Goodness-of-fit test for monotone proportional subdistribution hazards assumptions based on weighted residuals.

Recently goodness-of-fit tests have been proposed for checking the proportional subdistribution hazards assumptions in the Fine and Gray regression model. Zhou, Fine, and Laird proposed weighted Schoenfeld-type residuals tests derived under an assumed model with specific form of time-varying regression coefficients. Li, Sheike, and Zhang proposed an omnibus test based on cumulative sums of Schoenfeld-type residuals. In this article, we extend the class of weighted residuals tests by allowing random weights of Schoenfeld-type residuals at ordered event times. In particular, it is demonstrated that weighted residuals tests using monotone weight functions of time are consistent against monotone proportional subdistribution hazards assumptions. Extensive Monte Carlo studies were conducted to evaluate the finite-sample performance of recent goodness-of-fit tests. Results from simulation studies show that weighted residuals tests using monotone random weight functions commonly used in non-proportional hazards regression settings tend to be more powerful for detecting monotone departures than other goodness-of-fit tests assuming no specific time-varying effect or misspecified time-varying effects. Two examples using real data are provided for illustrations. Copyright © 2016 John Wiley & Sons, Ltd.

First-Line Chemotherapy for Metastatic Esophageal Squamous Cell Carcinoma: Clinico-Biological Predictors of Disease Control.

OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

BACKGROUND: Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. METHODS/DESIGN: PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. DISCUSSION: This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. TRIAL REGISTRATION: NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program.

BACKGROUND: Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting. METHODS: REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models. RESULTS: Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis. CONCLUSION: The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib. TRIAL REGISTRATION: Clinicaltrials.gov NCT02310477 .

Sentinel lymph node identification using superparamagnetic iron oxide particles versus radioisotope: The French Sentimag feasibility trial.

BACKGROUND AND OBJECTIVES: The French Sentimag feasibility trial evaluated a new method for the localization of breast cancer sentinel lymph node (SLN) using Sienna+®, superparamagnetic iron oxide particles, and Sentimag® detection in comparison to the standard technique (isotopes ± blue dye). METHODS: We conducted a prospective multicentric paired comparison trial on 115 patients. SLN localization was performed using both the magnetic technique and the standard method. Detection rate and concordance between magnetic and standard tracers were calculated. Post-operative complications were assessed after 30 days. RESULTS: Results are based on 108 patients. SLN identification rate was 98.1% [93.5-99.8] for both methods, 97.2% [92.1-99.4] for Sienna+® and 95.4% [89.5-98.5] for standard technique. A mean of 2.1 SLNs per patient was removed. The concordance rate was 99.0% [94.7-100.0%] per patient and 97.4% [94.1-99.2] per node. Forty-six patients (43.4%) had nodal involvement. Among involved SLNs, concordance rate was 97.7% [88.0-99.9] per patient and 98.1% [90.1-100.0] per node. CONCLUSIONS: This new magnetic tracer is a feasible method and a promising alternative to the isotope. It could offer benefits for ambulatory surgery or sites without nuclear medicine departments. J. Surg. Oncol. 2016;113:501-507. © 2016 Wiley Periodicals, Inc.

A phase III randomized multicenter trial evaluating cognition in post-menopausal breast cancer patients receiving adjuvant hormonotherapy.

Cognitive impairment, especially verbal episodic memory and executive function impairments, has been considered to be a possible adverse effect of aromatase inhibitors (AI). This phase III open-label study compared the impact of tamoxifen and AI on verbal episodic memory (Rey auditory verbal learning test-RAVLT) and other cognitive functions (visual memory, psychomotor speed, and executive functions) after 6 and 12 months of treatment in breast cancer patients undergoing adjuvant hormonotherapy. Menopausal chemo-naïve patients with resectable breast cancer were randomly assigned (1:1) at the end of the radiotherapy to receive tamoxifen or AI. Neuropsychological assessments, self-reported quality of life, and depression assessments were performed at baseline, before any hormonal treatment, and at 6 and 12 months. Mixed design analysis models of variance was used to compare the evolution of the scores between the groups during follow-up. A total of 74 evaluable patients were enrolled (Tamoxifen arm, n = 37; AI arm, n = 37; letrozole n = 18; anastrozole n = 16; exemestane n = 3). The median age at inclusion was 61 years (range, minimum 49-maximum 69). The patient and breast cancer characteristics were well balanced between arms. After 6 months, no significant differential effect of AI or tamoxifen was observed on the RAVLT. Moreover, considering the other cognitive measures and the quality of life questionnaires, there were also no differences between the groups during the 1-year follow-up. In this study, AI has not demonstrated worse adverse effects on cognitive functions than tamoxifen during a 1-year follow-up.

Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.

BACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial. METHODS/DESIGN: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients. DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

CSF CA 15-3 in breast cancer-related leptomeningeal metastases.

UNLABELLED: The sensitivity of CSF cytology, the standard method for diagnosis of leptomeningeal metastases (LM), is low. Serum cancer antigen 15-3 (CA 15-3) is frequently used for the monitoring of patients with breast cancer (BC) and is a laboratory test available in most centers. The aim of the current study was to determine the feasibility of measuring CSF CA 15-3 and CA 15-3 CSF/serum ratio in patients with BC-related LM. Serum and CSF CA 15-3 values were evaluated in 20 BC patients with LM (Group 1), 20 patients with LM from other primary cancers (Group 2), 20 BC patients with parenchymal brain metastases only (Group 3) and 20 controls (Group 4). CSF and serum were collected on the same day. Serum and CSF CA 15-3 were assessed by an automatized immuno-enzymatic technology (TRACE(®) technology, KRYPTOR Automate, Brahms Society, France). In univariate analysis, BC patients with LM (Group 1) compared to other groups, a significantly elevated serum CA 15-3 (median 51 U/ml, range 12-2819) and CSF CA 15-3 (median 8.7 U/ml, range 0.1-251) was observed. Additionally, the CSF/serum ratio of CA 15-3 was significantly higher in this group of patients (median 0.18, range 0.002-4.40). Multivariate analysis identified a cut-off for CSF CA15-3 with 80 % sensitivity and 70 % specificity. CONCLUSIONS: The current study confirms the feasibility of determining CSF CA 15-3 using a widely available technology. Evaluation of the CSF CA 15-3 may be useful in the diagnosis and management of BC-related LM but further studies are needed.

6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.

BACKGROUND: Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer. METHODS: We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901. FINDINGS: 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001). INTERPRETATION: After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care. FUNDING: French National Cancer Institute.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BACKGROUND: To identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC). METHODS: In this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. RESULTS: During follow up (median: 6 [0.4-9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treatment (HR = 1.9 [1.2-3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0-3.2], p = 0.040). CONCLUSION: One EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

SHARE: a French multicenter phase III trial comparing accelerated partial irradiation versus standard or hypofractionated whole breast irradiation in breast cancer patients at low risk of local recurrence.

The standard treatment for breast cancer patients at low risk of recurrence is based on conservative surgery followed by radiation therapy delivered to the whole breast. The accelerated partial breast irradiation (APBI) concept, developed more than 15 years ago, could be an option in selected patients. However, the ideal patient profile for APBI is still not clearly identified. Recent reports from the American Society for Radiation Oncology (ASTRO) and the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) have suggested selection criteria for "suitable patients" who could receive APBI outside of clinical trials. Currently, there are 6 ongoing phase III trials. All are characterized by a significant heterogeneity regarding inclusion criteria and stratification factors. The French UNICANCER trial (SHARE; ClinicalTrials.gov identifier NCT01247233) will randomize 2,800 patients in 3 arms: APBI (1 week) using 3-dimensional (3D) conformal radiotherapy, standard radiotherapy (6.5 weeks), and hypofractionated radiotherapy (3 weeks). In this article, we review the reported retrospective studies as well as older randomized trials. We will also describe the differences between the 6 ongoing phase III trials and the particularities of the French SHARE trial.

What does a modified-Fibonacci dose-escalation actually correspond to?

BACKGROUND: In most phase I oncology trials, it is often stated that the dose increments follow a "modified-Fibonacci sequence". This term, however, is vague. METHODS: To better characterize this sequence, we reviewed 81 phase I trials based on this concept. RESULTS: Out of 198 phase I oncology trials, 81 (41%) are based on modified-Fibonacci series. Actual incremental ratios varied in a large range from 0.80 to 2.08. The median of actual increments was about 2.00, 1.50, 1.33, 1.33, 1.33, 1.33, 1.30, 1.35…. The "modified Fibonacci-sequence" gathers heterogeneous variation of the genuine sequence, which does not tend to a constant number at higher dose-levels. CONCLUSION: This confusing term should be avoided.

Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial.

BACKGROUND: Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate. RESULTS: From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32-76 years). The median duration of treatment was 5.2 months (range, 0.7-8.5 months), and a median of nine cycles was given per patient (range, 1-12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8-39.7 months). The objective response rate was 80.9% (95% CI, 65.9%-91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6-10.4 months), respectively. The most frequent grade 3-4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%). CONCLUSION: The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.

Utility-based optimization of combination therapy using ordinal toxicity and efficacy in phase I/II trials.

An outcome-adaptive Bayesian design is proposed for choosing the optimal dose pair of a chemotherapeutic agent and a biological agent used in combination in a phase I/II clinical trial. Patient outcome is characterized as a vector of two ordinal variables accounting for toxicity and treatment efficacy. A generalization of the Aranda-Ordaz model (1981, Biometrika 68, 357-363) is used for the marginal outcome probabilities as functions of a dose pair, and a Gaussian copula is assumed to obtain joint distributions. Numerical utilities of all elementary patient outcomes, allowing the possibility that efficacy is inevaluable due to severe toxicity, are obtained using an elicitation method aimed to establish consensus among the physicians planning the trial. For each successive patient cohort, a dose pair is chosen to maximize the posterior mean utility. The method is illustrated by a trial in bladder cancer, including simulation studies of the method's sensitivity to prior parameters, the numerical utilities, correlation between the outcomes, sample size, cohort size, and starting dose pair.

Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy.

PURPOSE: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, > or =3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. EXPERIMENTAL DESIGN: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). RESULTS: Overall, 13 and 21 patients were found to possess a total of <4 and > or =4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had > or =4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had > or =4 SNPs (P < 0.001). CONCLUSIONS: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.

Early stopping rules in clinical trials based on sequential monitoring of serious adverse events.

Several multistage or group sequential statistical methods have been developed for defining stopping rules in terms of efficacy in phase II and III clinical trials, but they rely on interim analyses after the inclusion of a fixed number of patients. These methods, however, need to be adapted for the evaluation of serious adverse events (SAEs), which can occur relatively early in the trial. A high frequency of their occurrence may require the trial to close early. The methods developed here define stopping rules after the occurrence of each SAE by comparing the number of patients included to the number of patients satisfying maximum SAE criteria. The nominal type I error, power, and average sample number (ASN) under specific hypotheses are obtained through simulations. Data from a clinical trial are presented as an example.

Predicting distant dissemination in patients with early breast cancer.

BACKGROUND: Prediction of distant metastases is of paramount importance in the knowledge and management of breast cancer patients. The objective of this study was to assess conventional prognostic factors in a large database of patients with early breast cancer, including those with small tumors diagnosed through regional screening, to determine the risk of distant dissemination. METHODS: The study included 4,797 patients of the Stockholm database who did not receive systemic adjuvant treatments. The main endpoint was metastasis free-interval. Individual risks of distant metastasis were estimated using the regression coefficients of the significant prognostic factors in Cox multivariate analyses. For each level of metastatic risk the pattern of failure was analyzed by a model assuming competing risks. RESULTS: The three independent significant prognostic factors were histologic tumor size, number of involved axillary lymph nodes and progesterone receptor level. However, the latter factor added limited additional information of borderline clinical significance. Thus, subsequent estimations were done with a prognostic score taking into account only the former two most performant factors in the whole population. The risk of distant metastasis of observed values of tumor size categories fitted with published results of a series containing significantly larger tumors. A large variation of tumor size predicts 10-year distant metastasis risk ranging from below 10% up to 90%. Tumors of 10 mm or less had a 10-year metastatic risk of less than 10%. CONCLUSIONS: The results of this study are consistent with a linear effect of tumor size, within the range of data, on 10-year distant dissemination probabilities. Further refinement on prognostic value is needed for tumors of 15 mm or less.

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan.

PURPOSE: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial. EXPERIMENTAL DESIGN: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1. RESULTS: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005]. CONCLUSIONS: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.