Int J Clin Oncol DOI 10.1007/s10147-014-0705-3
ORIGINAL ARTICLE
A phase I trial of preoperative S-1 in combination with oxaliplatin and pelvic radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis Masayuki Ohue • Tetsuya Hamaguchi • Yoshinori Ito • Daisuke Sakai Shingo Noura • Yusuke Kinugasa • Shin Fujita • Yasuhiro Shimada • Norio Saito • Yoshihiro Moriya
•
Received: 17 March 2014 / Accepted: 27 April 2014 Ó Japan Society of Clinical Oncology 2014
Abstract Background The purpose of this phase I study of the dose escalation of oxaliplatin in combination with oral S-1 and pelvic radiation preoperatively for poor-risk lower rectal cancer was to determine the dose-limiting toxicity (DLT) and recommended dose of oxaliplatin. Methods Patients with cT4 and lateral pelvic lymph node metastasis, and without distant metastasis (cM0), were treated with weekly oxaliplatin, oral S-1 40 mg/m2 twice daily for 5 days a week, and radiation. A total of 5 weekly doses of oxaliplatin were planned. RT was administered to a total dose of 50.4 Gy in 28 fractions. Results We enrolled 11 patients between December 2009 and January 2012. DLTs were observed at dose level 1 (50 mg/m2) in two patients, one of whom experienced grade 3 aspartate aminotransferase elevation and a grade 3 alanine aminotransferase increase, and the other developed grade 4 hypokalemia and a grade 3 alanine aminotransferase increase. Five patients at dose level 2 (60 mg/m2) showed no DLTs. The hematological toxicities in all
patients were mild and reversible. One patient showed distant metastasis after chemoradiation. Ten of the 11 patients achieved R0 resection by mesorectal resection and lateral lymph node dissection; three of the 10 underwent combined resection of the other organs. Conclusion This phase I trial of preoperative S-1 in combination with oxaliplatin and radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis revealed that the recommended dose of oxaliplatin was 60 mg/m2 weekly.
M. Ohue (&) S. Noura Division of Colon and Rectal Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan e-mail: [email protected]
Y. Kinugasa Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
T. Hamaguchi Y. Shimada Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan Y. Ito Division of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan D. Sakai Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
Keywords Lower rectal cancer T4 Lateral pelvic lymph node metastasis S-1 Oxaliplatin Preoperative chemoradiation
Introduction In Europe and North America, preoperative chemoradiation (CRT) followed by total mesorectal excision
S. Fujita Department of Surgery, Tochigi Cancer Center Hospital, Utsunomiya, Japan N. Saito Colorectal and Pelvic Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan Y. Moriya Colorectal Surgery Division, Japanese Red Cross Medical Center, Tokyo, Japan
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(TME) is the standard surgical procedure for locally advanced lower rectal cancer [1, 2]. In Japan, however, TME with lateral lymph node dissection (LND) is the standard procedure in patients with clinical stage II or stage III lower rectal cancer [3]. Several papers have compared these procedures retrospectively and revealed there were no significant differences regarding the disease-free survival and overall survival [4, 5]. The pelvic recurrence rate of rectal cancer without radiation in a Japanese study with 1,647 patients was 9.6 % [6]. T4 and lateral pelvic lymph node metastasis in lower rectal cancer were the strongest predictive factors of local recurrence and cannot be cured by TME alone [4, 7], which is defined as ‘‘poor-risk’’ in this study. Therefore, combining preoperative CRT, TME and LND may provide a more powerful strategy to control the recurrence of such poor-risk lower rectal cancer. Fluorouracil-based preoperative CRT reduces local recurrences compared with either preoperative radiation alone or CRT in the postoperative settings [8, 9]; however, it has not yet been proved to enhance either the disease-free or overall survival [8]. Oxaliplatin in combination with an infusional fluorouracil has become a standard first-line treatment for metastatic colorectal cancer, and improved overall survival and disease-free survival of stage II or III colon cancer patients have been observed in the adjuvant setting [10]. An oral fluoropyrimidine derivative, S-1, was reported to enhance the effects of radiotherapy in an in vivo model [11, 12]. The combination of S-1 and oxaliplatin (SOX) was revealed to be effective and easily manageable without central vein access for patients with metastatic colorectal cancer [13]. The SOX regimen proved to be non-inferior to the combination of capecitabine and oxaliplatin for first-line treatment of metastatic colorectal cancer, with less occurrence of hand–foot syndrome [14]. In order to develop a new intensive CRT regimen for poor-risk lower rectal cancer patients undergoing mesorectal excision (ME) and LND, this multi-institutional phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of oxaliplatin.
Patients and methods The protocol was approved by the Institutional Review Board of each participating hospital. This study was conducted in compliance with the Japanese Ethical Guideline for Clinical Studies and the Declaration of Helsinki Principles. Written informed consent was obtained from all the patients. Eligibility criteria Tumor staging was based on the TNM classification [15]. For the N staging, metastasis to lateral pelvic lymph nodes, which include the common iliac node, internal iliac node, external iliac node and obturator node, was defined as N3 in this study according to the Japanese classification [16]. Patients entering the study had histologically confirmed rectal adenocarcinoma with the lower tumor margin below the peritoneal reflection. The tumors had evidence of invasion to adjacent organs (cT4) and lateral pelvic lymph node enlargement [i.e., lymph nodes with a short-axis diameter of more than 10 mm as shown by magnetic resonance imaging (MRI), with sections of 5 mm or less]. Patients were aged between 20 and 75 years, with a performance status of 0 or 1, and no history of chemotherapy, pelvic surgery or irradiation, We included patients with leukocytes C3,000/L and B12,000/lL, platelets C100 9 103/lL, total bilirubin B1.5 mg/dL, aspartate aminotransferase or alanine aminotransferase B100 IU/L, creatinine B1.2 md/dL and creatinine clearance C60 mL/ min/body. Treatment This was a multi-institutional phase I study of escalating doses of oxaliplatin combined with S-1 (Taiho Pharmaceutical, Tokyo, Japan) and concurrent preoperative conventionally fractionated radiotherapy (SOX-RT) for poorrisk lower rectal cancer. As shown in Fig. 1, the first group of three patients received oxaliplatin at 50 mg/m2 (level 1) as a 2-h infusion on days 1, 8, 15, 22 and 29. S-1 (40 mg/m2) was given orally twice daily, 5 days a week. Radiotherapy was delivered with a megavoltage equipment (15 MV) using a
Day 1 8 15 Radiotherapy S-1 Oxaliplatin Radiotherapy, 50.4 Gy in 28 fractions; S-1, 40mg/m2, twice daily; Oxaliplatin, 40
22
29
36
60 mg/m2 on days 1, 8, 15, 22 and 29.
