Carlo Aschele

Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial

PURPOSE To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation.

PURPOSE To determine if fluorouracil (FUra) has different mechanisms of action as a function of the dose schedule used. DESIGN The preclinical and clinical literature relating toxicity and antitumor effects of FUra as a function of its dose schedule, with and without modulating agents, was reviewed. RESULTS The data support the hypothesis that FUra may be considered to be two different drugs, depending on its dose schedule (bolus v continuous infusion [CI]). CONCLUSION These results suggest that additional therapeutic benefit may be obtained from FUra regimens by (1) appropriate schedule-dependent modulation, (2) the sequential or alternating use of cycles of bolus followed by cycles of CI FUra appropriately modulated, or (3) hybrid regimens, ie, those that contain both pulse and CI schedules.

Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial

CRA4008 Background: Oxaliplatin (OXA) enhances the efficacy of FU-based chemotherapy in colon cancer. This randomized phase III trial investigated the effect of adding OXA to preoperative (preop) FU-based pelvic chemoradiation (CRT) in patients (pts) with locally-advanced rectal cancer. METHODS Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or lymphnode involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq × 6) (Arm B). Surgery was scheduled 6-8 weeks after completing CRT. Overall survival was the primary endpoint. A protocol-planned analysis of local tumor response to preop treatment (secondary end-point) is the object of this report. RESULTS 747 pts from 41 Italian centers were randomized between 12/2003 and 8/2008 (arm A/B: 379/368). Pretreatment characteristics in arm A/B: median age 63/62 years; male:female 2:1; median distance from anal verge 6 cm; T4 16/14%, N+ 63/65%. Overall grade 3-4 toxicity rates on treated pts (mainly diarrhoea) were 8% and 24% (arm A/B, p<0.001). 96/90% of pts (arm A/B) received > 90% of the planned RT. 82% of Arm B pts had > 5 oxa courses. 358/342 pts (arm A/B) had surgery at a median of 52/53 days from the end of CRT, 14 pts in each arm were not operated (progression 8, death 5, other/unknown 15) and surgery data are not yet available for 19 pts. Pathologic response data analyzed on the randomized population are reported in the table . CONCLUSIONS The addition of weekly OXA to standard FU-based preop CRT significantly increases toxicity without affecting local tumor response. The reduced pathologic M+ rate suggests a potential effect on distant micrometastases. Longer follow-up is needed to assess the impact on efficacy endpoints. [Table: see text] No significant financial relationships to disclose.

Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: Lessons from a systematic review of recent randomized trials

PURPOSE A common hypothesis is that neo-adjuvant treatment in rectal cancer, is able to increase sphincter saving surgery. This review studies data relevant to this question. STUDY SELECTION A total of 17 randomized trials were analysed. RESULTS Since 1976, the rate of sphincter saving surgery increased from 20% to 75%. In none of the 17 trials it was possible to demonstrate a significant benefit of the neo-adjuvant regimens on the rate of sphincter saving surgery. There was a reduction in the risk of 5-year local recurrence partly due to these neo-adjuvant treatments. These neo-adjuvant regimens had no significant impact on the overall 5-year survival. CONCLUSIONS None of the neo-adjuvant treatments tested was able to demonstrate an increase in the rate of sphincter saving surgery. The improvement in conservative surgery is mainly due to technical changes in surgery. Organ preservation after complete clinical response appears as an interesting hypothesis to test.

Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study)

BACKGROUND The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. PATIENTS AND METHODS Patients had rectal adenocarcinoma, cT3N+ or cT4N-/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5-fluorouracil-oxaliplatin with concurrent RT. Rectal surgery was carried out 7-8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. RESULTS Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3-4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. CONCLUSIONS In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3-4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT.

Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil

We have recently demonstrated that continuous-infusion (CI) 5-fluororacil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m2 per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) of FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU+LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU+LV.

