Cancer Chemother Pharmacol (2015) 76:29–34 DOI 10.1007/s00280-015-2764-1

ORIGINAL ARTICLE

Pilot study of modified FOLFOX6 adjuvant chemotherapy for high‑risk rectal cancer treated with neoadjuvant chemoradiotherapy Soo Jung Lee1 · Byung Woog Kang1 · Yee Soo Chae1 · Seung Hyun Cho2 · Hye Jin Kim3 · Su Yeon Park3 · Jun Seok Park3 · Gyu Seog Choi3 · Jong Gwang Kim1 

Received: 18 October 2014 / Accepted: 29 April 2015 / Published online: 9 May 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  Purpose  Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision is considered the standard of care for patients with locally advanced adenocarcinoma of the middle/low rectum. The present study evaluated the feasibility of using modified FOLFOX6 regimen as an adjuvant treatment for high-risk patients with locally advanced rectal cancer (LARC) treated with neoadjuvant CRT. Methods  Forty patients with LARC (ypT3–4 or N+) treated with neoadjuvant CRT were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between December 2011 and December 2012. All the patients underwent rectal surgery with curative intent 8 weeks after the end of the neoadjuvant treatment. Adjuvant chemotherapy using modified FOLFOX6 regimen was then delivered for 3 months. Results  The treatments were generally well tolerated. Dose reduction was recorded in 11 of the 40 patients (27.5 %). The incidence of febrile neutropenia was 5 %, the incidence of grade 3 or 4 asthenia was 10 %, and the * Jong Gwang Kim [email protected] 1

Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hogukno, Buk‑gu, Daegu 702‑210, Korea

2

Department of Radiology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea

3

Department of Surgery, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea







incidence of grade 3 gastrointestinal adverse events was 5 % during treatment. Treatment discontinuation caused by toxic effects or any other reasons was observed in six patients (15 %). The reasons for discontinuation were asthenia (n  = 2, 5 %), diarrhea (n  = 2, 5 %), acute renal failure (n  = 1, 2.5 %), and relapse during chemotherapy (n  = 1, 2.5 %). With a median follow-up duration of 18 months, six patients (15 %) relapsed and one patient (2.5 %) died of disease progression. The estimated 3-year disease-free survival and overall survival rates were 84.2 and 97.3 %, respectively. Conclusions  Postoperative adjuvant modified FOLFOX6 regimen was found to be feasible for patients with LARC treated with neoadjuvant CRT. Keywords  Rectal cancer · FOLFOX · Adjuvant chemotherapy · Feasibility

Introduction Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is considered the standard of care for patients with locally advanced adenocarcinoma of the middle/low rectum, as it provides the opportunity to downstage tumors, increases sphincter preservation, and decreases the risk of locoregional recurrence when compared with postoperative treatment, even though no improvement in overall survival has been observed [1, 2]. However, the tumor response to neoadjuvant CRT varies considerably among patients, ranging from the complete disappearance of the tumor in about 15–20 % of cases to a lack of any pathological change or even tumor progression during the treatment. It is also well known that poor

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responders to neoadjuvant CRT have a higher recurrence rate and worse overall survival when compared to good responders including a pathologic complete response [3–5]. Although studies before the era of TME demonstrated improved survival outcomes associated with adjuvant chemotherapy among patients with resected rectal cancer [6], the benefit of adjuvant chemotherapy after CRT and surgery in the modern era is assumed on the basis of the results of adjuvant therapy trials for colon cancer [6]. However, Bosset et al. [7] reported that adjuvant 5-fluorouracil (5-FU)/leucovorin (LV) chemotherapy after preoperative radiotherapy (with or without chemotherapy) did not affect disease-free survival (DFS) or overall survival (OS) in the long-term results of the EORTC 22921 randomized study that examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. For colon cancer, the benefit of adding oxaliplatin to infusional 5-FU and LV was established in the MOSAIC (Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer) trial [8]. This study proved the efficacy of adding oxaliplatin, a third-generation platinum, which then led to the approval of FOLFOX as the standard adjuvant treatment for stage III colon cancer after a curative resection. Accordingly, the present study evaluated the feasibility of a modified FOLFOX6 regimen for high-risk patients with locally advanced rectal cancer (LARC) treated with neoadjuvant CRT.

