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Neoadjuvant Capecitabine and Oxaliplatin Followed by Synchronous Chemoradiation and Total Mesorectal Excision in Magnetic Resonance Imaging–Defined Poor-Risk Rectal Cancer
Abstract
To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) –defined poor-risk rectal cancer.
MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending ≥ 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine.
Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis.
Surgery is the primary modality for cure in rectal cancer. However, local recurrence rates of 25% to 40% have been reported after conventional resection.1,2 Despite a lack of randomized data comparing total mesorectal excision (TME) with conventional surgery, recurrence rates of less than 10%1,3-5 and superior survival1,6 have been reported with TME. In rectal cancer, involvement of the histologic circumferential resection margin (CRM), which is defined as tumor ≤ 1 mm from the resection margin, has been shown to be an important prognostic factor, resulting in both higher rates of local recurrence4,5,7-10 and poorer survival,4,7,8 even after TME surgery.11
In the Dutch study comparing TME with or without preoperative short-course (25 Gy in 5 fractions) radiotherapy (RT), preoperative RT significantly improved local control compared with TME alone without impacting on survival.12 More recently, preoperative long-course fluorouracil (FU) -based chemoradiotherapy (CRT) has been shown to significantly improve local control compared with either postoperative CRT13 or preoperative long-course RT (45 Gy in 25 fractions).14,15
We have previously demonstrated that neoadjuvant protracted venous infusion (PVI) FU and mitomycin (MMC) as a prelude to synchronous CRT can be administered with negligible risk of disease progression and low risk of systemic spread.16 This treatment strategy allowed R0 resection in 82% of patients with locally advanced rectal cancer, including patients with initial CRM involvement.
Oxaliplatin and infused FU/leucovorin (LV) is now considered as one of the standards of care in advanced colorectal cancer.17,18 The substitution of infused FU/LV by capecitabine has also been shown recently to be as efficacious when combined with oxaliplatin.19 Concomitant RT and oxaliplatin with either FU/LV or capecitabine can achieve pathologic complete response (pCR) rates of 15% to 28% in locally advanced rectal cancer.20-23 Therefore, in our current protocol, we substituted MMC and PVI FU with oxaliplatin and capecitabine during neoadjuvant chemotherapy and used capecitabine during CRT. This study represents, for the first time, the implementation of a preoperative treatment strategy based on magnetic resonance imaging (MRI) assessment on the potential resection margin and, in addition, a prolonged block of systemic-dose chemotherapy before synchronous CRT.
This study was approved by the local scientific and research ethics committee (Local Research Ethics Committee No. 1973). Signed written informed consent was obtained from each patient.
The eligibility criteria were as follows: MRI-defined poor-risk histologically proven adenocarcinoma of rectum; no previous chemotherapy or RT; no evidence of metastatic disease on clinical examination and computed tomography (CT) of chest, abdomen, and pelvis; WHO performance status of 0 to 2; and adequate hematologic (WBC count > 3 × 109/L, neutrophil > 1.5 × 109/L, and platelet > 100 × 109/L), renal (serum creatinine ≤ 1× upper limit of normal range or calculated creatinine clearance > 50 mL/min), and liver function (serum bilirubin < 1.5× upper limit of normal range). Before January 2004, only patients with clinically significant cardiac disease, arrhythmias, or angina pectoris were excluded. After a clinically significant frequency of cardiotoxicity was observed, the protocol was amended to exclude patients with previous history of stable angina, arrhythmia, and acute coronary syndrome even if controlled with medication or with myocardial infarction within the last 12 months. Hypertension was not an exclusion criterion.
Before entry onto the study, all patients were assessed by a multidisciplinary team comprising medical, radiation, and surgical oncologists, gastroenterologists, and radiologists. Patients were considered to have poor-risk disease on the basis of high-resolution, thin-slice (3 mm) MRIs of the pelvis, which were performed as previously described (Appendix).24,25 MRI criteria for poor-risk disease were as follows: tumor extending to within 1 mm of or beyond the mesorectal fascia (ie, CRM involved or threatened), T3 low-lying tumor at or below the levators, tumor extending 5 mm or more into perirectal fat, tumor invading surrounding structures or peritoneum (T4), and T1-4N2 tumors. Apart from MRI of the pelvis, all patients were required to have a CT scan of the chest, abdomen, and pelvis and carcinoembryonic antigen measurement.
