Safety and outcome of chemoradiotherapy in elderly patients with rectal cancer: results from two French tertiary centres.

BACKGROUND: The risks of chemoradiotherapy in elderly patients with rectal cancer have not yet been well-characterised. METHODS: We retrospectively reviewed the charts of patients with rectal cancer over 70 years old who were treated with chemoradiotherapy in two French university hospitals. RESULTS: A total of 125 patients were evaluated. Mean age was 75.1 ± 4.1 years and ranged from 70 to 90 years. Adverse effects ≥ grade 2 were observed in 32% of the patients and adverse effects ≥ grade 3 in 15%. Dose reduction for toxicity was performed in 18% of the patients and chemoradiotherapy discontinuation was necessary in 9%. Postoperative morbidity was 16% with two treatment-related deaths. Two-year survival rate was 84%. No variables had any influence on treatment-related adverse events. CONCLUSIONS: In selected elderly patients, chemoradiotherapy is well-tolerated, without any significant increase in adverse events, and the results are similar to those recorded in younger patients.

Esophageal cancer in the elderly: an analysis of the factors associated with treatment decisions and outcomes.

BACKGROUND: Only limited data has been reported so far regarding oesophageal cancer (EC) in elderly patients. The aim of the study is to identify the baseline parameters that influenced therapeutic decision. METHODS: All consecutive patients 70 years or older being treated for EC were retrospectively analyzed. Patients without visceral metastasis were divided into two groups: treatment with curative intent (chemoradiotherapy, surgery, radiotherapy, mucosectomy or photodynamic therapy) or best supportive care (BSC). Patients with metastasis were divided into two groups: palliative treatment (chemotherapy, chemoradiotherapy or radiotherapy) or BSC. RESULTS: Two hundred and eighty-two patients were studied. Mean age was 76.5 ± 5.5 years and 22.4% of patients had visceral metastasis. In patients without visceral metastasis (n = 220) the majority had treatment with curative intent (n = 151) whereas in patients with metastasis (n = 62) the majority had BSC (n = 32). Severe adverse events (≥ grade 3) were observed in only 17% of the patients. Patients without specific carcinologic treatment were older, had more weight loss, worse WHO performance status and Charlson score in multivariate analysis. DISCUSSION: Our results suggest that elderly patients with an EC could benefit from cancer treatment without major toxicities. Weight loss, WHO performance status and the Charlson score could be used to select the appropriate treatment in an elderly patient.

Dietary fatty acids and recurrence of colorectal adenomas in a European intervention trial.

Epidemiological studies have provided inconsistent data about the role of dietary fatty acids in colorectal cancer, and few studies have addressed their role in colorectal adenoma. The aim of the study was to assess the risk of overall adenoma recurrence associated with dietary consumption of total fat, subtypes of fat, and specific fatty acids (oleic acid, linoleic acid, alpha-linolenic acid). The study sample was composed of 523 patients with confirmed adenomas at the index colonoscopy, 35 to 75 yr old, who completed the European fiber-calcium intervention trial and had an initial dietary assessment using a qualitative and quantitative food questionnaire. The overall 3-yr recurrence rate was 22.6% (118 out of 523 patients). There were no significant associations between overall adenoma recurrence and either total fat, subtypes of fat, or specific fatty acids. However, polyunsaturated fatty acids and linoleic acid were both moderately but significantly associated with distal and multiple recurrence. No significant associations were observed with recurrence of proximal or advanced adenomas. Our findings do not support the hypothesis of strong associations between dietary fatty acids and recurrence of colorectal adenomas. The hypothesis of a differential role of specific fatty acids according to colorectal subsites deserves further investigation.

Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1).

OBJECTIVES: PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer. METHODS: Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively. RESULTS: The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23). CONCLUSION: The trial failed to demonstrate non-inferiority of raltitrexed. FUNDING: Free drugs and financial support from AstraZeneca.

Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer.

