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Oxaliplatin Plus Dual Inhibition of Thymidilate Synthase During Preoperative Pelvic Radiotherapy for Locally Advanced Rectal Carcinoma: Long-Term Outcome
Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 3, pp. 670–676, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2009.12.007
CLINICAL INVESTIGATION
Rectum
OXALIPLATIN PLUS DUAL INHIBITION OF THYMIDILATE SYNTHASE DURING PREOPERATIVE PELVIC RADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CARCINOMA: LONG-TERM OUTCOME ANTONIO AVALLONE, M.D.,* PAOLO DELRIO, M.D.,y BIAGIO PECORI, M.D.,z FABIANA TATANGELO, M.D,{ ANTONELLA PETRILLO, M.D.,z NIGEL SCOTT, M.D.,x PIETRO MARONE, M.D.,y LUIGI ALOI, M.D.,z CLAUDIA SANDOMENICO, M.D.,* SECONDO LASTORIA, M.D.,z VINCENZO ROSARIO IAFFAIOLI, M.D.,* DARIO SCALA, M.D.,y GIOVANNI IODICE, M.D.,* ALFREDO BUDILLON, M.D., PH.D.,k AND PASQUALE COMELLA, M.D.* Departments of *Gastrointestinal Medical Oncology, ySurgery Oncology, zDiagnostic Imaging and Radiotherapy, {Pathology, and Experimental Pharmacology, National Cancer Institute, Naples, Italy; and xDepartment of Pathology, St. James University Hospital, Leeds, United Kingdom
k
Purpose: To assess the safety and efficacy of oxaliplatin (OXA) plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy (RT) in patients with poor prognosis for rectal carcinoma. Methods and Materials: Sixty-three patients with the following characteristics, a clinical (c) stage T4, cN1-2, or cT3N0 of #5 cm from the anal verge and/or with a circumferential resection margin (CRM) of #5 mm (by magnetic resonance imaging), received three biweekly courses of chemotherapy with OXA, 100 mg/m2; raltitrexed (RTX), 2.5 mg/m2 on day 1, and 5-fluorouracil (5-FU), 900 mg/m2 (31 patients) or 800 mg/m2 (32 patients); levo-folinic acid (LFA), 250 mg/m2 on day 2, during pelvic RT (45 Gy). Pathologic response was defined as complete pathological response (ypCR), major (tumor regression grade(TRG) 2 to 3, with ypCRM-ve and ypN-ve) or minor or no response (TRG4 to -5, or ypCRM+ve, or ypN+ve). Adjuvant 5-FU/LFA regimen was given in cases of cT4, ypN+ve, or ypCRM+ve. Results: Overall, neutropenia (40%) and diarrhea (13%) were the most common grade $3 toxicities, and tolerability was better with a 5-FU dose reduction. No significant difference in pathologic response was seen according 5-FU dosage: overall, a ypCR was obtained in 24 (39%) patients, and a major response in 20 (32%) patients. The 5-year probability of freedom from recurrence was 80% (95% confidence interval, 68%–92%); it was 56% for the minor/no response group, while it was around 90% for both the ypCR and the major response group. Conclusions: OXA, RTX, and 5-FU/LFA administered during pelvic RT produced promising early and long-term results in rectal carcinoma patients with poor prognosis. The postoperative treatment strategy applied in our study supports the risk-adapted approach in postoperative management. Ó 2011 Elsevier Inc. Rectal cancer, MRI staging, Neoadjuvant chemoradiation, Oxaliplatin, Thymidilate synthase inhibition.
INTRODUCTION
underlining the need for a more effective systemic therapy. On the other hand, retrospective analyses suggest that locally advanced RCs are heterogeneous tumors with different prognoses (6) and that not all patients need a preoperative and/or intensified approach. For many years, 5-FU has been the only drug associated with local RT, because of its radiosensitizing and cytotoxic effects, due mainly to its inhibition of thymidilate synthase (TS), a key enzyme in the synthesis of DNA, which also
Despite recent improvement in the treatment of locally advanced rectal cancer (RC), the best strategy for management of this disease remains challenging. Indeed, the wide adoption of total mesorectal excision has resulted in a significant decline of local recurrence (1). Moreover, preoperative radiotherapy (RT) and 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) may further reduce local recurrence (2–5) but do not have any impact on distant metastases or survival,
Conflict of interest: none. Acknowledgment—The authors thank Dr. Alessandra Trocino, National Cancer Institute of Naples, for providing excellent bibliographic service and assistance. Received Sept 30, 2009, and in revised form Nov 28, 2009. Accepted for publication Dec 1, 2009.
Reprint requests to: Antonio Avallone, MD, Department of Gastrointestinal Medical Oncology, National Cancer Institute, via M. Semmola, 80131 Naples, Italy. Tel: (39)0815903629; Fax: (39)0815903821; E-mail: [email protected] This work was partially supported by the Italian League for the Fight Against Cancer. Presented at the Gastrointestinal Cancers Symposium, Orlando, FL, January 19–21, 2007. 670
OXA plus TS inhibition and preop RT in rectal Ca d A. AVALLONE et al.
exhibits an oncogene-like activity (7). Notably, TS overexpression resulted in an independent negative prognostic factor in rectal cancer patients (8). Raltitrexed (RTX) is a specific TS inhibitor, which differs from 5-FU in its binding site, which has a radiosensitizing effect and is active in advanced colorectal cancer (9). In vitro data and clinical studies have shown a synergistic antitumor effect for RTX and 5-FU when a sequential exposure (5-FU given 24 hr after RTX) was assessed (10, 11). An even greater synergism occurs when the wild-type p53 and mutant colorectal cancer cell lines are exposed (24 hr after RTX) to levo-folinic acid (LFA) and 5-FU (5-FU/LFA): the addition of LFA induced a distinct blockage of the S-phase cell cycle, potentiating apoptosis (12). Interestingly, preclinical studies have also shown that LFA rescued life-threatening toxicities of RTX (13). Oxaliplatin (OXA), besides its cytotoxic effect caused by the formation of intra- and interstrand platinum-DNA adducts, also has radiosensitizing properties (14) and induces a down-regulation of TS expression in colon cancer cells (15). Postsurgical treatment with OXA and 5-FU/LFA improves the disease-free survival and overall survival (OS) of patients with resected stage III colon cancer (16, 17). In addition, the combination of OXA with 5-FU/LFA (18) or RTX (19) showed a significant activity in chemonaive metastatic colorectal cancer patients, and the triplet combination of OXA, RTX, and 5-FU/LFA was tolerated and active also in heavily pretreated patients (20). In a previous phase I study, we found that the maximum tolerated doses for this triplet during preoperative pelvic RT were 120 mg/m2 for OXA, 2.5 mg/m2 for RTX, 250 mg/m2 for LFA, and 900 mg/m2 for 5-FU. Neutropenia and diarrhea were the dose-limiting toxicities. Therefore, the previous dose level was selected as the recommended dose for this combination, which produced a high rate of complete (TRG1) or subtotal (TRG2) tumor regression in 31 patients with poor prognoses for locally advanced RC (21). With the aim of better estimating the activity and further improving the safety of the combination, we subsequently tested a slight dose reduction of 5-FU in 32 additional patients. Here we report the comparative safety and activity data, and the long-term freedom from recurrence (FFR) and OS of treated patients.
