A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer

The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3-4 N0-2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4-6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m(-2) day(-1) (n=3), 1000 mg m(-2) day(-1) (n=6), 1250 mg m(-2) day(-1) (n=3), 1650 mg m(-2) day(-1) (n=3), 1800 mg m(-2) day(-1) (n=8) and 2000 mg m(-2) day(-1) (n=5). The mean age was 62.3 years (range: 33-80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1-11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m(-2) day(-1) (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m(-2) day(-1) had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m(-2) day(-1) after reaching MTD. None of the eight patients at dose level 1800 mg m(-2) day(-1) developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m(-2) day(-1), given as 1000 mg m(-2) twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m(-2) day(-1) when given in this schedule.     

局部晚期低位直肠癌术前同步放化疗的疗效观察

目的 探讨术前同步放化疗治疗局部晚期低位直肠癌的安全性和有效性.方法 对临床分期属T3/T4低位直肠癌患者分为A组和B组.A组28例患者,给予术前放疗,同步口服卡培他滨.B组26例患者直接给予手术.结果 A组和B组根治术率分别为82.1％和50.0％ (P ＜0.01),保肛率分别为64.3％和26.9％ (P＜0.0...     

Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study

Background

Fluorouracil-based preoperative chemoradiotherapy has become the standard treatment for stage II/III rectal cancer. In order to improve the overall survival (OS) and disease-free survival (DFS), we added oxaliplatin to the standard treatment, and compared the effectiveness of these two treatment patterns.

Methods

A total of 206 patients enrolled in the prospective study had histologically confirmed rectal cancer of clinical stage II/III during July 2007 to July 2010. They were randomized into the experimental group received oxaliplatin and capecitabine in combination with radiotherapy, and the control group received capecitabine in combination with radiotherapy. All patients received surgery in 6−10 weeks after chemoradiotherapy and adjuvant chemotherapy with mFOLFOX6. The primary endpoints were DFS and OS, and the secondary endpoints included toxicity, compliance, and histopathological response.

Results

The 3-year OS in the experimental group and the control group was 90.29% vs. 86.41% (P>0.05), and the 3-year DFS was 80.58% vs. 69.90% (P>0.05). The pathological complete remission (pCR) rates were 23.30% and 19.42%, respectively (P=0.497). The 3-year local recurrence rates were 4.85% vs. 5.83% (P=0.694), and the 3-year distant metastasis rates were 16.50% and 28.16%, respectively (P=0.045). There were no significant differences in most grade 3−4 toxicities between two groups, however, grade 3−4 diarrhea occurred in 16.50% (17/103) of the experimental group, compared with 6.80% (7/103) of the control group (P=0.030). Also, the total grade 3−4 acute toxicity showed a significant difference (10.68% vs. 21.36%, P=0.037).

Conclusions

The experimental treatment did not lead significantly improved OS and DFS, and thus longer follow-up is warranted for our patient cohort. Adding oxaliplatin to capecitabine-based preoperative chemoradiotherapy can significantly reduce metastasis, but has only minimal impact on local recurrence. Although grade 3−4 toxicity rate increased (primarily gastrointestinal toxicity), patients can stand to be followed up with allopathic treatment.     

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m(-2) for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome.     

A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer

We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.     

Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study

The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4 + 5.4) Gy. Concurrently, irinotecan 40 mg m(-2) once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m(-2) twice daily were administered. Surgery was performed 4-6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand-foot syndrome at the 825 mg m(-2) dose level. The maximum tolerated dose of capecitabine was 750 mg m(-2). Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer.     

Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer

PURPOSE: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. RESULTS: Radiologic examination showed that tumor volume decreased by 68.2% +/- 20.5% in the FL group and 68.3% +/- 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). CONCLUSION: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.     

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer

Background:

Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT.

Methods:

Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment.

Results:

Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%.

Conclusions:

Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.     

Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.     

Clinical outcomes of mild hyperthermia for locally advanced rectal cancer treated with preoperative radiochemotherapy

Purpose: The aim of this report was to determine the impact of hyperthermia (HT) on preoperative radiochemotherapy for locally advanced rectal cancer.

Materials and methods: Between 1996 and 2007, 235 patients with locally advanced rectal cancer were treated with concurrent preoperative radiochemotherapy with or without HT. The total dose of radiotherapy was 39.6?Gy for 109 patients (group A) and 45?Gy for 126 patients (group B). Two or three cycles of chemotherapy were administered. Hyperthermia was given immediately after radiotherapy.

Results: In the HT subgroup of group A, more patients achieved down-staging of T stage when compared to the non-HT subgroup (57.9% versus 38%, p?=?0.047). For the cN+ subgroup of all patients, the number of patients with ypN+ were significantly less in the HT subgroup (25% versus 50%, p?=?0.022). In group A, HT appeared to reduce distant metastasis, increase disease-free survival, and improve overall survival.

Conclusions: HT seemed to increase the response of both primary tumour and lymph nodes to preoperative radiochemotherapy in patients with locally advanced rectal cancer. The relationship between increased response by HT and survival should be confirmed by a large prospective randomised trial.     

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy

Background:

Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.

Methods:

We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak''s tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.

Results:

Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found.

Conclusion:

Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.     

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.     

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2)

Background:

The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery.

Methods:

Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (⩽1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m⁻² b.i.d. and irinotecan 50 mg m⁻²; Dose level 2: capecitabine 650 mg m⁻² b.i.d. and irinotecan 60 mg m⁻²; Dose level 3: capecitabine 825 mg m⁻² b.i.d. and irinotecan 60 mg m²; Dose level 4: capecitabine 825 mg m⁻² b.i.d. and irinotecan 70 mg m⁻².

Results:

Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as ⩽1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%.

Conclusion:

In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m⁻² b.i.d. days 1–35 and weekly IV irinotecan at 60 mg m⁻² weeks 1–4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.