Departments of 1 Medical Oncology, 2 Radiotherapy and 3 Surgery, Padova University Hospital, Padova; 4 Clinical Epidemiology Unit, Regional Cancer Centre, Padova University Hospital, Padova; 5 Department of Medical Oncology and Cancer Prevention, E. O. Ospedali Galliera, Genova, Italy
* Correspondence to: Dr C. Aschele, Department of Medical Oncology and Cancer Prevention, E. O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genova, Italy. Tel: +39-010-5634502; Fax: +39-010-5634500; Email: aschele{at}tin.it
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Abstract |
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Patients and methods: Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m2, weekly for 6 weeks) and FUra (200225 mg/m2/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level.
Results: In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m2/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0.
Conclusions: Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.
Key words: 5-fluorouracil, neoadjuvant chemoradiation, oxaliplatin, phase III study, rectal cancer
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Introduction |
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The availability of new drugs that may be combined with FUra offers a major opportunity to improve the control of distant metastases in LARC. In particular, two randomised phase III clinical trials have demonstrated the higher activity of different oxaliplatin (OXA)/FUra/leucovorin (LV) combinations as compared to the same regimens of FUra/LV alone in metastatic colorectal cancer [7, 8
]. More recently, the superiority of combined OXA and FUra/LV over the same FUra/LV regimen alone has been demonstrated even in the adjuvant setting [9
]. Of note, preclinical studies have also shown OXA to be a potent radiosensitising agent [10
]. This drug thus has the potential to improve both the control of micrometastases at distant sites and the local activity of pelvic chemoradiation.
Although the best sequence of surgery, radiation and chemotherapy remains to be determined, recent data indicate that preoperative chemoradiation significantly improves local control, acute and late toxicity and the rates of sphincter-preserving surgeries as compared to postoperative chemoradiation [11]. In this setting, combination chemotherapy concurrent with RT may also allow maximum tumour shrinkage before surgery. This may be particularly important in low-lying tumours when sphincter preservation is attempted [12
] and in patients with bulky T3, T4 and tethered tumours where R0 resections are difficult to achieve unless the tumour is adequately shrunk before the operation [13
]. Emerging data suggesting that the degree of response to preoperative chemoradiation is associated with long-term outcome [14
, 15
] lend further support to the use of combination chemotherapy concurrent to preoperative radiation in LARC.
The feasibility of combining OXA with FUra and RT has been established for monthly regimens where OXA is given in the first and last week of radiation [1618
]. More dense schedules may optimise the inhibition of sublethal, radiation-induced DNA damage repair [19
] and may allow a higher OXA dose and dose intensity, with a potential enhancement of local and systemic activity. In addition, acute toxicity may be reduced through dose fractionation.
We have thus developed and tested in this phase III study a novel chemoradiation regimen that incorporates OXA, administered weekly, into a standard regimen of infusional FUra and RT. Infused FUra was preferred to bolus for the backbone of this regimen because of the superiority shown in combination with RT in the postoperative setting [20] and the favourable toxicity profile observed preoperatively [21
].
The aim of the phase I part of this study was to set the recommended doses (RDs) of OXA and FUra, administered as a 2-h infusion weekly for 6 weeks and as a 6-week continuous infusion, respectively, concurrent to preoperative pelvic RT (50.4 Gy). The subsequent phase II part was aimed at investigating the safety and clinical activity (in terms of pathological response) of this regimen on an expanded cohort of patients treated at the RDs.
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Patients and methods |
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Study design
Phase I section (dose-finding). Consecutive cohorts of three or more patients were accrued, treated and observed for at least 1 week after the end of chemoradiation at each dose level. If a dose-limiting toxicity (DLT) was observed the corresponding cohort was expanded to include at least six patients. The maximum-tolerated dose (MTD) was defined as the dose level at which DLTs occurred in more than one third of patients (two or more out of three/three or more out of six patients). DLTs were defined as follows: grade IV or protracted (>7 days) grade III neutropenia, grade IV or protracted grade III thrombocytopenia, grade IIIIV stomatitis, grade IV or grade III lasting more than 24 h diarrhoea, grade III neurotoxicity. Any event resulting in RT or chemotherapy discontinuation or RT interruption for longer than 2 days was also considered to be a DLT. The RDs for the phase II part of the trial and further development of this regimen were defined to correspond to the dose level immediately preceding the MTD or to the last studied dose level if the MTD was not reached.
Phase II section (assessment of activity). A Fleming's one stage design was used with a decision rule requiring at least six pathologic complete responses (pCRs) among 24 patients treated at the RD in order to discriminate between a 10% (uninteresting) and a 30% (interesting) pCR rate with a 0.05/0.20 and ß error, respectively, and declare the regimen active and worth testing in further studies [22
].