Twelve weeks of neoadjuvant chemotherapy were administered. Oxaliplatin (130 mg/m2) was delivered every 3 weeks, and capecitabine was administered orally at a dose of 2,000 mg/m2/d divided into two split doses for 14 days followed by 7 days of rest repeated every 3 weeks. Dose adjustment was made in the event of toxicity, which was assessed according to National Cancer Institute Common Toxicity Criteria version 2.26
On completion of 12 weeks of neoadjuvant chemotherapy, patients began CRT. RT was delivered by a two-phase technique; both phases were conformally (CT) planned. Phase 1 delivered a total of 45 Gy in 25 daily fractions and encompassed the primary tumor and pelvic lymph nodes. During phase 2, the protocol aim was to deliver 9 Gy in 5 fractions covering the tumor, either clinically palpable or visible on imaging, with a 2-cm margin in all directions. Patients received concomitant capecitabine at a reduced dose of 1,650 mg/m2/d continuously without interruption. If patients already had dose reduction to capecitabine during neoadjuvant chemotherapy, the same proportional dose reduction was made during synchronous CRT.
TME was performed 6 weeks after the completion of CRT. The final choice of surgical procedure (abdominoperineal [AP] or anterior resection) was at the surgeons' discretion, although a recommendation was suggested by the multidisciplinary team.
After recovery from surgery, patients were to receive another 12 weeks of capecitabine at a dose of 2,500 mg/m2/d for 14 days followed by 7 days of rest.
Clinical tumor response was measured using MRI scans. MRI scans of the pelvis were repeated after neoadjuvant chemotherapy (week 12) and after synchronous CRT (week 22) to assess primary tumor response. All pre- and post-treatment MRI scans were reviewed independently by one radiologist (G.B.). The local T and N stage and tumor measurements were made according to previously published criteria.24 Radiologic tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors guidelines.27 CT scans of the chest, abdomen, and pelvis were repeated after CRT at 22 weeks (ie, 4 weeks after finishing RT) and after the final completion of postoperative capecitabine. The primary intention of CT scans was to exclude the development of distant metastases.
During neoadjuvant chemotherapy, particular inquiry was made regarding symptoms of rectal bleeding, pelvic pain/tenesmus, and diarrhea/constipation. Disappearance or attenuation of these tumor-related symptoms was recorded at each hospital visit. Data regarding the time between commencement of treatment and resolution of symptoms were collected weekly.
pCR was defined as the absence of any residual tumor cells detected in the resected specimen, and pCR was used as the primary end point in the study. Carefully matched whole-mount sections of the surgical specimen were made to correlate with the MRI findings and aid histologic interpretation (Appendix). Tumor specimens were examined for resection margin involvement. Tumor downstaging was defined as a reduction of at least one level in T or N staging (eg, T3 to T2 or N2 to N0).
This phase II study was originally designed using the optimal two-stage design.28 A pCR rate of 20% was considered acceptable (p1), and a pCR rate of 5% was ruled out as unacceptable (p0). In the first stage, if more than one patient achieved a pCR out of 21 patients, then the study would proceed to the second stage with a further 20 patients. If more than four patients responded of the total of 41 patients, then the treatment was considered suitable for further evaluation (one-sided α = .05, 90% power). At the end of the first stage, five patients had already achieved pCR, and therefore, this study was expanded using the Simon one-stage design with the Ahern exact P value28 to estimate more precisely the pCR rate. With a sample size of 60 patients, if seven or more patients achieved pCR, then the treatment would be considered suitable for evaluation in definitive phase III studies (one-sided α = .03, 96.9% power) because current standard FU-based preoperative CRT yields pCR rates of 8% to 11%.13,15
Failure-free survival (FFS) was calculated from the date of trial entry until disease progression, relapse, or death from any cause. Overall survival (OS) was calculated from the date of trial entry until death from any cause or censored at last follow-up. Both FFS and OS were estimated using the Kaplan-Meier method.29 All end points were updated in August 2005, and analyses were performed using SPSS package version 12 (SPSS Inc, Chicago, IL).
Between November 2001 and August 2004, 79 patients were recruited onto the study. Two patients were ineligible; one patient was ineligible because of metastatic bone disease at presentation demonstrated at radiology review, and the other patient could not receive protocol treatment as a result of deterioration in renal function. Table 1 lists the baseline characteristics.
