Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: A phase II trial☆
Article Outline
- Abstract
- Materials and methods
- Results
- Discussion
- Conclusion
- Conflict of interest statement
- Acknowledgment
- Appendix A. Supplementary data
- References
- Copyright
Abstract
Purpose
We aimed to assess the safety and efficacy of preoperative intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced mid-low rectal cancer using a concomitant boost technique.
Materials and methods
Patients with resectable locally advanced mid-low rectal cancer (node-negative ⩾T3 or any node-positive tumor) were eligible. The eligible patients received IMRT to 2 dose levels simultaneously (50.6 and 41.8
Gy in 22 fractions) with concurrent capecitabine 825mg/m2 twice daily 5days/week. The primary end point included toxicity, postoperative complication, and pathological complete response rate (ypCR). The secondary endpoints included local recurrence rate, progression-free survival (PFS), and overall survival (OS).
Results
Sixty-three eligible patients were enrolled; five patients did not undergo surgery. Of the 58 patients evaluable for pathologic response, the ypCR rate was 31.0% (95% CI 19.1–42.9). Grade 3 toxicities included diarrhea (9.5%), radiation dermatitis (3.2%), and neutropenia (1.6%). There was no Grade 4 toxicity reported. Four (6.9%) patients developed postoperative complications. Two-year local recurrence rate, PFS, and OS were 5.7%, 90.5%, and 96.0%, respectively.
Conclusions
The design of preoperative concurrent boost IMRT with oral capecitabine could achieve high rate of ypCR with an acceptable toxicity profile.
Keywords: Intensity-modulated radiotherapy, Capecitabine, Rectal cancer
While surgery remains the most important treatment for rectal cancer, local recurrence is still a serious problem after conventional surgery [1], [2]. Total mesorectal excision (TME) has been widely used for rectal cancer, and has been shown to reduce local recurrence rates to less than 10% [3], [4], [5], likely due to improved circumferential margins. Nevertheless, a large previous trial has also confirmed that preoperative radiotherapy could further improve the local control rate in patients who had undergone a standardized total mesorectal excision [6].
Compared with preoperative radiotherapy alone, the addition of 5-fluorouracil (5-FU) could further increase the pathologic complete response rate (ypCR) and local control [7], [8]. There is also emerging evidence that ypCR is a strong positive prognostic factor [9]. Recent studies have demonstrated that the oral fluoropyrimidine, capecitabine, may be comparable with intravenous 5-FU in neoadjuvant treatment of rectal cancer, with the advantage of oral administration [10], [11], [12].
Dose escalation studies have suggested that increasing radiation doses can improve pathological complete response rates. However, the proximity of critical structures (e.g. small bowel, bladder, and femoral heads) to the target volumes usually limits the dose which can be safely delivered by standard three-dimensional conformal radiotherapy (3DCRT) techniques. Intensity-modulated radiotherapy (IMRT) is increasingly being used to treat gross tumor with greater accuracy but with potentially less damage to normal tissue compared to 3DCRT. While a study had previously suggested the feasibility of preoperative accelerated IMRT with capecitabine [13], with only eight evaluable patients recruited, conclusions cannot be drawn. The aim of this trial was to evaluate whether the combination of IMRT with a concomitant boost technique with capecitabine could achieve high rate of ypCR with tolerable toxicities. This prospective trial was launched in 2007 in Beijing Cancer Hospital. Here, we report the results of the efficacy and safety of this new combining strategy, including local recurrence rate, progression-free survival (PFS), and overall survival (OS).
Materials and methods
Patients
This trial was approved by the ethics committee of Beijing Cancer Hospital in 2007, in accordance with the Helsinki Declaration. All patients had given informed consent before recruitment. Pre-treatment evaluation included a complete history, physical examination, complete laboratory tests, and pre-operative staging. Complete laboratory tests included complete blood counts, urine and stool analysis, liver and kidney function tests, and gastrointestinal tumor markers. Pre-operative staging included total colonoscopy, chest X-ray, abdominal ultrasound, and pelvic computed tomography (CT) scans. Endoscopic ultrasound (EUS), and/or pelvic magnetic resonance imaging (MRI) scans were used to determine the clinical T/N (cT/N) classification. In cases of staging discrepancy between the two modalities, the higher stage was recorded. The 6th edition of TNM staging standard of American Joint Committee on Cancer (AJCC) was utilized.
