Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer

https://doi.org/10.1016/j.ejso.2010.05.017Get rights and content

Abstract

Aims

The aim of this study was to evaluate the usefulness of neoadjuvant systemic chemotherapy using irinotecan, 5-FU, and leucovorin (LV) for the treatment of locally advanced rectal cancer, which was a powerful ploychemotherapy in those days in Japan.

Methods

Between 2001 and 2004, 26 patients with T3 or T4 and N0-2 non-metastatic resectable rectal cancer were selectively enrolled in this study. Neoadjuvant chemotherapy consisted of two cycles of irinotecan (80 mg/m2), 5-FU (500 mg/m2), and LV (250 mg/m2) on days 1, 8, and 15 for 4 weeks. Surgical resection was performed in all the patients 2–4 weeks after the completion of chemotherapy.

Results

Overall down-staging was observed in 15 patients. T level and N level down-staging were observed in 12 and 13 patients, respectively. A pathological complete response was observed in one patients. The median follow-up period was 75 months (range, 8–97 months). Recurrences occurred in 5 patients including pelvic relapses in 3 and distant metastases in 2. The 5-year relapse-free and overall survival rates were 74% and 84%, respectively.

Conclusions

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.

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.

References (37)

  • M. Dahlberg et al.

    Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study

    Dis Colon Rectum

    (1998)
  • H. Birgisson et al.

    Swedish rectal cancer trial group:adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish rectal cancer trial

    J Clin Oncol

    (2005)
  • S. Fujita et al.

    Lateral pelvic lymph node dissection for advanced lower rectal cancer

    Br J Surg

    (2003)
  • M. Kusters et al.

    A comparison between the treatment of low rectal cancer in Japan and the Netherlands, focusing on the patterns of local recurrence

    Ann Surg

    (2009)
  • E. Van Cutsem et al.

    Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer

    N Engl J Med

    (2009)
  • J. Tol et al.

    Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer

    N Engl J Med

    (2009)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • L.B. Saltz et al.

    Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group

    N Engl J Med

    (2000)
  • Cited by (57)

    • The 2017 Assisi Think Tank Meeting on rectal cancer: A positioning paper

      2020, Radiotherapy and Oncology
      Citation Excerpt :

      pCR rates ranged from 7% to 35%. Since patient cohorts were small and the studies were non-randomised, with short follow-ups, they were unable to show any impact on metastatic disease or local recurrence [61–64]. However, the proof of principle encouraged many current studies to explore neoadjuvant chemotherapy.

    • BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC)

      2018, Heliyon
      Citation Excerpt :

      FOLFOXIRI and bevacizumab appears active as 4/10 (40%) achieved a complete clinical response. Other studies of NACT alone with and without bevacizumab in rectal cancer have reported higher pCR rates after NACT alone with a range of 7%–25% (Table 10) [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24], but some have included more liberal entry criteria, less advanced tumours and less in-depth pathology assessment without a defined dissection protocol for pCR. The NAR score was developed from the NSABP-R04 trial data as a measure of down-staging and as a surrogate endpoint for clinical trials involving CRT [7].

    View all citing articles on Scopus
    View full text