Figure 1 shows the progress of all patients during the trial. Of the 77 eligible patients who commenced neoadjuvant oxaliplatin and capecitabine, nine patients did not finish the entire course of neoadjuvant chemotherapy. Three patients, who received neoadjuvant chemotherapy, omitted CRT and proceeded directly to surgery. Of these patients, one patient had a major response and developed bowel perforation after only one course of treatment. At surgery, no primary tumor could be identified, and histology showed residual focus in one lymph node only. Two other patients had favorable response to neoadjuvant chemotherapy and declined CRT. After CRT, two further patients declined AP resection, whereas another patient, who had a stroke and myocardial infarction during treatment, was considered unfit to undergo general anesthesia.
Table 2 lists the radiologic tumor responses. After neoadjuvant chemotherapy, the objective response rate was 88% (95% CI, 78% to 95%). After CRT, the objective response rate increased to 97% (95% CI, 90% to 100%). Overall, 86% of patients had an improvement in symptoms. Of the patients with symptoms, 71% had diminished pelvic pain/tenesmus, 90% had improvement in diarrhea/constipation, 100% had reduced rectal bleeding, and 93% had weight stabilization or weight gain. Table 3 lists the symptomatic improvement and time to complete resolution of symptoms. The median time to complete resolution of symptoms was 32 days (interquartile range, 21 to 68 days).
Forty-three patients underwent an anterior resection, and 24 underwent an AP resection. Three patients were still considered inoperable at laparotomy. Of the 67 patients who underwent TME, R0 resections were achieved in all but one patient (99%). pCR was observed in 16 patients (24%; 95% CI, 14% to 36%). In a further 32 patients (48%), only microscopic tumor foci were found. On an intent-to-treat basis, pCR was achieved in 16 (21%; 95% CI, 12% to 32%) of 77 patients. Compared with baseline MRI, 51 (76%) of 67 patients had downstaging of their primary tumor in T only (n = 13), N only (n = 14), or both T+N (n = 24) staging. Table 4 shows the comparison between baseline MRI and post-treatment histologic staging. In 16 (62%) of 26 patients, T3 tumors corresponded to only microscopic foci that were still through the muscularis propria. Thirty-two patients had low-lying tumors below the levator; 12 (38%) of these 32 patients had sphincter-saving surgery after our treatment program. Of the 18 patients who underwent AP resection, four were found to have pCR.
Table 5 lists the incidences of grade 3 to 5 toxicities during neoadjuvant chemotherapy and during CRT. Four deaths occurred during neoadjuvant chemotherapy. We observed a clinically significant occurrence of cardiac/thromboembolic (CTE) toxicity during neoadjuvant oxaliplatin/capecitabine, which led to three mortalities. This prompted our protocol amendment in January 2004 (see Patients and Methods). Table 6 shows an account of these CTE toxicities. Nine patients did not finish neoadjuvant chemotherapy; six patients did not finish because of CTE toxicity, one patient had neutropenic colitis leading to multiorgan failure and death, one patient had grade 4 diarrhea requiring defunctioning colostomy, and one patient had dramatic tumor response leading to bowel perforation, as mentioned previously.
With a median follow-up time of 23 months, the 1-year FFS rate was 87% (95% CI, 77% to 93%). Two local and eight distant recurrences (liver, n = 4; lung, n = 3; and peritoneum, n = 1) have been observed so far. The 1-year OS rate was 95% (95% CI, 87% to 98%). Figure 2 shows the FFS and OS for all eligible patients.
In this study, objective tumor responses were seen in 88% of patients after neoadjuvant oxaliplatin and capecitabine. Moreover, this was accompanied by rapid symptomatic relief occurring within a median of 32 days after commencement of neoadjuvant chemotherapy (ie, just over one cycle of treatment). The radiologic response rate further improved to 97% after synchronous CRT. R0 resection was achieved in 99% of patients. The pCR rate of 24% was encouraging considering the advanced nature of most patients' rectal cancer. With a prolonged 12-week block of full systemic-dose neoadjuvant chemotherapy before CRT, no disease progression was seen during preoperative treatment. Furthermore, preliminary survival data were encouraging, although further follow-up would be required to see whether reduction of distant metastasis and, thereby, improvement of OS can be achieved with this approach.
