Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer
Introduction
In the past two decades, the multidisciplinary management of rectal cancer has changed worldwide. Total mesorectal excision (TME) has become the standard surgical technique for the treatment of rectal cancer, resulting in a reduction in the local recurrence rate.1, 2 Studies performed prior to the era of TME favored the use of preoperative, rather than postoperative, radiotherapy to improve local control.3 Recently, several randomized trials have confirmed the value of preoperative short-course radiation and long-term fractionated radiation with concurrent 5-FU-based chemotherapy for the treatment of locally advanced rectal cancer.4, 5, 6 Although neoadjuvant chemoradiotherapy improves local control, its effect on survival remains controversial because of the frequency of distant relapse.
In Western countries, preoperative radiotherapy or chemoradiotherapy has become a standard treatment for locally advanced rectal cancer. However, these modalities are not commonly used in Japan because of concerns regarding postoperative morbidities, such as fistulas, venous thromboembolism, anorectal dysfunction, and small bowel complications,7, 8, 9 as well as the efficacy of extensive lymph node dissection in the pelvis for achieving local control.10, 11
Systemic chemotherapy for non-resectable or metastatic colorectal cancer has also markedly changed in the last decades. Folinic acid, fluorouracil (bolus and continuous infusion), and oxaliplatin (FOLFOX regimen) or folinic acid, fluorouracil (bolus and infusion), and irinotecan (FOLFIRI regimen) with or without molecular-targeted therapy (using the anti-VEGF antibody bevacizumab or the anti-EGFR antibody cetuximab) are currently regarded as first-line chemotherapy regimens and have resulted in marked improvements in the survival of patients with metastatic colorectal cancer in Japan and Western countries.12, 13, 14, 15 Before the introduction of FOLFOX and FOLFIRI therapy, the combination of irinotecan, fluorouracil (bolus), and leucovorin (IFL therapy; also known as Saltz’s regimen) was widely accepted as a first-line systemic chemotherapy beginning in 2000 in Japan, providing a superior outcome to that of fluorouracil and leucovorin (LV).16
To further improve the survival of patients with resectable advanced rectal cancer without using radiation therapy, we conducted this study to clarify whether the administration of IFL (the powerful chemotherapy available at the time) as a neoadjuvant systemic chemotherapy could improve patient survival and local control.
Section snippets
Eligibility criteria
Between 2001 and 2004, patients with histopathologically confirmed, locally advanced non-metastatic resectable rectal adenocarcinoma (T3 or T4 and N0-N2) were enrolled in this study. Other eligibility criteria were as follows: 1) tumor located within 12 cm of the anal verge (mid/lower rectum), as determined using a colonoscopy; 2) a patient age of 75 years or younger at the time of enrollment; 3) no severe impairments in major organ functions, including the heart, lung, liver, kidney, and bone
Patient characteristics
Between August 2001 and January 2004, 26 patients were enrolled in this study at our institute. The patient characteristics are shown in Table 1. The median age was 62 years (range, 46–75 years). Eighteen and 8 of the 26 patients were men and women, respectively. The number of patients in each clinical stage before chemotherapy was 6 in T3N0, 17 in T3N1-2, and 3 in T4N1-2. The median tumor size was 33 mm (range, 12–65 mm), and the median distance from the anal verge of the tumor was 5 cm
Neoadjuvant therapy for rectal cancer
Neoadjuvant chemoradiation or radiation is now a standard therapy for locally advanced rectal cancer in the Western world because of the good local control that this treatment provides.4, 5, 6 Furthermore, obtaining a pCR as a result of neoadjuvant chemoradiation is considered to have a survival benefit and to improve the chance of sphincter preservation.18, 19, 20, 21 Consequently, many phase II trials of neoadjuvant chemoradiation using two or more cytotoxic agents with or without
Conclusion
Neoadjuvant systemic chemotherapy comprised of a combination of multi-drugs as irinotecan, 5-FU, and LV may be beneficial to the prognoses of patients with locally advanced rectal cancer.
Role of the funding sources
There is no involvement of funding sources.
Conflict of interest
The authors declare having no conflict of interest.
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