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
Publication: Journal of Clinical Oncology
Abstract
Purpose
To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer.
Patients and Methods
Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here.
Results
Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014).
Conclusion
Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.
Introduction
Fluorouracil-based preoperative chemoradiotherapy represents a standard option for the initial treatment of locally advanced rectal cancer (LARC). Randomized clinical trials have indeed shown that fluorouracil concomitant to preoperative radiation reduces local recurrences compared with either preoperative radiation without chemotherapy1,2 or chemoradiotherapy delivered in the postoperative setting.3 Fluorouracil-based preoperative chemoradiotherapy also results in enhanced tumor shrinkage compared with preoperative radiation alone (with downstaging/downsizing of the initial tumor mass in large proportions of patients and 10% to 15% showing a complete tumor sterilization at surgery).1,4 Although clear-cut evidence is lacking, this might, in turn, facilitate radical resection for large/more advanced tumors and sphincter-preserving surgery in patients with low-lying tumors. Adding fluorouracil to radiation, however, has no impact on metastases at distant sites that remain in the 30% range despite optimized surgery with total mesorectal excision (TME), preoperative or postoperative radiation, and concomitant plus sequential fluorouracil- based chemotherapy.5
The platinum derivative oxaliplatin is effective in combination with fluorouracil both as adjuvant treatment after resection of intraperitoneal colon cancer6 and as palliative treatment in patients with metastatic disease.7 Preclinical studies have also shown oxaliplatin to be a potent radiosensitizing agent.8 Its combination with fluorouracil and radiation in the preoperative treatment of LARC may thus improve both the control of micrometastases at distant sites and primary tumor shrinkage before surgery.
In this trial, a standard preoperative chemoradiotherapy regimen (50.4 Gy in 28 daily fractions with concomitant infused fluorouracil at the dose of 225 mg/m2/d) was compared with the same regimen plus oxaliplatin given weekly at the dose of 60 mg/m2, building on the results of a previous phase I/II study.9 The trial was launched in December 2003 and performed within a network of 41 Italian centers (Studio Terapia Adiuvante Retto [STAR] network). Overall survival is the primary end point. A protocol-planned analysis of pathologic response to preoperative treatment is the object of the present report.
Patients and Methods
Study Population
Patients with biopsy-proven rectal adenocarcinoma and radiologic evidence of penetration through the whole bowel wall (cT3-T4) and/or involvement of the regional lymph nodes (cN1-2) were eligible for this trial, provided that the tumor was located within 12 cm from the anal verge, was resectable on the basis of clinical assessment (no evidence of infiltration of the pelvic wall, prostate, or base of the urinary bladder), and there were no distant metastases. Other eligibility requirements were WHO performance status 0 to 2; adequate liver, renal and bone marrow function; and age ≤ 75 years. Prior treatment for this disease, previous pelvic radiotherapy, and history of any other tumors except for basal cell carcinoma of the skin and carcinoma in situ of the uterine cervix were exclusion criteria, as well as any concomitant illness potentially affecting treatment compliance, pregnancy, or lack of effective contraception. The study was approved by the ethics committee of each participating institution, and written informed consent was obtained from each patient before inclusion. Baseline assessment included a complete colonoscopy with rigid rectoscopy, computed tomography of the pelvis and/or transrectal ultrasonography, and computed tomography of the liver and chest (or ultrasound/x-ray). Lymph nodes measuring more than 5 mm were considered positive.
Randomization and Treatment
After stratification by center and stage (T4 and/or N1-2 v T3N0), patients were randomly assigned to receive radiotherapy with either concomitant infused fluorouracil (arm A) or concomitant infused fluorouracil plus weekly oxaliplatin (arm B) in a 1:1 ratio. Random assignment was centrally performed with the use of permuted blocks of variable size.
Radiotherapy.
A total of 50.4 Gy was delivered with high-energy photons (≥ 4 MV) in 28 daily fractions of 1.8 Gy, Monday to Friday over a period of approximately 6 weeks. The target volume included all the macroscopic tumor with a minimum margin of 3 cm, the mesorectum, and the internal iliac and presacral nodes up to L5/S1 junction. External iliac and inguinal nodes were irradiated in stage cT4 tumors and in those extending into the anal canal, respectively. Dose distribution was defined in at least three axial sections from CT or conventional simulator. Dose was prescribed at the intersection of beam axes according to the International Commission on Radiation Units and Measurements recommendations.
