Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. METHODS: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. FINDINGS: We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, p(interaction)=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, p(interaction)=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation. INTERPRETATION: Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. FUNDING: None.

Dosimetric impact of different multileaf collimators on prostate intensity modulated treatment planning.

AIM: The main purpose of this study is to perform a dosimetric comparison on target volumes and organs at risks (OARs) between prostate intensity modulated treatment plans (IMRT) optimized with different multileaf collimators (MLCs). BACKGROUND: The use of MLCs with a small leaf width in the IMRT optimization may improve conformity around the tumor target whilst reducing the dose to normal tissues. MATERIALS AND METHODS: Two linacs mounting MLCs with 5 and 10 mm leaf-width, respectively, implemented in Pinnacle(3) treatment planning system were used for this work. Nineteen patients with prostate carcinoma undergoing a radiotherapy treatment were enrolled. Treatment planning with different setup arrangements (7 and 5 beams) were performed for each patient and each machine. Dose volume histograms (DVHs) cut-off points were used in the treatment planning comparison. RESULTS: Comparable planning target volume (PTV) coverage was obtained with 7- and 5-beam configuration (both with 5 and 10 mm MLC leaf-width). The comparison of bladder and rectum DVH cut-off points for the 5-beam arrangement shows that 52.6% of the plans optimized with a larger leaf-width did not satisfy at least one of the OARs' constraints. This percentage is reduced to 10.5% for the smaller leaf-width. If a 7-beam arrangement is used the value of 52.6% decreases to 21.1% while the value of 10.5% remains unchanged. CONCLUSION: MLCs collimators with different widths and number of leaves lead to a comparable prostate treatment planning if a proper adjustment is made of the number of gantry angles.

Perioperative high-dose-rate brachytherapy in the treatment of recurrent malignant gliomas.

PURPOSE: To assess the feasibility and effectiveness of perioperative high-dose-rate brachytherapy for recurrent malignant gliomas. PATIENTS AND METHODS: Between 2005 and 2008, 21 patients (14 males and seven females) with relapsed malignant glioma underwent a second surgery followed by a brachytherapy implant in the surgical cavity. Median age was 60 years, and median Karnofsky performance status 80. A single fraction of 18 Gy specified at 5 mm depth was administered perioperatively. Then, the applicator was removed nonsurgically. Mean postoperative hospitalization time was 3 days. RESULTS: At the time of analysis, 15 patients (71%) had died and six (29%) were alive. Median follow-up was 32.3 months. Median overall survival from diagnosis amounted to 21.7 months. Median survival after recurrence was 8.0 months, and 6-month progression-free survival 42%. Patients were stratified into classes according to the prognostic recursive partitioning analysis. CONCLUSION: Perioperative brachytherapy has proven to be safe and well tolerated in patients with recurrent malignant glioma. No severe toxicity was reported, and the treatment has proven to be effective in symptomatic recurrences of malignant gliomas.

Accuracy of endoanal ultrasound in the follow-up assessment for squamous cell carcinoma of the anal canal treated with radiochemotherapy.

BACKGROUND: Radiochemotherapy has largely replaced surgery in the treatment for squamous cell cancer of the anal canal. Transanal ultrasonography is well documented as an important investigation method in the management of anal carcinoma. This study aimed to evaluate the accuracy of endoanal ultrasound in the study of the postradiation findings and to distinguish between postradiation fibrosis, residual tumor, and local recurrence. METHODS: The study enrolled 16 consecutive patients with biopsy-proven squamous carcinoma of the anal canal between 2003 and 2006. All the patients underwent a pretreatment and at least four posttreatment endosonographies, according to the follow-up period. All the patients were treated with the same radiochemotherapy protocol. RESULTS: Nine patients had stage uT2 disease; none had uT3 disease; and seven had uT4 disease. There was no evidence of residual tumor in the T2 group after treatment. In the T4 patients after treatment, ultrasound demonstrated tumor regression or abnormalities considered to be radiation-induced changes rather than residual diseases. Only for three patients was a posttreatment biopsy performed to evaluate recurrence (two uT2 and one uT4). Surgical treatment of recurrence was performed for two uT4 patients. CONCLUSIONS: Endoanal ultrasound is a safe and effective method for evaluating and following anal cancer before and after treatment. Experience and evaluation during the period of the ultrasonographic abnormalities could give a clear idea concerning the evolution of the anal tumors treated with radiochemotherapy.

Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients.