Fig. 1 Treatment scheme. Radiotherapy: 45 Gy in 25 fractions and 5.4 Gy in three fractions. S-1: 40 mg/m2, twice daily on days 1–5, 8–12, 15–19, 22–26 and 29–33. Oxaliplatin: 40–60 mg/m2, weekly on days 1, 8, 15, 22 and 29
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three- or four-field technique. Treatment in the prone position using bowel displacement devices such as belly boards was recommended. Three-dimensional treatment planning was required. The total dose was set at 50.4 Gy in 28 fractions over 6 weeks. The gross tumor volume is defined as the primary tumor and the metastatic lymph nodes C10 mm along the short axis. The clinical target volume (CTV) included the primary tumor with a 2-cm craniocaudal margin, metastatic lymph nodes and regional lymph nodes. The regional lymph nodes included mesorectal, presacral, obturator, internal iliac and common iliac lymph nodes. The planning target volume (PTV) was defined as CTV plus 0.5–1 cm margin to account for physiological movement and daily setup error. After treatment with 45 Gy to the PTV, a booster dose of 5.4 Gy was administered to the reduced PTV, including the primary tumor and metastatic lymph nodes, up to a total dose of 50.4 Gy. The reference point of radiation doses was set at the center of the PTV. Patients were evaluated at baseline and weekly during chemoradiation. Five to six weeks after completion of the chemoradiation, patients were also reevaluated, and the tumor responses to chemoradiation were assessed by Computed tomography (CT) and MRI. If the reassessment revealed that there had been no disease progression compared to the pre-treatment evaluation and the patient remained a candidate for an R0 resection, the patient underwent ME with LND on both sides as described previously [17, 18], within 6–8 weeks after the completion of the chemoradiation. The cancer-invaded organs and tissues surrounding the rectum, including the pelvic autonomic nerves, were also resected to achieve R0 resection. If the reassessment revealed that the patient was not a candidate for an R0 resection, the patient proceeded to other treatments and was no longer treated according to this protocol.
care was given (Common Terminology Criteria for Adverse Events, version 3.0), which was observed during or up to 14 days after the completion of chemoradiation. The administration of less than two-thirds of the scheduled total S-1 or oxaliplatin dose and more than eight successive days of discontinuation of radiation due to adverse effects were also considered to indicate DLT. Three patients were planned to be entered at each level, and the subsequent dose levels were not opened until all three patients in the previous level (or all additional patients whose toxicity required more patients to be treated) had reached the 2-week point beyond the completion of the chemoradiation and surgery. (a) If none of the three patients experienced a DLT, then recruitment began at the next level. (b) If a DLT was seen in one out of the three patients, three additional patients were recruited at this dose level. If DLTs were observed in one or two of the six patients, then recruitment began at the higher level. If DLTs were observed in three or more patients, then recruitment began at the lower level. (c) If two or more of the first three patients had DLTs, no further dose escalation took place, and DLT was defined at that dose level. The MTD was defined as the oxaliplatin dose at which three or more of six patients experienced DLT. It was permitted that four or more patients could be entered at the same level due to a time lag in entry from multiple institutions, and then recruitment proceeded according to the protocol regulations (data not shown). The Protocol Review Committee approved this study in November 2009. This trial was registered in the UMIN Clinical Trials Registry, Number 00002845.