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ease, prior pelvic RT or CT, and previous cancer. Other inclusion and exclusion criteria were reported previously (21). Baseline work-up performed within 6 weeks before the initiation of study treatment included rectocolonoscopy with biopsy, determination of carcinoembryonic antigen serum level, endorectal ultrasound, chest, thoracic, and abdominopelvic computed tomography (CT) scan, and abdominopelvic MRI.
Chemoradiotherapy treatment Conformal RT was delivered by a three-field box technique to a total dose of 45 Gy over 5 weeks (1.8 Gy/day five fractions/ week). Details of treatment planning, definition of irradiated fields, and quality control were previously reported (21). Chemotherapy consisted of three biweekly cycles of OXA, 100 mg/m2 (2-hr infusion), followed by RTX, 2.5 mg/m2 (30-min infusion) on day 1. On day 2, LFA, 250 mg/m2 (2-hr infusion), followed by 5-FU, 900 or 800 mg/m2 (bolus) was administered. Dose adjustments for adverse events were reported previously (21). Acute side effects were scored according to the National Cancer Institute Common Toxicity Criteria version 2. Late toxicity was assessed using the SOMA-LENT scale (22).
Surgery Surgery was planned 8 weeks after the completion of CRT, and an anterior or abdominal–peritoneal resection with total mesorectal excision was performed on the basis of restaging. The colonic anastomosis was protected by a loop ileostomy, which was later reversed after endoscopic assessment of the anastomotic integrity.
Pathology
This study was approved by the local ethics committee and was conducted in accordance with the Helsinki Declaration. Signed written informed consent was obtained from each patient.
Postsurgical pathology examination provided a macroscopic description of the mesorectum and of the former tumor-bearing area; at least four paraffin blocks were processed, and an additional larger area block was embedded. If no tumor was visible, the entire suspicious area was sliced and embedded. CRM was judged to be involved if the microscopic tumor was #1 mm from the radial resection margin. The TRG was independently assessed by two pathologists (FT and NS) and scored according to a five-point system (23). Briefly, TRG1 was a complete tumor regression (regardless of the presence of acellular mucine lakes), and TRG2 was a nearly complete tumor regression with extensive fibrosis; TRG3 presented with clear evidence of residual cancer cells but with predominant fibrosis; TRG4 was a residual of cancer cells outgrowing fibrosis; TRG5 was the absence of regressive changes. In the case of discrepancy between the two pathologists, the worse TRG score was assigned. A complete pathology response (ypCR) was defined as the absence of viable tumor cells in the primary tumor and lymph nodes; a major response consisted of TRG2 to -3 without CRM involvement and nodal metastases, while a TRG4 to -5 or CRM involvement or nodal metastases, were classified as minor/no response.
Patient selection
Adjuvant chemotherapy and follow-up
Eligibility criteria required histologically confirmed, untreated rectal adenocarcinoma with poor prognostic presentation, including clinical (c)T4, cN1-2, or cT3N0 located in the lower third of the rectum and/or a circumferential resection margin (CRM) of #5 mm by magnetic resonance imaging (MRI). Additional inclusion criteria were an ECOG performance status of #2, age $18 years, and adequate organ function. Main exclusion criteria were metastatic dis-
Adjuvant 5-FU, 370 mg/m2, and LFA, 20 mg/m2 weekly for 4 months, were delivered only to patients with cT4 lesions or who were ypN positive or had ypCRM of #1 mm. Pelvic MRI, chest and abdominopelvic CT scans, carcinoembryonic antigen serum level tests, and rectoscopy procedures were performed every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter.
METHODS AND MATERIALS
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Statistical design and analysis As previously reported (21), the original statistical design called for at least 19 patients with TRG1 to -2 among 46 treated patients to accept the hypothesis of 50% activity, and this result was already obtained among the first 31 treated patients. Therefore, we decided to obtain a better estimate of the activity and to improve the tolerability of this treatment, testing a 5-FU dose reduction in a comparable number of patients. FFR was defined as the time from initial treatment to the documented local or distant recurrence (whichever occurred first), or last follow-up. Patients who died without recurrence were censored for this analysis. OS was defined as the time from initial treatment until death for any cause or to last follow-up. Cancer-specific survival (CSS) was defined as the time to death for rectal cancer or to the last follow-up. FFR, OS, and CSS rates were estimated using the Kaplan-Meier method (24). Proportions were estimated with their 95% confidence interval (CI) and compared with a chi-square or Fisher’s exact test when appropriate. Risk of recurrence according to an initial Gunderson risk score and to pathology response was assessed by Cox analysis and expressed as a hazard ratio (HR) with 95% CI (25).
RESULTS From July 2002 to September 2006, a total of 63 patients (31 in the first series, 32 in the second series) were enrolled. Baseline characteristics did not differ between the two series (Table 1). It should be underlined that 6 of 10 T3N0 tumors were either located in the lower third of the rectum or had a CRM of #5 mm. Safety All but one patient of the first series, whose participation was discontinued because of toxicity after 41.5 Gy, completed RT in a median of 37 (range, 32–53) days. As to chemotherapy, 9 (16%) patients (7 in the first series and 2 in the second series) received less than three cycles because of severe or persistent toxicity. Mean (relative) dose intensity was 46 mg/m2/week (92%) for OXA and 1.16 mg/m2/week (92%) for RTX in both series, while it was 378 mg/m2/ week (84%) and 361 mg/m2/week (90%) for 5-FU in the first and second series, respectively. The toxicity profiles registered during CRT were similar in the two series of patients (Table 2). Neutropenia and diarrhea were the most common grade $3 adverse events, but they were short lasting and easily managed. However, it should be noted that neutropenia (grade 4, 9% vs. 22%) and diarrhea (grade 3, 6% vs. 19%) were less pronounced in the second series. Surgery and pathologic response Surgery was performed after a median of 8.2 (range, 4.4– 15.7) weeks from the end of CRT. All but one patient who underwent a local excision were referred for radical surgery, which was an anterior resection in 55 cases and an abdominal–peritoneal resection in 7 cases. Twelve of 15 (80%) patients with a distal tumor border #3 cm from the anal verge (in whom an abdominal–peritoneal resection was supposed to be necessary before CRT) were subsequently con-
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verted to a sphincter-sparing resection. Sixty (97%) patients had an ypCRM-ve resection (R0). Pathology tumor downstaging occurred in 51 of 62 (82%) patients. As for the TRG classification, there was a concordance between pathologists in 51 (81%) cases. Interobserver discrepancy mainly occurred (9 of 12 cases) in scoring TRG2 and TRG3. According to the worst assigned score, TRG was as follows: TRG1 in 25 (40%) patients, TRG2 in 16 (25%) patients, TRG3 in 13 (21%) patients, and TRG4 in 9 (14%) cases. No TRG5 was registered. No significant differences in TRG were observed between the two series (Table 3). With a median of 37 (range, 10–80) lymph nodes retrieved, nodal metastases were detected in 12 (ypN1, 9 cases; ypN2, 3 cases) of 62 (19%) patients. In detail, nodal metastases were detected in one case each of patients showing a TRG1 (4%) or a TRG2 (6%), while they were detected in 6 patients with a TRG3 (46%) and 4 patients with a TRG4 (44%). Overall, pathology nodal downstaging occurred in 40 of 52 (77%) patients. No upstaging of T or N stage was observed. Table 1. Demographic and clinical characteristics of enrolled patients
Characteristics
First series (n = 31) (% of total)
Gender Males 16 (52) Females 15 (48) Median age 56 (29–74) (range) ECOG performance status 0 12 (39) 1 17 (55) 2 2 (6) Gunderson risk Intermediate 4 (13) T2N1 1 T3N0 3 Moderately high 14 (45) T3N1 14 T4N0 0 High 13 (42) T3N2 7 T4N1-2 6 Distance from the anal verge <5 cm 15 (48) >5 cm 16 (52) Circumferential resection margin <5 mm 19 (61) >5 mm 9 (29) Not evaluated* 3 (10) Baseline carcinoembryonic antigen serum level <5 UI/l 21 (68) >5 UI/l 10 (32)
Second series (n = 32) (% of total)
Whole series (n = 63) (% of total)
16 (50) 16 (50) 61 (27–79)
32 (51) 31 (49) 58 (27–79)
5 (16) 26 (81) 1 (3)
17 (27) 43 (68) 3 (5)
7 (22) 0 7 15 (47) 14 1 10 (31) 8 2
11 (17) 1 10 29 (46) 28 1 23 (37) 15 8
19 (59) 13 (41)
34 (54) 29 (46)
24 (75) 7 (22) 1 (3)
43 (68) 16 (26) 4 (6)
17 (53) 15 (47)
38 (60) 25 (40)
* Because of the presence of a metal prosthesis.