Chemotherapy.
Fluorouracil was infused continuously through an implantable subcutaneous intravenous access device at the dose of 225 mg/m2/d for all the duration of radiotherapy. In arm B, patients received a 2-hour intravenous infusion of oxaliplatin at 60 mg/m2 on the first day of each week of radiotherapy for a total of six courses.
Dose reduction criteria.
Surgery and postoperative treatment.
Surgery was planned 6 to 8 weeks after the end of chemoradiotherapy. TME was advised, whereas each operating surgeons chose the type of resection for low-lying tumors. Fluorouracil-based adjuvant chemotherapy was planned for all patients achieving a curative resection irrespective of the pathologic stage.
Pathology Procedures
The resected specimens were processed and examined as described by Quirke et al.12 The extent of residual tumor was classified according to the fifth International Union Against Cancer TNM staging system.13 A post-therapy pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens including the primary tumor area, the whole mesorectal fat, and the resected lymph nodes (ypT0N0), regardless the presence of mucin lakes.
R0 and R1 were defined as histologically tumor-free or infiltrated resection margins; R2a and R2b were defined as local or distant macroscopic residual tumor.14 Radial resection margins were defined as negative when the distance to the tumor was more than 1 mm. Regression of the primary tumor was also determined semiquantitatively according to a modified Dworak scale15 based on the amount of viable tumor versus the amount of fibrosis: grade 0 to 1/2, dominant tumor mass with fibrosis in less than 50%; grade 3, fibrosis outgrowing the tumor mass; grade 4, fibrotic mass without viable tumor cells.
Data Management and Statistics
The study was primarily designed to detect a 30% reduction in mortality rates with the addition of oxaliplatin (252 deaths/690 patients required to have an 80% power at the 5% two-sided significance level). ypCR is the primary measure of outcome for this protocol-planned comparative analysis of response to preoperative treatment. All the randomly assigned patients were included in the ypCR analysis irrespective of eligibility, treatment actually received, and surgery (intention-to-treat population). This resulted in a power of 80% to detect a 8% absolute difference in ypCR rates (assuming a 12% rate in the control arm). Safety and compliance were analyzed on all subjects receiving at least one dose of study drugs according to treatment actually received (safety population). Proportions were compared with the standard χ2 test for heterogeneity or, when appropriate, the Fisher's exact test. Estimates of odds ratios (ORs) were obtained by logistic regression analyses. Continuous variables were compared with the Mann-Whitney U or t test. All reported P values are two-sided. Statistical analyses were performed at the Istituto Toscano Tumori–Clinical Trials Coordination Center in Florence, Italy.
Results
From November 2003 through August 2008, 747 patients were randomly assigned at 41 Italian institutions. Eight patients were not eligible. Five patients in arm A and seven patients in arm B did not receive any preoperative therapy. In arm B, four patients had preoperative radiotherapy alone or with out-of-study chemotherapy, whereas five patients were treated with radiotherapy and infused fluorouracil without oxaliplatin (Fig 1).
The study groups were balanced in terms of baseline patient and tumor characteristics (Table 1). Altogether, approximately 15% of patients had cT4 tumors, and radiologic evidence of lymph nodes involvement was reported in 65%.
| Characteristic | RT and FU (n = 379) | Oxaliplatin Plus RT and FU (n = 368) | ||
|---|---|---|---|---|
| No. | % | No. | % | |
| Age, years | ||||
| Median | 63 | 62 | ||
| Range | 20-75 | 33-75 | ||
| Sex | ||||
| Male | 259 | 68 | 245 | 67 |
| Female | 120 | 32 | 123 | 33 |
| WHO performance status | ||||
| 0 | 330 | 87 | 324 | 88 |
| 1 | 48 | 13 | 44 | 12 |
| 2 | 1 | 0.3 | 0 | 0 |
| Distance from anal verge, cm | ||||
| < 4 | 89 | 23 | 70 | 19 |
| 4-8 | 202 | 53 | 213 | 58 |
| > 8 | 81 | 21 | 76 | 21 |
| Undetermined/data missing | 7 | 2 | 9 | 2 |
| Tumor stage* | ||||
| T1-2 | 7 | 2 | 17 | 5 |
| T3 | 307 | 81 | 300 | 82 |
| T4 | 65 | 17 | 50 | 14 |
| Undetermined T | 0 | 0 | 1 | 0.3 |
| Nodal stage* | ||||
| N0 | 134 | 35 | 122 | 33 |
| N1-2 | 242 | 64 | 246 | 67 |
| Undetermined N | 3 | 1 | 0 | 0 |
Abbreviations: FU, infusional fluorouracil; RT, radiotherapy.
