3566 Background: Phase I/II data showed that ciclosporin (Cs) profoundly reduces the hepatobiliary clearance of irinotecan (Ir), and suggested that 40% standard dose Ir with concurrent Cs (IrCs) may give equal efficacy to standard Ir, with less diarrhoea. PICCOLO is a multicentre randomized controlled trial in which patients (pts) with aCRC, progressing after prior therapy, were randomised to Ir or IrCs. It was designed to detect non-inferior efficacy with reduced toxicity. Methods: Eligible pts had: measurable aCRC, progressive during/after ≥1 prior regimen with fluoropyrimidines ± other drugs; no prior Ir; WHO PS 0-2. Before summer 2008, pts were allocated 1:1:1 (without prospective KRAS analysis) to Ir, IrCs or Ir/panitumumab. Thereafter, KRAS was analysed prospectively and pts with mutated or undetermined KRAS were allocated 1:1 to Ir (irinotecan 350 mg/m2 [300 mg/m2 if ≥70 yrs or PS2], q3w), or IrCs (irinotecan 140 mg/m2 [120 mg/m2 if ≥70 yrs or PS2] d1, Cs 3 mg/kg tds d0-2, q3w). The primary efficacy endpoint was % pts alive and progression-free at 12 wks, with a lower non-inferiority boundary of -10.6% (80% power, 2.5% significance). Grade ≥3 diarrhoea within 12 wks was a key secondary endpoint. PFS, OS, RR, QoL and loperamide use were also assessed. Analysis was performed on both the ITT and per-protocol populations. Results: 672 pts were randomised between Ir and IrCs. Median age was 64 yrs; 92% were PS0/1; 95% had received prior oxaliplatin; KRAS was mut in 60%, wt in 25%, unknown in 15%. ITT analysis showed 179/335 (53.4%) patients to be progression-free at 12 wks in the Ir arm, 159/337 (47.2%) in the IrCs arm. The difference was therefore -6.3% and the 95% CI crossed the prespecified non-inferiority margin (13.8%, +1.3%). Gr ≥3 diarrhoea was uncommon in both arms (Ir 12.2%; IrCs 10.1% pts), but fewer IrCs patients took loperamide within 12 wks (Ir 67.8%; IrCs 52.2%, p<0.001). Conclusions: As anticipated, IrCs was associated with less diarrhoea as assessed by loperamide use, but severe diarrhoea was uncommon in both arms. However, we failed to prove non-inferiority of IrCs compared with Ir, so cannot recommend it as a standard treatment option based on these data.

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 m 2 ; 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.

In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m−2 to 60 mg m−2 to 70 mg m−2 to identify the maximum tolerated dose (60 mg m−2). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m−2 per day) for 5 weeks. Irinotecan (60 mg m−2) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.

13519 Background: Preoperative downstaging chemoradiation has become standard treatment for locally advanced unresectable rectal cancer. Oral CAP is potentially more convenient as a radiation sensitiser than infusional fluoropyrimidine regimes. This study evaluated the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of daily CAP plus weekly i.v. CPT-11 when used in combination with RT in locally advanced rectal cancer. Methods: Patients had an adenocarcinoma of the rectum (lower limit within 12 cm of the anal verge) which on MRI was T3 within 2 mm of the mesorectal outer edge, T4, or any T3 within 5 cm of the anal verge. There were no distant metastases on staging investigations. Patients received planned pelvic RT to 45 Gy in 25 daily fractions over five weeks, concurrent with oral CAP daily throughout RT (including weekends) and a 60 minute infusion of i.v. CPT-11 weeks 1, 2, 3 and 4. Doses of CAP and CPT-11 were gradually escalated in cohorts of three patients. Results: The most common DLT was diarrhoea. Initially dose level (D/L) 3 was chosen as the recommended dose for phase II. However, unacceptable toxicity was encountered in the first 12 patients treated at D/L 3 (see Table). Thus D/L 2 is now being expanded to 60 patients for phase II. 40 patients have thus far potentially been eligible for resection: 5 (13%) could not be resected (2 deteriorated, 2 developed metastases, 1 died during treatment), 32 (80%) had R0 and 3 (7%) R1 resection. 9 (25%) had a pathological complete response (pCR) and 7 (20%) ‘near’ pCR. 5 (9%) of 57 patients had a defunctioning stoma pre-RT. Conclusions: The RD for this regime is 60 mg/m2 i.v. CPT-11 weeks 1, 2, 3, 4 and 650 mg/m2 bd of oral CAP daily. This demonstrates promising signs of efficacy. The RD is currently being studied in an expanded phase II cohort of 60 patients. D=diarrhea; F=febrile neutropenia; A=anorexia; L=lethargy; N=nausea/vomiting. [Table: see text] No significant financial relationships to disclose.