Our definition of poor-risk rectal cancer was based on several lines of evidence. First, CRM involvement in rectal cancer has been found to be a poor prognostic factor for both local recurrence and survival in patients who have TME.4,6,11 Second, T3 tumors extending more than 5 mm beyond the muscularis propria were shown to have a significantly higher locoregional recurrence rate and poorer 5-year cancer-specific survival.30 Third, patients with low-lying tumors requiring AP resections had higher rates of CRM involvement, more local recurrence, and poorer survival rates compared with patients undergoing anterior resection despite the use of TME.31 Finally, in a recent pooled analysis of five randomized rectal adjuvant studies, patients with T4 and N2 tumors had poorer survival despite the use of triple-modality (surgery, chemotherapy, and RT) treatment compared with patients with lower T and N staging.32 Therefore, our cohort of patients represented a group with particularly adverse outcomes who would require an aggressive preoperative treatment strategy. In our recent audit of new rectal cancer patients presenting to our cancer network,33 60% of patients with T3 tumors had tumors that extended less than 5 mm beyond the muscularis propria on baseline MRI. In addition, a third of patients with T1-2 tumors had N1 disease. All of these early T3 and N1 patients would have been included in other preoperative CRT trials, again illustrating our stringent criteria for distinctively poor-risk patients.
The use of MRI has been validated in previous studies,34,35 and the reproducibility and generalizability of this technique have been shown in a recent, multicenter, prospective magnetic resonance imaging and rectal cancer European equivalence study (MERCURY), which demonstrated statistical equivalence in measurement of tumor spread compared with the histopathologic gold standard.36 Moreover, there was good agreement between the central radiologist and the participating radiologists in our trial, reinforcing the fact that the MRI entry criteria used in our study can be adequately and reproducibly assessed by radiologists.
Several randomized studies have recently been reported evaluating the use of preoperative FU-based CRT. A German trial compared preoperative CRT with postoperative CRT.13 Although no disease-free survival (DFS) or OS differences were seen between the two arms, a significant reduction in local recurrence was seen with preoperative CRT. Two other studies performed by the European Organisation for Research and Treatment of Cancer14 and Fédération Francophone de Cancérologie Digestive15 compared preoperative CRT with preoperative RT alone. Preoperative CRT again resulted in lower local recurrence without any survival benefit. Interestingly, in all three studies, no impact was seen on distant metastasis with preoperative CRT. Two possible explanations for this observation were that the chemotherapeutic agents used in these studies (FU/LV) were administered at doses adequate only for radiosensitizing local effect but not adequate to have a systemic effect and that FU and LV were suboptimal chemotherapeutic agents.
In the adjuvant setting for colon cancer, both capecitabine and oxaliplatin have been shown to be equivalent or superior in DFS compared with bolus and/or infused FU/LV, respectively, although no significant OS improvement has been observed yet.37-39 The combination of oxaliplatin and capecitabine has shown promising clinical activity in advanced colorectal cancer40 and was noninferior compared with oxaliplatin/infused FU.19 Therefore, it was rational for us to investigate oxaliplatin and capecitabine as neoadjuvant chemotherapy. In our study, all patients underwent repeat MRI scans after neoadjuvant oxaliplatin/capecitabine and after synchronous CRT to assess response in the primary tumor. In our previous study, neoadjuvant PVI FU and MMC produced a response rate of 28% (95% CI, 14% to 45%),16 whereas oxaliplatin and capecitabine in this study produced a response rate of 88% (95% CI, 78% to 95%).
The pCR rate of 24% in this study was encouraging, and furthermore, another 48% of patients had only microscopic tumor foci seen on resected specimen, with clear pathologic CRM observed in all but one patient. The pathologic downstaging rate was 76%, probably understating the dramatic downsizing effect of our treatment program considering many patients had bulky disease before treatment. The degree of histologic tumor regression after preoperative CRT has been assessed in the German study.41 Complete and intermediate primary tumor (not including nodal) response was associated with improved DFS (P = .006), although in multivariate analyses, only pathologic nodal staging predicted DFS, local recurrence, and distant metastasis rates. Further follow-up in our group of patients with microscopic tumor foci might elucidate whether their outcome is similar to patients achieving pCR. Nevertheless, three patients remained inoperable after our treatment program. The majority of our patients had tumor involving the CRM before treatment, rendering curative resections precarious. Indeed, two of these three patients had good responses, leading to extensive extramural fibrosis on post-CRT MRI with loss of conventional resection planes. This resulted in fixation of pelvic structures, and surgical resection was not attempted.