*
Defined as the worst stage based on all available imaging (pelvic computed tomography and/or transrectal ultrasound).
Compliance and Acute Toxicity
Compliance (Table 2) and safety (Table 3) were analyzed on 379 patients treated with fluorouracil alone (including five patients randomly assigned in arm B) and 352 receiving weekly oxaliplatin plus fluorouracil along with radiation (Fig 1). In arm B, 233 (66%) of 352 patients starting treatment as assigned had all the six planned weekly administrations of oxaliplatin, and 293 (83%) received at least five oxaliplatin infusions. Fifty-three patients (15%) had a reduction of the oxaliplatin dose. Seventy-five percent of patients thus received at least 80% of the planned cumulative dose of oxaliplatin, with a mean delivered dose intensity of 58 mg/m2/wk. Compliance with fluorouracil administration was reduced among patients treated with oxaliplatin compared with patients treated with radiation and fluorouracil alone (Table 2), resulting in a lower proportion receiving at least 80% of the planned cumulative dose of the fluoropyrimidine (90% in arm A v 80% in arm B; P < .001). Regarding radiotherapy, 348 (92%) of 379 patients treated with fluorouracil alone and 295 (84%) of 352 patients treated with oxaliplatin plus fluorouracil received the full planned dose (P < .001). Ninety-seven percent and 91% received at least 45 Gy (P < .001). Toxicity was the reason for treatment discontinuation in 4% and 17% of patients in arms A and B, respectively.
| Treatment | RT and FU (n = 379) | Oxaliplatin Plus RT and FU (n = 352) | ||
|---|---|---|---|---|
| No. | % | No. | % | |
| Radiotherapy | ||||
| Full dose (≥ 50.4 Gy) | 348 | 92 | 295 | 84 |
| ≥ 90% of planned | 368 | 97 | 319 | 91 |
| ≥ 80% of planned | 375 | 99 | 331 | 94 |
| Fluorouracil | ||||
| Weeks of infusion | ||||
| 6 | 320 | 84 | 244 | 69 |
| 5+ | 360 | 95 | 309 | 88 |
| 4+ | 370 | 98 | 326 | 93 |
| Delivered/planned dose (cumulative) | ||||
| ≥ 80% | 340 | 90 | 282 | 80 |
| Delivered dose intensity, mg/m2/wk | ||||
| Mean* | 1,569 | 1,555 | ||
| SD | 127 | 82 | ||
| Oxaliplatin | ||||
| Weekly courses | ||||
| 6 | — | — | 233 | 66 |
| 5+ | — | — | 293 | 83 |
| 4+ | — | — | 317 | 90 |
| Dose reductions (at least 1 cycle) | — | — | 53 | 15 |
| Delivered/planned dose (cumulative) | — | — | ||
| ≥ 80% | — | — | 264 | 75 |
| Delivered dose intensity, mg/m2/wk | ||||
| Mean† | 58 | |||
| SD | — | 4 | ||
Abbreviations: FU, infusional fluorouracil; RT, radiotherapy; SD, standard deviation.
*
Planned FU dose intensity: 1,575 mg/m2/wk.