PURPOSE: The aim of the study was to evaluate the relationship between serum carcinoembryonic antigen (CEA) kinetic and response to chemotherapy in patients with unresectable metastasis of colorectal cancer. PATIENTS AND METHODS: The kinetic was calculated using the slope of an exponential-regressive curve connecting the semi-logarithmic values of CEA. Receiver operating characteristic (ROC) curves were drawn to select the CEA slope thresholds to define patients with progressive or responsive disease with the highest sensitivity, specificity, and diagnosis accuracy odds ratio (DOR). The correlation between the CEA slopes and progression-free survival (PFS) was evaluated by the Cox model and Kaplan-Meier methods. RESULTS: A total of 122 patients were included. Progression defined by CEA slope greater than +0.05 resulted in sensitivity of 85.7%, specificity of 85.1%, and DOR of 34. The area under the ROC (AUROC) curve was 0.885 (95% CI, 0.815 to 0.936; P = .0001). Response defined by CEA slope less than -0.2 resulted in sensitivity of 74.7%, specificity of 82.5%, and DOR of 16. The AUROC curve was 0.847 (95% CI, 0.770 to 0.906; P = .0001). The difference between AUROC curves calculated with six or four CEA values was not significant. PFS was correlated with CEA slopes (hazard ratio, 4.6; 95% CI, 2.48 to 8.57). The median PFS was 10 months for patients with CEA slope values less than -0.2 months versus 6 months for patients with CEA slope values greater than -0.2 (P < .0001). CONCLUSION: These results suggest that the CEA kinetic is an accurate, simple, and noninvasive method to identify the disease progression in patients with unresectable metastasis of colorectal cancer.

Baseline nutritional status is predictive of response to treatment and survival in patients treated by definitive chemoradiotherapy for a locally advanced esophageal cancer.

OBJECTIVES: To assess the impact of baseline nutritional status on treatment response and survival in nonmetastatic patients with a locally advanced esophageal cancer (LAEC) treated with definitive chemoradiotherapy (CRT). METHODS: One hundred five patients with LAEC treated by definitive CRT were retrospectively included. The CRT regimen was based on an external radiotherapy (RT) delivered concomitantly to a cisplatin-based chemotherapy (CT). Patients were considered to have a complete response (CR) to CRT when no residual tumor was detected on CT scan and esophagoscopy performed 2 months after the end of CRT. Multivariate analysis of predictive factors of response to CRT and survival were performed using a logistic regression and a Cox model, respectively. RESULTS: Mean value of baseline nutritional parameters was significantly different between nonresponder (N = 42) and responder (N = 63) patients to CRT (weight loss 10%vs 5.8%, P= 0.0047; serum albumin level 35 g/L vs 38.7 g/L, P= 0.0004; BMI 22.8 kg/m2vs 25.2 kg/m2, P= 0.01). In multivariate analysis, serum albumin level > 35 g/L was the only independent predictive factor of CR to CRT (P= 0.009). Independent prognostic factors of survival were BMI > 18 kg/m2 (P= 0.003), dysphagia Atkinson score <2 (P= 0.008), dose of RT > 50 Grays (Gy) (P < 0.0001) and CR to CRT (P < 0.0001). CONCLUSIONS: Survival was influenced by baseline nutritional status as well as dysphagia, dose of RT, and CR to CRT. Despite the retrospective design of the study, our results may provide the concept basis for performing a prospective nutritional intervention study in patients treated by definitive CRT for an esophageal cancer.

Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.

PURPOSE: Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer. Therefore, a randomized trial was carried out to compare, in responders only, chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors. PATIENTS AND METHODS: Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. Patients with response and no contraindication to either treatment were randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three cycles of FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10%. RESULTS: Of 444 eligible patients, 259 were randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma. Two-year survival rate was 34% in arm A versus 40% in arm B (hazard ratio for arm B v arm A = 0.90; adjusted P = .44). Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P < .001). The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P = .002). Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P = .02). CONCLUSION: Our data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.

A simple method for the routine detection of somatic quantitative genetic alterations in colorectal cancer.