OXA plus TS inhibition and preop RT in rectal Ca d A. AVALLONE et al.
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Table 2. Acute adverse events registered during chemoradiotherapy treatment First series (n = 31)
Toxicity Hematologic neutropenia Febrile neutropenia Thrombocytopenia Anemia Gastrointestinal Nausea/vomiting Colitis Diarrhea Stomatitis Proctitis Metabolic/laboratory Hyperbilirubinemia Transaminases Skin toxicity Fatigue Fever Sensory neuropathy
Second series (n = 32)
All Grade
Grade 3
Grade 4
All Grade
Grade 3
Grade 4
All Grade
Grade 3
Grade 4
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
17 5 5 0
55 16 16
5 0 0 0
16
7 2 0 0
22 6
21 6 4 1
65 19 12 3
10 3 0 0
31 9
3 1 0 0
9 3
38 11 9 1
60 17 14 2
15 3 0 0
24 5
10 3 0
16 5
15 3 13 0 5
48 9 42 16
0 0 6 1 0
0 0 0 0 0
17 2 17 2 9
53 6 53 6 28
0 0 2 0 0
0 0 0 0 0
32 5 30 3 14
51 8 48 5 22
0 0 8 1 0
13 9 13 9 16
0 0 0 0 0 0
0 0 0 0 0 0
1 6 4 2 1 5
3 19 12 6 3 16
0 0 0 0 0 0
0 0 0 0 0 0
1 10 7 6 4 10
2 16 11 9 6 16
0 0 0 0 0 0
0 4 3 4 3 5
19 3
In the whole series, a ypCR was obtained in 24 (39%; 95% CI, 27%–52%) patients, a major response in 20 (32%; 95% CI, 21%–45%) patients, while minor/no response was registered in 18 (29%; 95% CI, 18%–42%) patients. No significantly different response rates were seen according to baseline patients characteristics (Table 4). Surgical complications and late side effects There were no intra- or postoperative deaths. Twenty-two postsurgical complications occurred in 19 (30%) patients (anastomotic fistula in 4 patients; rectovaginal fistula in 3 patients; bladder fistula in 1 patient; anastomotic stenosis in 5 patients; pelvic abscesses in 5 patients; delayed perineal healing in 2 patients; bowel adhesion in 1 patient; and anastomotic dehiscence in 1 patient [a patient who refused loop ileostomy]). Eight (13%) patients required an additional surgical procedure. Moderate or severe late anorectal or sexual dysfunctions were reported in 25 (40%) patients: higher stool frequency (8 patients), fecal and gas incontinence (3 patients), constipation (2 patients), erectile dysfunction (7 patients), retrograde ejaculation (2 patients), and severe dyspareunia (3 patients). No significant differences Table 3. Tumor regression grade according to treatment Tumor regression grade TRG1 TRG2 TRG3 TRG4 TRG5 Total
Whole series (n = 63)
Fist series n = 31 (%)
Second series n = 32 (%)
Whole series n = 63 (%)
13 (42) 9 (29) 3 (10) 6 (19) 0 31 (100)
12 (38) 7 (22)* 10 (31) 3 (9) 0 32 (100)
25 (40) 16 (25)* 13 (21) 9 (14) 0 63 (100)
* Including a patient referred for local excision.
6
13 2
0 0 0 0 0 0 0 0 0 0 0
in postsurgical complications and late side effects were observed in the two series of patients. Adjuvant treatment and follow-up Eighteen patients (2 achieving a major response and 16 showing a minor/no response) received adjuvant chemotherapy after a median interval of 5.9 (range, 4.3–11) weeks from surgery. As of March 2009, 10 patients (5 in each series) showed disease recurrence (3 patients had both a local and a distant recurrence; 7 patients had only a distant recurrence). A local and distal recurrence occurred in the single patient who underwent a local excision. Of note, 7 patients (1 patient with ypCRM+ and 6 patients with ypN+) of 18 (39%) who received the adjuvant treatment had a relapse, as opposed to 2 of 44 (4%) patients who did not receive any postoperative chemotherapy. Table 4. Complete and major pathologic responses according to baseline Gunderson risk, clinical CRM, and location of the primary tumor Characteristics (no. of patients)
Complete Major response response n = 20 Total % of total n = 24
Gunderson risk Intermediate (11) Moderately high (29) High (23) Clinical CRM* <5 mm (43) >5 mm (16) Distance from the anal verge <5 cm (34) >5 cm (29) * Not evaluated in 4 cases.
5 13 6
4 7 9
9 20 15
82 69 65
17 6
15 5
32 11
74 69
13 11
12 8
25 19
73 65
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After a median follow-up of 60 (range, 30–80) months, the 5-year probability of FFR was 80% (95% CI, 68%–92%). The 5-year FFR was lower for the high-risk group (71%; 95% CI, 50%–92%) than for the intermediate or moderately high-risk group, but this difference was not significant (Fig. 1). At 5 years, the probability of FFR did not differ between the complete and major responders (just one recurrence was observed in each of these two groups), and it was over 90% for these patents. On the contrary, it was significantly lower (56%; 95% CI, 32%–81%) for minor/non-responders (HR, 5.1; 95% CI, 1.6–16.9; p = 0.007) (Fig. 2). Eight patients (3 for causes unrelated to cancer) eventually died; therefore, the 5-year OS was 87% (95% CI, 77%–97%), while the 5-year CSS was 92% (95% CI, 85%–99%). DISCUSSION The results of our study confirm that the combination of OXA, RTX, and 5-FU/LFA delivered during pelvic RT in poor-prognosis RC patients was well tolerated. Indeed, acute toxicity was acceptable, no intra- or postoperative death occurred, and the incidence of postsurgical complications was comparable with that reported with other oxaliplatinbased preoperative CRT regimens (26–27). However, severe neutropenia and diarrhea were less pronounced with the slight 5-FU dose reduction, and the improved tolerability translated to better compliance with the planned CT treatment. Despite the lower 5-FU dosage, we did not observe a reduction of clinical activity. Indeed, we reported a similar proportion of TRG1 and TRG2 in the two consecutive series. In our opinion, the 97% R0 rate and the 39% rate of ypCR reported are impressive considering the advanced disease stage in most patients. Indeed, this ypCR rate was nearly twice that reported in other phase II trials (28). Only one study reported a similarly high ypCR rate (29), but it did not use the MRI in the preoperative staging and did not include cT4 tumors.