†
Planned oxaliplatin dose intensity: 60 mg/m2/wk.
| Toxicity | Grade 1-2 | Grade 3-4 | P | ||||||
|---|---|---|---|---|---|---|---|---|---|
| RT and FU (n = 379) | Oxaliplatin Plus RT and FU (n = 352) | RT and FU (n = 379) | Oxaliplatin Plus RT and FU (n = 352) | ||||||
| No. | % | No. | % | No. | % | No. | % | ||
| Diarrhea | 167 | 44 | 165 | 47 | 16 | 4 | 54 | 15 | < .001 |
| Nausea | 65 | 17 | 125 | 36 | 0 | 0 | 6 | 2 | .012 |
| Vomiting | 19 | 5 | 80 | 23 | 0 | 0 | 4 | 1 | .054 |
| Abdominal pain | 61 | 16 | 87 | 25 | 0 | 0 | 6 | 2 | .012 |
| Anemia | 72 | 19 | 80 | 23 | 2 | 0.5 | 0 | 0 | .500 |
| Radiation dermatitis | 150 | 40 | 126 | 36 | 7 | 2 | 16 | 5 | .037 |
| Neurosensory | 2 | 0.5 | 124 | 35 | 0 | 0 | 5 | 1 | .026 |
| Dysuria | 106 | 28 | 95 | 27 | 2 | 0.5 | 3 | 1 | .677 |
| Asthenia | 75 | 20 | 109 | 31 | 0 | 0 | 11 | 3 | < .001 |
| Fever | 16 | 4 | 80 | 23 | 0 | 0 | 4 | 1 | .054 |
| Overall | 291 | 77 | 244 | 69 | 29 | 8 | 85 | 24 | < .001 |
NOTE. Toxicities occurring at grade 1 to 2 in ≥ 20% of the patients and/or grade 3 to 4 in ≥ 2% of the patients are reported in the table. All P values are for comparison between grade 3 to 4 versus grade 0, 1, 2 between the two arms.
Abbreviations: FU, infusional fluorouracil; RT, radiotherapy.
The overall incidence of grade 3 to 4 adverse events during preoperative treatment was 24% in the oxaliplatin arm versus 8% with fluorouracil alone (P < .001; Table 3). Higher rates of diarrhea (15.3% v 4.2%; P < .001), radiation dermatitis (4.5% v 1.8%; P = .037), and asthenia (3.1% v 0%; P < .001) accounted for this difference, whereas the incidence of severe hematologic toxicity was similarly low in the two arms (Table 3). Thirty-seven percent of the patients treated with oxaliplatin (n = 129) experienced peripheral neurosensory toxicity that reached grade 3 in five patients (1.4%). There were three deaths potentially related to preoperative chemoradiotherapy (one in arm A and two in arm B).
Surgery
Surgery was performed in 362 (96%) of 379 patients in arm A and 351 (95%) of 368 in arm B at a median interval from the end of chemoradiotherapy of 51.5 days (range, 14 to 112 days) and 53 days (range, 5 to 247 days), respectively. Fifteen patients in each arm did not undergo surgery. Four patients had immediate surgery without any preoperative treatment (Fig 1).
Resection could not be performed in four patients who underwent surgery because of peritoneal carcinomatosis and liver involvement (arm A, n = 1) or locally unresectable disease (arm A, n = 2; arm B, n = 1) found at laparotomy. One patient in arm A and three in arm B had transanal local excision. Three hundred fifty-eight and 347 patients (arms A and B, respectively) therefore had surgical resection aimed at cure. An abdominoperineal resection or Hartmann procedure was performed in 144 patients (21% and 19% of the patients who underwent surgery in arms A and arm B, respectively). Twenty-seven patients had macroscopic residual disease (21 patients in arm A v six patients in arm B). Intra-abdominal distant metastases were observed in 18 patients (arm A, n = 16; arm B, n = 2). The rate of intraoperative and postoperative complications was equally low in the two arms. Three patients in each arm (1%) died within 60 days from surgery (Table 4).