PURPOSE: In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients. METHODS AND MATERIALS: The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT). RESULTS: Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules. CONCLUSION: A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

High-dose-rate brachytherapy in a large squamous cell carcinoma of the hand.

PURPOSE: High-dose-rate (192)Ir-based brachytherapy can be used as an exclusive treatment of large skin tumors when teletherapy or surgery is not feasible. A case of an extended inoperable skin epithelioma of the hand is reported; the lesion involved the first finger, the tenar, the palm, and the back. METHODS AND MATERIALS: A detailed description of an individual case is reported. A customized mold was created for the patient, to administer a fractionated brachytherapy treatment in a reproducible way. RESULTS: A total dose of 50Gy was administered in 10 fractions, after a time schedule of three fractions per week. The treatment was well tolerated and the acute effects (mainly, epitheliolysis) were resolved completely within a month after the treatment. CONCLUSIONS: Nine months after the treatment, the malignant lesion completely disappeared and the cosmetic results are quite satisfactory. Therefore, we conclude that the treatment technique is well adaptable to any particular geometry and that the fractionation scheme has proven to be well tolerated and effective in tumor eradication.

Quality indicators in radiotherapy.

BACKGROUND AND PURPOSE: There is a widespread and increasing tendency to develop hospital performance indicators in the field of accreditation/certification systems and quality benchmarking. A study has been undertaken to develop a set of performance indicators for a typical radiotherapy Centre and to evaluate their ability to provide a continuous quality improvement. MATERIALS AND METHODS: A working group consisting of radiation oncologists, medical physicists and radiation technologists under the coordination of experts in health technology assessment has elaborated a set of general indicators able to monitor performances and the quality level of a typical radiotherapy Centre. The work has been carried out through four steps: a preliminary set of indicators was selected; data on these indicators were collected in a number of Italian radiotherapy Centres and medical physics Services; problems in collection and analysis of data were discussed; a final set of indicators was developed. RESULTS: A final set of 13 indicators is here presented. They concern general structural and/or operational features, health physics activities and accuracy and technical complexity of the treatment. CONCLUSIONS: The indicators tested in a few Italian Centres of radiotherapy and medical physics Services are now ready to be utilized by a larger community.

Brain recurrences in patients with ovarian cancer: report of 12 cases and review of the literature.

The aim of the investigation was to assess 12 cases of brain recurrences among ovarian cancer patients who had undergone surgery followed by platinum-based chemotherapy. Brain lesions were the first recurrence in 4 (33%) patients, the second recurrence in 7 (58%), and the fourth recurrence in one patient. The median time from ovarian cancer diagnosis to brain metastasis detection was 33.5 months (range, 13.5-86.5 months), brain metastases were multiple in 6 (50%) cases, and extra-cranial disease was present in 7 (58%) cases. Brain recurrence was symptomatic in 10 patients and the clinical presentation included impaired deambulation, extremity weakness, seizure, headache, nausea/vomiting and visual disturbance. Out of the 6 patients with single brain metastases, one underwent surgery, one had surgical excision followed by whole brain irradiation, 3 patients received stereotactic radiotherapy (followed by chemotherapy for coexistent extra-abdominal recurrence in one), and one had only symptomatic treatment. Out of the 6 patients with multiple brain metastases, four received whole brain irradiation (followed by chemotherapy for concomitant extra-cranial recurrence in one case), one patient had gamma-knife irradiation of three cerebral lesions (followed by chemotherapy for concurrent abdominal recurrence), and one patient had only symptomatic treatment. The median overall survival from diagnosis of brain metastasis was 8.3 months (range, 1-28 months), and it was not related to the number of brain metastases (multiple versus single), presence or absence of extra-cranial disease, or interval between ovarian cancer diagnosis and brain metastasis detection (<33.5 months versus > or =33.5 months). In conclusion, brain metastasis from ovarian cancer can represent a late manifestation of the disease, associated with a very poor prognosis.

Synergistic antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, with gemcitabine and ionizing radiation against pancreatic cancer.

PURPOSE: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. EXPERIMENTAL DESIGN: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. RESULTS: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. CONCLUSIONS: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.

Dose tracking assessment for image-guided radiotherapy of the prostate bed and the impact on clinical workflow.