Several phase I and II studies have evaluated oxaliplatin, FU/LV, and capecitabine in rectal cancer, with pCR rates of 15% to 28% found in larger phase II studies.20-23,42-50 These results were promising considering that preoperative FU-based CRT resulted in pCR rates of only 8% and 11.7% in the German13 and Fédération Francophone de Cancérologie Digestive15 studies, respectively. With the use of preoperative FU-based CRT and TME, 5-year local recurrence rates of 6% to 8% are now reported.13-15 The next big hurdle would be the reduction of distant metastasis and prolongation of survival. In our previous study assessing MMC and FU, distant metastasis occurred in 28% of patients after only 15 months, whereas in this study, distant metastasis was seen in 10% of patients with a follow-up time of 23 months.
We observed a clinically significant frequency of CTE toxicity during neoadjuvant chemotherapy, which resulted in three deaths, although we used the same dose schedule as a large, multicenter, phase II study that reported no increased CTE toxicity.40 At the start of our study, we included patients with medically controlled ischemic heart disease who would have been excluded in other phase III studies. Many of our patients had bulky pelvic tumor, increasing the risk for venous thromboembolism. However, there might also be under-reporting of CTE toxicities in other advanced colorectal cancer trials because investigators might attribute these events to the underlying disease rather than trial treatment. We have pooled the data from this study and another phase II study that used the same dose schedule of oxaliplatin/capecitabine in advanced colorectal cancer.51 Cardiotoxicity was observed in 6.5% of a cohort of 153 patients. The majority of these events occurred during the first cycle of treatment; thus, physicians and patients need to be aware of these complications so that discontinuation of treatment and the appropriate intervention may be instituted without delay. A further patient died from neutropenic colitis, again highlighting the need for initiating immediate supportive measures when diarrhea occurs, especially around the time of anticipated neutropenia. Neoadjuvant oxaliplatin and capecitabine therapy was not associated with any other unexpected increased incidence of toxicity, and it did not increase the frequency of severe adverse events during CRT in our study. Because of the low cumulative dose of oxaliplatin (520 mg/m2) used in our study, no grade ≥ 3 neurologic toxicity was seen.
In conclusion, capecitabine and oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection. In view of this promising activity, we are now conducting a multicenter randomized study using this treatment approach with or without cetuximab, which is a monoclonal antibody against the epidermal growth factor receptor.
MRI protocol. Scans were performed using 1.5T MRI scanners. The protocol used a thin 3-mm section turbo spin-echo T2-weighted technique using a surface pelvic phased-array coil. For all tumors, scans were performed perpendicular to the long axis of the tumor. Coronal imaging was performed for all tumors arising at or below the levator muscle origins. Images were stored in digital imaging and communications in medicine (DICOM) format on compact disc. No bowel preparation, air insufflation or intravenous antispasmodic agents were used. For a 1.5T MRI scanner, four sequences were used.
After a coronal localizer, sagittal scans were required from inner pelvic sidewall to sidewall using a 24-cm field of view, 5-mm contiguous/interleaved slices (no gap), and repetition time more than 2,500ms and less than 5,000ms (ms = 85). These acquisitions were used to plan thin-section oblique axial images. Axial T2FSE acquisitions of the anatomic pelvis were made by using a 24-cm field of view, a 5-mm contiguous section thickness, 4,000/85, 512 × 256 matrix, an echo train length of eight, no fat saturation, a 32 kHz bandwidth, and two signals acquisitions (2NEX). The sagittal T2-weighted images obtained were then used to plan T2-weighted thin-section axial images through the rectal cancer and adjacent perirectal tissues. These images were performed perpendicular to the long axis of the rectum. These were obtained by using a 16-cm field of view, a 3-mm section thickness, no intersection gap, 4,000/85, a 256 × 256 matrix, an echo train length of eight, no fat saturation, a 32 kHz bandwidth, and four acquisitions (4NEX).
Histologic examination. The surgical specimens were fixed by instilling formalin into the lumen of the intact rectum and floating the specimen in a vat of formalin. The specimen was serially sectioned transversely to retain the relationships between rectum and mesorectal surgical margins. The slices that included the area covering the location of the pretreatment tumor were selected for preparation of whole-mount sections.