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

PURPOSE To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. PATIENTS AND METHODS DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin-modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. RESULTS Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P =.04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. CONCLUSION Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

Liver targeting of autologous erythrocytes loaded with doxorubicin

ERYTHROCYTES HAVE been proposed in animal models as carriers of cytotoxic drugs or as bioreactors converting prodrugs to active drugs [ 1,2]. Doxorubicin has been encapsulated in human and animal erythrocytes [3-71. Treatment of the doxorubicin-loaded erythrocytes with glutaraldehyde, a bifunctional reagent, prevented the fast efflux of doxorubicin from the cells and produced their specific targeting to the liver of mice and dogs [4-71. The present research aimed to extend these experimental studies to the clinic. A 51-year-old male had a colorectal carcinoma, massively metastatic to the liver (60% tumour involvement). The primary tumour was removed surgically and, at the time our study started, the disease was confined to the liver and slowly progressing. The patietit had an ECOG performance status of 2. He had previously failed three lines of chemotherapy (5fluorouracil, fotemustine, mitomycin), either systemic or locoregional, through a Port-a-cath implanted in the hepatic artery at the time of surgery. Informed consent was obtained from the patient. Freshly drawn erythrocytes were loaded with doxorubicin by simple diffusion [6]; the yield of encapsulation of the drug was 2 mg/ml of packed cells. Glutaraldehyde treatment (0.15% and 0.30% final concentration) was performed after encapsulation of doxorubicin [6]. This treatment substantially reduced the rate of doxorubicin efflux in vitro (more than 70% of the drug retained after 210 min at 37°C). For in viva distribution studies erythrocytes were labeled with 99mTc [8] prior to encapsulation. All manipulations were performed under sterile pyrogen-free conditions. Figure 1 shows the time-radioactivity curves over the regions of liver and heart, after administration through hepatic artery of 99mTc labeled native (a) and unloaded GA treated (b) erythrocytes. Unlike the native cells, showing a rapid transit from the liver to systemic circulation (a), the glutaraldehyde treated erythrocytes were almost completely retained by the liver (b), up to 24 hours after injection (not shown). No accumulation of

Chemotherapy for operable and advanced colorectal cancer

The majority of colorectal cancer patients receive chemotherapy either to palliate advanced unresectable disease or to reduce the risk of recurrence after radical surgery. Thanks to the improvements in systemic chemotherapy, in the last 20 years the median survival time for patients with unresectable metastatic disease has indeed progressively increased from less than 6 to almost 24 months and recurrences after radical surgery in patients with early-stage tumors have been halved. Although colorectal cancer incidence increase with aging, there is limited scientific evidence based on prospective clinical trials to guide the management of elderly colorectal cancer patients. In addition, aging is a continuum process making strict cut-off difficult to define and homogeneous subgroups hard to identify. There is significant heterogeneity also as regards comorbidities, overall physical ability, mental health and functional status. Specific guidelines for the medical treatment of elderly colorectal cancer patients are therefore difficult to draw. While fit patients are generally treated with adult protocols and frail individuals rarely receive chemotherapy, managing the intermediate vulnerable patients requires a careful balance between the biological and psycho-social costs of treatment, the aggressiveness of the tumor and its perception by the patient. In this review, the major achievements of chemotherapy in the treatment of colorectal cancer will be described and the available data addressing the extension of these chemotherapy programs to elderly patients will be discussed. Special emphasis will be given to the development of specific treatment strategies depending on the degree of disease aggressiveness. Empirical suggestions to adapt the chemotherapy programs developed for adult fit patients to subjects with various degrees of vulnerability and frailty will also be given along with practical indications for the use of specific chemotherapeutic agents in the presence of some common elderly-related comorbidities.

Phase II trial of 5-fluorouracil and the natural l isomer of folinic acid in the treatment of advanced colorectal carcinoma

Between February 1991 and July 1992, 79 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study of combined 5-fluorouracil (5-FU) and l-folinic acid (FA). 5-FU 370 mg/m2/day was administered for 5 consecutive days as an intravenous (i.v.) bolus injection preceded by l-FA 100 mg/m2/day with the same administration modality. Treatment was given every 4 weeks until progression. 79 patients were evaluable for toxicity and 64 for response. 2 patients (3%) achieved a complete remission and 8 (12.5%) a partial remission, 33 (52%) had stable disease and 21 patients (33%) had progressive disease. Median duration of remission was 32.5 weeks and median survival for all evaluable patients was 64.5 weeks. Substantial to severe side-effects occurred in 39% of patients. Dose-limiting toxicity (grade 3-4) was mainly diarrhoea (18%) and mucositis (15%). Nausea/vomiting, cutaneous toxicity, leucopenia, alopecia and conjunctivitis of grade 3-4 occurred respectively in 6, 4, 2.5, 1 and 1% of cases. Toxicity appeared to be substantially similar to that characteristic of combined 5-FU and the chiral mixture of d,l-FA. Efficacy was within the range of that observed with the 5-FU/d,l-FA combination, although at the lower level.