BACKGROUND: The cumulative dose was compared with the planned dose among fourteen patients undergoing image-guided, intensity-modulated radiotherapy of the prostate bed. Moreover, we investigated the feasibility of adding dose tracking to the routine workflow for radiotherapy. METHODS: Daily cone beam computed tomography was conducted for image-guided radiotherapy, and weekly cumulative delivered doses were calculated for dose tracking. Deformable image registration was applied to map weekly dose distributions to the original treatment plan and to create a cumulative dose distribution. The dose-volume histogram (DVH) cut-off points for the rectum and bladder and the planning target volume (PTV), were used to compare the planned and cumulative delivered doses. The additional time required by the departmental staff to complete these duties was recorded. RESULTS: The PTV coverage of the delivered treatment did not satisfy the expected goal for three patients (V98% >98%). In another three patients, the DVH cut-off point for the bladder was higher than the limits, while for the rectum, treatment was as expected in all cases (two patients failed both their bladder constraints and the PTV coverage). Overall, four patients did not satisfy one or more criteria at the end of their treatment. CONCLUSIONS: A well-defined strategy for dose tracking assessment is feasible, would have minimal impact on the workload of a radiotherapy department, and may offer objective information to support radiation oncologists in making decisions about adaptive procedures.

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer.

During the last decades there has been a continuing evolution in the surgical approach of squamous cell carcinoma of the vulva that has been traditionally treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. Patients with T1 tumour are usually treated with radical local excision, if the lesion is unifocal and the remainder of the vulva is normal. Patients with T1a disease have no risk of groin metastases and do not need lymphadenectomy, whereas those with T1b disease need ipsilateral inguinal-femoral lymphadenectomy if the lesion is lateral, and bilateral lymphadenectomy if the lesion is midline. Modifications of the surgical technique of deep femoral lymphadenectomy and the mapping of sentinel node can offer new interesting therapeutic perspectives. Postoperative adjuvant pelvic and groin irradiation is warranted for patients with two or more or macroscopically involved groin nodes. Locally advanced squamous cell carcinoma of the vulva has been long surgically treated with en-block radical vulvectomy and bilateral inguinal-femoral lymphadenectomy plus partial resection of urethra, vagina or anum, or by exenteration, with severe postsurgical complications, poor quality of life, and unsatisfactory survival rates. 5-Fluorouracil [5-FU] or 5-FU- and cisplatin-based chemotherapy concurrent with irradiation followed by tailored surgery represents an attractive therapeutic option for advanced disease, planned to avoid such ultra-radical surgical procedures and, hopefully, to improve patient outcome. Chemotherapy has also been used in neoadjuvant setting, with contrasting and generally unsatisfactory results, and in palliative treatment of patients with distant metastases. Surgery is the primary treatment also for vulvar malignancies other than squamous cell carcinoma, whereas the clinical usefulness of adjuvant irradiation or chemotherapy is still to be defined. Primary chemoradiation can be also used for advanced carcinoma of the Bartholin gland or for advanced adenocarcinoma associated with extramammary Paget's disease. The drugs used for chemotherapy of metastatic melanomas or sarcomas of the vulva are the same employed for the melanomas or sarcomas developed in other sites.

Long-term results in patients affected by testicular seminoma treated with radiotherapy: risk of second malignancies.

AIMS: To report clinical results in patients with testicular seminoma treated with postoperative radiotherapy with regard to survival, acute and late toxicity, and risk of second malignancy. MATERIALS AND METHODS: 176 stage I-Il testicular seminoma patients treated with radiotherapy from 1964 to 1994 at the Radiotherapy Division of Pisa University, using 60Co or Linac, were analyzed retrospectively. The follow-up ranged from 0.13 to 32.37 years, with a median of 12.1 years. The observed numbers of second malignancies were compared with those expected, taking into account age, sex, and incidence rates from the Tuscany Tumor Registry. RESULTS: Overall and specific survival at 10-15 years were 89-82% and 93-92%, respectively. Multivariate analysis revealed a significantly better survival in patients younger than 50 years and in those treated with Linac. Severe late sequelae occurred in 8% of the patients. Sixteen second malignancies were observed (14 solid tumors and 2 leukemias); median latency was 13 years (range, 3-27) and the observed/expected ratio 1.4 (P not significant). Solid cancers were localized in the bladder (2), kidney (2), skin (2), stomach (1), prostate (1), lung (1), larynx (1), uvea (1) and contralateral testicle (1); 1 patient presented an intestinal carcinoid and 1 a metastasis from an unknown primary. The risk of a second malignancy was higher in the patient group receiving less than 4000 cGy (observed/expected, 2.8; P = 0.015). CONCLUSIONS: The study confirmed the high cure rate in stage I-II seminomas after postoperative radiotherapy. Incidence of a second malignancy was higher than expected, but the difference was not statistically significant.

Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model.

OBJECTIVE: Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. METHODS: Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody. RESULTS: ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis, substantially increasing the level of necrosis seen when combined with radiation therapy. The combination of radiation therapy, ZD6126, and ZD1839 induced the greatest effects on tumor growth and angiogenesis. CONCLUSION: This first report shows that a selective vascular-targeting agent (ZD6126) + an anti-epidermal growth factor receptor agent (ZD1839) and radiation have additive in vivo effects in a human cancer model. Targeting the tumor vasculature offers an excellent strategy to enhance radiation cytotoxicity. Polytargeted therapy with agents that interfere with both growth factor and angiogenic signaling warrants further investigation.

Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer.

PURPOSE: Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient's sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. METHODS: Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. FINDINGS: The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5-15% had pCR and were disease free after 2 years (excellent prognosis), 65-75% had no pCR but were disease free (good prognosis) and 15-30% had neither pCR nor 2yDFS (poor prognosis). INTERPRETATION: Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies.

Long-term safety of orbital radiotherapy for Graves' ophthalmopathy.

We investigated the long-term side-effects of orbital radiotherapy (OR) in 204 patients with Graves' ophthalmopathy (GO), irradiated from 1972-1996 [44 by cobalt unit (CU) and 160 by linear accelerator (LA), mostly combined with glucocorticoids], with a 5- to 25-yr follow-up (median, 11 yr). Cataract was observed in 21 patients (10%) 3-21 yr after OR, with a higher (not significant) prevalence in CU-treated patients (18% vs. 8% in LA-treated patients). The prevalence of cataract was higher, although not significantly, in CU-treated patients aged less than 60 yr, but not in LA-treated patients, compared with the general population. Mild, asymptomatic retinopathy was observed in 1 of 7 patients (14%) with diabetes and hypertension, in 1 of 31 patients (3%) with hypertension alone, and in 0 of 11 patients with diabetes alone. No tumors were observed in 157 patients submitted to computed tomography scan of orbital and adjacent regions. In conclusion, OR is a safe treatment, not associated with an increased frequency of cataract, provided a high voltage apparatus is used. Hypertension, especially if associated with diabetes, may represent a relative contraindication, as it may cause retinopathy. Although no secondary tumors were detected, due to the long latency of radiation-induced tumors, OR should be restricted to patients older than 35 yr.

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer.

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT).

BACKGROUND AND PURPOSE: To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS: From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS). RESULTS: 634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B. CONCLUSIONS: In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

Predictive factors for oropharyngeal mycosis during radiochemotherapy for head and neck carcinoma and consequences on treatment duration. Results of mycosis in radiotherapy (MIR): a prospective longitudinal study.

BACKGROUND AND PURPOSE: Oropharyngeal mycosis (OPM) is a complication of radiotherapy (RT) treatments for head and neck (H&N) cancer, worsening mucositis and dysphagia, causing treatment interruptions and increasing overall treatment time. Prophylaxis with antifungals is expensive. Better patient selection through the analysis of prognostic factors should improve treatment efficacy and reduce costs. MATERIALS AND METHODS: A multicentre, prospective, controlled longitudinal study, with ethics committee approval, examined H&N cancer patients who were candidates for curative treatments with radio-chemotherapy. Patients were divided in groups according to OPM appearance: before the starting of RT (cases), during RT (new cases) and never (no cases). RESULTS: Of 410 evaluable patients, 20 were existing cases, 201 new cases and 189 did not report OPM. In our study OPM appears in 42.4% of people >70years and in 58.2% of younger individuals (p=0.0042), and in 68.6% of women versus 50.8% of men (p=0.0069). Mucositis and dysphagia were higher and salivation reduced among people with OPM (p<0.0000). Patients with OPM had longer hospitalization (p=0.0002) and longer (>12days) treatment interruptions (p=0.0288). CONCLUSIONS: Patients with OPM had higher toxicity and a greater number of long treatment interruptions. Analyses of prognostic factors can help clinicians understand OPM distribution and select patients with the highest probability of OPM for antifungal prophylaxis.

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.

Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials.

PURPOSE: The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up. PATIENTS AND METHODS: All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms. RESULTS: The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome. CONCLUSION: The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).