BACKGROUND & AIMS: Several quantitative genetic alterations have been suggested to have in colorectal cancer (CRC) either a prognostic or a therapeutic predictive value. Routine detection of these alterations is limited by the absence of simple methods. METHODS: The somatic quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF) is based on the simultaneous amplification under quantitative conditions of several dye-labeled targets both from tumor and nonmalignant tissues. For each patient, the resulting QMPSF fluorescent profiles are superimposed, and quantitative changes are simply detected by an increase or decrease of the corresponding fluorescent peaks. Two assays were developed and applied to 57 CRC: a "bar code" exploring several loci with known prognostic value and a "kinogram" studying the copy number change of kinase genes, against which inhibitors have been developed. RESULTS: The bar code revealed that the most frequent alterations were the gain of AURKA/20q13 (53%) and MYC/8q24 (39%) and heterozygous deletion of DCC/18q21.3 (39%) and TP53/17p13 (23%). The kinogram detected a gene copy number increase for AURKA, PTK2, MET, and EGFR in 53%, 37%, 33%, and 28% of the tumors, respectively. QMPSF results were validated by comparative genomic hybridization and multiplex real-time polymerase chain reaction on genomic DNA. CONCLUSIONS: The somatic QMPSF is a simple method able to detect simultaneously on a routine basis several quantitative changes in tumors. Its flexibility will allow the integration of clinically relevant genes. This high throughput method should be a valuable complementary tool of fluorescent in situ hybridization and comparative genomic hybridization.

Response to definitive chemoradiotherapy and survival in patients with an oesophageal adenocarcinoma versus squamous cell carcinoma: a matched-pair analysis.

OBJECTIVES: The impact of the histological tumour type in patients treated with definitive chemoradiotherapy (CRT) for an oesophageal cancer is not well established. The aim of this retrospective matched-pair analysis was to evaluate the clinical complete response (CCR) to definitive CRT and the outcome between 2 groups of patients. METHODS: Fifty-seven patients with an oesophageal adenocarcinoma (ADC) were matched according to the tumour stage and the WHO performance as well as the CRT regimen status including 57 patients with an oesophageal squamous cell carcinoma (SCC). CRT was based on radiotherapy combined with a cisplatin-based chemotherapy. RESULTS: A CCR was observed in 40 patients (70.2%) with an SCC as compared with 26 patients (45.6%) with an ADC (p = 0.013). SCC patients received significantly more of planned cisplatin and radiotherapy doses than ADC patients (82.0 vs. 67.7%, p = 0.042, and 92.5 vs. 84.5%, p = 0.023, respectively). In responders to CRT, local recurrence was significantly more frequent in SCC patients (52.5 vs. 26.9%, p = 0.046). Median survival in all patients as well as in responders to CRT was not different between the 2 groups. CONCLUSION: Our study showed that treatment completion and CCR to definitive CRT were more frequent in SCC with, however, more local recurrences in these patients. Further studies are required to confirm this difference in response rate to definitive CRT according to histological type of the tumour in oesophageal cancer.

Impact of radiation schedule and chemotherapy duration in definitive chemoradiotherapy regimen for esophageal cancer.

UNLABELLED: Impact of radiotherapy (RT) schedule on local response and duration of the 5-fluorouracil/cisplatin (5 FU/CDDP) chemotherapy (CT) on m are still questioning in chemoradiotherapy (CRT) regimen in esophageal carcinoma. AIM: Evaluate two RT schedules and two different CT durations by a retrospective comparison of the CRT regimens used by two centres between 1994 and 2000. METHODS: In centre I (regimen I), patients received 2 CT concomitantly to a continuous RT (50 Gy/25 fractions/5 weeks). In centre II (regimen II), patients received 6 CT, 3 were concomitant to a split course RT (20 Gy/10 fractions x 3 courses) and 3 CT were delivered after CRT. RESULTS: A total of 129 patients were included, 74 in centre I and 55 in centre II respectively. Main patient characteristics were similar between the two groups. Clinical complete response to CRT was significantly more frequent in regimen I (83.8% vs 65.4%; P=0.02). The median overall survival (OS) was 20 months in regimen I and 22 months in regimen II (NS). During follow-up, responder patients to CRT in regimen II experienced significant fewer metastasis (51.6% vs 27.8%; P=0.03) with a trend to an increased 5-year survival (19.4% vs 11.3%) and OS (26.5 vs 21.0 months) (NS). Grade 3-4 toxicities were not different. CONCLUSION: Clinical complete response to CRT was significantly more frequent with a continuous RT whereas additional CT after CRT significantly reduced metastasis occurrence. CRT regimen in esophageal carcinoma may be more effective using a continuous RT schedule and additional CT courses after CRT completion.