Results Patient characteristics
Assessment of the toxicity and response The primary endpoint was to determine the DLT, MTD and RD of oxaliplatin, with the planned doses being 40 (level 0), 50 (level 1) and 60 mg/m2 (level 2). The upper limit of the oxaliplatin dose of 60 mg/m2 was decided with careful consideration of patient safety, because the RD of oxaliplatin was reported to be 50 mg/m2 according to previous studies and on-going randomized trials [19, 20]. The secondary endpoints included the determination of the safety profile, compliance and the preliminary efficacy of the regimen. DLT was defined as grade 4 neutrophils or platelets, or grade 3 or 4 non-hematological toxicity excluding nausea, vomiting, anorexia, diarrhea, proctitis or burn associated with chemoradiation that recovered to grade 2 or less within 3 days when adequate supportive
A total of 11 patients were enrolled in this phase I study between December 2009 and January 2012 from participating cancer center hospitals. The patient characteristics are listed in Table 1. Eight patients had T4 disease and six patients had lateral pelvic lymph node metastases on MRI and CT. DLT and recommended dose level Adverse effects were observed in all patients. Table 2 lists the most common clinical adverse events and abnormal laboratory findings experienced by patients treated at each dose level. There were three DLTs in two of the six patients treated at dose level 1 (oxaliplatin 50 mg/m2 once a week). One patient developed grade 2 vomiting in weeks 4 and 5, and grade 3 aspartate aminotransferase (AST)
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Int J Clin Oncol Table 1 Patient characteristics Age (years), median (range)
57.0 (39–75)
Gender Male
8
Female
3
ECOG performance status 0–1
11
Body surface area (m2), median (range)
1.846 (1.319–2.080)
2
Body mass index (kg/m ), median (range)
25.0 (17.7–31.6)
Pre-operative clinical stage (MRI and CT) T4N0
3
T4N1
2
T2N3
1
T3N3
2
T4N3
3
Initial CEA level (ng/mL), median (range)
6.9 (4.5–171.9)
ECOG Eastern Cooperative Oncology Group, CEA carcinoembryonic antigen Table 2 grade)
Acute toxicities according to oxaliplatin levels (worst Level 1 (n = 6)
Level 2 (n = 5)
Grade 1–4 (n)
Grade 1–4 (n)
Grade 3–4 (n)
Grade 3–4 (n)
Hematological Hemoglobin
6
0
2
0
Neutrophils
5
0
4
0
Platelets
4
0
2
0
Anorexia Nausea
4 4
0 0
2 3
0 0
Vomiting
2
0
0
0
Stomatitis
2
0
1
0
Diarrhea
2
1
2
0
Anal or rectal pain
5
0
1
0
Non-hematological
Fever
2
0
1
0
Burn
2
0
0
0
Neuropathy
3
0
2
0
Allergy
0
0
1
0
Hyperbilirubinemia
2
0
1
0
AST abnormality
4
1
3
0
ALT abnormality
5
2
3
0
Hyponatremia
2
0
2
0
Hypokalemia
3
1
1
0
Creatinine elevation
2
0
0
0
Toxicities when only one patient had a G1 level toxicity were omitted AST aspartate aminotransferase, ALT alanine aminotransferase
associated with grade 3 alanine aminotransferase (ALT) elevation in week 5. S-1 was interrupted for ten doses during weeks 4 and 5 in this patient. However, full doses of
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oxaliplatin and radiation were given with no delay. The other patient experienced grade 4 hypokalemia and grade 3 alanine aminotransferase elevation in week 5. Grade 3 diarrhea in week 4 was also observed in this patient, who recovered to grade 2 within 3 days with supportive care, and was not judged as a DLT according to the protocol criteria. S-1 was interrupted for seven doses during weeks 4 and 5 and the fifth oxaliplatin dose was reduced from 60 to 50 mg/m2 in this patient. Radiation was delivered on schedule. There were no DLTs in five patients at dose level 2 (oxaliplatin 60 mg/m2 once a week). However, one patient developed a grade 2 allergic reaction to oxaliplatin in week 4 and the fifth oxaliplatin infusion was interrupted based on the primary physicians’ judgment. Dose escalation in this study was stopped at 60 mg/m2 once a week (level 2) according to the protocol regulations. Although the MTD was not reached, it was defined as the recommended dose of oxaliplatin. The most frequently detected adverse event was neutropenia, which occurred in nine of 11 patients (82 %) and was reversible in all patients. There was no significant myelosuppression, and no grade 3–4 neutropenia or thrombocytopenia. An ALT abnormality was the next most common adverse event, and occurred in eight of 11 patients (73 %), and was associated with DLT in two patients, as described previously. In level 1, four of the six patients required S-1 dose reduction due to DLTs and other adverse effects, such as grade 3 diarrhea, grade 2 diarrhea and grade 2 vomiting. Oxaliplatin reduction was required in only one patient due to the DLT. In level 2, one patient required oxaliplatin dose reduction due to a grade 2 allergy. The proportions of the total dose to planned dose of SOX were 93.2 and 99.3 % in level 1, and 100 and 99.3 % in level 2. There was full compliance (no reduction in the planned dose or duration of treatment) with radiation therapy in each level. Surgery Ten of the 11 patients underwent ME with LND within 6–8 weeks after the completion of CRT (Table 3). One patient developed peritoneal dissemination and para-aortic lymph node metastasis, the response of which was judged to be progressive disease, and received other treatment than that indicated by the protocol (Table 3, patient no. 4). Of the eight patients with cT4 tumors, five received only ME and LND, whereas the other three patients received additional organ resection due to tumor invasion. Sphincter-preserving surgery was performed in six out of the 10 patients. The median length of the operation was 378 min (range 240–698) and the median blood loss was 668 mL (range 137–1760). Two patients received blood
Int J Clin Oncol Table 3 Response to chemoradiotherapy Patient no.
Level
Oxaliplatin dose (mg/m2)
cTN
Mesorectal LN metastasis suspected
Lateral LN metastasis suspected
Operation
ypTN
Histological grading
Mesorectal pN
Lateral pN
1
1
50
T4N1
Yes
No
LAR
T3N0
G1
0/10
0/5
2
1
50
T2N3
Yes
Yes
APR
T0N0
G3
0/9
0/29
3 4
1 1
50 50
T3N3 T4N3
Yes Yes
Yes Yes
APR Not done
T2N3
G2
0/0
1/12
5
1
50
T3N3
No
Yes
LAR
T1N3
G2
0/2
1/17
6
1
50
T4N3
Yes
Yes
PPE
T4N3
G1
1/10
5/11
7
2
60
T4N0
No
No
LAR
T3N0
G1
0/19
0/21
8
2
60
T4N3
Yes
Yes
LAR
T3N3
G1
1/10
1/7
9
2
60
T4N0
No
No
APR
T3N0
Gl
0/8
0/16
10
2
60
T4N1
Yes
No
LAR
T4N0
G2
0/26
0/9
11
2
60
T4N0
No
No
LAR
T3N0
G2
0/14
0/14
LAR low anterior resection, APR abdominoperineal resection, PPE posterior pelvic exenteration
transfusions intraoperatively, and one patient required the use of a primary rectus abdominis muscle flap to prevent pelvic dead space infection after a posterior pelvic exenteration. Of the 10 patients, grade 2 postoperative complications were observed in two patients with ileus, two with urinary retention, and one with a pelvic infection after abdominoperineal resection, all of whom recovered with conservative treatment. There were no other serious postoperative complications, such as anastomotic leakage. The postoperative hospital stay was a median of 18.5 days (range 11–28). There were no perioperative deaths in this study. Pathological findings Of the 11 patients treated with SOX-RT, all underwent surgery except one who developed distant metastases (Table 3). All 10 patients underwent R0 resection. Tumor downstaging was defined by a comparison of the clinical TN stage prior to the treatment (as determined by pelvic MRI and CT) with the histopathological stage post-surgery. Reductions of the T stage and N stage were observed in eight of 10 patients (80 %) and three of the seven cN-positive patients (43 %), respectively. If lymph nodes are divided into mesorectal and lateral areas according to the location, mesorectal lymph node metastasis disappeared in five of six patients (83 %) and lateral lymph node metastasis disappeared in only one of five patients (20 %). However, this difference was not statistically significant by Fisher’s exact test (P = 0.0801). A pathological complete response occurred in one of 10 patients (10 %) at the level 1 dose (Table 3, patient no. 2) and half of the patients had a grade 2 or 3 response.