Fig. 1. Probability of FFR according to the initial Gunderson risk (circles = intermediate risk; squares = moderately high risk; triangles = high risk).
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In addition, we observed an elevated proportion (32%) of major responses, while no TRG5 was reported. It is noteworthy that pathology responses were obtained regardless of the initial stage and applying a very careful histological assessment, as proven by the median number of retrieved lymph nodes. This finding demonstrated, unlike other reports (30), the feasibility of an accurate lymph node evaluation even after an intensified preoperative CRT approach. An additional remarkable finding was the proportion of sphincter preservation in patients with lower tumor location. The long-term follow-up gives further strength to our results. Indeed, the 5-year 80% FFR confirms the durable disease control achieved by our treatment. Although the cross-trial comparison is problematic, we would recall some studies in which inclusion criteria were similar to ours. In the CORE trial (31), in which capecitabine and OXA were combined with pelvic RT, an 11% ypCR rate, a 3-year 55% progression free-survival, and a 75% OS were reported. Two other studies, in which irinotecan or OXA were added to 5-FU/LFA during pelvic RT, showed similar results (32, 33). Moreover, four cycles of neoadjuvant full-dose OXA and capecitabine given before CRT treatment yielded results inferior to ours while inducing an unpredictable rate (5%) of toxic deaths (34). Another important point of our study is the selective adjuvant treatment policy. There is no general agreement on the benefit of adjuvant CT after preoperative CRT. In this regard, EORTC trial 22921 failed to demonstrate a significant impact on OS of postoperative CT (3). Furthermore, retrospective analysis of the CAO/ARO/AIO-94 trial questioned the delivery of adjuvant CT on the basis of pretreatment findings (35). Interestingly, in that analysis, a prognostic value of the TRG was suggested at univariate analysis, while a ypN+ resulted the strongest prognostic factor in the multivariate model. Moreover, the persistence of a CRM involvement was recognized as a strong prognostic factor even after a preoperative CRT approach (36).
Fig. 2. Probability of FFR according to the pathology response (circles = complete response; squares = major response; triangles = minor/no response). The patient referred for local excision was excluded from analysis.
OXA plus TS inhibition and preop RT in rectal Ca d A. AVALLONE et al.
On the other hand, retrospective analyses have demonstrated the favorable prognostic value of ypCR (37) and ypN0 (38), independently of adjuvant CT. However, an accurate postoperative pathology evaluation is essential to obtain a correct prognostic information. Indeed, in tumors defined as ypN0, the number of lymph nodes examined correlated with the outcome (39). In our study, pathology findings showed a greater prognostic value than pretreatment clinical factors. In particular, we observed that not only patients achieving a ypCR but also those with a major response may have a favorable outcome without adjuvant CT. Indeed, the 5-year FFR was around 90% for both groups of patients. Conversely, 5-year FFR was 56% for the minor/no response group, even though 16 patients of 18 received adjuvant CT. Consequently, we speculate that patients with ypCR or major response would not require a postoperative treatment at all, while patients with minor/no response need a postoperative approach with noncross-resistant drugs. Several reasons could explain the high efficacy of our CRT. First, it should be noted that the main target of our regimen was TS, which exhibits oncogene-like activity (7) and is related to prognosis in RC (8). Preclinical data have shown that a sequential dual inhibition of TS by RTX and 5-FU/ LFA translated into a synergistic cytotoxicity in the wildtype p53 and mutant colorectal cancer cells (12). Moreover, OXA was proven to induce a TS down-regulation in colon cancer cells (15) and to potentiate the effect of TS inhibition through the down-regulation of deoxyuridine triphosphate nucleotide hydrolase (40). Second, exposure of colon cancer cells to RTX/5-FU/LFA induced an S-phase block greater than that produced by 5-FU/LFA or RTX/5-FU alone (12). Moreover, OXA was reported to induce a prolonged cell accumulation into the G2/M
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phases (41). All these cell cycle perturbations could be crucial for increasing the sublethal damage of RT. Third, cytotoxic drugs were administered during RT at doses that were close to those usually used in the treatment of metastatic colorectal cancer patients (18, 19). Interestingly, a direct correlation between the dose of OXA (#85 mg/m2 vs. >85 mg/m2) actually delivered over 2 weeks and the activity of regimens in which OXA was combined with 5-FU (FOLFOX) has been reported in these patients (42). Moreover, preclinical studies have also shown that the radiosensitizing property of OXA is dose dependent, suggesting the existence of a threshold dose (14, 41). Few data are available for long-term morbidity after CRT and total mesorectal excision in RC patients, and current knowledge comes from trials of short-course RT (43). Moderate or severe late toxicity in our study was similar to that reported in those studies. However, the occurrence of this late toxicity emphasizes the need for tailoring the surgical management according to the prediction of response. In this regard, we have previously demonstrated that [18F]fluorodeoxyglucose positron emission tomography may have a promising role in early identification of responder patients who could benefit from a less aggressive surgery (44). CONCLUSIONS In conclusion, we have shown that a slight reduction of 5-FU dosage induced a greater tolerability of the combination of OXA, RTX, and 5-FU/LFA delivered during pelvic RT without impairing its activity. This combination obtained promising early and long-term results in poor-prognosis locally advanced RC patients, although these results deserve to be confirmed in a larger population. The selective adjuvant treatment strategy applied in our study also supports a riskadapted approach in postoperative management.
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15. Yeh KH, Cheng AL, Wan JP, et al. Down-regulation of thymidylate synthase expression and its steady-state mRNA by oxaliplatin in colon cancer cells. Anticancer Drugs 2004;15: 371–376. 16. Andre` T, Boni C, Navarro M, et al. 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 2009;27:3109–3116. 17. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 2007;25:2198–2204. 18. De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-Line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938– 2847. 19. Cascinu S, Graziano F, Ferrau` F, et al. Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD). Ann Oncol 2002;13:716–720. 20. Comella P, Casaretti R, Crucitta E, et al. Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: A salvage regimen for colorectal cancer patients. Br J Cancer 2002;86:1871–1875. 21. Avallone A, Delrio P, Guida C, et al. Biweekly oxaliplatin, raltitrexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I-II study. Br J Cancer 2006;94:1809– 1815. 22. Dische S, Saunders MI. Complexity and simplicity in the measurement and recording of adverse effects of cancer treatment. Radiother Oncol 2003;66:249–251. 23. Mandard AM, Dalibard F, Mandard JC, et al. Pathologic assessment of tumor regression grade after pre-operative chemoradiotherapy of esophageal carcinoma: Clinicopathologic correlations. Cancer 1994;73:2680–2686. 24. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 25. Cox DR. Regression models and life tables. J R Stat Soc 1972; 34:187–202. 26. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003;21:3098–3104. 27. Machiels JP, Duck L, Honhon B, et al. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: The RadiOxCape study. Ann Oncol 2005;16:1898–1905. 28. Avallone A, Delrio P, Aloj L, et al. Locally advanced rectal cancer: Combined chemotherapy during preoperative radiation therapy. In: Hayat MA, editor. Methods of cancer diagnosis, therapy and prognosis, vol. 4. Springer; 2009. pp. 411–437. 29. Mehta VK, Cho C, Ford JM, et al. Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 2003;55:132–137. 30. Wichmann MW, Muller C, Meyer G, et al. Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer. Arch Surg 2002;55:2006–2010.