Study procedures
Pre-treatment work-up. Pretreatment evaluation included a complete medical history and physical examination, full blood cell count and blood chemistry, rigid rectoscopy in the Sim's position, air-contrasted pelvic computed tomography (CT) and/or transrectal ultrasonography (TRUS), liver and chest CT scan (or ultrasound/X-ray) and colonoscopy.
Radiotherapy. Patients were irradiated in a prone position using a four-field box technique with high-energy photons (6 MV). The target volume included all the macroscopic tumour, the mesorectum and the internal iliac and presacral nodes up to the L5/S1 junction. External iliac and inguinal nodes were irradiated in stage cT4 tumours and in those extending into the anal canal, respectively. The upper border of the radiation fields was at the L5/S1 interspace. The distal border was 5 cm below the distal extent of the macroscopic tumour or at the bottom of the obturator foramina. Lateral limits of the antero-posterior and postero-anterior fields were 1.5 cm lateral to the margins of the bony pelvis. Lateral fields encompassed the entire sacrum posteriorly and extended anteriorly to the posterior or anterior margin of the symphysis pubis in stage cT3 and cT4 tumours, respectively. A total RT dose of 50.4 Gy, as specified according to the International Commission on Radiation Units and Measurements guidelines, was delivered in 28 daily fractions of 1.8 Gy, Monday to Friday over a period of approximately 6 weeks.
Chemotherapy. All treatment was administered on an out-patient basis. FUra was infused continuously for all the duration of RT through an implantable subcutaneous i.v. access device using a portable elastomeric pump, at a dose of 200 (dose-levels 14) or 225 (dose level 5) mg/m2/day. OXA was given as a 2-h i.v. infusion at 25, 35, 45 (dose levels 1, 2 and 3, respectively) or 60 (dose levels 4 and 5) mg/m2 on the first day of each week of RT for a total of six courses. All patients received premedication with antiserotoninergic drugs and corticosteroids.
Toxicity monitoring and dose reduction criteria. Toxicity was monitored weekly during treatment and 710 days after completing chemoradiation and graded according to the National Cancer Institute Common Toxicity Criteria (NCICTC), version 2.0 [23, 24
]. Chemotherapy was interrupted in the face of grade III toxicity and resumed at full doses if symptoms resolved to grade 0 or I within 24 h, at 50% of the original dose if toxicity resolved within 7 days and definitively stopped in all other cases. For grade IV toxicity, chemotherapy discontinuation was planned with only RT resumed after resolution to grade 0I.
Surgery and postoperative treatment. Surgery was planned 68 weeks after the end of chemoradiation. TME was advised while the type of resection (sphincter preservation) in low-lying tumours was left to the discretion of the surgeon provided that a free distal margin 1 cm was maintained. Adjuvant FUra-based postoperative chemotherapy was planned for all patients achieving a curative resection (R0) regardless of the degree of response to preoperative chemoradiation.
Assessment of pathologic response. Visible residual tumour or the corresponding fibrotic area as well as perirectal lymph nodes, distal and lateral resection margins and mesorectal tissue distal to the tumour were examined to assess the radicality of the surgical resection and to determine the pathologic stage according to the AJCCTNM classification [25]. Tumor down-staging was determined by comparing the pathologic stage with the baseline clinical TNM stage, as assessed by pre-treatment TRUS and/or pelvic CT scan. Complete pathologic response was defined as the absence of residual tumour cells in the surgical specimen regardless of the presence of mucine lakes.
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Results |
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One of the first three patients accrued at the fourth (OXA 60 mg/m2 and FUra 200 mg/m2) and fifth (last planned: OXA 60 mg/m2 and FUra 225 mg/m2) dose level experienced dose-limiting grade III diarrhoea (not requiring parentheral rehydration but lasting more than 48 h). Additional patients were thus accrued in these cohorts without other DLTs nor alterations of the planned treatment (Table 2).
Since no further dose escalation was planned, OXA 60 mg/m2 and FUra 225 mg/m2 were defined as the recommended doses for this regimen.
Toxicity and compliance at the recommended doses
Toxicity. Among the nineteen additional patients accrued at the RDs in the phase II part of the study, three experienced grade III diarrhoea requiring parenteral rehydration and/or potassium replacement (in the third, fourth and last week of treatment, respectively). Diarrhoea resolved to grade I or less within 35 days and did not preclude completion of all the planned RT in all the three patients. The incidence of grade III diarrhoea among the 25 patients globally treated at OXA 60 mg/m2 and FUra 225 mg/m2 was thus 16%. Local dermatitis (12%) and anaemia (4%) represented the only other grade III toxicities (Table 3).