Predictive factors of survival in patients treated with definitive chemoradiotherapy for squamous cell esophageal carcinoma.

AIM: The aim of the study was to evaluate the predictive factors of survival in patients with locally advanced squamous cell esophageal carcinoma (LASCOC) treated with definitive chemoradiotherapy (CRT) regimen based on the 5FU/CDDP combination. METHODS: All patients with LASCOC treated with a definitive CRT using the 5FU/CDDP combination between 1994 and 2000 were retrospectively included. Clinical complete response (CCR) to CRT was assessed by esophageal endoscopy and CT-scan 2 mo after CRT completion. Prognostic factors of survival were assessed using univariate and multivariate analysis by the Cox regression model. RESULTS: A total of 116 patients were included in the study. A CCR to CRT was observed in 86/116 (74.1%). The median survival was 20 mo (range 2-114) and the 5-year survival was 9.4%. Median survival of responder patients to CRT was 25 mo (range 3-114) as compared to 9 mo (range 2-81) in non-responder patients (P < 0.001). In univariate analysis, survival was associated with CCR (P < 0.001), WHO performance status < 2 (P = 0.01), tumour length < 6 cm (P = 0.045) and weight loss < 10% was in limit of significance (P = 0.053). In multivariate analysis, survival was dependant to CCR (P < 0.0001), weight loss < 10% (P = 0.034) and WHO performance < 2 (P = 0.046). CONCLUSION: Our results suggest that survival in patients with LASCOC treated with definitive CRT was correlated to CCR, weight loss and WHO performance status.

Palliative esophageal stent placement using endoscopic guidance without fluoroscopy.

AIMS: Fluoroscopy is not available in every endoscopic unit. This situation leads to delays in treatment or to transfer of patients to other centres for stent insertion. We assessed safety and effectiveness of expandable esophageal metal stent placement under endoscopic control without fluoroscopy using a thin gastroscope. PATIENTS AND METHODS: From October 2002 to June 2004, thirty-three consecutive patients have been included for esophageal stent placement under endoscopic control alone with a nasogastroscope (5.9 mm). A proximal release covered stent (Ultraflex; Boston Scientific Microvasive) was used. Indications were malignant esophageal stricture (N = 26), malignant extrinsic compression (N = 2 ) and esophago-respiratory neoplastic fistulae (N = 5). RESULTS: Stent placement using endoscopic control alone was successful in 30/33 (90%) patients. Complications occurred in 11 patients. Early complications (<7 days) included one death from pulmonary embolism, severe retrosternal pain needing transient morphinic treatment (N = 2) and GERD despite antisecretory therapy (N = 1). Late complications included: food impaction (N = 1), tumour overgrowth-related obstruction of the stent (N = 5) and one late esophago-respiratory fistula at 4 months at the proximal end of the stent. Relief of dysphagia was obtained for all patients at 48 hours and dysphagia score decreased from 3.1 before stent to 1.2 at 1 month (P < 0.05). CONCLUSION: Expandable esophageal stents can be accurately and safely placed using endoscopy with a thin gastrosocope. This method obviates the requirement of fluoroscopic access, lacking in many centres, and avoids exposure to X-ray.

Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study.