Discussion This phase I study (SOX-RT) showed a tolerable toxicity in patients with poor-risk lower rectal cancer. Although a MTD was not reached, we determined the RD of oxaliplatin to be 60 mg/m2/week according to the protocol regulations. DLTs such as ALT or AST abnormalities and hypokalemia, which may be induced by grade 3 diarrhea, were observed only at level 1 (two patients) but not at level 2, which suggests that these grade 3–4 toxicities may not be correlated with oxaliplatin dose escalation. The low rate of grade 3–4 diarrhea may be due to the selection of oxaliplatin instead of irinotecan, because irinotecan, which is also a key drug in the treatment of colorectal cancer, has major intestinal toxicity, particularly diarrhea [21]. No grade 3–4 hematological toxicities were seen in this study. We performed TME and LND with preoperative SOXRT for patients with T4 tumors and lateral pelvic lymph node metastasis who were not considered to be cured by TME alone (beyond TME). One patient with cT4N3 developed distant metastasis before surgery and the other 10 patients tolerated the surgery with LND and combined resections, which were more invasive than conventional TME alone. The perioperative complications were not severe in any of these patients, and were considered to be acceptable. The pathological findings revealed that all these patients obtained R0 resections. This SOX-RT study achieved a higher reduction rate of T stage (80 %) than N stage (43 %). There may have been some differences in sensitivity to CRT among the main tumors, mesorectal lymph node metastases and lateral pelvic lymph node metastases. However, we cannot draw any conclusions about this possibility due to the small number of patients included in the trial.
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Recently, the results have been published of large trials comparing preoperative chemoradiotherapy with fluoropyrimidine (fluorouracil or capecitabine) and oxaliplatin versus fluoropyrimidine alone in locally advanced rectal cancer [20, 22, 23]. A meta-analysis of these studies revealed that adding weekly oxaliplatin to fluoropyrimidine in the neoadjuvant CRT for locally advanced rectal cancer appeared to modestly increase the pathological complete response rate and reduce the rate of intra-abdominal or perioperative metastases. Although fluoropyrimidine and oxaliplatin significantly increased the grade 3–4 toxicity, it did not result in more surgical complications or postoperative deaths within 60 days [24]. Moreover, a Korean team published phase I and II studies of SOX-RT [25, 26] and recommended administering S-1 at 40 mg/m2 twice daily on days 1–14 and 22–35, oxaliplatin at 50 mg/m2 on days 1, 8, 22 and 29 with a chemotherapy gap on days 15–21, and radiation at 50.4 Gy. In the present study protocol for the SOX-RT regimen, we administered a high oxaliplatin dose without a chemotherapy gap, and performed more invasive surgery such as LND and combined resection of adjacent organs for more poor-risk lower rectal cancer. In conclusion, this phase I trial of preoperative S-1 in combination with oxaliplatin and radiation (SOX-RT) for patients with poor-risk lower rectal cancer was safely performed and revealed that the RD of oxaliplatin is 60 mg/m2. Acknowledgments We thank Drs. Tatsuya Ioka and Hiroshi Nokihara for their critical advice. Oxaliplatin was provided for the first three patients by Yakult Co., Ltd. before its acceptance by the health insurance system in Japan. This study was supported by Grants-in-Aids for the National Cancer Center Research and Development Fund [23-A-14] from the Ministry of Health, Labour and Welfare of Japan. Conflict of interest Daisuke Sakai belongs to the department which has been endowed by Yakult Honsha Co., Ltd. The other authors declare that they have no conflict of interest.