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31. Sebag-Montefiore D, Rutten H, Rullier E, et al. Three-year survival results of CORE (Capecitabine, Oxaliplatin, Radiotherapy, and Excision) study of pre-operative chemoradiation and post-operative chemotherapy in patients with MRI defined locally advanced rectal adenocarcinoma [abstract). Proceedings of the ASCO Gastrointestinal Cancers Symposium, San Francisco, January 15–17 2009; abstract no. 447. 32. Sebag-Montefiore D, Glynne-Jones R, Falk S, et al. A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: A Colorectal Clinical Oncology Group (CCOG) study. Br J Cancer 2005;93:993–998. 33. Glynne-Jones R, Falk S, Maughan TS, et al. A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: A Colorectal Clinical Oncology Group study. Br J Cancer 2007;96:551–558. 34. Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006; 24:668–674. 35. Ro¨del C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005;23:8688–8696. 36. Gosens M, Klaassen RA, Tan-Go I, et al. Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma. Clin Cancer Res 2007;13:6617–6623. 37. Capirci C, Valentini V, Cionini l, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: Long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008;72:99–107. 38. Fietkau R, Barten M, Klautke G, et al. Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 2006;49:1284–1292. 39. Tepper JE, O’Connell MJ, Niedzwiecki D, et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19:157–163. 40. Wilson PM, Fazzone W, LaBonte MJ, et al. Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage. Nucleic Acids Res 2009;37:78–95. 41. Folkvord S, Flatmark K, Seierstad T, et al. Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: Does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity? Radiother Oncol 2008;86:428–434. 42. Maindrault-Gœbel F, de Gramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol 2000;11:1477–1483. 43. Birgisson H, Pa˚hlman L, Gunnarsson U, et al. Late adverse effects of radiation therapy for rectal cancer–a systematic overview. Acta Oncologica 2007;46:504–516. 44. Cascini GL, Avallone A, Delrio P, et al. 18F-FDG PET is an early predictor of pathologic tumor response to preoperative radiochemotherapy in locally advanced rectal cancer. J Nucl Med 2006;47:1241–1248.
doi:10.1016/j.ijrobp.2009.12.007
CLINICAL INVESTIGATION
Rectum
OXALIPLATIN PLUS DUAL INHIBITION OF THYMIDILATE SYNTHASE DURING PREOPERATIVE PELVIC RADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CARCINOMA: LONG-TERM OUTCOME ANTONIO AVALLONE, M.D.,* PAOLO DELRIO, M.D.,y BIAGIO PECORI, M.D.,z FABIANA TATANGELO, M.D,{ ANTONELLA PETRILLO, M.D.,z NIGEL SCOTT, M.D.,x PIETRO MARONE, M.D.,y LUIGI ALOI, M.D.,z CLAUDIA SANDOMENICO, M.D.,* SECONDO LASTORIA, M.D.,z VINCENZO ROSARIO IAFFAIOLI, M.D.,* DARIO SCALA, M.D.,y GIOVANNI IODICE, M.D.,* ALFREDO BUDILLON, M.D., PH.D.,k AND PASQUALE COMELLA, M.D.* Departments of *Gastrointestinal Medical Oncology, ySurgery Oncology, zDiagnostic Imaging and Radiotherapy, {Pathology, and Experimental Pharmacology, National Cancer Institute, Naples, Italy; and xDepartment of Pathology, St. James University Hospital, Leeds, United Kingdom
k
Purpose: To assess the safety and efficacy of oxaliplatin (OXA) plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy (RT) in patients with poor prognosis for rectal carcinoma. Methods and Materials: Sixty-three patients with the following characteristics, a clinical (c) stage T4, cN1-2, or cT3N0 of #5 cm from the anal verge and/or with a circumferential resection margin (CRM) of #5 mm (by magnetic resonance imaging), received three biweekly courses of chemotherapy with OXA, 100 mg/m2; raltitrexed (RTX), 2.5 mg/m2 on day 1, and 5-fluorouracil (5-FU), 900 mg/m2 (31 patients) or 800 mg/m2 (32 patients); levo-folinic acid (LFA), 250 mg/m2 on day 2, during pelvic RT (45 Gy). Pathologic response was defined as complete pathological response (ypCR), major (tumor regression grade(TRG) 2 to 3, with ypCRM-ve and ypN-ve) or minor or no response (TRG4 to -5, or ypCRM+ve, or ypN+ve). Adjuvant 5-FU/LFA regimen was given in cases of cT4, ypN+ve, or ypCRM+ve. Results: Overall, neutropenia (40%) and diarrhea (13%) were the most common grade $3 toxicities, and tolerability was better with a 5-FU dose reduction. No significant difference in pathologic response was seen according 5-FU dosage: overall, a ypCR was obtained in 24 (39%) patients, and a major response in 20 (32%) patients. The 5-year probability of freedom from recurrence was 80% (95% confidence interval, 68%–92%); it was 56% for the minor/no response group, while it was around 90% for both the ypCR and the major response group. Conclusions: OXA, RTX, and 5-FU/LFA administered during pelvic RT produced promising early and long-term results in rectal carcinoma patients with poor prognosis. The postoperative treatment strategy applied in our study supports the risk-adapted approach in postoperative management. Ó 2011 Elsevier Inc. Rectal cancer, MRI staging, Neoadjuvant chemoradiation, Oxaliplatin, Thymidilate synthase inhibition.
INTRODUCTION
underlining the need for a more effective systemic therapy. On the other hand, retrospective analyses suggest that locally advanced RCs are heterogeneous tumors with different prognoses (6) and that not all patients need a preoperative and/or intensified approach. For many years, 5-FU has been the only drug associated with local RT, because of its radiosensitizing and cytotoxic effects, due mainly to its inhibition of thymidilate synthase (TS), a key enzyme in the synthesis of DNA, which also
Despite recent improvement in the treatment of locally advanced rectal cancer (RC), the best strategy for management of this disease remains challenging. Indeed, the wide adoption of total mesorectal excision has resulted in a significant decline of local recurrence (1). Moreover, preoperative radiotherapy (RT) and 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) may further reduce local recurrence (2–5) but do not have any impact on distant metastases or survival,
Conflict of interest: none. Acknowledgment—The authors thank Dr. Alessandra Trocino, National Cancer Institute of Naples, for providing excellent bibliographic service and assistance. Received Sept 30, 2009, and in revised form Nov 28, 2009. Accepted for publication Dec 1, 2009.