PURPOSE: To evaluate response rate and toxicity of irinotecan and oxaliplatin plus fluorouracil (FU) and leucovorin (Folfirinox) in advanced pancreatic adenocarcinoma (APA). PATIENTS AND METHODS: Chemotherapy-naive patients with histologically proven APA and bidimensionally measurable disease were treated with Folfirinox therapy every 2 weeks, which comprised oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus leucovorin 400 mg/m(2) followed by bolus FU 400 mg/m(2) on day 1, then FU 2,400 mg/m(2) as a 46-hour continuous infusion. Quality of life (QOL) was assessed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). RESULTS: Forty-seven patients were entered, and 46 received treatment. Thirty-five patients (76%) had metastatic disease. A total of 356 cycles were delivered, with a median of eight cycles per patient (range, one to 24 cycles). All patients were assessable for safety. No toxic death occurred. Grade 3 to 4 neutropenia occurred in 52% of patients, including two patients with febrile neutropenia. Other relevant toxicities included grade 3 to 4 nausea (20%), vomiting (17%), and diarrhea (17%) and grade 3 neuropathy (15%; Levi's scale). The confirmed response rate was 26% (95% CI, 13% to 39%), including 4% complete responses. Median time to progression was 8.2 months (95% CI, 5.3 to 11.6 months), and median overall survival was 10.2 months (95% CI, 8.1 to 14.4 months). Between baseline and end of treatment, patients had improvement in all functional scales of the EORTC QLQ-C30, except cognitive functioning. Responders had major improvement in global QOL. CONCLUSION: With a good safety profile, a promising response rate, and an improvement in QOL, Folfirinox will be further assessed in a phase III trial.

Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected?

OBJECTIVES: In asymptomatic patients presenting with non-resectable synchronous metastatic disease from colorectal adenocarcinoma, the beneficial effect of resecting the primary tumor remains to be documented. The aim of this study was to compare survival of patients with metastatic colorectal cancer who underwent elective resection of the primary tumor to those who did not. METHODS: A retrospective analysis of patients with metastatic colo-rectal cancer treated between June, 1996 and December, 1999 was performed. Overall survival was compared between patients who underwent first-line resection of the primary colorectal tumor (group 1) or those who did not undergo elective resection of the primary (group 2). The probability of surgical resection of the primary tumor for gastrointestinal complications in group 2 was evaluated. RESULTS: Thirty-one and 23 patients were included in groups 1 and 2 respectively. Five patients (21.7%, 95% confidence interval CI95% 4.9-38.5%) in group 2 required surgical treatment for intestinal obstruction due to the primary tumor. Two clinical characteristics were significantly different between groups 1 and 2: rectal localization (9.7% versus 34.7%; P=0.03) and presence of fewer than three metastases (29.0% versus 4.3%; P=0.03). Survival curves were not significantly different (logrank). Median duration of survival was 21 and 14 Months, respectively (P=0.718). CONCLUSION: In patients with non-resectable synchronous metastatic disease, non-surgical management of the primary tumor is a rational alternative if asymptomatic. A prospective randomized trial integrating the quality-of-life factor should be organized.

Prognostic value of TP53 transcriptional activity on p21 and bax in patients with esophageal squamous cell carcinomas treated by definitive chemoradiotherapy.

PURPOSE: The aim of this study was to evaluate biologic factors on survival and clinical response after definitive concomitant chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC). METHODS AND MATERIALS: TP53 protein hyperexpression (immunochemistry [IHC]) and functional assay (FA) of TP53, measuring the ability of TP53 to transactivate p21 and bax reporter systems, were performed in patients with ESCC treated by CRT. The impact of parameters studied on survival and clinical response to CRT was assessed. RESULTS: Thirty-eight patients with ESCC were included. TP53 alterations were detected in 84.2% of cases with FA. All TP53 mutations abolished the transactivation of p21 and bax reporter systems. After CRT, complete response rate was 55.3%. The median survival of the population was 17.5 months. Serum albumin (p = 0.002), weight loss <10% (p = 0.005), and response to treatment (p < 0.001) were significantly linked with survival. TP53 alteration in FA was not significantly predictive of response to CRT (p = 0.132) nor survival (p = 0.154). CONCLUSIONS: Our results suggest that wild-type TP53 in ESCC could be associated with good response to definitive CRT. However, the small rate of ESCC with wild-type TP53 suggests that systematic determination of TP53 status is not appropriate for the management of the ESCC population.