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5. Kusters M, Beets GL, van de Velde CJ et al (2009) A comparison between the treatment of low rectal cancer in Japan and the Netherlands, focusing on the patterns of local recurrence. Ann Surg 249:229–235 6. Kobayashi H, Mochizuki H, Sugihara K et al (2007) Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study. Surgery 141:67–75 7. Sugihara K, Kobayashi H, Kato T et al (2006) Indication and benefit of pelvic sidewall dissection for rectal cancer. Dis Colon Rectum 49:1663–1672 8. Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123 9. Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740 10. Andre T, Boni C, Navarro M et al (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–3116 11. Takechi T, Nakano K, Uchida J et al (1997) Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 39:205–211 12. Zeng L, Ou G, Itasaka S et al (2008) TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis. Cancer Sci 99:2327–2335 13. Yamada Y, Tahara M, Miya T et al (2008) Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer. Br J Cancer 98:1034–1038 14. Hong YS, Park YS, Lim HY et al (2012) S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, noninferiority phase 3 trial. Lancet Oncol 13:1125–1132 15. Sobin L, Wittekind C (2009) TNM classification of malignant tumours, 7th edn. Wiley-Liss, New York 16. Japanese Society of Cancer of the Colon and Rectum (2006) General rules for clinical and pathological studies on cancer of the colon, rectum, and anus, 7th edn. Kanehara, Tokyo 17. Moriya Y, Sugihara K, Akasu T et al (1995) Nerve-sparing surgery with lateral node dissection for advanced lower rectal cancer. Eur J Cancer 31A:1229–1232 18. Mori T, Takahashi K, Yasuno M (1998) Radical resection with autonomic nerve preservation and lymph node dissection techniques in lower rectal cancer surgery and its results: the impact of lateral lymph node dissection. Langenbecks Arch Surg 383:409–415 19. Rodel C, Liersch T, Hermann RM et al (2007) Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:110–117 20. Gerard JP, Azria D, Gourgou-Bourgade S et al (2010) Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 28:1638–1644 21. Hecht JR (1998) Gastrointestinal toxicity of irinotecan. Oncology 12:72–78 22. Aschele C, Cionini L, Lonardi S et al (2011) Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 29:2773–2780 23. Rodel C, Liersch T, Becker H et al (2012) Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13:679–687
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ORIGINAL ARTICLE
A phase I trial of preoperative S-1 in combination with oxaliplatin and pelvic radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis Masayuki Ohue • Tetsuya Hamaguchi • Yoshinori Ito • Daisuke Sakai Shingo Noura • Yusuke Kinugasa • Shin Fujita • Yasuhiro Shimada • Norio Saito • Yoshihiro Moriya
•
Received: 17 March 2014 / Accepted: 27 April 2014 Ó Japan Society of Clinical Oncology 2014
Abstract Background The purpose of this phase I study of the dose escalation of oxaliplatin in combination with oral S-1 and pelvic radiation preoperatively for poor-risk lower rectal cancer was to determine the dose-limiting toxicity (DLT) and recommended dose of oxaliplatin. Methods Patients with cT4 and lateral pelvic lymph node metastasis, and without distant metastasis (cM0), were treated with weekly oxaliplatin, oral S-1 40 mg/m2 twice daily for 5 days a week, and radiation. A total of 5 weekly doses of oxaliplatin were planned. RT was administered to a total dose of 50.4 Gy in 28 fractions. Results We enrolled 11 patients between December 2009 and January 2012. DLTs were observed at dose level 1 (50 mg/m2) in two patients, one of whom experienced grade 3 aspartate aminotransferase elevation and a grade 3 alanine aminotransferase increase, and the other developed grade 4 hypokalemia and a grade 3 alanine aminotransferase increase. Five patients at dose level 2 (60 mg/m2) showed no DLTs. The hematological toxicities in all
patients were mild and reversible. One patient showed distant metastasis after chemoradiation. Ten of the 11 patients achieved R0 resection by mesorectal resection and lateral lymph node dissection; three of the 10 underwent combined resection of the other organs. Conclusion This phase I trial of preoperative S-1 in combination with oxaliplatin and radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis revealed that the recommended dose of oxaliplatin was 60 mg/m2 weekly.
M. Ohue (&) S. Noura Division of Colon and Rectal Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan e-mail: [email protected]
Y. Kinugasa Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
T. Hamaguchi Y. Shimada Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan Y. Ito Division of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan D. Sakai Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
Keywords Lower rectal cancer T4 Lateral pelvic lymph node metastasis S-1 Oxaliplatin Preoperative chemoradiation
Introduction In Europe and North America, preoperative chemoradiation (CRT) followed by total mesorectal excision
S. Fujita Department of Surgery, Tochigi Cancer Center Hospital, Utsunomiya, Japan N. Saito Colorectal and Pelvic Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan Y. Moriya Colorectal Surgery Division, Japanese Red Cross Medical Center, Tokyo, Japan
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(TME) is the standard surgical procedure for locally advanced lower rectal cancer [1, 2]. In Japan, however, TME with lateral lymph node dissection (LND) is the standard procedure in patients with clinical stage II or stage III lower rectal cancer [3]. Several papers have compared these procedures retrospectively and revealed there were no significant differences regarding the disease-free survival and overall survival [4, 5]. The pelvic recurrence rate of rectal cancer without radiation in a Japanese study with 1,647 patients was 9.6 % [6]. T4 and lateral pelvic lymph node metastasis in lower rectal cancer were the strongest predictive factors of local recurrence and cannot be cured by TME alone [4, 7], which is defined as ‘‘poor-risk’’ in this study. Therefore, combining preoperative CRT, TME and LND may provide a more powerful strategy to control the recurrence of such poor-risk lower rectal cancer. Fluorouracil-based preoperative CRT reduces local recurrences compared with either preoperative radiation alone or CRT in the postoperative settings [8, 9]; however, it has not yet been proved to enhance either the disease-free or overall survival [8]. Oxaliplatin in combination with an infusional fluorouracil has become a standard first-line treatment for metastatic colorectal cancer, and improved overall survival and disease-free survival of stage II or III colon cancer patients have been observed in the adjuvant setting [10]. An oral fluoropyrimidine derivative, S-1, was reported to enhance the effects of radiotherapy in an in vivo model [11, 12]. The combination of S-1 and oxaliplatin (SOX) was revealed to be effective and easily manageable without central vein access for patients with metastatic colorectal cancer [13]. The SOX regimen proved to be non-inferior to the combination of capecitabine and oxaliplatin for first-line treatment of metastatic colorectal cancer, with less occurrence of hand–foot syndrome [14]. In order to develop a new intensive CRT regimen for poor-risk lower rectal cancer patients undergoing mesorectal excision (ME) and LND, this multi-institutional phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of oxaliplatin.