Reprint requests to: Antonio Avallone, MD, Department of Gastrointestinal Medical Oncology, National Cancer Institute, via M. Semmola, 80131 Naples, Italy. Tel: (39)0815903629; Fax: (39)0815903821; E-mail: [email protected] This work was partially supported by the Italian League for the Fight Against Cancer. Presented at the Gastrointestinal Cancers Symposium, Orlando, FL, January 19–21, 2007. 670
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exhibits an oncogene-like activity (7). Notably, TS overexpression resulted in an independent negative prognostic factor in rectal cancer patients (8). Raltitrexed (RTX) is a specific TS inhibitor, which differs from 5-FU in its binding site, which has a radiosensitizing effect and is active in advanced colorectal cancer (9). In vitro data and clinical studies have shown a synergistic antitumor effect for RTX and 5-FU when a sequential exposure (5-FU given 24 hr after RTX) was assessed (10, 11). An even greater synergism occurs when the wild-type p53 and mutant colorectal cancer cell lines are exposed (24 hr after RTX) to levo-folinic acid (LFA) and 5-FU (5-FU/LFA): the addition of LFA induced a distinct blockage of the S-phase cell cycle, potentiating apoptosis (12). Interestingly, preclinical studies have also shown that LFA rescued life-threatening toxicities of RTX (13). Oxaliplatin (OXA), besides its cytotoxic effect caused by the formation of intra- and interstrand platinum-DNA adducts, also has radiosensitizing properties (14) and induces a down-regulation of TS expression in colon cancer cells (15). Postsurgical treatment with OXA and 5-FU/LFA improves the disease-free survival and overall survival (OS) of patients with resected stage III colon cancer (16, 17). In addition, the combination of OXA with 5-FU/LFA (18) or RTX (19) showed a significant activity in chemonaive metastatic colorectal cancer patients, and the triplet combination of OXA, RTX, and 5-FU/LFA was tolerated and active also in heavily pretreated patients (20). In a previous phase I study, we found that the maximum tolerated doses for this triplet during preoperative pelvic RT were 120 mg/m2 for OXA, 2.5 mg/m2 for RTX, 250 mg/m2 for LFA, and 900 mg/m2 for 5-FU. Neutropenia and diarrhea were the dose-limiting toxicities. Therefore, the previous dose level was selected as the recommended dose for this combination, which produced a high rate of complete (TRG1) or subtotal (TRG2) tumor regression in 31 patients with poor prognoses for locally advanced RC (21). With the aim of better estimating the activity and further improving the safety of the combination, we subsequently tested a slight dose reduction of 5-FU in 32 additional patients. Here we report the comparative safety and activity data, and the long-term freedom from recurrence (FFR) and OS of treated patients.
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ease, prior pelvic RT or CT, and previous cancer. Other inclusion and exclusion criteria were reported previously (21). Baseline work-up performed within 6 weeks before the initiation of study treatment included rectocolonoscopy with biopsy, determination of carcinoembryonic antigen serum level, endorectal ultrasound, chest, thoracic, and abdominopelvic computed tomography (CT) scan, and abdominopelvic MRI.
Chemoradiotherapy treatment Conformal RT was delivered by a three-field box technique to a total dose of 45 Gy over 5 weeks (1.8 Gy/day five fractions/ week). Details of treatment planning, definition of irradiated fields, and quality control were previously reported (21). Chemotherapy consisted of three biweekly cycles of OXA, 100 mg/m2 (2-hr infusion), followed by RTX, 2.5 mg/m2 (30-min infusion) on day 1. On day 2, LFA, 250 mg/m2 (2-hr infusion), followed by 5-FU, 900 or 800 mg/m2 (bolus) was administered. Dose adjustments for adverse events were reported previously (21). Acute side effects were scored according to the National Cancer Institute Common Toxicity Criteria version 2. Late toxicity was assessed using the SOMA-LENT scale (22).
Surgery Surgery was planned 8 weeks after the completion of CRT, and an anterior or abdominal–peritoneal resection with total mesorectal excision was performed on the basis of restaging. The colonic anastomosis was protected by a loop ileostomy, which was later reversed after endoscopic assessment of the anastomotic integrity.
Pathology
This study was approved by the local ethics committee and was conducted in accordance with the Helsinki Declaration. Signed written informed consent was obtained from each patient.
Postsurgical pathology examination provided a macroscopic description of the mesorectum and of the former tumor-bearing area; at least four paraffin blocks were processed, and an additional larger area block was embedded. If no tumor was visible, the entire suspicious area was sliced and embedded. CRM was judged to be involved if the microscopic tumor was #1 mm from the radial resection margin. The TRG was independently assessed by two pathologists (FT and NS) and scored according to a five-point system (23). Briefly, TRG1 was a complete tumor regression (regardless of the presence of acellular mucine lakes), and TRG2 was a nearly complete tumor regression with extensive fibrosis; TRG3 presented with clear evidence of residual cancer cells but with predominant fibrosis; TRG4 was a residual of cancer cells outgrowing fibrosis; TRG5 was the absence of regressive changes. In the case of discrepancy between the two pathologists, the worse TRG score was assigned. A complete pathology response (ypCR) was defined as the absence of viable tumor cells in the primary tumor and lymph nodes; a major response consisted of TRG2 to -3 without CRM involvement and nodal metastases, while a TRG4 to -5 or CRM involvement or nodal metastases, were classified as minor/no response.
Patient selection
Adjuvant chemotherapy and follow-up
Eligibility criteria required histologically confirmed, untreated rectal adenocarcinoma with poor prognostic presentation, including clinical (c)T4, cN1-2, or cT3N0 located in the lower third of the rectum and/or a circumferential resection margin (CRM) of #5 mm by magnetic resonance imaging (MRI). Additional inclusion criteria were an ECOG performance status of #2, age $18 years, and adequate organ function. Main exclusion criteria were metastatic dis-
Adjuvant 5-FU, 370 mg/m2, and LFA, 20 mg/m2 weekly for 4 months, were delivered only to patients with cT4 lesions or who were ypN positive or had ypCRM of #1 mm. Pelvic MRI, chest and abdominopelvic CT scans, carcinoembryonic antigen serum level tests, and rectoscopy procedures were performed every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter.
METHODS AND MATERIALS
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Statistical design and analysis As previously reported (21), the original statistical design called for at least 19 patients with TRG1 to -2 among 46 treated patients to accept the hypothesis of 50% activity, and this result was already obtained among the first 31 treated patients. Therefore, we decided to obtain a better estimate of the activity and to improve the tolerability of this treatment, testing a 5-FU dose reduction in a comparable number of patients. FFR was defined as the time from initial treatment to the documented local or distant recurrence (whichever occurred first), or last follow-up. Patients who died without recurrence were censored for this analysis. OS was defined as the time from initial treatment until death for any cause or to last follow-up. Cancer-specific survival (CSS) was defined as the time to death for rectal cancer or to the last follow-up. FFR, OS, and CSS rates were estimated using the Kaplan-Meier method (24). Proportions were estimated with their 95% confidence interval (CI) and compared with a chi-square or Fisher’s exact test when appropriate. Risk of recurrence according to an initial Gunderson risk score and to pathology response was assessed by Cox analysis and expressed as a hazard ratio (HR) with 95% CI (25).