Eligibility criteriaAll patients had histologically confirmed rectal adenocarcinoma within 10cm from the anal verge, with no evidence of distant metastases. The T/N classification was stage T3 or resectable (surgery deemed possible to achieve a R0 or R1 resection) T4 with any N, or any T with N1 or N2 disease. Patients presenting with T2N0 tumors located within 5cm from the anal verge could also be included. The age at diagnosis was between 18 and 75years. Patients were also required to have a World Health Organization (WHO) performance status of 0 or 1 with adequate liver, kidney, and bone marrow function.
Patients who had prior history of chemotherapy or pelvic radiation therapy were excluded. Patients with a history of other malignancy within 5years were also excluded. Other exclusion criteria included acute obstructive symptoms, unresectable disease, sensitivity to fluoropyrimidines, or any serious comorbidities deemed not suitable to receive chemoradiotherapy.
Treatment
This trial was a single-arm, non-randomized single-institution prospective trial of preoperative concomitant boost IMRT combined with capecitabine in patients with T3–4/N+, resectable, mid-low primary rectal cancer.
Patients underwent CT-based simulation with 5mm slices, in the prone position with a full bladder. The scan extended from the L2 vertebral body to below the perineum. Intravenous contrast was used in all patients. A custom immobilization device was used to minimize setup variability. Daily patient positioning was performed using skin marks and weekly portal films. The gross target volumes (GTV) and clinical target volumes (CTV) were contoured on axial CT scan slices. GTV was defined as primary tumor (including the mesorectal space around primary tumor) and involved lymph nodes. The CTV was defined as primary tumor, mesorectal region, presacral region, mesorectal lymph nodes, lateral lymph nodes, internal iliac lymph node chain, and pelvic wall area [14]. The external iliac lymph nodes were considered part of the CTV when anterior organ involvement was suspected and the inguinal lymph nodes were included only when the tumor was invading the lower third of the vagina or when there was major tumor extension into the internal and external anal sphincter. The superior border of pelvic fields was the L5–S1 interspace, and the inferior border was the bottom of the obturator foramen or the anal verge for low-lying tumors. The radiation dose was prescribed to planning target volumes (PTV). The PTVs of the GTV and CTV were created by adding a 5mm margin.
Concomitant boost IMRT consisted of two dose levels: PTVs to GTV and CTV received 50.6 and 41.8Gy, respectively, with 10MV photons. Treatment was delivered in 22 fractions of 2.3 and 1.9Gy, respectively, five times per week over 30days. The boost to the primary tumor (GTV) would be administered synchronously with the whole pelvis (CTV) radiotherapy. The 95% isodose line was planned to encompass the 95% PTV as a planning objective. Five-field dynamic IMRT technique was used to shape the fields. The small bowel, bladder, and femoral heads were contoured and designated as organs at risk. For the bladder, the constraints were that no more than 50% of the volume should receive more than 25Gy, and no more 20% of the volume should receive more than 45Gy. According to previous reports [15], [16], the constraints for the small bowel were that no more than 150cm3 of the volume should receive more than 15Gy, no more than 80cm3 should receive more than 45Gy, and no more than 20cm3 should receive more than 50Gy. The constraints of femoral head were that no more than 50% of the volume should receive more than 20Gy, and no more than 20% of the volume should receive more than 30Gy.
