A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer.

A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer Willeke F, Horisberger K, Kraus-Tiefenbacher U et al. British Journal of Cancer, 2007, 96, 912-917

During the past two decades the prognosis of patients with localised rectal cancer has improved. Advances in surgical techniques, including total mesorectal excision (TME), and chemoradiation have contributed to significantly diminish the local failure rate. Involvement of the rectal circumferential resection margin ([less than or equal to] 1 mm) has been shown to be an important prognostic factor resulting in both higher rates of local recurrence and shorter survival [1].

Pre-operative chemoradiation has shown some advantages over postoperative chemoradiation: better tissue oxygenation and drug perfusion can enhance the radiation efficacy, decreasing the pelvic tumour burden. Downstaging is feasible, leading to an increased sphincter preservation rate. There is also an improved compliance of the chemoradiation therapy if given before surgery.

A meta-analysis involving a systematic overview of 8507 patients from 22 randomised trials comparing outcomes of surgery alone for rectal cancer or combined with pre-operative or postoperative radiotherapy, conclusively showed that pre-operative radiotherapy reduced the risk of local recurrence in patients with resectable disease, with greatest benefit when patients received a pre-operative radiation dose over 30 Gy [2]. The superiority of pre-operative chemoradiation was demonstrated in a Phase III trial with 823 patients with stage II and III disease, which showed improved regional control and less acute and late toxicity when compared with postoperative treatment. However, overall survival was not significantly improved [3].

Pathological complete response (pCR) as a marker of the efficacy of pre-operative chemoradiotherapy strategies appears to be associated, in non-randomised studies, with an improvement in disease-free survival. A higher pCR rate is apparently evident in studies using two chemotherapy drugs concomitant with radiation. 5-Fluorouracil (5-FU) has been the backbone drug of the regimen, usually administered as a continuous infusion, but has recently been replaced by capecitabine. A number of Phase I/II studies in rectal cancer have demonstrated that capecitabine is effective and well tolerated in combination with pre-operative radiotherapy, simplifies chemoradiation and provides a convenient treatment option [4]. Combining capecitabine with cytotoxic agents such as oxaliplatin and irinotecan has the potential to further improve anti-tumour efficacy in patients receiving pre-operative chemoradiation at the local and distant levels.

The primary objectives of the Phase II study reported here were to evaluate the efficacy and safety of pre-operative chemoradiation with capecitabine and irinotecan in stage T3/T4 rectal cancer with unknown or nodal involvement, and to assess surgical morbidity and mortality. Secondary objectives were assessment of the local and distant failure rate. The authors previously defined, in a Phase I trial, the maximum tolerable chemotherapy dose of the drug combination, concurrently with three-dimensional conformal conventionally fractionated radiotherapy. The patients were scheduled to receive irinotecan (50 mg/[m.sup.2], weekly for 5 consecutive weeks) and capecitabine (500 mg/[m.sup.2] twice daily, on days 1-38), with 28 concurrent daily fractions of 1.8 Gy radiation therapy on 5 days a week up to a dose of 50.4 Gy. TME surgery was scheduled for 4-6 weeks after the completion of chemoradiation.

Grade 3 and 4 main toxicities reported among the 36 patients recruited into the study were 25% leukocytopenia (neutropenic fever was not reported) and 11% diarrhoea with a median duration of 6 days. Grade 2 toxicities were diarrhoea in 42% of patients, nausea and vomiting in 28%, anaemia in 25%, and leukopenia and radiation dermatitis, both in 19% of patients. One patient had a reversible episode of ventricular fibrillation, probably related to capecitabine treatment.

Two patients were excluded from surgery, one because of metastatic disease and the other because of refusal. Postoperative morbidity comprised complicated wound healing in 26%, anastomotic leakage in 12% and abscess in 9% of the patients. Two patients (6%) died because of septic complications.

A pCR of the tumour was observed in 15% of the patients. Tumour and lymph node status were downstaged in 53% and 63% of cases, respectively. Two of the patients recruited had initially resectable liver metastases and one had a non-confirmed pleural carcinomatosis, all of which became non-resectable after chemoradiation therapy. A different approach with an initial metastasectomy followed by rectal chemoradiation and surgery could have been a useful alternative for these patients. One patient did not receive surgery because of non-resectable metastases detected immediately before resection. Three more patients developed postoperative metastases and another one had a local recurrence which was treated with salvage surgery.

At a cost of considerable toxicity, local recurrence is now less of a problem whereas distant metastasis remains the most common form of treatment failure. New treatment objectives must increase the pCR rate, diminish toxicity, and significantly reduce the distant failure rate. Patients should receive the best available systemic therapy as part of the treatment strategy, either before or after the surgical procedure [5]. Inhibitors of multiple signalling pathways are being incorporated into the armamentarium of treatment for the metastatic setting through well-designed clinical trials.

The authors of the present paper have also recently established [6] the feasibility of chemotherapy with capecitabine, weekly irinotecan, cetuximab (an anti-epidermal growth factor receptor antibody) and pelvic radiotherapy for patients with locally advanced rectal cancer. Doses were chosen according to Phase I methods: cetuximab at full dose (400 mg/[m.sup.2] on day 1 and 250 mg/[m.sup.2] weekly thereafter), irinotecan 40 mg/[m.sup.2] weekly and capecitabine 500 mg/[m.sup.2] twice daily, on days 1-38 was finally recommended. Grade 3 diarrhoea affected one of six patients on this dose regimen.

An increase in the vascular endothelial growth factor (VEGF) signalling pathway is associated with poor outcomes in rectal cancer patients. Inhibitors of this pathway enhance the effects of chemotherapy and radiation therapy on tumour cytotoxicity in preclinical models. Besides stopping the formation of new tumour vessels, normalisation of cancer vasculature with anti-angiogenic therapy leads to tumour response to radiation and induces a pressure gradient across the vasculature improving drug penetration in the tumour which may further increase efficacy. New combinations of chemotherapy regimens with these target therapies (such as sunitinib, a relevant multiple inhibitor of class III, V and XII tyrosine kinase with anti-angiogenic and anti-proliferative activities) should be properly studied. Phase I study results with bevacizumab, oxaliplatin and 5-FU in rectal cancer treatment are already available [7].

Surrogate markers for identification of efficacy of these new agents is a critical issue in these trials. A reduction of the percentage of viable circulating endothelial cells in conjunction with the levels of VEGF family proteins in the plasma is a potential marker which should be further evaluated [8]. Additional prospective studies will be required, using these new combinations and strategies, to improve the present results in the treatment of rectal cancer.

References

[1.] Wibe A, Rendedel PR, Svensson E et al. Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer. Br J Surg, 2002, 89, 327-334.

[2.] Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet, 2001, 358, 1291-1304.

[3.] Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med, 2004, 351, 1731-1740.

[4.] Glynne-Jones R, Dunst J and Sebag-Montefiore D. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been? Ann Oncol, 2006, 17, 361-371.

[5.] Chau I, Brown G, Cunningham D et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol, 2006, 24, 668-674.

[6.] Hofheinz RD, Horisberger K, Woernle C et al. Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys, 2006, 66,1384-1390.

[7.] Czito BG, Bendell JC, Willett CG et al. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase I trial results. Int J Radiat Oncol Biol Phys, 2007, 68, 472-478.

[8.] Willett CG, Boucher Y, Duda DG et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol, 2005, 23, 8136-8139.

(1) Medical Oncology Department, Elche University Hospital,Alicante, Spain