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There was no grade III peripheral sensitive neuropathy. Reversible grade I or grade II cold-related paresthesias/dysesthesias were observed in 17 (68%) and three (12%) of 25 patients, respectively (Table 3).
One patient experienced hypertransaminasemia beginning on the fourth week and reaching grade III during the fifth week of chemoradiation. Bilirubin and all the other liver enzymes remained within the range of normal values. Treatment was not interrupted and transaminase values began to decrease during the last week of chemotherapy, returning within the normal limits 1 week after the end of chemoradiation.
Compliance. All patients received the full planned RT dose (50.4 Gy) and only nine of 150 weeks of radiation (6%) were administered with delays (114 days). Only five out of 150 (3%) weeks of chemotherapy were omitted for toxicity (n=4) or refusal (n=1). Eighty-four percent of the patients treated with the RDs completed six full courses of chemotherapy. Ten chemotherapy courses (7%) were delayed (n=6) or modified (n=4) because of toxicity while infusional FUra was withheld due to central venous catheter (CVC)-related problems in three courses (2%).
Antitumour activity
All the patients were operated on, with intent to cure, at a median of 44 days (range 2665 days) from the end of chemoradiation. Forty-one patients (89%) had a radical R0 resection. The remaining five patients (11%) had peritoneal carcinomatosis discovered at the time of surgery (n=2), a positive distal margin (n=1) and a circumferential resection margin <1 mm (n=2). Surgery consisted of a low anterior resection in 42 cases while abdominal perineal resection was performed in four patients. A sphincter-sparing surgical procedure could be performed in 21 of 25 patients with tumours located within 6 cm from the anal verge at pre-treatment evaluation.
No perioperative deaths were encountered in this study. Re-operation was required in four patients (anastomotic dehiscence in two; pelvic abscess in one; emoperitoneum in one). Other surgical complications as well as anorectal function in the patients that had sphincter-saving surgery will be detailed in a separate report.
Among the 25 patients treated with the recommended OXA and FUra doses, seven did not show any residual tumour in the pathologic specimen [pCR 28.0%, 95% confidence interval (CI) 21.334.6%], 14 had the tumour down-staged as compared to pre-treatment assessment (56%), three maintained the pre-treatment stage (12%) and one developed peritoneal carcinomatosis (4%). The primary tumour (T-category) was down-staged in 5/7 (71%) and 15/18 (83%) of the patients with cT4 and cT3 tumours, respectively. Lymph-node metastases were detected in the tumour samples of three patients (12%) as compared to 21 of 25 patients (84%) showing evidence of nodal involvement at pre-treatment evaluation. Nodal status down-staging was thus achieved in 86% of the patients. Twelve of the down-staged patients, had a ypT1-2N0 stage (48%). This level of activity was similar to that observed on the whole population of 46 patients (pCR, 12; ypT1-2N0, 18).
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Discussion |
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In the phase I part of the trial, the OXA dose could in fact be escalated up to 60 mg/m2/week in combination with 225 mg/m2/day of infused FUra with two episodes of grade III diarrhoea representing the only DLTs observed in the dose escalation phase. Assessment of toxicity on the 25 patients treated at these doses in the phase II part of the study confirms the high tolerability with a 16% overall incidence of grade III diarrhoea and other immediate toxicities not exceeding grade II except for anaemia and dermatitis. Neurotoxicity, a potential concern because of the frequent OXA administration and the potential curability of this patient population, mainly consisted of grade I, with grade II limited to three patients receiving the highest OXA dose (fourth and fifth dose levels). OXA 60 mg/m2, given weekly, and FUra 225 mg/m2/day, administered as a prolonged infusion for the duration of RT, are therefore the doses recommended for further development of this regimen.
The favourable toxicity profile of this regimen is reflected in the high treatment compliance with the full planned dose of radiation delivered in all the patients and only 3% of the chemotherapy courses omitted because of toxicity. Surgical morbidity was also acceptable, with no perioperative deaths and only four patients requiring reoperation.
This high tolerability is particularly relevant considering that OXA and FUra were combined with a 50.4 Gy RT course. In previous studies of this combination [16, 26
, 27
] the RT dose was in fact generally limited to 45 Gy. Of note, the median treatment volume in this study was also high (data not shown) owing to the large proportion of cT4 tumours where irradiation was extended to the external iliac nodes.