Capecitabine was administered at a dose level of 825mg/m2 orally twice daily, 5days/week during radiotherapy. Dose reductions recommendations were as follows:mg/m2 orally twice daily, 5days/week; if the patients experienced Grade 2 hematologic toxicities again, oral capecitabine would be stopped, with the radiotherapy being continued alone. For Grade 3/4 hematologic toxicities, concurrent chemoradiotherapy would be interrupted until toxicity resolved to Grade 1/2, then chemoradiotherapy would resume with a dose reduction of capecitabine to 400mg/m2; if patients experienced Grade 3 hematologic toxicities again, concurrent chemoradiotherapy would be interrupted until toxicity resolved to Grade 1/2, then oral capecitabine would be stopped, with the patient continuing radiotherapy alone; if the patient with radiotherapy alone experienced Grade 3 hematologic toxicities, radiotherapy would also be stopped early.mg/m2. For Grade 4 non-hematologic toxicities except diarrhea, capecitabine would be abandoned, with radiotherapy continuing alone. For Grade 4 diarrhea, concurrent chemoradiotherapy would be interrupted until toxicity resolves to Grade 2/3, and then radiotherapy would be resumed without capecitabine.
All patients underwent reassessment of clinical staging and resectability by surgeons before surgery, with total colonoscopy and pelvic EUS/MRI. The resectable patients received TME 6–8weeks after completion of chemoradiotherapy. The choice between abdominoperineal resection and anterior resection was left to the discretion of the attending surgeon. Patients with low rectal cancer (defined as ⩽5cm from the anal verge) undergoing sphincter-preserving surgery would also receive prophylactic ileostomy. These patients would also undergo colonoscopy before ileostomy closure 3months after surgery. Administration of adjuvant chemotherapy was individualized, with no specific recommendations.
Study endpoints
The primary endpoint included toxicity, postoperative complications (within 30days of surgery) and pathological complete response (ypCR) rates. ypCR was defined as Grade 4 according to the Dworak classification system [17], [18], where 0=no regression; 1=dominant tumor mass with obvious fibrosis and/or vasculopathy (<25% tumor regression); 2=dominantly fibrotic changes with few tumor cells or groups (26–50% tumor regression); 3=very few (difficult-to-find microscopically) tumor cells in fibrotic tissue with or without mucous substance (>50% tumor regression); and 4=no tumor cells, only fibrotic mass. The secondary endpoints included local recurrence rate, PFS, and OS.
Follow-up
All patients were evaluated weekly for adverse events during the chemoradiotherapy. Patients were then evaluated every 3months for the first year, every 6months for the second and third year, and annually for the fourth and fifth years. Post-treatment follow-up included measurement of complete blood counts, liver and kidney function, and gastrointestinal tumor markers. The patients would also receive chest X-ray, abdominal ultrasound, pelvic CT scans for follow-up. Toxicities were analyzed according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0.
Statistical analysis
According to Fleming and A’Hern’s one-stage phase II design [19], [20], a sample size of 57 was required to accept the hypothesis that the pCR rate was greater than 30% with 85% power and to reject the hypothesis that the pCR rate was less than or equal to 15% with 5% significance. On the basis of the assumption that 10% of the patients were not assessable, we planned to enroll 63 patients in this study.
OS was calculated from the date of trial entry to the date of death from any cause or to the date of last follow-up. PFS was calculated from the date of study entry until disease progression (recurrence, metastasis, or death from any cause). We used the Kaplan–Meier method to estimate OS and PFS. The log-rank test was used to test the significance level, with a value of P⩽0.05 considered to be statistically significant. We undertook analyses with SPSS 11.5 statistical software (SPSS Inc., Chicago, IL).
Results
Between May 2007 and December 2009, a total of 63 eligible patients received preoperative IMRT combined with oral capecitabine. Five patients withdrew from the study after the completion of chemoradiotherapy: two had complete clinical response and three declined abdominoperineal resection. Fig. 1 shows the trial profile, and Table 1 lists the patient characteristics. The median follow-up time was 22.5months (range=9.7–42.3months).
Fig. 1.
Trial profile. Abbreviations: CRT, combination of concurrent boost intensity-modulated radiotherapy (GTV 50.6
Gy/22 fractions, CTV 41.8Gy/22 fractions) with capecitabine (825mg/m2 twice daily 5days/week); TME, total mesorectal excision.
