Gerardo Rosati

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.

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.

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.

Phase II Trial of Oxaliplatin and Tegafur/Uracil and Oral Folinic Acid for Advanced or Metastatic Colorectal Cancer in Elderly Patients

Objectives: Colorectal cancer is usually diagnosed in elderly patients. Since there is clear evidence that such patients are under-treated and under-represented or even excluded from clinical studies and there are no reliable and prospective data on the feasibility and efficacy of an oxaliplatin (L-OHP)-based chemotherapy in this setting, we have tested the L-OHP plus oral uracil/tegafur (UFT) and oral folinic acid (FA) combination as first-line therapy in patients with advanced or metastatic colorectal cancer (MCRC) aged 70 or older. Patients and Methods: Forty-seven patients with advanced or MCRC, aged over 70, were treated with L-OHP 65 mg/m2 as an intravenous 3-hour infusion on day 1 and 8 plus UFT 300 mg/m2 and FA 90 mg in 3 divided doses given orally on days 1–14 for each 3-week cycle. Patients were followed by a geriatric and a quality of life (QoL) assessment with specific scales and EORTC-QLQ-C30 questionnaire. Results: All patients were assessable for toxicity and 45 for response to treatment. Complete response was achieved in 2 patients (4%) and partial response in 22 (47%) [overall response rate, 51%; 95% confidence interval (CI): 40.7–61.2%]; 18 patients (38%) had stable disease, and 5 (11%) had disease progression. The median duration of response was 8 months (range, 3–19+ months). After a minimum follow-up of 17 months, the median time to disease progression and the median overall survival were 8.0 (95% CI: 6.7–9.3%) and 14.1 (95% CI: 11.0–17.1%) months, respectively. Regimen safety was manageable. Most adverse events were mild to moderate, and this did not result in QoL impairment. The most common grade 3–4 treatment-related adverse events were diarrhea (17%), neutro- and thrombocytopenia (2%), laryngeal spasm (2%), and peripheral neuropathy (12.7%). No treatment-related deaths occurred. Conclusions: These results confirmed that this tested chemotherapy combination is active with acceptable tolerability and QoL maintenance in elderly patients with advanced or MCRC.

Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival.

It was the objective to determine in this retrospective study whether thymidylate synthase (TS), p53, bcl-2, Ki-67 and p27 in Dukes’ stage B and stage C (AJCC/UICC stage II and III) colorectal adenocarcinoma were predictive of disease-free survival (DFS) and overall survival (OS). Paraffin-embedded specimens from 103 patients with colorectal cancer, treated with surgery between October 1994 and September 1999, were examined for TS expression, p53, bcl-2, Ki-67 and p27 using immunohistochemistry; 51 cases were Dukes’ stage B and 52 cases were Dukes’ stage C disease. Adjuvant 5-FU-based chemotherapy was given to all patients, while 31 having rectal malignancy also received pelvic radiotherapy. Data were associated with the recurrence rate and survival. With a median follow-up of 5 years, 38 patients (36.8%) developed recurrence and as many patients (36.8%) died. TS was overexpressed in 16 cases (15.6%), p53 nuclear oncoprotein accumulation in >10% of cells occurred more frequently [61 of 103 cases (59.3%)], positive expression of bcl-2 protein in >10% of cells was observed in 41 of 103 cases (39.9%), 57 patients (55.4%) showed immunohistochemical expression of Ki-67 and there were 75 cases (72.9%) with p27 accumulation. The pathological stage was the only independent prognostic factor for DFS (p = 0.042). Sex, as well as age and biological prognostic factors, had no significant impact value on DFS and OS. A multivariate analysis of OS demonstrated that stage C, p53 negative and Ki-67 positive were associated significantly with an unfavorable outcome and a worse median OS (p = 0.035 and t ratio = 2.48). Some biological characteristics such as p53 and Ki-67 status may provide useful prognostic information in addition to the classical clinicopathological parameters. However, further studies are needed to clarify the value of adopting biological prognostic factors into clinical practice.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer

BACKGROUND Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01640782.BACKGROUND Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180mg/m2 day 1, LV 100mg/m2 as 2h infusion and 5-FU 400mg/m2 as bolus, days 1 and 2 followed by 600mg/m2/day as 22h continuous infusion, q14 for four cycles) followed by docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01640782.

Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study

BACKGROUND To determine the efficacy and tolerability of capecitabine combined with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in patients with advanced/metastatic colorectal cancer aged > or =70 years. PATIENTS AND METHODS Patients aged > or =70 years were randomly assigned to receive CAPOX [oxaliplatin 65 mg/m(2) intravenously (i.v.) days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d] or CAPIRI (irinotecan 80 mg/m(2) i.v. days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d). The primary study end point was overall response rate (ORR). RESULTS Ninety-four patients were enrolled. In an intent-to-treat analysis, 2 complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX (ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with median survival times of 19.3 months and 14.0 months (P = 0.165), respectively. Global health status was improved in 45% and in 21% of patients in the CAPOX and CAPIRI arms, respectively. The most common treatment-related grade 3-4 adverse events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052) and neutropenia (23% versus 6%; P = 0.021). CONCLUSION CAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated.

A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma

BACKGROUND Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV NCT02409472.

First-line chemotherapy with fluorouracil and folinic acid for advanced Colorectal cancer in elderly patients: A phase II study

Background Colorectal cancer is one of the most common cancers in the elderly. Information on tolerability and efficacy of 5-Fluorouracil-based chemotherapy in such patients is limited. Primary aim of the study was to describe tolerability and activity of chemotherapy with the “de Gramont” schedule (FU bolus [400 mg/m2] + FU continuous infusion [600 mg/m2] + folinic acid [100 mg/m2] on days 1 and 2, every 2 weeks), in patients with advanced colorectal cancer aged 70 or older. Patients and methods Patients aged 70 or more, with stage IV colorectal cancer, ECOG performance status not worse than 2. Results Thirty-four patients were treated at two participating centers. Seven (20.6%, 95% exact CI = 8.7–37.9) had an objective response, complete in 3 and partial in 4 patients. Five cases of unacceptable toxicity were registered (2 cardiac, 1 each for liver, anemia and diarrhea). Fitting the statistical model to the observed data indicated that the treatment was sufficiently active and tolerated. Conclusions The de Gramont scheme is active and tolerated in elderly patients with advanced colorectal cancer.

Docetaxel and cisplatin in locally advanced or metastatic squamous-cell carcinoma of the head and neck: A phase II study of the Southern Italy Cooperative Oncology Group (SICOG)

BACKGROUND Docetaxel is one of the most promising new drugs against squamous-cell carcinoma of the head and neck (SCCHN), while cisplatin is one of the most active single agents. A phase I study has shown the feasibility of the combination of the two drugs, and activity in SCCHN has been seen. PATIENTS AND METHODS Patients with locally advanced, inoperable, or metastatic SCCHN, never pretreated with radiotherapy or chemotherapy, received three courses of docetaxel 75 mg/m2 and cisplatin 100 mg/m2, every three weeks. Thereafter, responsive metastatic patients received additional chemotherapy, while patients with locally advanced disease underwent radiation therapy. RESULTS Forty-six patients (forty-five with locally advanced, one with metastatic disease) were entered into the study. Ten patients did not complete three courses of chemotherapy because of early death; one patient discontinued treatment after one course. Twenty-one objective responses were observed (46%, 95% confidence interval (CI): 31%-60%), including five complete responses (11%) and sixteen partial responses (35%). Following induction chemotherapy plus radiation therapy, 9 of 21 evaluable patients were rendered disease free, while 8 additional patients had a partial response. After a median follow-up of 18 months, the median duration of response was 12 months, (range 3-25+), and the median overall survival was 11 months. Six early deaths were considered possibly treatment-related (sepsis following grade 4 neutropenia in two cases, hypovolemic shock following severe diarrhea in four cases). Neutropenia was the most severe toxicity (grade 3-4 in 28 patients, median duration 4 days); diarrhea and vomiting were the most troublesome non-haematologic toxicities (grade 4 in 4 and 3 patients, respectively). CONCLUSIONS The combination of docetaxel and cisplatin is active in SCCHN, but toxicity is substantial. This schedule does not appear to offer any advantage compared with conventional regimens.