Jean Pierre Gerard

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).

A new approach to the management of epidermoid carcinoma of the anal canal

Until recently most squamous cell carcinomas of the anal canal were treated by radical surgery. Radiation therapy was only considered for palliation in case of inoperable tumors. Important progress has been made in the knowledge of the natural history of the disease and in the field of radiotherapy. Anal canal squamous cell carcinoma should not be treated any longer by the same procedure as adenocarcinoma of the lower rectum, because both these diseases differ markedly. Multimodality therapy with radiotherapy as first approach has been considered. This series of 121 cases treated since 1971 and followed more than three years suggests that three protocols based on irradiation followed or not by surgery should be used according to the extent of the disease. Of the 72 patients with resectable tumor, the five‐year survival rate was 65%. Three‐quarters of the patients cured had normal anal function. The rate of death from cancer was 18%. The method requires an accurate assessment of the extent of the tumor and of its pelvic lymphatic spread. Great care must be taken in planning treatment in a close cooperation between radiotherapist and surgeon.

Long‐term results of the Lyons R90‐01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter‐saving surgery in rectal cancer

Preoperative radiotherapy has been shown to improve local control and 5-year survival in patients with resectable rectal cancer1. A long interval between preoperative radiotherapy and surgery provides increased tumour downstaging and a non-significant trend towards increased anal sphincter preservation2. The influence of this interval on long-term results remains unknown. The aim of this prospective multicentre randomized trial was to evaluate the impact of the interval between preoperative radiotherapy and surgery on the long-term results of the treatment of rectal cancer.

Role of Radiotherapy With Surgery for T3 and Resectable T4 Rectal Cancer: Evidence From Randomized Trials

PurposeThe main treatment for resectable rectal cancer T2–T4 N0–N2 M0 is surgery. The benefit of preoperative or postoperative radiation therapy can be analyzed in terms of improvement of local control, sphincter preservation, and survival weighted against increased toxicity.MethodsOnly randomized trials can provide strong evidence of a positive cost-benefit ratio of such combined approach. The most recent trials were reviewed.ResultsThree randomized trials, including the latest German CAO-ARO trial, have demonstrated the superiority of preoperative radiotherapy with or without chemotherapy (vs. postoperative) in terms of local control and toxicity. The Ducth TME trial showed that even with modern standard surgery, preoperative radiotherapy improved local control. Preoperative irradiation using a high dose in a small volume and a long interval before surgery may improve sphincter preservation (Lyon trials). Concurrent chemoradiation (FFCD 9203, EORTC 22921, did not significantly improve sphincter preservation or survival but significantly reduced the local recurrence rate.ConclusionsIn 2005 examination of randomized trials provides evidence for the benefit of preoperative chemoradiation in improving local control and probably sphincter preservation in rectal cancer. Randomized trials should be designed to further demonstrate improved sphincter preservation and to increase survival using adjuvant medical treatments.

Endocavitary radiation therapy

Endocavitary radiation therapy (Endo RT) is performed mainly with a contact x-ray tube. Interstitial brachy-therapy is a supplementary method to boost the tumor bed. Only strictly selected patients can be treated for cure by Endo RT. More than 1,000 patients have been treated in Europe and North America, since 1950. In T1 N0 adenocarcinoma, the primary local control rate is close to 90%. The overall 5-year survival is between 60% and 90% depending on patient selection. Careful follow-up is necessary because the majority of local failures can be salvaged, usually by radical surgery. The main advantages of Endo RT are a fully ambulatory and simple treatment that can be applied even in frail or elderly inoperable patients, a low risk of complications, and an inexpensive treatment. Results show it is possible to perform curative treatment in patients with more advanced rectal carcinoma. With the combination of external-beam radiation therapy and Endo RT in stage T2–3 N0-1 tumors, the primary local control rate is around 70%, and the incidence of severe radiation toxicity is less than 5%. Overall 5-year survival is between 50% and 70%. Endo RT can also be used as an adjuvant treatment after local excision, in the treatment of villous adenomas, and for palliation of advanced inoperable tumors.