Table 1. Patient characteristics (n=63).
| Characteristic | Data |
|---|---|
| Gender [n (%)] | |
| Male | 41 (65.1) |
| Female | 22 (34.9) |
| Age [median (range)] (years) | 58 (25–75) |
| ECOG PS [n (%)] | |
| 0 | 13 (20.6) |
| 1 | 50 (79.4) |
| cTumor stagea [n (%)] | |
| T2 | 3 (4.8) |
| T3 | 54 (85.7) |
| T4 | 6 (9.5) |
| cNode stagea [n (%)] | |
| N0 | 11 (17.5) |
| N1 | 18 (28.6) |
| N2 | 34 (53.9) |
| Tumor differentiation [n (%)] | |
| Well differentiated | 15 (23.8) |
| Moderately differentiated | 31 (49.2) |
| Poorly differentiated | 6 (9.5) |
| Uncertain differentiation type | 11 (17.5) |
| Distance from anal verge [n (%)] (cm) | |
| ⩽5 | 54 (85.7) |
| 5.1–10 | 9 (14.3) |
| Median distance (cm) | 4.0 |
aEndoscopic ultrasound and/or pelvic magnetic resonance imaging was used to decide the clinical T/N stage. The higher stage was taken into consideration. |
Toxicity during chemoradiation
A total of 63 patients were available for toxicity evaluation. Grade 3 toxicities included diarrhea (six patients, 9.5%), radiation dermatitis (two patients, 3.2%), and neutropenia (one patient, 1.6%). There was no Grade 4 toxicity reported. For the six patients with Grade 3 diarrhea, the dose of capecitabine was reduced to 400mg/m2, and they finished the subsequent treatment. For the one with Grade 3 neutropenia after two weeks of chemoradiotherapy, the chemoradiotherapy was interrupted until toxicity resolved to Grade 1, and the dose of capecitabine was also reduced to 400mg/m2 in the subsequent treatment. All 63 patients completed the planned radiotherapy treatment.
Surgical procedure and complications
Surgery was performed after a median interval of 50.5days (range=27–73days). Of the 58 patients who underwent TME, 41 (70.7%) patients received low anterior resection and the remaining patients received abdominoperineal resection. Of the 50 patients with low rectal cancer (⩽5cm from anal verge), 33 patients received prophylactic ileostomy with sphincter-preserving surgery. The sphincter preservation rate for the low rectal patients was 66% (33 out of 50). All primary tumor resections had negative proximal, distal, and radial margins (R0 resections).
Four (6.9%) patients developed post-operative complications, which consisted of two patients with rectovaginal fistulae and two patients with anastomotic fistulae (all of whom required surgical intervention). None developed post-operative infection.
Pathologic response
Pathologic analysis was performed on 58 eligible patients. According to the Dworak classification system for pathologic downstaging, there were 19, 9, 11, 13, and 6 patients with a score of 4, 3, 2, 1, and 0, respectively (Table 2). Comparison of pre-chemoradiation clinical (c) stages with post-operative pathologic (yp) stages is shown in Table 2. Down-staging of the primary tumor and lymph nodes was observed in 33 (56.9%) and 38 (79.2%) patients, respectively. The total tumor down-staging rate was 79.3% (46/58). The primary tumor ypCR (ypT0) rate was 32.8% (19/58), of whom one still had persistent lymphadenopathy. The nodal ypCR rate of cN+ patients was 68.8% (33/48). The total ypCR (ypT0N0M0) rate was 31.0% (18/58) (95% CI 19.1–42.9).
Table 2. Change of T/N staging and TRG.