RESULTS From July 2002 to September 2006, a total of 63 patients (31 in the first series, 32 in the second series) were enrolled. Baseline characteristics did not differ between the two series (Table 1). It should be underlined that 6 of 10 T3N0 tumors were either located in the lower third of the rectum or had a CRM of #5 mm. Safety All but one patient of the first series, whose participation was discontinued because of toxicity after 41.5 Gy, completed RT in a median of 37 (range, 32–53) days. As to chemotherapy, 9 (16%) patients (7 in the first series and 2 in the second series) received less than three cycles because of severe or persistent toxicity. Mean (relative) dose intensity was 46 mg/m2/week (92%) for OXA and 1.16 mg/m2/week (92%) for RTX in both series, while it was 378 mg/m2/ week (84%) and 361 mg/m2/week (90%) for 5-FU in the first and second series, respectively. The toxicity profiles registered during CRT were similar in the two series of patients (Table 2). Neutropenia and diarrhea were the most common grade $3 adverse events, but they were short lasting and easily managed. However, it should be noted that neutropenia (grade 4, 9% vs. 22%) and diarrhea (grade 3, 6% vs. 19%) were less pronounced in the second series. Surgery and pathologic response Surgery was performed after a median of 8.2 (range, 4.4– 15.7) weeks from the end of CRT. All but one patient who underwent a local excision were referred for radical surgery, which was an anterior resection in 55 cases and an abdominal–peritoneal resection in 7 cases. Twelve of 15 (80%) patients with a distal tumor border #3 cm from the anal verge (in whom an abdominal–peritoneal resection was supposed to be necessary before CRT) were subsequently con-
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verted to a sphincter-sparing resection. Sixty (97%) patients had an ypCRM-ve resection (R0). Pathology tumor downstaging occurred in 51 of 62 (82%) patients. As for the TRG classification, there was a concordance between pathologists in 51 (81%) cases. Interobserver discrepancy mainly occurred (9 of 12 cases) in scoring TRG2 and TRG3. According to the worst assigned score, TRG was as follows: TRG1 in 25 (40%) patients, TRG2 in 16 (25%) patients, TRG3 in 13 (21%) patients, and TRG4 in 9 (14%) cases. No TRG5 was registered. No significant differences in TRG were observed between the two series (Table 3). With a median of 37 (range, 10–80) lymph nodes retrieved, nodal metastases were detected in 12 (ypN1, 9 cases; ypN2, 3 cases) of 62 (19%) patients. In detail, nodal metastases were detected in one case each of patients showing a TRG1 (4%) or a TRG2 (6%), while they were detected in 6 patients with a TRG3 (46%) and 4 patients with a TRG4 (44%). Overall, pathology nodal downstaging occurred in 40 of 52 (77%) patients. No upstaging of T or N stage was observed. Table 1. Demographic and clinical characteristics of enrolled patients
Characteristics
First series (n = 31) (% of total)
Gender Males 16 (52) Females 15 (48) Median age 56 (29–74) (range) ECOG performance status 0 12 (39) 1 17 (55) 2 2 (6) Gunderson risk Intermediate 4 (13) T2N1 1 T3N0 3 Moderately high 14 (45) T3N1 14 T4N0 0 High 13 (42) T3N2 7 T4N1-2 6 Distance from the anal verge <5 cm 15 (48) >5 cm 16 (52) Circumferential resection margin <5 mm 19 (61) >5 mm 9 (29) Not evaluated* 3 (10) Baseline carcinoembryonic antigen serum level <5 UI/l 21 (68) >5 UI/l 10 (32)
Second series (n = 32) (% of total)
Whole series (n = 63) (% of total)
16 (50) 16 (50) 61 (27–79)
32 (51) 31 (49) 58 (27–79)
5 (16) 26 (81) 1 (3)
17 (27) 43 (68) 3 (5)
7 (22) 0 7 15 (47) 14 1 10 (31) 8 2
11 (17) 1 10 29 (46) 28 1 23 (37) 15 8
19 (59) 13 (41)
34 (54) 29 (46)
24 (75) 7 (22) 1 (3)
43 (68) 16 (26) 4 (6)
17 (53) 15 (47)
38 (60) 25 (40)
* Because of the presence of a metal prosthesis.
OXA plus TS inhibition and preop RT in rectal Ca d A. AVALLONE et al.
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Table 2. Acute adverse events registered during chemoradiotherapy treatment First series (n = 31)
Toxicity Hematologic neutropenia Febrile neutropenia Thrombocytopenia Anemia Gastrointestinal Nausea/vomiting Colitis Diarrhea Stomatitis Proctitis Metabolic/laboratory Hyperbilirubinemia Transaminases Skin toxicity Fatigue Fever Sensory neuropathy
Second series (n = 32)
All Grade
Grade 3
Grade 4
All Grade
Grade 3
Grade 4
All Grade
Grade 3
Grade 4
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
17 5 5 0
55 16 16
5 0 0 0
16
7 2 0 0
22 6
21 6 4 1
65 19 12 3
10 3 0 0
31 9
3 1 0 0
9 3
38 11 9 1
60 17 14 2
15 3 0 0
24 5
10 3 0
16 5
15 3 13 0 5
48 9 42 16
0 0 6 1 0
0 0 0 0 0
17 2 17 2 9
53 6 53 6 28
0 0 2 0 0
0 0 0 0 0
32 5 30 3 14
51 8 48 5 22
0 0 8 1 0
13 9 13 9 16
0 0 0 0 0 0
0 0 0 0 0 0
1 6 4 2 1 5
3 19 12 6 3 16
0 0 0 0 0 0
0 0 0 0 0 0
1 10 7 6 4 10
2 16 11 9 6 16
0 0 0 0 0 0
0 4 3 4 3 5
19 3
In the whole series, a ypCR was obtained in 24 (39%; 95% CI, 27%–52%) patients, a major response in 20 (32%; 95% CI, 21%–45%) patients, while minor/no response was registered in 18 (29%; 95% CI, 18%–42%) patients. No significantly different response rates were seen according to baseline patients characteristics (Table 4). Surgical complications and late side effects There were no intra- or postoperative deaths. Twenty-two postsurgical complications occurred in 19 (30%) patients (anastomotic fistula in 4 patients; rectovaginal fistula in 3 patients; bladder fistula in 1 patient; anastomotic stenosis in 5 patients; pelvic abscesses in 5 patients; delayed perineal healing in 2 patients; bowel adhesion in 1 patient; and anastomotic dehiscence in 1 patient [a patient who refused loop ileostomy]). Eight (13%) patients required an additional surgical procedure. Moderate or severe late anorectal or sexual dysfunctions were reported in 25 (40%) patients: higher stool frequency (8 patients), fecal and gas incontinence (3 patients), constipation (2 patients), erectile dysfunction (7 patients), retrograde ejaculation (2 patients), and severe dyspareunia (3 patients). No significant differences Table 3. Tumor regression grade according to treatment Tumor regression grade TRG1 TRG2 TRG3 TRG4 TRG5 Total
Whole series (n = 63)
Fist series n = 31 (%)
Second series n = 32 (%)
Whole series n = 63 (%)
13 (42) 9 (29) 3 (10) 6 (19) 0 31 (100)
12 (38) 7 (22)* 10 (31) 3 (9) 0 32 (100)
25 (40) 16 (25)* 13 (21) 9 (14) 0 63 (100)
* Including a patient referred for local excision.
6
13 2
0 0 0 0 0 0 0 0 0 0 0
in postsurgical complications and late side effects were observed in the two series of patients. Adjuvant treatment and follow-up Eighteen patients (2 achieving a major response and 16 showing a minor/no response) received adjuvant chemotherapy after a median interval of 5.9 (range, 4.3–11) weeks from surgery. As of March 2009, 10 patients (5 in each series) showed disease recurrence (3 patients had both a local and a distant recurrence; 7 patients had only a distant recurrence). A local and distal recurrence occurred in the single patient who underwent a local excision. Of note, 7 patients (1 patient with ypCRM+ and 6 patients with ypN+) of 18 (39%) who received the adjuvant treatment had a relapse, as opposed to 2 of 44 (4%) patients who did not receive any postoperative chemotherapy. Table 4. Complete and major pathologic responses according to baseline Gunderson risk, clinical CRM, and location of the primary tumor Characteristics (no. of patients)
Complete Major response response n = 20 Total % of total n = 24
Gunderson risk Intermediate (11) Moderately high (29) High (23) Clinical CRM* <5 mm (43) >5 mm (16) Distance from the anal verge <5 cm (34) >5 cm (29) * Not evaluated in 4 cases.