Radiotherapy of high bile duct carcinoma using intracatheter iridium 192 wire

The authors developed an original procedure of endocurietherapy of high bile duct carcinoma. An iridium 192 wire is inserted into either a percutaneous transhepatic catheter or a surgically implanted external diversion catheter. The delivered dose varies between 10 and 60 Gy at 1 cm from the wire. Four of the seven patients analyzed also received external irradiation. There were no systemic or local complications. All patients experienced symptomatic relief and four are alive with no evidence of disease. This well‐tolerated procedure permits symptomatic palliation without excessive side effects for the patient. In some cases, a curative effect can be expected.

Modeling of Salivary Production Recovery After Radiotherapy Using Mixed Models: Determination of Optimal Dose Constraint for IMRT Planning and Construction of Convenient Tools to Predict Salivary Function

PURPOSE The mathematical relationship between the dose to the parotid glands and salivary gland production needs to be elucidated. This study, which included data from patients included in a French prospective study assessing the benefit of intensity-modulated radiotherapy (RT), sought to elaborate a convenient and original model of salivary recovery. METHODS AND MATERIALS Between January 2001 and December 2004, 44 patients were included (35 with oropharyngeal and 9 with nasopharyngeal cancer). Of the 44 patients, 24 were treated with intensity-modulated RT, 17 with three-dimensional conformal RT, and 2 with two-dimensional RT. Stimulated salivary production was collected for </=24 months after RT. The data of salivary production, time of follow-up, and dose to parotid gland were modeled using a mixed model. Several models were developed to assess the best-fitting variable for the dose level to the parotid gland. RESULTS Models developed with the dose to the contralateral parotid fit the data slightly better than those with the dose to both parotids, suggesting that contralateral and ipsilateral parotid glands are not functionally equivalent even with the same dose level to the glands. The best predictive dose-value variable for salivary flow recovery was the volume of the contralateral parotid gland receiving >40 Gy. CONCLUSION The results of this study show that the recommendation of a dose constraint for intensity-modulated RT planning should be established at the volume of the contralateral parotid gland receiving >40 Gy rather than the mean dose. For complete salivary production recovery after 24 months, the volume of the contralateral parotid gland receiving >40 Gy should be <33%. Our results permitted us to establish two convenient tools to predict the saliva production recovery function according to the dose received by the contralateral parotid gland.

Pathologic Response, When Increased by Longer Interval, Is a Marker but Not the Cause of Good Prognosis in Rectal Cancer: 17-year Follow-up of the Lyon R90-01 Randomized Trial

PURPOSE The Lyon R90-01 randomized trial investigated whether the interval between preoperative radiation therapy and surgery influenced rectal cancer outcome. Long-term results are reported here after a median follow-up of 17 years. METHODS AND MATERIALS Between February 1991 and December 1995, 210 patients from 29 French centers were randomly assigned (ratio of 1:1) to groups that waited either 2 weeks (short interval [SI]) or 6 to 8 weeks (long interval [LI]) between neoadjuvant radiation therapy and surgery. The primary endpoint was sphincter-preserving surgery. RESULTS LI group showed a better pathologic response (complete response or few residual cells) after radiation therapy than the SI group (26% vs 10.3%, P=.015). A better pathologic response was associated in multivariate analysis with significant improvement of overall survival (pT: P=.0293 and pN: P=.0048) but it was irrespective of the interval duration. The median follow-up was 17.2 years. The 5-, 10-, 15-, and 17-year overall survival rates were, respectively, 66.8%, 48.7%, 40.0%, and 34.0% for the SI group and, respectively, 67.1%, 53.5%, 41.9%, and 34.0% for the LI group. There were no significant differences between groups in terms of survival (P=.7656) or local recurrence rates (SI: 14.4% vs LI: 12.1%, respectively; P=.6202). Of 24 local disease recurrences, 20 (83%) occurred during the first 2 postoperative years, and all but one (96%) occurred during the first 5 postoperative years. The rate of second new malignancies was 9.4% (19 patients). CONCLUSIONS The radiation-induced sterilization rate of the preoperative cancer specimen was a marker of good prognosis. The interval duration (the treatment being the same) although it is modifying the sterilization rate has no impact on survival. Radiation therapy did not postpone local recurrence, because the rate of local relapse after 5 years was low. Radiation-induced cancers after radiation therapy were unusual and should not influence treatment decisions in adults.

Should the treatment of anal carcinoma be adapted in the elderly? A retrospective analysis of toxicities in a French center.