| pT0 | pT1 | pT2 | pT3 | pT4 | pN0 | pN1 | pN2 | |
|---|---|---|---|---|---|---|---|---|
| Clinical staging | ||||||||
| cT2 | 3 | 0 | 0 | 0 | 0 | – | – | – |
| cT3 | 16 | 1 | 10 | 24 | 0 | – | – | – |
| cT4 | 0 | 0 | 1 | 2 | 1 | – | – | – |
| T downstaging | 33/58 (56.9%) | |||||||
| cN0 | – | – | – | – | – | 10 | 0 | 0 |
| cN1 | – | – | – | – | – | 12 | 3 | 1 |
| cN2 | – | – | – | – | – | 21 | 5 | 6 |
| N downstaging | 38/48 (79.2%) | |||||||
| Total downstaging | 46/58 (79.3%) | |||||||
| ypCR | 18/58 (31.0%) | |||||||
| TRG 4 (complete regression)a | 19 (32.8%) | |||||||
| TRG 3 (>50% tumor regression) | 9 (15.5%) | |||||||
| TRG 2 (26–50% tumor regression) | 11 (19.0%) | |||||||
| TRG 1 (<25% tumor regression) | 13 (22.4%) | |||||||
| TRG 0 (no regression) | 6 (10.3%) | |||||||
aThe primary tumor ypCR (ypT0) rate. |
Adjuvant chemotherapy
Twenty-seven of 58 patients received adjuvant chemotherapy. Of the 15 patients with pathologically confirmed positive lymph node (ypN+) disease, 12 (80%) received adjuvant chemotherapy. There was no significant difference in the 2-year OS (95.8 vs. 95.7; P=0.688) or PFS (86.3 vs. 92.4; P=0.674) between patients with or without adjuvant chemotherapy.
Progression-free survival and overall survival
All 63 patients were included in the survival analysis on an intent-to-treat basis. To date, two patients have died from disease progression. There were five locoregional relapses and three systemic relapses (two with liver metastases and one with both bone and brain metastases). The 2-year cumulative local recurrence rate was 5.7%. Two-year PFS and OS for the entire cohort was 90.5% (95% CI 82.5–98.5) and 96.0% (95% CI 90.5–100.0), respectively (Fig. 2). Two-year PFS was 94.4% and 67.9% in the pathological down-staging group and the non-pathological down-staging group, respectively (P=0.039); and 2-year OS was 97.1% and 91.7% in these two groups, respectively (P=0.324).
Fig. 2.
Kaplan–Meier survival curves.
Discussion
The aim of this trial was to achieve good ypCR rates with tolerable toxicities. The results show the feasibility of this multi-modality strategy with a high ypCR rate and a low rate of ⩾Grade 3 toxicities.
For locally advanced rectal cancer, infused 5-FU, and oral fluoropyrimidines remain the standard agents to combine with preoperative radiotherapy [21]. The feasibility of preoperative accelerated IMRT with capecitabine had been confirmed by a previous study [13]. However, it was a small phase II trial with only 8 evaluable patients for analysis. The total dose of 55Gy to the gross tumor was higher than that in our study, which may have contributed to the high rate of Grade 4 diarrhea. Another similar trial design using hypofractionated radiotherapy and capecitabine in a phase I setting had shown unacceptable toxicity using a higher radiation dose to the gross tumor and a higher capecitabine dose than our study [22]. This suggests that our treatment schedule may have been a good compromise between efficacy and tolerability.
A retrospective review has shown that capecitabine, when compared to infusional 5-fluorouracil, seems to have superior efficacy with reasonable toxicities [10]. Long-term results from a randomized phase II trial adds further evidence that capecitabine-based preoperative chemoradiotherapy is a feasible treatment option for locally advanced rectal cancer [12]. Considering the comparable response with low toxicity, and convenience in the preoperative chemoradiotherapy setting, oral capecitabine has been widely used for preoperative chemoradiotherapy studies [10], [11], [12], [13], [23].
In order to achieve more benefit from preoperative treatment, some trials were designed to add new agent to standard FU-based preoperative chemoradiotherapy [23], [24]. However, most results have been discouraging, with increased toxicity rates without strong evidence of improved efficacy [23], [25], [26]. In our trial, we attempted to achieve better outcomes by improving the radiotherapy technique and optimizing dose distributions. Our ypCR rate of 31% is higher than many other trials, with manageable toxicities (⩾Grade 3 toxicity, 14.3%). Additionally, using oral capecitabine alone without intravenous therapy would increase patients’ convenience and compliance, and allow the entire treatment to be carried out in the out-patient setting, an advantage for cost- or space-constrained practices.