| Variable | RT and FU (n = 362) | Oxaliplatin Plus RT and FU (n = 351) | ||
|---|---|---|---|---|
| No. | % | No. | % | |
| Type of surgery | ||||
| Local excision | 1 | 0.3 | 3 | 0.9 |
| Laparotomy only | 3 | 0.8 | 1 | 0.3 |
| Anterior resection | 282 | 78 | 276 | 79 |
| Abdominoperineal resection | 72 | 20 | 64 | 18 |
| Hartmann's procedure | 4 | 1 | 4 | 1 |
| Other | 0 | 0 | 3 | 0.9 |
| Macroscopic residual disease* | ||||
| No | 340 | 94 | 344 | 98 |
| Local | 8 | 2 | 5 | 1 |
| Extrapelvic | 13 | 4 | 1 | 0.3 |
| Missing data | 1 | 0.3 | 1 | 0.3 |
| Intra-abdominal metastases | ||||
| No | 346 | 96 | 349 | 99 |
| Liver | 11 | 3 | 1 | 0.3 |
| Peritoneal | 4† | 1 | 1 | 0.3 |
| Lymph nodes | 1 | 0.3 | 0 | 0 |
| Intraoperative complications | 5 | 1 | 3 | 0.9 |
| Hemorrhage | 3 | 0.8 | 2 | 0.6 |
| Other | 2 | 0.6 | 1 | 0.3 |
| Postoperative complications | 80 | 22 | 83 | 24 |
| Surgical | 56 | 15 | 58 | 17 |
| Pelvic abscess | 11 | 3 | 14 | 4 |
| Local fistula | 5 | 1 | 7 | 2 |
| Ileus/obstruction | 9 | 2 | 4 | 1 |
| Other/undetermined | 31 | 9 | 33 | 9 |
| Medical | 24 | 7 | 25 | 7 |
| Death within 60 days | 3 | 0.8 | 3 | 0.9 |
Abbreviations: FU, infusional fluorouracil; RT, radiotherapy.
*
Includes patients with laparotomy only.
†
One patient also had liver metastases.
Pathology Findings
Seven hundred five TME specimens were available from patients who underwent preoperative treatment (Fig 1). Macroscopic residual disease (R2 resection) was documented in 17 patients in arm A and five patients in arm B, whereas six and seven patients, respectively, had an R1 resection. Fifteen and nine patients had a positive (≤ 1 mm) circumferential resection margin (7% v 4% in arms A and B, respectively, P = .239; 60.9% of data available; Table 5).
| Pathologic Finding | RT and FU (n = 358) | Oxaliplatin Plus RT and FU (n = 347) | P | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Tumor diameter, mm* | |||||
| Median | 25 | 20 | .195 | ||
| Range | 1-100 | 2-80 | |||
| Missing | 23 | 23 | |||
| ypT-stage | |||||
| 0 | 64 | 18 | 65 | 19 | .578 |
| 1 | 25 | 7 | 35 | 10 | |
| 2 | 106 | 30 | 94 | 27 | |
| 3 | 152 | 42 | 140 | 40 | |
| 4 | 11 | 3 | 13 | 4 | |
| Examined lymph nodes | |||||
| Median | 12 | 11 | .013 | ||
| Range | 0-47 | 0-42 | |||
| ypN-stage | |||||
| 0 | 264 | 74 | 247 | 71 | .630 |
| 1 | 63 | 18 | 63 | 18 | |
| 2 | 31 | 9 | 37 | 11 | |
| Tumor regression grade† | |||||
| 0-1-2 | 146 | 41 | 119 | 34 | .170 |
| 3 | 140 | 39 | 157 | 45 | |
| 4 | 62 | 17 | 60 | 17 | |
| Missing/undetermined | 10 | 3 | 11 | 3 | |
| Resection status | |||||
| R0 | 335 | 94 | 335 | 97 | .070‡ |
| R1 | 6 | 2 | 7 | 2 | |
| R2a | 5 | 1 | 4 | 1 | |
| R2b | 12 | 3 | 1 | 0.3 | |
| CRM status | |||||
| Positive (≤ 1 mm) | 15 | 7 | 9 | 4 | .239 |
| Negative | 203 | 93 | 202 | 96 | |
| Missing | 140 | 136 | |||
Abbreviations: CRM, circumferential resection margin; FU, infusional fluorouracil; RT, radiotherapy; TME, total mesorectal excision.
*
Excluding 129 patients with ypT stage = 0.
†
Dvorak score.
‡
R0 versus R1-2.
The ypCR rate was 16% in both arms (62 of 379 patients in arm A and 59 of 368 patients in arm B; odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent of patients in the fluorouracil and radiation group and 29% in the oxaliplatin plus fluorouracil and radiation arm had positive regional lymph nodes. Among the patients with residual tumor in the pathology specimen, the distribution according to the ypT subcategory, the median diameter of the resected tumor and the degree of tumor regression were also similar irrespective of the treatment arm (Table 5). Intra-abdominal distant metastases (ypM1) were detected in 11 and two patients who underwent surgery in arms A and B, respectively (2.9% v 0.5%; P = .014).
