Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma

Ancona, Ermanno; Ruol, Alberto; Santi, Stefano; Merigliano, Stefano; Sileni, V. Chiarion; Koussis, Haralabos; Zaninotto, Giovanni; Bonavina, Luigi; Peracchia, A.

doi:10.1002/1097-0142(20010601)91:11<2165::aid-cncr1245>3.3.co;2-8

Cited by 109 publications

(158 citation statements)

References 15 publications

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“…Some authors [8] reported up to 16% of treatment-related deaths with the same combination, even using chemotherapy alone. In a randomized study in operable patients [3], using preoperative CT alone, we were able to deliver 68% of three planned cycles of FU/cisplatin. In a similar study, Kelsen et al [24] delivered 71% of the planned CT preoperatively, and 38% postoperatively.…”

Section: Discussionmentioning

confidence: 99%

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Chiarion-Sileni

Innocente

Cavina³

et al. 2008

Cancer Chemother Pharmacol

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Purpose The aim of this study was to evaluate the activity and safety of oxaliplatin/5-Xuorouracil-based chemo-radiotherapy in patients with not radically resectable locally advanced esophageal cancer. Methods Fifty-nine patients with adeno or squamous-cell carcinoma received oxaliplatin (60 mg/m 2 ), and leucovorin (20 mg/m 2 on days 1, 8,15,29,36,43,50,57) followed by continuous infusion Xuorouracil (200 mg/m 2 per day on days 1-22 and 29-64) with radiotherapy (1.8 Gy daily fractions to a total dose of 45 Gy, from days 29 to 64). When feasible, surgery was scheduled 6-8 weeks after chemoradiotherapy completion. The primary endpoint was 1-year progression-free survival. Results Forty (68%) patients completed treatment without modiWcations. An objective clinical response was seen in 35 patients (59%). Esophagectomy was possible in 33 patients and a complete resection (R0) was achieved in 26 (79%) with 6 pathologic complete responses (pCR) and 3 near pCR.At a median follow-up of 39.7 months for the surviving patients, the median progression-free and overall survivals were 11 months (95% CI 6.5-14) and 18.5 months (95% CI 13-29). The 1-year progression-free and overall survivals were 47.5% (95% CI 34-59.5%) and 63% (95% CI 49-74%). Major toxicities were esophagitis (20% G3 and 5% G4) and diarrhea (8.5% G3 and 8.5% G4). Hematological toxicity (7% G3 and 3% G4) was less common; severe neurotoxicity (3% G3) was infrequent. Conclusions Concurrent oxaliplatin, leucovorin, Xuorouracil and radiotherapy followed or not by esophagectomy has a tolerable toxicity and promising activity in locally advanced esophageal cancer.

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Section: Discussionmentioning

confidence: 99%

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Chiarion-Sileni

Innocente

Cavina³

et al. 2008

Cancer Chemother Pharmacol

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“…The response rate reported with PF ranged from 35 to 40% (De Besi et al, 1986;Bleiberg et al, 1997;Ancona et al, 2001), whereas the 2-year survival rates of patients with locally advanced oesophageal cancer ranged from 8 to 55%, with a mean 27%. A better prognosis with chemoradiotherapy/chemotherapy (al-Sarraf et al, 1997;Stuschke et al, 2000;Kodaira et al, 2003;Polee et al, 2003) has been reported, but these series also included patients with potentially resectable carcinomas.…”

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confidence: 99%

“…The majority of studies on combined therapy showed longer survival for patients achieving a pathologic complete response (pCR), which can be obtained in 12 -40% of patients treated with PF combined therapy Ancona et al, 2001). Patients with a less advanced stage are more likely to achieve a pCR than those with a more advanced disease (Rohatgi et al, 2005).…”

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Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

Chiarion-Sileni

Corti

Ruol³

et al. 2007

Br J Cancer

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This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m À2 , cisplatin 75 mg m À2 on day 1 and fluorouracil 750 mg m À2 day À1 on days 2 -5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m À2 week À1 for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week À1 ). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2 -66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1 -12.4), and the 1-and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3 -4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified.

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“…These studies have indicated a complete response in 20 -40% of patients preoperatively treated with combined radiotherapy and chemotherapy (Ilson, 2004). However, with regard to survival, the benefit of combined neoadjuvant treatment modalities has only been confirmed unequivocally in the subset of patients who have a complete response at histopathological examination (Lerut et al, 1999;Ancona et al, 2001;Brücher et al, 2004). Finding parameters that might help identify those patients capable of benefiting from multimodal treatment modalities before the start of therapy would therefore be of considerable interest (Lerut et al, 1999;Ilson, 2004).…”

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The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

et al. 2007

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Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/ þ , cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P ¼ 0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P ¼ 0.0061) and p53-phospho (P ¼ 0.0064). Expression of p53 correlated with expression of p53-phospho (Po0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma.

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Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma

Cited by 109 publications

References 15 publications

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

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