One notable aspect of our study is the utilization of concurrent boost IMRT with the prescription dose of 50.6 and 41.8Gy in 22 fractions over 30days to the GTV and CTV, respectively. According to Fowler and Jones [27], [28], our protocol delivers a higher biologically equivalent dose (BED) of 48.4Gy to the GTV, compared to the standard schedule of 50.4Gy in 28 fractions over 38days, which has a lower BED of 40.9Gy. By the same calculation, the CTV BED is similar at 35.9Gy and 37.5Gy for the experimental schedule of 41.8Gy in 22 fractions and the standard schedule of 45Gy in 25 fractions, respectively. This increase in BED to the GTV but not the CTV could possibly have contributed to the high rate of ypCR in this trial, without incurring additional normal tissue toxicity. Another phase II trial using hyperfractionated accelerated radiotherapy achieved a 5-year actuarial local control rate of 91.7% [29]. Its fractionation schedule was designed to keep the overall treatment time as short as possible. Additional evidence of the benefit of pre-operative radiotherapy dose intensification also comes from the Studio Terapia Adiuvante Retto (STAR) and ACCORD 12/0405 Prodige 2 trials [23], [25], which is consistent with our results.
A randomised trial showed that conventionally fractionated chemoradiotherapy did not result in an increased sphincter preservation rate in comparison with short-term preoperative radiotherapy [30]. However, surgical decision-making based on pre-therapy tumor volume, short interval between radiation and surgery, and patient-related factors might have contributed to this result [31]. For patients with low rectal cancer (⩽5cm) in our trial, the sphincter-preserving rate was 66%, comparable with previous trials with capecitabine or 5-FU [13], [32], [33], [34]. All of these patients underwent prophylactic ileostomy surgery in order to prevent possible post-operative complications. Though the published evidence for prophylactic ileostomy is not strong, our low postoperative complication rate (6.9%) suggests that there could be some benefit.
The acute Grade 3 toxicity rate of 14.3% suggests that this combination was well tolerated. While increasing dose to the gross tumor could incur a higher risk for diarrhea, only 9.5% of patients experienced Grade 3 diarrhea. Other trials [26], [32] had shown Grade 3 hand-foot syndrome, which was mainly caused by oral capecitabine. However, the main Grade 3 toxicities in our trial were diarrhea, rarely radiation dermatitis and neutropenia. No patient had Grade 4 toxicity. The low acute toxicity might be related to taking lower capecitabine dose and applying the technique of IMRT. Surgical complications were an important concern for this new combination. In the trial, two patients developed rectovaginal fistulae and another two developed anastomotic fistulae, requiring surgery. This compares favorably with other studies, such as that by Sauer et al., where the rate of anastomotic leakage of any grade is 11% [33].
This trial had shown high ypCR rate of 31.0%. Of the 18 patients with ypCR, one patient died of disease progression (bone and brain metastasis) and another developed liver metastasis after 3years. There is a significant difference in the 2-year PFS for patients who were down-staged vs. those who were not (P=0.039), though not for 2-year OS. Similar to the findings of Capirci et al., the results thus far suggest that ypCR could be an important prognostic factor for long term outcome [9]. The 2-year PFS and OS in our trial is also encouraging (90.5% and 96.0%, respectively).
However, the limitations of our study should also be noted. Firstly, three patients with low rectal cancer presenting with cT2N0 were included in our trial, with the aim of sphincter preservation. All of them had ypCR, and 2 of them underwent sphincter-preserving surgery. Additionally, the follow-up is relatively short, and longer follow-up would be required to assess whether the high rate of ypCR could translate into benefits in PFS and OS.
Conclusion
The results of preoperative concomitant boost IMRT combined with oral capecitabine in patients with locally advanced, resectable mid-low primary rectal cancer showed encouraging rates of ypCR, tumor downstaging, and sphincter preservation with excellent tolerance. Longer follow-up is needed to confirm the improvement of PFS and OS. A phase III study based on this design would be warranted.
Conflict of interest statement
The authors indicate no potential conflict of interest.
Acknowledgment
This work was supported by the Beijing Cancer Hospital Funding.
Appendix A. Supplementary data
Supplementary data 1.
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☆ This trial is registered with chictr.org. Trial registry number: ChiCTR-TNC-10001094.
PII: S0167-8140(11)00408-7
doi:10.1016/j.radonc.2011.07.030
© 2011 Elsevier Ireland Ltd. All rights reserved.