Discussion
In this large randomized study, adding weekly oxaliplatin to preoperative fluorouracil and radiotherapy had no effect on primary tumor response. ypCR rates, the protocol-defined end point for this analysis, were identical in the two arms. All other measures of response to preoperative chemoradiotherapy were also equally distributed among patients treated with or without oxaliplatin, ruling out even minor and/or qualitative effects. Subgroups analyses, finally, failed to identify any group of patients achieving a response benefit with the combined regimen. In particular, ypCR rates were not increased among patients with more advanced tumors, nor in those with tumors located in the lower part of the rectum (data not shown).
These findings are unexpected. Oxaliplatin has been shown to increase tumor response when combined with fluorouracil in metastatic colorectal cancer7 and to be a potent radiosensitizing agent in preclinical studies.8 With our regimen, the cumulative dose delivered concurrent to radiation is also higher compared with other oxaliplatin-containing chemoradiotherapy schedules (360 v 200 to 260 mg/m2).16–18 Weekly administration, finally, might further enhance the inhibitory effect on the repair process of radiation-induced, sublethal DNA damage.19 ypCR rates in the 25% to 30% range were indeed reported in the phase I/II studies originally testing this regimen.9,20
The lower rate of ypCR observed in this randomized study likely reflects the larger sample size and the reduced impact of case selection and other variables that may affect response to preoperative chemoradiotherapy compared with phase II assessment. Accurate surgery, with more than 90% of patients having TME, a median of 12 examined lymph nodes, and rates of R0 resection among the highest reported in randomized trials, may have also contributed to the lower response rate compared with initial studies of this regimen.
Although slightly more patients did not start the assigned treatment and all compliance outcomes were significantly reduced in the group randomly assigned to receive oxaliplatin compared with the control group, the lower adherence to the treatment program is unlikely to explain the lack of response benefit. More than 80% of patients treated with oxaliplatin had in fact at least five administrations and more than 90% received at least 45 Gy. Moreover, ypCR rates were similar between the two arms also in exploratory analyses restricted to patients who received treatment as assigned and completed all the planned radiation and chemotherapy (data not shown).
The most likely explanation for the current results is therefore that, despite the preclinical rationale and promising phase II data, oxaliplatin is not a clinically effective radiation sensitizer, at least using the dose and regimen as described in this report. Findings from the recently reported Adjuvant Chemotherapy for Resected Colon Cancer at High Risk of Recurrence (ACCORD) 12/0405 Partenariat de Recherche en Oncologie Digestive (PRODIGE) 2 trial21 fully support this conclusion. In that study, a preoperative regimen of radiotherapy and capecitabine was compared with intensified preoperative radiotherapy and capecitabine plus weekly oxaliplatin on 598 patients with rectal cancer with eligibility requirements similar to those of our trial. Although ypCR rates were numerically increased in the oxaliplatin-containing arm, and other measures of primary tumor response were also improved, the difference in ypCR rates was small and did not reach statistical significance. In addition, these marginally positive effects could not be attributed to oxaliplatin because in the French trial, the radiotherapy dose was also increased in the experimental arm.
ypCR rates in the control arm seem to be higher in these two trials compared with those reported in less recent studies,1,3 probably as a result of optimized radiotherapy techniques and/or higher radiation doses.22,23 Continuous administration of the fluoropyrimidine during radiation treatment (protracted fluorouracil infusion in our study, oral capecitabine in the French study) may have also contributed to enhanced antitumor activity. It may thus be also hypothesized that optimal radiotherapy with optimal radiosensitization by fluoropyrimidines already maximizes local tumor responses with little (no) room for further improvement with the incorporation of additional radiosensitizing agents.