3747 Background: Pelvic radiotherapy (RT) may compromise the compliance and effectiveness of future chemotherapy (CT). Patients and Methods: 20 patients (15 male, 5 female), mean age 69 yrs (range 51–75) were studied in a prospective, multicenter, phase II study. All patients had recurrent or metastatic diease. All had received previous pelvic RT: 45Gy 25 fx (15), 45 Gy 30 fx (3), 45 Gy 20 fx (2) and 25 Gy 5 fx (1) at a 16 months prior to this study. Most patients had received concurrent chemoradiation (CRT). Patients were treated with a schedule consisting of oxaliplatin 85 mg/m2 on day 1 and 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv 22hour infusion with folinic acid on day 1 and 2. A maximum of eight cycles of CT were administered every two weeks. Results: A median number of 7 cycles of CT was given (range 3–8), with 132 cycles being given in total. There were 8 episodes of grade III neutropaenia (1 with sepsis). There were 4 episodes of grade III/IV diarrhoea, two of which required hospitalisation, but all resolved. In 18 evaluable patients patients the overall response rate was 33% (3 CR; 3 PR), with 2 patients having SD. Conclusion: This study shows that the combination of oxaliplatin, 5FU and folinic acid after high-dose pelvic RT is well tolerated and has comparable efficacy to that seen in other metastatic studies and a dose intensity equal to that achieved in adjuvant studies. Based on the results of this study, adjuvant oxaliplatin is being delivered in a randomised phase III study (CHRONICLE) following CRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Sanofi

3612 Background: Previously, we reported a Phase I study of radiotherapy with concurrent CPT-11 and 5FU for the treatment of locally advanced inoperable rectal cancer (Proc ASCO 2003, abst 1384). In combination with pelvic radiotherapy of 45 Gy in 25 daily fractions over five weeks, this established a recommended dose for CPT-11 of 60 mg/m2 given once per week, during weeks 1, 2, 3 and 4 as a 60 minute infusion, together with continuous infusional 5FU at 200 mg/m2 per day via a central line throughout radiotherapy, including weekends. This dose level was expanded to a cohort of thirty one patients for the present phase II assessment. Methods: All patients were initially staged using MRI. Patients with T3 (with threatened mesorectal edge on MRI scan) or T4 rectal cancer, were treated with the above regime. Surgery was performed 6 - 8 weeks following the completion of chemoradiation. Results: All patients completed chemoradiation as planned. There was only one grade 3 toxicity reported (diarrhoea) and the patient completed treatment successfully. Thirty-one patients entered, of whom twenty-nine (93%) underwent resection. Two patients were deemed inoperable because of unresectable pelvic disease. Sixteen patients (55%) had an anterior resection and thirteen patients (45%) had an abdomino-perineal resection. Twenty-six patients (87%) had complete excision of the tumour (Ro resection). Six patients (21%) had a complete response to chemoradiation (pCR). Four patients in addition (14%) had microfoci only of tumour remaining (near-pCR). Conclusions: Radiotherapy with concurrent CPT-11 and 5FU is a well tolerated treatment for locally advanced inoperable rectal cancer leading to a high probability of complete resection of the cancer. This treatment regime is currently being studied (in the NWCOG-2 trial), in a similar cohort of rectal cancer patients, but substituting Capecitabine for 5FU. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis UK

PURPOSE:To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose.METHODS AND MATERIALS:A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy.RESULTS:There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per day's extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each day's extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors.CONCLUSIONS:Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

PURPOSE:To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil.METHODS AND MATERIALS:A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed.RESULTS:With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa.CONCLUSION:The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

Purpose/Objectives:To evaluate results of accelerated radiothempy using the concomitant bcost technique for patients with squamous cell carcinoma of the base. of tongue.

Seventy-seven patients with small cell lung cancer were entered on a protocol comprising induction chemotherapy with cyclophosphamide 1 g m−2, adriamycin 40 mg mt-2 and vincristine 1.4 mg mt-2 (CAV) every 21 days for four to six cycles. The overall response rate was 72.8%. Twenty-six patients achieving complete remission received intensification with two further cycles of ifosfamide 5 g mt-2, mesna 8 g mt-2, methotrexate 30 mg mt-2 and etoposide 100 mg mt-2 per day for 3 days (IME). Six of the 15 patients in partial remission following CAV achieved a further remission on IME (response rate 40%). Median survival in the limited disease group was 11 months compared with 7 months in the extensive disease patients and four patients are alive at more than 2 yr follow up. There was no significant prolongation of the median survival (11 months) seen in those patients in complete remission who had negative second bronchoscopy examination. This sequential six drug regime produces high response rates in small cell lung cancer, and there is evidence of lack of cross-resistance between CAV and IME.

Forty-six previously untreated patients with advanced ovarian cancer were treated with combination chemotherapy comprising cisplatin 80 mg m-2 i.v. and cyclophosphamide 1 gm-2 i.v. every 28 days for 5 cycles. Eighty-five percent of patients received more than 75% of the calculated doses, and of 43 evaluable patients, a complete response was achieved in 31 (72%), a partial response in 4 (9.3%) and 8 patients had static or progressive disease. The actuarial survival of the whole group is 60% at a median follow-up of 2 years. Twenty-four patients in complete clinical or pathological remission were then treated with whole abdominal radiotherapy 2,500 cGy followed by a pelvic boost of 2,000 cGy. The pelvic boost was omitted in 3 patients, and the overall radiotherapy treatment time extended in a further 4 patients on account of myelosuppression. The actuarial survival of the 24 patients receiving both treatments at a median of 30 months follow-up is 75%. In the 10 patients with negative second-look procedures completing both treatments there have been no tumour related deaths at a median follow-up of 33 months.