Althoguh all authors completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
| Authors | Employment | Leadership | Consultant | Stock | Honoraria | Research Funds | Testimony | Other |
|---|---|---|---|---|---|---|---|---|
| Ian Chau | Roche (A); Sanofi-Aventis (A) | Roche (A); Sanofi-Aventis (A) | ||||||
| Gina Brown | Sanofi-Aventis (B) | |||||||
| David Cunningham | Roche (B); Sanofi-Aventis (B) | Roche (B); Sanofi-Aventis (B); Sanofi-Aventis (B) | ||||||
| Niall Tebbutt | Roche (A); Sanofi-Aventis (A) | Roche (A); Sanofi-Aventis (A) | ||||||
| Mark Hill | Roche (A); Sanofi-Aventis (A) | |||||||
| Paul J. Ross | Sanofi-Aventis (A) | Sanofi-Aventis (A) |
Dollar Amount Codes (A) <$10,000 (B) $10,000-99,999 (C) ≥$100,000 (N/R) Not Required
Conception and design: Ian Chau, Gina Brown, David Cunningham, Diana Tait, Andrew Wotherspoon, Andrew R. Norman, Niall Tebbutt
Administrative support: Alison Massey, Jacqueline Oates
Provision of study materials or patients: David Cunningham, Diana Tait, Mark Hill, Paul J. Ross
Collection and assembly of data: Ian Chau, Gina Brown, David Cunningham, Diana Tait, Andrew Wotherspoon, Andrew R. Norman, Alison Massey, Jacqueline Oates
Data analysis and interpretation: Ian Chau, Gina Brown, David Cunningham, Diana Tait, Andrew R. Norman, Niall Tebbutt, Mark Hill, Paul J. Ross
Manuscript writing: Ian Chau, Gina Brown, David Cunningham
Final approval of manuscript: Ian Chau, Gina Brown, David Cunningham, Diana Tait, Andrew Wotherspoon, Andrew R. Norman, Niall Tebbutt, Mark Hill, Paul J. Ross, Alison Massey, Jacqueline Oates
Fig 1. Trial progress. CRT, chemoradiotherapy; MI, myocardial infarction.
Fig 2. Failure-free survival (FFS) and overall survival (OS) for all eligible patients.
|
| Baseline Characteristic | Number of Patients (N = 77) | % | |
|---|---|---|---|
| Sex | |||
| Male | 41 | 53 | |
| Female | 36 | 47 | |
| Age, years | |||
| Median | 65 | ||
| Range | 36-82 | ||
| Performance status | |||
| 0 | 20 | 26 | |
| 1 | 55 | 71 | |
| 2 | 2 | 3 | |
| Poor-risk factors in rectal cancer as defined by MRI criteria | |||
| CRM threatened or involved, upper or mid rectal cancer | 40 | 52 | |
| Low-lying tumor at or below levators* | 32 | 42 | |
| Tumor extending 5 mm or more into perirectal fat | 32 | 42 | |
| Tumor invading surrounding structures or peritoneum, T4 | 18 | 23 | |
| T1-4N2 tumor | 27 | 35 | |
Abbreviations: MRI, magnetic resonance imaging; CRM, circumferential resection margin.
*Some of these tumors were also considered to be threatening the CRM.
|
| Response | After Chemotherapy (n = 68) | After Chemoradiation (n = 70) | ||||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |||
| Complete response | 3 | 4 | 14 | 20 | ||
| Partial response | 57 | 84 | 54 | 77 | ||
| Stable disease | 8 | 12 | 2 | 3 | ||
| Progressive disease | 0 | 0 | 0 | 0 | ||
| Objective response rate, % | 88 | 97 | ||||
| 95% CI | 78 to 95 | 90 to 100 | ||||
|
| Symptom | No. of Patients With Symptoms at Baseline | No. of Patients Without Symptoms After Treatment | % of Patients With Resolution of Symptoms | Median Time to Resolution of Symptoms (days) |
|---|---|---|---|---|
| Pelvic pain/tenesmus | 45 | 32 | 71 | 66 |
| Diarrhea/constipation | 50 | 45 | 90 | 44 |
| Rectal bleeding | 27 | 27 | 100 | 7 |
| Weight loss | 14 | 13 | 93 | 21 |
|
| Baseline Staging | Pathologic Staging (n = 67) | Pathologic Node Negative | Pathologic Node Positive | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| pT0 | pT1 | pT2 | pT3 | pT4 | |||||||
| T2 | 0 | 0 | 3 | 0 | 0 | ||||||
| T3 | 12 | 5 | 7 | 26* | 1 | ||||||
| T4 | 6 | 0 | 2 | 5 | 0 | ||||||
| Node negative | 15 | 5† | |||||||||
| Node positive | 29‡ | 18§ | |||||||||
*In 16 patients, T3 tumors corresponded to only microscopic foci that were still through the muscularis propria.