Materials and methods Patient eligibility All the enrolled patients had histologically proven T3/4, N± or T1/2, N+ rectal adenocarcinoma after neoadjuvant CRT based on the criteria of the seventh edition of the AJCC Cancer Staging Manual. In addition, there must have been no evidence of metastatic disease on CT scans of the abdomen and chest and FDG-PET/CT. All the tumors were staged using contrast-enhanced abdominal–pelvic magnetic resonance imaging (MRI) prior to treatment and after CRT. The N stage was assessed using MRI, and the pathological stage was determined by the local pathologist department based on a surgical specimen using the ypTNM system. The eligibility criteria for the patients were an age between 18 and 69, the absence of hematological diseases, a white blood cell count (WBC) of at least 4 × 109/L, platelet count of at least 100 × 109/L, hemoglobin of at least 80 g/L, alanine transaminase (ALT) and aspartate transaminase (AST) levels of at least 2.5-fold below the upper limit of normal (≤100 U/L), a normal kidney function (creatinine clearance ≥ 60 mL/min), and Eastern Cooperative

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Oncology Group (ECOG) status of 0–2. The Institutional Review Board of Kyungpook National University Medical Center (Daegu, Korea) approved this study, and all the patients provided informed consent. Preoperative and study treatment The CRT consisted of radiotherapy, delivered at a total dose of 4500 cGy in 25 daily fractions of 1.8 Gy in combination with a concurrent chemotherapy regimen of a 5-FU plus LV bolus infusion (‘Mayo’ regimen). One additional infusion of Mayo regimen after the end of the CRT was also administered. All the patients underwent rectal surgery (TME) with curative intent 8 weeks after the end of the neoadjuvant treatment. The adjuvant chemotherapy using modified FOLFOX6 regimen was then delivered for 3 months. The patients received the mFOLFOX6 every 2 weeks (1 cycle): 85 mg/m2 oxaliplatin (2-h infusion) on day 1 and 200 mg/ m2 LV on days 1 and 2, followed by 400 mg/m2 5-FU (bolus) and then 2400 mg/m2 5-FU (continuous infusion during 46 h). This treatment was continued for six cycles and discontinued after completion of the study treatment, the occurrence of an unacceptable toxic effect, any disease recurrence, or withdrawal of consent. Any adverse events were assessed according to the Common Toxicity Criteria of the National Cancer Institute version 4.0. Clinical follow‑up The patients were assessed after surgery, every 2 weeks during the treatment, then every 3 months for the first 2 years, every 6 months for the following 3 years, and once annually thereafter. The baseline assessment involved taking a medical history, a physical examination, biologic tests, and measurement of the serum level of the carcinoembryonic antigen (CEA). The patients were monitored for adverse effects throughout the treatment period and until 28 days after the last cycle of chemotherapy, unless the treatment-related toxic effects required additional followup. Chest X-rays and abdominal computed tomography scans were obtained every 6 months, plus a full colonoscopy was performed 6 months after surgery and then once every 3–5 years. FDG-PET/CT was ordered selectively in the case of any abnormalities during the examination. Statistical analyses The descriptive statistics are reported as the proportion and median. The primary endpoint was to determine the feasibility of six treatment cycles of mFOLFOX6, while the secondary endpoints were DFS, OS, and adverse events. OS was defined as the time from the date of surgery to death from any cause, while DFS was calculated from the date

Cancer Chemother Pharmacol (2015) 76:29–34

of diagnosis to the date of any events, including all local, regional, or distant recurrences. Kaplan–Meier curves were used to calculate the DFS and OS values. All the analyses were performed using SPSS (version 15.0; SPSS Inc., Chicago, IL).