5 13 6
4 7 9
9 20 15
82 69 65
17 6
15 5
32 11
74 69
13 11
12 8
25 19
73 65
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After a median follow-up of 60 (range, 30–80) months, the 5-year probability of FFR was 80% (95% CI, 68%–92%). The 5-year FFR was lower for the high-risk group (71%; 95% CI, 50%–92%) than for the intermediate or moderately high-risk group, but this difference was not significant (Fig. 1). At 5 years, the probability of FFR did not differ between the complete and major responders (just one recurrence was observed in each of these two groups), and it was over 90% for these patents. On the contrary, it was significantly lower (56%; 95% CI, 32%–81%) for minor/non-responders (HR, 5.1; 95% CI, 1.6–16.9; p = 0.007) (Fig. 2). Eight patients (3 for causes unrelated to cancer) eventually died; therefore, the 5-year OS was 87% (95% CI, 77%–97%), while the 5-year CSS was 92% (95% CI, 85%–99%). DISCUSSION The results of our study confirm that the combination of OXA, RTX, and 5-FU/LFA delivered during pelvic RT in poor-prognosis RC patients was well tolerated. Indeed, acute toxicity was acceptable, no intra- or postoperative death occurred, and the incidence of postsurgical complications was comparable with that reported with other oxaliplatinbased preoperative CRT regimens (26–27). However, severe neutropenia and diarrhea were less pronounced with the slight 5-FU dose reduction, and the improved tolerability translated to better compliance with the planned CT treatment. Despite the lower 5-FU dosage, we did not observe a reduction of clinical activity. Indeed, we reported a similar proportion of TRG1 and TRG2 in the two consecutive series. In our opinion, the 97% R0 rate and the 39% rate of ypCR reported are impressive considering the advanced disease stage in most patients. Indeed, this ypCR rate was nearly twice that reported in other phase II trials (28). Only one study reported a similarly high ypCR rate (29), but it did not use the MRI in the preoperative staging and did not include cT4 tumors.
Fig. 1. Probability of FFR according to the initial Gunderson risk (circles = intermediate risk; squares = moderately high risk; triangles = high risk).
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In addition, we observed an elevated proportion (32%) of major responses, while no TRG5 was reported. It is noteworthy that pathology responses were obtained regardless of the initial stage and applying a very careful histological assessment, as proven by the median number of retrieved lymph nodes. This finding demonstrated, unlike other reports (30), the feasibility of an accurate lymph node evaluation even after an intensified preoperative CRT approach. An additional remarkable finding was the proportion of sphincter preservation in patients with lower tumor location. The long-term follow-up gives further strength to our results. Indeed, the 5-year 80% FFR confirms the durable disease control achieved by our treatment. Although the cross-trial comparison is problematic, we would recall some studies in which inclusion criteria were similar to ours. In the CORE trial (31), in which capecitabine and OXA were combined with pelvic RT, an 11% ypCR rate, a 3-year 55% progression free-survival, and a 75% OS were reported. Two other studies, in which irinotecan or OXA were added to 5-FU/LFA during pelvic RT, showed similar results (32, 33). Moreover, four cycles of neoadjuvant full-dose OXA and capecitabine given before CRT treatment yielded results inferior to ours while inducing an unpredictable rate (5%) of toxic deaths (34). Another important point of our study is the selective adjuvant treatment policy. There is no general agreement on the benefit of adjuvant CT after preoperative CRT. In this regard, EORTC trial 22921 failed to demonstrate a significant impact on OS of postoperative CT (3). Furthermore, retrospective analysis of the CAO/ARO/AIO-94 trial questioned the delivery of adjuvant CT on the basis of pretreatment findings (35). Interestingly, in that analysis, a prognostic value of the TRG was suggested at univariate analysis, while a ypN+ resulted the strongest prognostic factor in the multivariate model. Moreover, the persistence of a CRM involvement was recognized as a strong prognostic factor even after a preoperative CRT approach (36).
Fig. 2. Probability of FFR according to the pathology response (circles = complete response; squares = major response; triangles = minor/no response). The patient referred for local excision was excluded from analysis.
OXA plus TS inhibition and preop RT in rectal Ca d A. AVALLONE et al.
On the other hand, retrospective analyses have demonstrated the favorable prognostic value of ypCR (37) and ypN0 (38), independently of adjuvant CT. However, an accurate postoperative pathology evaluation is essential to obtain a correct prognostic information. Indeed, in tumors defined as ypN0, the number of lymph nodes examined correlated with the outcome (39). In our study, pathology findings showed a greater prognostic value than pretreatment clinical factors. In particular, we observed that not only patients achieving a ypCR but also those with a major response may have a favorable outcome without adjuvant CT. Indeed, the 5-year FFR was around 90% for both groups of patients. Conversely, 5-year FFR was 56% for the minor/no response group, even though 16 patients of 18 received adjuvant CT. Consequently, we speculate that patients with ypCR or major response would not require a postoperative treatment at all, while patients with minor/no response need a postoperative approach with noncross-resistant drugs. Several reasons could explain the high efficacy of our CRT. First, it should be noted that the main target of our regimen was TS, which exhibits oncogene-like activity (7) and is related to prognosis in RC (8). Preclinical data have shown that a sequential dual inhibition of TS by RTX and 5-FU/ LFA translated into a synergistic cytotoxicity in the wildtype p53 and mutant colorectal cancer cells (12). Moreover, OXA was proven to induce a TS down-regulation in colon cancer cells (15) and to potentiate the effect of TS inhibition through the down-regulation of deoxyuridine triphosphate nucleotide hydrolase (40). Second, exposure of colon cancer cells to RTX/5-FU/LFA induced an S-phase block greater than that produced by 5-FU/LFA or RTX/5-FU alone (12). Moreover, OXA was reported to induce a prolonged cell accumulation into the G2/M
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phases (41). All these cell cycle perturbations could be crucial for increasing the sublethal damage of RT. Third, cytotoxic drugs were administered during RT at doses that were close to those usually used in the treatment of metastatic colorectal cancer patients (18, 19). Interestingly, a direct correlation between the dose of OXA (#85 mg/m2 vs. >85 mg/m2) actually delivered over 2 weeks and the activity of regimens in which OXA was combined with 5-FU (FOLFOX) has been reported in these patients (42). Moreover, preclinical studies have also shown that the radiosensitizing property of OXA is dose dependent, suggesting the existence of a threshold dose (14, 41). Few data are available for long-term morbidity after CRT and total mesorectal excision in RC patients, and current knowledge comes from trials of short-course RT (43). Moderate or severe late toxicity in our study was similar to that reported in those studies. However, the occurrence of this late toxicity emphasizes the need for tailoring the surgical management according to the prediction of response. In this regard, we have previously demonstrated that [18F]fluorodeoxyglucose positron emission tomography may have a promising role in early identification of responder patients who could benefit from a less aggressive surgery (44). CONCLUSIONS In conclusion, we have shown that a slight reduction of 5-FU dosage induced a greater tolerability of the combination of OXA, RTX, and 5-FU/LFA delivered during pelvic RT without impairing its activity. This combination obtained promising early and long-term results in poor-prognosis locally advanced RC patients, although these results deserve to be confirmed in a larger population. The selective adjuvant treatment strategy applied in our study also supports a riskadapted approach in postoperative management.
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