†Microscopic nodal deposits beyond resolution of magnetic resonance imaging.
‡Thirteen patients had nodal downstaging from N2 to N0.
§Seven patients had nodal downstaging from N2 to N1.
|
| Toxicity | No. of Patients | % |
|---|---|---|
| During neoadjuvant chemotherapy, n = 77 | ||
| Anemia | 1 | 1 |
| Neutropenia | 1 | 1 |
| Thrombocytopenia | 1 | 1 |
| Diarrhea | 9 | 12 |
| Stomatitis | 0 | 0 |
| Nausea and vomiting | 2 | 3 |
| Hand-foot syndrome | 2 | 3 |
| Infection | 1 | 1 |
| Febrile neutropenia | 0 | 0 |
| Neuropathy | 0 | 0 |
| Cardiac/thromboembolic toxicity | 8 | 10 |
| During chemoradiation, n = 70 | ||
| Anemia | 0 | 0 |
| Neutropenia | 4 | 6 |
| Thrombocytopenia | 1 | 1 |
| Lower GI | 3 | 4 |
| Genitourinary | 2 | 3 |
| Skin | 30 | 43 |
|
| Toxicity | No. of Patients | ||||
|---|---|---|---|---|---|
| Fatal | Nonfatal | Total | |||
| Myocardial infarction | 1 | 1 | 2 | ||
| Arrhythmia | 0 | 2 | 2 | ||
| Angina | 0 | 2 | 2 | ||
| Cardiac failure | 1 | 0 | 1 | ||
| Stroke | 0 | 1 | 1 | ||
| Pulmonary embolism | 1 | 0 | 1 | ||
*One patient had more than one toxic event.
Supported by an education grant from Sanofi-Aventis.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; and the 2nd Annual Gastrointestinal Cancers Symposium, Miami, FL, January 27-29, 2005.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
We express special thanks to all members of the Royal Marsden Hospital Rectal Cancer Study Group (in alphabetical order): Medical oncologists: D. Cunningham (Royal Marsden Hospital, London and Surrey), M. Hill (Royal Marsden Hospital, Surrey), and P. Ross (Royal Marsden Hospital, Surrey); Radiation oncologist: D. Tait (Royal Marsden Hospital, London and Surrey); Surgeons: M. Abulafi (Mayday University Hospital, Croydon), N. Bett (St Helier Hospital, Cashalton), I. Daniels (Pelican Cancer Foundation), R.J. Heald (Pelican Cancer Foundation), M. Henry (Royal Marsden Hospital, London), S. Fahrat (St Helier Hospital, Cashalton), D. Kumar (St George's Hospital, London), R. Leicester (St George's Hospital, London), M.A. Raja (Epsom General Hospital, Epsom), I. Swift (Mayday University Hospital, Croydon), and P. Toomey (Epsom General Hospital, Epsom); Pathologists: A. Arnaout (Mayday University Hospital, Croydon), L. Temple (Epsom General Hospital, Epsom), S. Sampson (St Helier Hospital, Cashalton), and A. Wotherspoon (Royal Marsden Hospital, London); Radiologists: N. Bees (Mayday University Hospital, Croydon), H. Blake (Mayday University Hospital, Croydon), G. Brown (Royal Marsden Hospital, London and Surrey), P. Bryne (Epsom and St Helier National Health Service Trust), C. George (Epsom and St Helier National Health Service Trust), N. Jeyadevan (Mayday University Hospital, Croydon), and M. Koh (Royal Marsden Hospital, London and Surrey); Gastroenterologists: J. Andreyev (Chelsea and Westminster Hospital, London) and M. Benson (St Helier Hospital, Carshalton).
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