Results Patient and tumor characteristics Forty patients with LARC were enrolled prospectively at Kyungpook National University Medical Center (Daegu, Korea) between December 2011 and December 2012. The clinicopathologic characteristics of these 40 patients are shown in Table 1. The median age of the patients was 57 years (range 36–69), and the ratio of males to females was 26 to 14. The clinical stages before preoperative CRT were as follows: 75 % of the patients had a stage III disease, and 25 % had a stage II disease. All the patients were operated on 8 weeks after the end of their CRT. Laparoscopic surgery was performed on 38 patients (95 %). The pathologic stages after CRT were as follows: stage II (n  = 23, 57.5 %) and stage III (n  = 17, 42.5 %). Tumor regression grades (TRGs) 1, 2, 3, and 4 were diagnosed in 9 (22.5 %), 15 (37.5 %), 14 (35 %), and 2 (5 %) patients, respectively. Adverse effects Neutropenia, asthenia, diarrhea, and nausea were the most frequent grade 3 or 4 adverse effects (Table 2). Although oxaliplatin-induced peripheral neuropathy was common (85 %), most of these events were grade 1 or 2. Grade 3 peripheral neuropathy during treatment appeared in three patients (7.5 %). Plus after the ending of the treatment, two patients (5 %) showed persistent neurosensory symptoms. A dose reduction was applied to 11 patients (27.5 %). Grade 3 or 4 neutropenia was observed in five patients (12.5 %). An adverse gastrointestinal effect was also seen in 12 patients (30 %). Four patients (10 %) experienced grade 3 or 4 asthenia during the treatment, two of four patients completed all six cycles after a 20 % dose reduction, and two patients (5 %) discontinued the chemotherapy. Six patients (15 %) discontinued the treatment due to toxic effects. The reasons for discontinuation were asthenia (n  = 2, 5 %), diarrhea (n  = 2, 5 %), acute renal failure (n  = 1, 2.5 %), and relapse during the chemotherapy

31 Table 1  Patient characteristics N = 40

%

Age (years) Sex  Male  Female Clinical staging  II  IIIA  IIIB  IIIC Tumor site (from anal verge, cm)  Lower (1–5 cm)  Middle (6–10 cm) Type of surgery  Open/laparoscopic Pathologic staging  ypT   ypT0/T1/T2/T3/T4  ypN   N0/N1/N2  yp stage   II   III Histologic differentiation  Well  Moderate  Poor Lymphovascular invasion Tumor regression grade  1  2  3  4 Number of infusions  6  5  4  1 Dose reductions Relapse  Local  Distant   Liver   Lung

57

(36–69)

26 14

65.0 35.0

10 1 19 10

25.0 2.5 47.5 25.0

18 23

42.5 57.5

2/38

5.0/95.0

2/0/1/35/2

5.0/0/2.5/87.5/5.0

24/10/6

60.0/25.0/15.0

23 17

57.5 42.5

3 36 1 2

7.5 90.0 2.5 5.0

9 15 14 2

22.5 37.5 35.0 5.0

34 1 4 1 11 6 2 4 3 1

85.0 2.5 10.0 2.5 27.5 15.0 5.0 10.0 7.5 2.5

Death

1

2.5

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Table 2  Adverse events (N = 40) Adverse events

Grade 1–2 N (%)

Grade 3 N (%)

Grade 4 N (%)

Hematological Neutropenia Febrile neutropenia Thrombocytopenia Anemia

4 (10.0 %) 0 4 (10.0 %) 2 (5.0 %)

5 (12.5 %) 2 (5.0 %) 0 0

1 (2.5 %) 0 0 0

Non-hematological Diarrhea Nausea Vomiting Asthenia AST/ALT elevation Peripheral neuropathy Dermatitis Stomatitis

10 (25.0 %) 22 (55.0 %) 14 (35.0 %) 10 (25.0 %) 2 (5.0 %) 31 (77.5 %) 2 (5.0 %) 13 (32.5 %)

2 (5.0 %) 3 (7.5 %) 0 2 (5.0 %) 0 3 (7.5 %) 0 0

0 0 0 2 (5.0 %) 0 0 0 0

Acute renal failure

0

1 (2.5 %)

0

No grade 5 adverse events or treatment-related mortality occurred

(n  = 1, 2.5 %). One patient developed acute renal failure that occurred within 7 days after the first cycle of the study treatment and recovered renal function after dialysis. No treatment-related mortality (TRM) was associated with the chemotherapy. Survival analysis Among 40 patients, six (15 %) experienced relapses, including two locoregional and four distant relapses.

