Complete Response of Para-Aortic and Lateral Pelvic Lymph Node Recurrence of Rectal Cancer Treated to S-1 Monotherapy

This report presents a case of para-aortic and lateral pelvic lymph node recurrence of rectal cancer that showed complete response to S-1 monotherapy. A 69-year-old man underwent low anterior resection for rectal cancer in 2007. Para-aortic lymph and right lateral pelvic lymph node recurrence occurred in 2008. He received a fluorouracil/folinic acid plus oxaliplatin regimen; however, G4 neutropenia and G3 fatigue were experienced. We started S-1 monotherapy as a salvage treatment. Abdominal computed tomography did not reveal any para-aortic and lateral pelvic lymph nodes recurrence after 10 cycles of S-1 monotherapy. Hence, response in this case was classified as a complete response. No recurrence was noted 36 months after the complete response. S-1 monotherapy is likely to be effective in treating patients with metastatic colorectal cancer who do not respond to standard combination chemotherapy.


Introduction
The introduction of oxaliplatin and irinotecan into combination regimens with fluorouracil (5-FU) has been a major advance in the treatment of patients with metastatic colorectal cancer (MCRC). Oxaliplatin/5-FU/folinic acid (FOLF-OX-4) is the standard first-line chemotherapy in patients with MCRC [1,2]. The common grade 3/4 adverse events associated with FOLFOX-4 are neutropenia and granulocytopenia; therefore, treatment might be discontinued because of such adverse events in patients treated with FOLFOX-4 [1,2]. S-1 is an oral anticancer agent containing tegafur, a metabolically activated prodrug of 5-FU, and 2 biochemical modulators [3]. Three phase 2 trials reported that S-1 monotherapy showed response similar to that of infusional 5-FU/ folinic acid as the first-line treatment in patients with MCRC [4][5][6]. Two studies showed that salvage S-1 monotherapy was effective and well tolerated in MCRC patients after the failure of irinotecan-based or oxaliplatin-based chemotherapy [7,8]. Here, we report a case of para-aortic and lateral pelvic lymph node recurrence of rectal cancer that showed complete response (CR) to S-1 monotherapy after discontinuance of FOLFOX-4 because of grade 4 adverse events.

Case Report
A 69-year-old man with mild liver dysfunction due to chronic type C hepatitis, underwent low anterior resection for rectal cancer in 2007. Pathological examination showed a well-differentiated adenocarcinoma invading the perirectal tissues, with metastatic involvement in 1 of the 15 lymph nodes removed (T4 N1M0/Stage IIIB), (Fig. 1). The patient underwent 5 cycles of tegafur-uracil plus oral leucovolon therapy (UFT/LV) as adjuvant chemotherapy without any adverse events. In 2008, abdominal computed tomography (CT) after UFT/LV showed swollen para-aortic and right lateral pelvic lymph nodes (Fig. 2a, b). Thus, para-aortic and pelvic lymph nodes recurrence of rectal cancer was diagnosed. We started a FOLFOX-4 regimen in March 2008. However, the patient experienced G4 neutropenia and G3 fatigue (according to the Common Terminology Criteria for Adverse Events Version 4.0), and therefore had to discontinue FOLFOX-4. We started S-1 administration (100 mg/day twice on days 1 -14, every 3 weeks) as salvage treatment in May 2008. Abdominopelvic CT after 5 cycles of S-1 showed reduction of the swollen para-aortic lymph nodes (Fig. 2c, d).
Another series of abdominal CT performed after 10 cycles of S-1 monotherapy showed complete disappearance of swollen para-aortic and lateral pelvic lymph nodes (Fig.  2e, f). Hence, response in this case was classified as a CR. The patient did not experience any adverse events during the S-1 monotherapy. No signs of recurrence or metastasis were noted 36 months after CR was confirmed.  tients with MCRC. However, these regimens involve continuous infusions of 5-FU that requires catheter replacement and regular visits to the clinic [2]. Grade 3/4 neutropenia is more common with FOLFOX-4 than with 5-FU/ folinic acid [1,2]. Oral 5-FU prodrugs capecitabine and UFT/LV have already been proven to show an efficacy equivalent to that of an intravenous 5-FU/folinic acid regimen in patients of MCRC, but with less toxicity than the 5-FU regimen [9][10][11]. Furthermore, capecitabine plus oxaliplatin therapy was noninferior to FOLFOX-4 as a first-line treatment for MCRC [2]. These oral 5-FU prodrugs have the advantage of reducing intravenous drug administration and associated visits to the clinic. S-1 is an oral anticancer agent containing tegafur, a metabolically activated prodrug of 5-FU, with 2 biochemical modulators of 5-FU metabolism: 5-chloro-2, 4-dihydroxypyridine that inhibits 5-FU degeneration by dihydroxypyridine dehydrogenase and potassium oxonate that reduces the incidence of 5-FU-induced gastrointestinal side effects [3]. Three phase2 trials have demonstrated that S-1 achieved responses similar to those of infusional 5-FU/folinic acid and had acceptable toxicity profile as first-line treatment in patients with MCRC [4][5][6]. Shibahara et al reported equivalent efficacy and safety between S-1 and UFT/LV in patients with MCRC [12]. Two studies showed that salvage S-1 monotherapy was effective and well tolerated in MCRC patients after failure of irinotecan-based or oxaliplatin-based chemotherapy [7,8]. Recent studies demonstrated that the combination of S-1 and oxaliplatin or irinotecan could be an additional therapeutic options for patients with MCRC [13][14][15]. S-1 is usually administrated for 4 weeks, followed by a 2-week drug-free period. However, adverse reactions related to S-1 therapy commonly begin to appear in 2 -3 weeks after treatment starts. Therefore, a 2-week regimen of S-1 followed by a 1-week drug-free period might mitigate adverse reactions and prolong the medication period [16]. Our patient did not experience any severe adverse events during 10 cycles of the 2-week regimen of S-1.
In conclusion, we experienced a case of para-aortic and lateral pelvic lymph node recurrence of rectal cancer that showed CR to salvage S-1 monotherapy after the failure of a FOLFOX-4 regimen. S-1 is likely to be an effective, welltolerated and convenient therapeutic option for patients with advanced colorectal cancer.

Disclosure Statement
The authors have no conflicts of interest to declare.