Patients and methods The protocol was approved by the Institutional Review Board of each participating hospital. This study was conducted in compliance with the Japanese Ethical Guideline for Clinical Studies and the Declaration of Helsinki Principles. Written informed consent was obtained from all the patients. Eligibility criteria Tumor staging was based on the TNM classification [15]. For the N staging, metastasis to lateral pelvic lymph nodes, which include the common iliac node, internal iliac node, external iliac node and obturator node, was defined as N3 in this study according to the Japanese classification [16]. Patients entering the study had histologically confirmed rectal adenocarcinoma with the lower tumor margin below the peritoneal reflection. The tumors had evidence of invasion to adjacent organs (cT4) and lateral pelvic lymph node enlargement [i.e., lymph nodes with a short-axis diameter of more than 10 mm as shown by magnetic resonance imaging (MRI), with sections of 5 mm or less]. Patients were aged between 20 and 75 years, with a performance status of 0 or 1, and no history of chemotherapy, pelvic surgery or irradiation, We included patients with leukocytes C3,000/L and B12,000/lL, platelets C100 9 103/lL, total bilirubin B1.5 mg/dL, aspartate aminotransferase or alanine aminotransferase B100 IU/L, creatinine B1.2 md/dL and creatinine clearance C60 mL/ min/body. Treatment This was a multi-institutional phase I study of escalating doses of oxaliplatin combined with S-1 (Taiho Pharmaceutical, Tokyo, Japan) and concurrent preoperative conventionally fractionated radiotherapy (SOX-RT) for poorrisk lower rectal cancer. As shown in Fig. 1, the first group of three patients received oxaliplatin at 50 mg/m2 (level 1) as a 2-h infusion on days 1, 8, 15, 22 and 29. S-1 (40 mg/m2) was given orally twice daily, 5 days a week. Radiotherapy was delivered with a megavoltage equipment (15 MV) using a
Day 1 8 15 Radiotherapy S-1 Oxaliplatin Radiotherapy, 50.4 Gy in 28 fractions; S-1, 40mg/m2, twice daily; Oxaliplatin, 40
22
29
36
60 mg/m2 on days 1, 8, 15, 22 and 29.
Fig. 1 Treatment scheme. Radiotherapy: 45 Gy in 25 fractions and 5.4 Gy in three fractions. S-1: 40 mg/m2, twice daily on days 1–5, 8–12, 15–19, 22–26 and 29–33. Oxaliplatin: 40–60 mg/m2, weekly on days 1, 8, 15, 22 and 29
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three- or four-field technique. Treatment in the prone position using bowel displacement devices such as belly boards was recommended. Three-dimensional treatment planning was required. The total dose was set at 50.4 Gy in 28 fractions over 6 weeks. The gross tumor volume is defined as the primary tumor and the metastatic lymph nodes C10 mm along the short axis. The clinical target volume (CTV) included the primary tumor with a 2-cm craniocaudal margin, metastatic lymph nodes and regional lymph nodes. The regional lymph nodes included mesorectal, presacral, obturator, internal iliac and common iliac lymph nodes. The planning target volume (PTV) was defined as CTV plus 0.5–1 cm margin to account for physiological movement and daily setup error. After treatment with 45 Gy to the PTV, a booster dose of 5.4 Gy was administered to the reduced PTV, including the primary tumor and metastatic lymph nodes, up to a total dose of 50.4 Gy. The reference point of radiation doses was set at the center of the PTV. Patients were evaluated at baseline and weekly during chemoradiation. Five to six weeks after completion of the chemoradiation, patients were also reevaluated, and the tumor responses to chemoradiation were assessed by Computed tomography (CT) and MRI. If the reassessment revealed that there had been no disease progression compared to the pre-treatment evaluation and the patient remained a candidate for an R0 resection, the patient underwent ME with LND on both sides as described previously [17, 18], within 6–8 weeks after the completion of the chemoradiation. The cancer-invaded organs and tissues surrounding the rectum, including the pelvic autonomic nerves, were also resected to achieve R0 resection. If the reassessment revealed that the patient was not a candidate for an R0 resection, the patient proceeded to other treatments and was no longer treated according to this protocol.
care was given (Common Terminology Criteria for Adverse Events, version 3.0), which was observed during or up to 14 days after the completion of chemoradiation. The administration of less than two-thirds of the scheduled total S-1 or oxaliplatin dose and more than eight successive days of discontinuation of radiation due to adverse effects were also considered to indicate DLT. Three patients were planned to be entered at each level, and the subsequent dose levels were not opened until all three patients in the previous level (or all additional patients whose toxicity required more patients to be treated) had reached the 2-week point beyond the completion of the chemoradiation and surgery. (a) If none of the three patients experienced a DLT, then recruitment began at the next level. (b) If a DLT was seen in one out of the three patients, three additional patients were recruited at this dose level. If DLTs were observed in one or two of the six patients, then recruitment began at the higher level. If DLTs were observed in three or more patients, then recruitment began at the lower level. (c) If two or more of the first three patients had DLTs, no further dose escalation took place, and DLT was defined at that dose level. The MTD was defined as the oxaliplatin dose at which three or more of six patients experienced DLT. It was permitted that four or more patients could be entered at the same level due to a time lag in entry from multiple institutions, and then recruitment proceeded according to the protocol regulations (data not shown). The Protocol Review Committee approved this study in November 2009. This trial was registered in the UMIN Clinical Trials Registry, Number 00002845.