Distant metastasis was observed in the liver (n  = 3) and lungs (n  = 1). Five (31.3 %) patients with yp stage III experienced disease recurrence, while one (4.3 %) patient with yp stage II disease. For six patients who relapsed, the TRG after CRT was as follows: TRG1 (n = 1), TRG2 (n = 4), and TRG3 (n = 1), and two patients did not complete their planned cycles of FOLFOX6 because of adverse effects. Three patients underwent surgical resection after recurrence (two locoregional relapses and 1 liver metastasis). Systemic treatment including FOLFIRI with or without cetuximab was administered to four patients. In addition, one patient (2.5 %) died of metastasis. With a median follow-up duration of 18 months, the estimated 3-year DFS and OS rates were 84.2 and 97.3 %, respectively (Fig. 1).

Discussion This study evaluated the feasibility of a modified FOLFOX6 regimen for high-risk patients with LARC treated with neoadjuvant CRT followed by TME. As a result, the findings suggest that adding oxaliplatin to infusional 5-FU and LV for patients with ypT3–4 and/or ypN+ rectal cancer is feasible and not associated with any significant toxicity in an adjuvant setting. The current standard of care for LARC is neoadjuvant CRT followed by TME. While the benefit of adjuvant chemotherapy in LARC after neoadjuvant CRT is uncertain, distant metastasis persists a major cause of death in patients with rectal cancer after curative treatment. To date, 5-FU plus LV chemotherapy is commonly used as an adjuvant treatment for LARC [9–11]. However, the role of adjuvant

Fig. 1  Kaplan–Meier survival curves a 3-year overall survival (97.3 %) b 3-year disease-free survival (84.2 %)

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chemotherapy for patients with LARC after neoadjuvant CRT remains controversial. For example, the long-term results of the EORTC 22921 trial failed to show any survival benefit of adjuvant fluorouracil-based chemotherapy [7]. In previous studies, patients with ypT3–4 and/or ypN+ disease had a higher recurrence rate and worse overall survival when compared to patients with ypT0–2N0 disease [3, 5, 12–14]. For example, Park et al. [5] reported that a pathologically assessed treatment response to neoadjuvant CRT was correlated with oncologic outcomes and could be an early surrogate marker in LARC patients. They suggested that patients with a poor tumor response (ypT3–4 and/or N+) to preoperative CRT needed intensified adjuvant treatment. For colon cancer, the benefit of adding oxaliplatin to 5-FU and LV was already demonstrated in a large randomized trial [8], which proved a survival gain for 5-FU plus oxaliplatin and led to the use of FOLFOX regimen as the standard adjuvant therapy for stage III colon cancer. Yet, while many guidelines recommend the same adjuvant chemotherapy strategies used in colon cancer for rectal cancer, there is insufficient evidence to lend support to the addition of oxaliplatin to the adjuvant chemotherapy in patients with resected LARC after neoadjuvant CRT [15, 16]. In the current study, six cycles of the modified FOLFOX6 regimen were found to be tolerable in LARC patients after neoadjuvant CRT. Although neutropenia, asthenia, diarrhea, and nausea were the most frequent grade 3 or 4 adverse effects, no TRM was associated with the chemotherapy, and dose reduction only occurred in 27.5 % of the patients. Fifteen percent of the patients discontinued treatment due to treatment-related toxic effects or patient refusal. While oxaliplatin-induced peripheral neuropathy was the main safety concern, most of these events were grade 1 or 2. The recent ADORE trial for rectal cancer also showed similar adverse event profiles to the current results [17]. They reported that the most common grade 3 or worse events were neutropenia (36 %), febrile neutropenia (