In these two trials, adding oxaliplatin to fluoropyrimidine-based chemoradiotherapy significantly increased acute toxicity, with rates of grade 3 to 4 events of approximately 24%. Although other studies addressing the same issue are still ongoing,24 the increased toxicity coupled with the lack of response benefit obtained in two phase III trials involving approximately 1,500 patients does not support regulatory acts extending the indications of oxaliplatin to the preoperative treatment of rectal cancer.25 These data also argue against the use of oxaliplatin/fluorouracil/radiotherapy as a platform for the incorporation of biologic agents in the treatment of this disease. Disappointing results have indeed been reported in multiple studies investigating bevacizumab or epidermal growth factor receptor inhibitors added to oxaliplatin-based preoperative chemoradiotherapy.26,27 Alternative strategies need to be developed for patients where maximum local response is necessary. Induction chemotherapy may optimize the delivery of (new) active drugs in the preoperative setting.28,29 Image-guided radiotherapy techniques allowing to increase the dose delivered to the tumor while sparing the surrounding normal tissues are also actively investigated.30–32
This study was primarily designed to show a survival improvement with the addition of oxaliplatin. This is based on the hypothesis that oxaliplatin might effectively treat systemic micrometastases. The lack of effect on primary tumor response does not preclude this goal. The oxaliplatin dose used in this study, selected to have potential systemic activity, may be higher than the optimal radiosensitizing dose. Excess toxicity may have thus counterbalanced any positive interaction with radiation. The biologic mechanisms responsible for systemic cytotoxicity and radiosensitization may also be different. In addition, in rectal cancer phase III trials, differences in long-term outcome do not seem to be predicted comparing ypCR rates between treatment arms.33 The lower frequency of extrapelvic metastases found at surgery in patients treated with oxaliplatin lends support to this hypothesis. This finding also suggests that this regimen may be part of the treatment strategy for patients with LARC and synchronous metastases at distant sites.
In summary, adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy has no effect on response of the primary rectal tumor and regional lymph nodes, at least with the weekly regimen used in this study. Single-agent fluoropyrimidine thus remains the standard chemotherapy in this setting. Follow-up is ongoing to assess the impact on efficacy end points. Mature data will also enable us to determine whether the reduced rates of early metastases found at surgery will translate into a benefit in long-term outcome. Molecular profiles are also being investigated to identify predictors of tumor response and/or long-term outcome and improve the knowledge of the biologic mechanisms underlying sensitivity or resistance to chemoradiotherapy in LARC.
Acknowledgment
Supported by a grant from sanofi-aventis. sanofi-aventis also provided the oxaliplatin for the study.
Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 29-June 3, 2009; and at the 11th World Congress on Gastrointestinal Cancers, Barcelona, Spain, June 24-27, 2009.
See accompanying editorial on page 2746; listen to the podcast by Dr Miksad at www.jco.org/podcasts
Written on behalf of the Studio Terapia Adiuvante Retto (STAR) Network investigators.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Carlo Aschele, sanofi-aventis (C), Roche (C), Amgen (C) Stock Ownership: None Honoraria: Carlo Aschele, sanofi-aventis, Roche; Salvatore Artale, Merck Serono, Novartis Research Funding: None Expert Testimony: None Other Remuneration: None
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Appendix
STAR Network Institutions and Investigators Participating in the Study
