

Rödel, Claus; Grabenbauer, Gerhard G.; Papadopoulos, Thomas; Bigalke, Marc U; Günther, Klaus; Schick, Christoph; Peters, Andrea; Sauer, Rolf; Rödel, Franz

doi:10.1016/s0360-3016(01)02643-8

Cited by 117 publications

(63 citation statements)

References 40 publications

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“…In the clinical setting, we and others have previously shown that a high level of pretreatment apoptosis emerged as a significant predictor of tumor regression after preoperative radiochemotherapy in rectal cancer (4)(5)(6). In vitro studies, using colorectal cancer cell lines with different intrinsic radiosensitivities further confirmed that spontaneous and radiation-induced apoptosis correlated closely with radiation response (7).…”

Section: Introductionsupporting

confidence: 57%

Survivin as a Radioresistance Factor, and Prognostic and Therapeutic Target for Radiotherapy in Rectal Cancer

et al. 2005

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Apoptosis levels have been shown to predict tumor response to preoperative radiochemotherapy in rectal cancer. Recently, the prominent role of survivin, a structurally unique member of the inhibitor of apoptosis protein family, has been shown in colorectal cancer tumorigenesis and prognosis. In this study, we investigated whether survivin plays a direct role in mediating radiation resistance. We used short interfering RNA molecules to decrease survivin in radioresistant SW480 and intermediately radioresistant HCT-15 colorectal cancer cells. This resulted in a significant decrease of survivin mRNA and protein expression with a maximum at 24 to 48 hours after transfection. If irradiated during this sensitive period, an increased percentage of apoptotic cells and an increased caspase 3/7 activity in parallel with a decreased cell viability and a reduced clonogenic survival was shown. These effects were more pronounced in the radioresistant SW480 cell line with a radiation-induced cytotoxicity enhancement factor at 10% and 50% survival of 1.8 to 2.2 for SW480 and 1.5 to 1.7 for HCT-15, respectively. Furthermore, transfection with survivin short interfering RNA increased levels of G 2 -M arrest and levels of DNA double-strand breaks in irradiated cells. These observations indicate that cell cycle and DNA repair mechanisms may be associated with apoptosis induction in tumor cells that are otherwise resistant to killing by radiation. In a translational study of 59 patients with rectal cancer treated with a combination of radiotherapy and chemotherapy, increased survivin expression was inversely related to the levels of apoptosis, and was also associated with a significantly higher risk of a local tumor recurrence. (Cancer Res 2005; 65(11): 4881-7)

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Section: Introductionsupporting

confidence: 57%

Survivin as a Radioresistance Factor, and Prognostic and Therapeutic Target for Radiotherapy in Rectal Cancer

et al. 2005

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“…As for apoptosis, cancer cell apoptosis in biopsy before CRT was correlated with tumour regression whereas apoptosis inhibitory protein Bcl-2 expression indicated no correlation with regression (Rödel et al, 2002). In addition, L-type amino-acid transporter 1 (LAT1) is highly expressed in malignant tumours to support growth and proliferation, and the inhibition of LAT1 activity led to cancer cell apoptosis (Kim et al, 2008).…”

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confidence: 99%

High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction

et al. 2009

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BACKGROUND: Recently, preoperative chemoradiation therapy (CRT) for rectal cancer has been increasingly used as a neoadjuvant treatment. In the present study, the relation between histological response to CRT and immunohistochemical markers in biopsy specimens was investigated. METHODS: Biopsy specimens from a total of 60 patients were collected before preoperative CRT with S-1 and irinotecan, and liniac 45 Gy. Immunohistochemical staining for Ki67, Mcm3, Bax, Bcl-2, ssDNA, Grp78, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), CD34, vascular endothelial growth factor, nestin, and L-type amino-acid transporter 1 was performed to allow comparison of the Ki67 labelling index (LI), Bax score, TS score, DPD score, microvessel density by CD34, and Grp78 score with cancer regression. RESULTS: When the cases were divided into responders (Dworak grades 3 and 4) and non-responders (grades 1 and 2) groups, good correlations were evident with Ki67 LI, Bax, Grp78, and TS expression. On multiple logistic regression analysis, Ki67 LI, Bax, and TS scores were found to be independent factors. With their use in a logistic model, P-values could predict responder cases with a sensitivity of 82.8% and a specificity of 83.9%. CONCLUSION: Using this system, treatment strategy for locally advanced rectal cancers can be determined before chemoradiation.

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“…En dos grandes series publicadas durante los últimos 5 años se demuestra que el único factor predictivo de RPC es un período de espera mayor a 8 semanas luego del término de la XRTQ 12,13 . En estos estudios, igual que en esta serie, índices como: edad, sexo, localización, etapa del tumor y diferenciación no se asociaron a RPC.…”

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“…En estos estudios, igual que en esta serie, índices como: edad, sexo, localización, etapa del tumor y diferenciación no se asociaron a RPC. Incluso el estudio de algunos marcadores moleculares tampoco ha sido de utilidad 13,14 . En nuestra serie hubo 4 pacientes que fueron sometidos a una resección abdominoperineal cuyo estudio de la pieza operatoria demostró una RPC.…”

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Respuesta patológica completa en pacientes sometidos a neoadyuvancia en cáncer de recto

et al. 2013

Rev Chil Cir

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Pathologic complete response in patients with neoadjuvant chemoradiotherapy for rectal cancer Background: The standard treatment of locally advanced rectal cancer (RC) of the middle and lower third of the rectum is neoadjuvant chemoradiotherapy (XRQT) follow by oncologic resection. After this treatment in 15-25% of the cases, the pathologist reports complete pathological response (pCR). Aim: To describe demographic, clinical and survival data of patients with pCR undergoing chemoradiotherapy and radical resection for RC. Material and Methods: Historic cohort study. In a prospectively maintained database between 2000 and 2010, we identified patients with RC, who underwent neoadjuvant chemoradiotherapy according to protocol, followed by radical resection. The preoperative staging was obtained by clinical examination, endoscopy, rectal ultrasound, CT scan of chest, abdomen and pelvis and pelvic MRI. Demographic data, tumor location, time between the end of XRTQ and surgery, postoperative staging (according AJCC) and survival, were collected. Results: 119 patients received preoperative XRTQ, 65% male, with a mean age of 58 years. The most frequent tumor site was the lower third (63%). Surgery was performed 8 weeks after the end of XRTQ. Of 119 patients with XRTQ, 15.1% had a pCR. Overall survival was 75%, and cancerspecific survival was 80.4% at 5 years in patients without pCR. For patients with pCR, the 5 year survival estimates for overall and cancer specific survival was 100%. We did not identify factors associated with pCR. Conclusions: In this study, pCR was comparable to other larger series reported elsewhere. No factors associated with pCR were identified.Key words: Pathological complete response, rectal cancer, neoadjuvant chemoradiotherapy. ResumenIntroducción: El cáncer de recto (CR) de tercio medio e inferior localmente avanzado se trata con radio-quimioterapia (XRTQ) preoperatoria. Luego XRQT y resección quirúrgica, 15-25% presentan respuesta patológica completa (RPC) de la lesión. Objetivo: Comparar características demográficas, clínicas y sobrevi-

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Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer

Cited by 117 publications

References 40 publications

Survivin as a Radioresistance Factor, and Prognostic and Therapeutic Target for Radiotherapy in Rectal Cancer

Survivin as a Radioresistance Factor, and Prognostic and Therapeutic Target for Radiotherapy in Rectal Cancer

High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction

Respuesta patológica completa en pacientes sometidos a neoadyuvancia en cáncer de recto

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