Results Patient characteristics
Assessment of the toxicity and response The primary endpoint was to determine the DLT, MTD and RD of oxaliplatin, with the planned doses being 40 (level 0), 50 (level 1) and 60 mg/m2 (level 2). The upper limit of the oxaliplatin dose of 60 mg/m2 was decided with careful consideration of patient safety, because the RD of oxaliplatin was reported to be 50 mg/m2 according to previous studies and on-going randomized trials [19, 20]. The secondary endpoints included the determination of the safety profile, compliance and the preliminary efficacy of the regimen. DLT was defined as grade 4 neutrophils or platelets, or grade 3 or 4 non-hematological toxicity excluding nausea, vomiting, anorexia, diarrhea, proctitis or burn associated with chemoradiation that recovered to grade 2 or less within 3 days when adequate supportive
A total of 11 patients were enrolled in this phase I study between December 2009 and January 2012 from participating cancer center hospitals. The patient characteristics are listed in Table 1. Eight patients had T4 disease and six patients had lateral pelvic lymph node metastases on MRI and CT. DLT and recommended dose level Adverse effects were observed in all patients. Table 2 lists the most common clinical adverse events and abnormal laboratory findings experienced by patients treated at each dose level. There were three DLTs in two of the six patients treated at dose level 1 (oxaliplatin 50 mg/m2 once a week). One patient developed grade 2 vomiting in weeks 4 and 5, and grade 3 aspartate aminotransferase (AST)
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Int J Clin Oncol Table 1 Patient characteristics Age (years), median (range)
57.0 (39–75)
Gender Male
8
Female
3
ECOG performance status 0–1
11
Body surface area (m2), median (range)
1.846 (1.319–2.080)
2
Body mass index (kg/m ), median (range)
25.0 (17.7–31.6)
Pre-operative clinical stage (MRI and CT) T4N0
3
T4N1
2
T2N3
1
T3N3
2
T4N3
3
Initial CEA level (ng/mL), median (range)
6.9 (4.5–171.9)
ECOG Eastern Cooperative Oncology Group, CEA carcinoembryonic antigen Table 2 grade)
Acute toxicities according to oxaliplatin levels (worst Level 1 (n = 6)
Level 2 (n = 5)
Grade 1–4 (n)
Grade 1–4 (n)
Grade 3–4 (n)
Grade 3–4 (n)
Hematological Hemoglobin
6
0
2
0
Neutrophils
5
0
4
0
Platelets
4
0
2
0
Anorexia Nausea
4 4
0 0
2 3
0 0
Vomiting
2
0
0
0
Stomatitis
2
0
1
0
Diarrhea
2
1
2
0
Anal or rectal pain
5
0
1
0
Non-hematological
Fever
2
0
1
0
Burn
2
0
0
0
Neuropathy
3
0
2
0
Allergy
0
0
1
0
Hyperbilirubinemia
2
0
1
0
AST abnormality
4
1
3
0
ALT abnormality
5
2
3
0
Hyponatremia
2
0
2
0
Hypokalemia
3
1
1
0
Creatinine elevation
2
0
0
0
Toxicities when only one patient had a G1 level toxicity were omitted AST aspartate aminotransferase, ALT alanine aminotransferase
associated with grade 3 alanine aminotransferase (ALT) elevation in week 5. S-1 was interrupted for ten doses during weeks 4 and 5 in this patient. However, full doses of
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oxaliplatin and radiation were given with no delay. The other patient experienced grade 4 hypokalemia and grade 3 alanine aminotransferase elevation in week 5. Grade 3 diarrhea in week 4 was also observed in this patient, who recovered to grade 2 within 3 days with supportive care, and was not judged as a DLT according to the protocol criteria. S-1 was interrupted for seven doses during weeks 4 and 5 and the fifth oxaliplatin dose was reduced from 60 to 50 mg/m2 in this patient. Radiation was delivered on schedule. There were no DLTs in five patients at dose level 2 (oxaliplatin 60 mg/m2 once a week). However, one patient developed a grade 2 allergic reaction to oxaliplatin in week 4 and the fifth oxaliplatin infusion was interrupted based on the primary physicians’ judgment. Dose escalation in this study was stopped at 60 mg/m2 once a week (level 2) according to the protocol regulations. Although the MTD was not reached, it was defined as the recommended dose of oxaliplatin. The most frequently detected adverse event was neutropenia, which occurred in nine of 11 patients (82 %) and was reversible in all patients. There was no significant myelosuppression, and no grade 3–4 neutropenia or thrombocytopenia. An ALT abnormality was the next most common adverse event, and occurred in eight of 11 patients (73 %), and was associated with DLT in two patients, as described previously. In level 1, four of the six patients required S-1 dose reduction due to DLTs and other adverse effects, such as grade 3 diarrhea, grade 2 diarrhea and grade 2 vomiting. Oxaliplatin reduction was required in only one patient due to the DLT. In level 2, one patient required oxaliplatin dose reduction due to a grade 2 allergy. The proportions of the total dose to planned dose of SOX were 93.2 and 99.3 % in level 1, and 100 and 99.3 % in level 2. There was full compliance (no reduction in the planned dose or duration of treatment) with radiation therapy in each level. Surgery Ten of the 11 patients underwent ME with LND within 6–8 weeks after the completion of CRT (Table 3). One patient developed peritoneal dissemination and para-aortic lymph node metastasis, the response of which was judged to be progressive disease, and received other treatment than that indicated by the protocol (Table 3, patient no. 4). Of the eight patients with cT4 tumors, five received only ME and LND, whereas the other three patients received additional organ resection due to tumor invasion. Sphincter-preserving surgery was performed in six out of the 10 patients. The median length of the operation was 378 min (range 240–698) and the median blood loss was 668 mL (range 137–1760). Two patients received blood
Int J Clin Oncol Table 3 Response to chemoradiotherapy Patient no.