Ospedale S.Lazzaro, Alba (CN) (S. Camera, M. Franchini); Azienda USL 8, Arezzo (S. Borghesi, P. Ponticelli); C.R.O. Aviano (PN) (A. Buonadonna, A. De Paoli, R. Sigon); Ospedali Riuniti, Bergamo (G. Beretta, E. Sarti); Ospedale S.Orsola-Malpighi, Bologna (B. Cola, B. Iacopino, S. Pini, C. Pinto, L. Tardio); Ospedale S.Maurizio, Bolzano (C. Graiff, M. Petric, M. Wimmer); Ospedale di Camposampiero (PD) (R.Cavallo, F. Gaion, A. Morabito); Multimedica Castellanza (VA) (E. Bucci, P. Canino, G. Wizemann); Ospedale Garibaldi Nesima, Catania (S. Cordio, G. Giannone, F. Marletta); Ospedale Cervesi, Cattolica (RN) (G.L. Garulli, E. Pasquini); A.O. S.Croce e Carle, Cuneo (F. Borghi, C. Granetto, A. Melano); Presidio Ospedaliero di Faenza (R. Riccardi, S. Tamberi); Ospedale S.Croce, Fano (PU) (L. Landa, R. Mattioli); Ospedale di Feltre (BL) (G. De Carli, T. Iannone, R. Segati); Ospedali Galliera, Genova (C. Aschele, G. Binda, M.L. Vitali); Ospedale Mater Salutis, Legnago (VR) (A. Bonetti, F. Campostrini, F. Lanza); ASL 6 Livorno (M. Bosio, A. Falcone, M. Viti); A.O. Carlo Poma, Mantova (E. Aitini, A. Di Marco, L. Gerard); ASL 1 Massa Carrara (A. Del Freo, M. Lombardi, A. Tagliagambe); IRST, Meldola (FC) (M. Giannini, E. Lucci, P. Rosetti); Ospedale Niguarda Ca' Granda, Milano (S. Artale, F. Bracco, R. Pugliese); Ospedale San Paolo, Milano (P. Foa, R. Lazzari, E. Opocher); A.O.U. di Modena (F. Bertoni, G. Luppi, A. Rossi); Ospedale S.Gerardo, Monza (A. Bugatti, R.M. Niespolo, M. Vaghi); A.O.U. Maggiore della Carità, Novara (O. Alabiso, M. Garavoglia, M. Krengli); Istituto Oncologico Veneto, Padova (F. Bergamo, M.L. Friso, S. Lonardi, S. Pucciarelli); A.O. S.Chiara, Pisa (A. Cavazzana, A. Grandinetti, C. Laliscia, S. Ricci, S. Romeo); Ospedale S.Carlo, Potenza (V. Fusco, G. Rosati, G. Tramutola); Azienda USL, Ravenna (G. Cruciani, E. Emiliani, D. Guglielminetti); Ospedale Infermi, Rimini (G. Francioni, G. Oliviero, F. Perini); CROB, Rionero in Vulture (PZ) (A.M. Bochicchio, V. Fusco, G. La Torre); Ospedale S.Giovanni Calabita Fatebenefratelli, Roma (D.C. Corsi, M. Leone, A. Pilloni); Istituto Clinico Humanitas, Rozzano (MI) (M. Bignardi, R. Doci, M.C. Tronconi); Presidio Ospedaliero di Saronno (S. Bracelli, G. Samori, C. Verusio); AOVV, Sondrio (A. Bertolini, E. Menatti); Ospedale S.G. Moscati, Taranto (S. Pisconti, M. Saccò, G. Silvano); A.O. San Giovanni Battista–Molinette, Torino (L. Ciuffreda); Ospedale S.Chiara, Trento (G. Ambrosini, C. Eccher, G. Pani); A.O.U. S.Maria della Misericordia, Udine (G. Chiaulon, V. Durastante, N. Pella).
Information & Authors
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© 2011 by American Society of Clinical Oncology.
History
Published online: May 23, 2011
Published in print: July 10, 2011
Authors
Author Contributions
Conception and design: Carlo Aschele, Luca Cionini, Luca Boni
Administrative support: Sara Lonardi, Maurizio Gallo
Provision of study materials or patients: Carlo Aschele, Luca Cionini, Sara Lonardi, Carmine Pinto, Stefano Cordio, Gerardo Rosati, Salvatore Artale, Angiolo Tagliagambe, Giovanni Ambrosini, Paola Rosetti, Andrea Bonetti, Maria Emanuela Negru, Maria Chiara Tronconi, Gabriele Luppi, Giovanni Silvano, Domenico Cristiano Corsi, Anna Maria Bochicchio, Germana Chiaulon
Collection and assembly of data: Carlo Aschele, Luca Cionini, Sara Lonardi, Carmine Pinto, Stefano Cordio, Gerardo Rosati, Salvatore Artale, Angiolo Tagliagambe, Giovanni Ambrosini, Paola Rosetti, Andrea Bonetti, Maria Emanuela Negru, Maria Chiara Tronconi, Gabriele Luppi, Giovanni Silvano, Domenico Cristiano Corsi, Anna Maria Bochicchio, Germana Chiaulon, Maurizio Gallo, Luca Boni
Data analysis and interpretation: Carlo Aschele, Sara Lonardi,Luca Boni
Manuscript writing: All authors
Final approval of manuscript: All authors
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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. JCO 29, 2773-2780(2011).
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