Since OXA was well tolerated up to the last planned dose-level, further escalation could have been theoretically attempted. However, the highest dose for escalation was set at 60 mg/m2 in order to avoid chronic neurotoxicity. Electrophysiological alterations indicating chronic neurological impairment have indeed been described at a cumulative OXA dose of 410 mg/m2 [28, 29
] and a threshold dose below 500 mg/m2 has been reported for development of grade III neurotoxicity [30
]. In addition, 60 mg/m2 corresponds to 75% of the MTD of weekly OXA combined with infused FUra without RT in advanced colorectal cancer [31
].
Even though the MTD was not reached, the total delivered dose of OXA in this study is substantially higher compared to other recently developed chemoradiation regimens (360 versus 260200 mg/m2) [16, 17
, 32
].
Furthermore, the dose-intensity of OXA reached with this regimen is approximately 50% higher compared to the bi-weekly and tri-weekly regimens commonly used in the treatment of metastatic colorectal cancer without radiotherapy [79
]. This is clinically relevant as it may result in improved control of micrometastatic disease at distant sites that currently represent the main site of failure in LARC. The low toxicity despite this high cumulative dose may depend on the weekly schedule we have used allowing dose fractionation. This may be particularly true for neurotoxicity. All the patients treated with monthly OXA in combination with FUra and preoperative RT in a previously published study did, in fact, develop neurotoxicity, despite a substantially lower cumulative OXA dose (260 mg/m2) compared to the present study (360 mg/m2) [18
].
Seven out of 25 patients treated with the recommended OXA and FUra doses in the phase II part of this trial did not show any residual tumour in their resected sample. According to our statistical design, this level of activity allowed us to declare the regimen active and worth pursuing in further clinical studies. Twelve additional patients had a ypT1-2N0 residual tumour. Approximately 75% of the treated patients had thus either a pCR or residual tumour confined within the muscularis layer of the rectal wall. This may be clinically relevant since lack of perirectal fat penetration and node involvement after chemoradiation has been reported to correlate with a better long-term outcome [14, 15
].
The high clinical activity of this regimen is also reflected in the high rates of radical surgery with negative margins (R0) and sphincter-saving operations. Two thirds of the T4 tumours achieving an R0 resection and 80% of the low-lying tumours operated on with a sphincter-saving procedure were in fact in patients down-staged after chemoradiation (data not shown).
Despite the limitations of a non-randomised comparison, this level of activity appears to be higher compared to our previous experiences with FUra-based chemoradiation [33, 34
] with pCR rates that are almost doubled. The efficacy of this regimen compares well even to that reported for other combinations of OXA, FUra and RT [16
18
]. This may depend on the higher OXA dose delivered concurrent to radiation. This high activity may also depend on enhanced radiosensitisation achieved through weekly OXA administration, potentially allowing optimised inhibition of radiation-induced, sublethal DNA damage repair. Whether this increased local activity will determine an increase in local control will remain to be determined in larger and controlled studies.
Of note, simplified regimens of weekly OXA and concurrent radiation with infused FUra replaced by oral fluoropyrimidines have already been shown to be feasible with promising clinical activity in preliminary studies [32, 35
]. This might substantially increase the convenience of this regimen. Weekly administration thus appears to represent a promising way of combining OXA and pelvic radiation.
The OXA and FUra doses used in this regimen are potentially active systemically. Although treatment duration is limited, this regimen might thus have an impact also on micrometastatic disease, especially considering the high OXA dose intensity (60 mg/m2/week compared to 42.5 mg/m2/week in the regimens commonly used in metastatic colorectal cancer) [79
] and the rapid cytotoreductive effects of the platinum derivative [7
, 8
]. This regimen might thus allow maximisation of local control and tumour shrinkage before surgery and also improve systemic control. In addition, it might then be part of the treatment programs for patients with LARC and synchronous distant metastases.
The main goals of our study were to find a suitable dose of weekly OXA to be safely combined with standard infusional FUra and concurrent preoperative pelvic radiation therapy and to preliminarily test the clinical activity of this regimen. We believe that both of these goals have been achieved as systemically-active doses of OXA could be combined with full, standard doses of infused FUra and radiation with an acceptable toxicity and a high treatment compliance, and evidence has been provided of a promising level of clinical activity.
Based on these results, a randomised trial has been started comparing this regimen to standard infused FUra and pelvic radiation. Molecular and pharmacogenetic studies aimed at identifying specific groups of patients more likely to benefit from this intensified approach are also planned. Finally, the low toxicity of this regimen leaves room for incorporation of further agents. This may be particularly important in the light of the recent development of novel, target-oriented therapies for the treatment of colorectal cancer [3638
].
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Acknowledgements |
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Received for publication October 14, 2004. Revision received January 29, 2005. Accepted for publication February 7, 2005.
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References |
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