Level
Oxaliplatin dose (mg/m2)
cTN
Mesorectal LN metastasis suspected
Lateral LN metastasis suspected
Operation
ypTN
Histological grading
Mesorectal pN
Lateral pN
1
1
50
T4N1
Yes
No
LAR
T3N0
G1
0/10
0/5
2
1
50
T2N3
Yes
Yes
APR
T0N0
G3
0/9
0/29
3 4
1 1
50 50
T3N3 T4N3
Yes Yes
Yes Yes
APR Not done
T2N3
G2
0/0
1/12
5
1
50
T3N3
No
Yes
LAR
T1N3
G2
0/2
1/17
6
1
50
T4N3
Yes
Yes
PPE
T4N3
G1
1/10
5/11
7
2
60
T4N0
No
No
LAR
T3N0
G1
0/19
0/21
8
2
60
T4N3
Yes
Yes
LAR
T3N3
G1
1/10
1/7
9
2
60
T4N0
No
No
APR
T3N0
Gl
0/8
0/16
10
2
60
T4N1
Yes
No
LAR
T4N0
G2
0/26
0/9
11
2
60
T4N0
No
No
LAR
T3N0
G2
0/14
0/14
LAR low anterior resection, APR abdominoperineal resection, PPE posterior pelvic exenteration
transfusions intraoperatively, and one patient required the use of a primary rectus abdominis muscle flap to prevent pelvic dead space infection after a posterior pelvic exenteration. Of the 10 patients, grade 2 postoperative complications were observed in two patients with ileus, two with urinary retention, and one with a pelvic infection after abdominoperineal resection, all of whom recovered with conservative treatment. There were no other serious postoperative complications, such as anastomotic leakage. The postoperative hospital stay was a median of 18.5 days (range 11–28). There were no perioperative deaths in this study. Pathological findings Of the 11 patients treated with SOX-RT, all underwent surgery except one who developed distant metastases (Table 3). All 10 patients underwent R0 resection. Tumor downstaging was defined by a comparison of the clinical TN stage prior to the treatment (as determined by pelvic MRI and CT) with the histopathological stage post-surgery. Reductions of the T stage and N stage were observed in eight of 10 patients (80 %) and three of the seven cN-positive patients (43 %), respectively. If lymph nodes are divided into mesorectal and lateral areas according to the location, mesorectal lymph node metastasis disappeared in five of six patients (83 %) and lateral lymph node metastasis disappeared in only one of five patients (20 %). However, this difference was not statistically significant by Fisher’s exact test (P = 0.0801). A pathological complete response occurred in one of 10 patients (10 %) at the level 1 dose (Table 3, patient no. 2) and half of the patients had a grade 2 or 3 response.
Discussion This phase I study (SOX-RT) showed a tolerable toxicity in patients with poor-risk lower rectal cancer. Although a MTD was not reached, we determined the RD of oxaliplatin to be 60 mg/m2/week according to the protocol regulations. DLTs such as ALT or AST abnormalities and hypokalemia, which may be induced by grade 3 diarrhea, were observed only at level 1 (two patients) but not at level 2, which suggests that these grade 3–4 toxicities may not be correlated with oxaliplatin dose escalation. The low rate of grade 3–4 diarrhea may be due to the selection of oxaliplatin instead of irinotecan, because irinotecan, which is also a key drug in the treatment of colorectal cancer, has major intestinal toxicity, particularly diarrhea [21]. No grade 3–4 hematological toxicities were seen in this study. We performed TME and LND with preoperative SOXRT for patients with T4 tumors and lateral pelvic lymph node metastasis who were not considered to be cured by TME alone (beyond TME). One patient with cT4N3 developed distant metastasis before surgery and the other 10 patients tolerated the surgery with LND and combined resections, which were more invasive than conventional TME alone. The perioperative complications were not severe in any of these patients, and were considered to be acceptable. The pathological findings revealed that all these patients obtained R0 resections. This SOX-RT study achieved a higher reduction rate of T stage (80 %) than N stage (43 %). There may have been some differences in sensitivity to CRT among the main tumors, mesorectal lymph node metastases and lateral pelvic lymph node metastases. However, we cannot draw any conclusions about this possibility due to the small number of patients included in the trial.
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Recently, the results have been published of large trials comparing preoperative chemoradiotherapy with fluoropyrimidine (fluorouracil or capecitabine) and oxaliplatin versus fluoropyrimidine alone in locally advanced rectal cancer [20, 22, 23]. A meta-analysis of these studies revealed that adding weekly oxaliplatin to fluoropyrimidine in the neoadjuvant CRT for locally advanced rectal cancer appeared to modestly increase the pathological complete response rate and reduce the rate of intra-abdominal or perioperative metastases. Although fluoropyrimidine and oxaliplatin significantly increased the grade 3–4 toxicity, it did not result in more surgical complications or postoperative deaths within 60 days [24]. Moreover, a Korean team published phase I and II studies of SOX-RT [25, 26] and recommended administering S-1 at 40 mg/m2 twice daily on days 1–14 and 22–35, oxaliplatin at 50 mg/m2 on days 1, 8, 22 and 29 with a chemotherapy gap on days 15–21, and radiation at 50.4 Gy. In the present study protocol for the SOX-RT regimen, we administered a high oxaliplatin dose without a chemotherapy gap, and performed more invasive surgery such as LND and combined resection of adjacent organs for more poor-risk lower rectal cancer. In conclusion, this phase I trial of preoperative S-1 in combination with oxaliplatin and radiation (SOX-RT) for patients with poor-risk lower rectal cancer was safely performed and revealed that the RD of oxaliplatin is 60 mg/m2. Acknowledgments We thank Drs. Tatsuya Ioka and Hiroshi Nokihara for their critical advice. Oxaliplatin was provided for the first three patients by Yakult Co., Ltd. before its acceptance by the health insurance system in Japan. This study was supported by Grants-in-Aids for the National Cancer Center Research and Development Fund [23-A-14] from the Ministry of Health, Labour and Welfare of Japan. Conflict of interest Daisuke Sakai belongs to the department which has been endowed by Yakult Honsha Co., Ltd. The other authors declare that they have no conflict of interest.
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