To the Editor: Persons over the age of 65 years are the fastest growing segment of world population and cancer has a higher incidence in older patients; 60% of all cancer diagnoses and 80% of all cancer-related deaths in the United States involve elderly patients. This increasingly older cancer population poses clinical, personal, familial, and ethical problems and could require specific management. In elderly patients, the choice between the standard treatment (even if it could be more toxic) and palliative supportive treatments is often difficult. Despite evidences in favor of the use of standard treatments in elderly patients, in the real life, toxicities still are a major issue for clinicians’ decision. Age by itself often does not represent a negative prognostic factor, as shown in a study by Pignon et al on 1619 patients from EORTC trials, who did not find differences in acute or late complications, or in survival, among different age groups of patients treated with pelvic irradiation for various malignancies. Anal canal cancer is a rare disease. Radiochemotherapy (RT-CT) ±brachytherapy (BRT) is the standard treatment; median 5-year local control (LC) and overall survival (OS) rates are from 61% to 65% and from 65% to 70%, respectively. Even if 2 large randomized trials confirmed the superiority of RT-CT over RT alone, in terms of both LC and colostomyfree survival, several reports support the use of low-dose RT combined with CT, with very interesting rates of downstaging, LC, and survival. These reports could suggest that lowdose RT±CT could be an important treatment option for elderly patients. Looking at the literature, only 3 retrospective reports analyzing RT-CT for elderly patients with anal canal cancer exist; they present small numbers of patients and the use of different schedules of treatments. For these reasons, any conclusion could be carried out. Valentini et al treated 10 elderly patients with rectal cancer and 7 with anal cancer (median age, 79 y) by a “split course” FUMIR RT-CT with a curative (10 patients) or a palliative goal (7 patients). Sixteen patients completed the planned treatment, with a reported 12% grade (G) 3 Radiation Therapy Oncology Group (RTOG) hematologic toxicity and 6% of G3 RTOG skin toxicity and without intestinal and urinary G3 reactions. Allal et al treated 42 patients (median age, 81 y) by exclusive RT (21 patients) or concomitant RT-CT [mitomycin C and 5-fluorouracil (FU)]. The median dose of pelvic RT was 39.6Gy, followed by a boost with either BRT or external RT after a median interval of 43 days (median dose, 20Gy). Median follow-up was 48 months; 95% of patients completed the planned treatment, with acute toxicity resulting in shortening of the planned first irradiation sequence in 2 patients (1 in each group) and an unplanned treatment break in 11 patients (4 in the RT group and 7 in the RT-CT group). G3 acute toxicities occurred in both RT and RT-CT group (32% vs. 68%, respectively). Particularly, 5 patients in the RT-CT group presented G3-4 late complications. These patients also presented G2-3 leukopenia (25%) and G2-3 fatigue (58%). One G2 cardiac toxicity related to 5-FU occurred in 1 patient. The investigators did not find differences between 5-year OS and actuarial LC rate. Charnley et al treated 16 elderly patients with anal cancer (median age, 81 y) by RT-CT. RT was delivered to the tumor volume plus a margin of 3 cm in all directions (total dose, 30Gy) and concurrent CT consisted of 5-FU (600mg/m given over 24 h on days 1 to 4 of RT). All 16 patients completed treatment as planned, with only 1 reported G3 toxicity (skin). We would report our preliminary data about 13 elderly patients (median age, 78 y; range, 75 to 90 y) treated by RT (6 patients) or RT-CT (7 patients), followed by BRT. The analysis of the toxicities has been the primary endpoint of our analysis. Exclusive RT was delivered by 3Gy fractions (total dose, 30 to 39Gy) to the tumor by a direct perineal field. RT-CT was delivered by 2Gy fractions (total dose, 46Gy) delivered to the tumor and the pelvic nodes by 4 orthogonal fields. Seven patients received concomitant CT: 5 of 7 patients received cisplatin (75mg/m in day 1) and 5-FU (750mg/ m/d by continuous intravenous infusion for five days) during first and last week of RT, 1 patient received weekly cisplatin (40mg/m, cardiac contraindication to 5-FU), and 1 patient received weekly 5-FU (500mg/m, moderate chronic renal failure). All patients received BRT boost (median dose, 20Gy; range, 3.6 to 30Gy) on initial site and/or on residual disease (depending on the response). Finally, all patients received the prescribed treatment (RT or RTCT+BRT). One patient receiving an anticoagulant treatment experienced acute rectal bleeding during BRT after 3.6Gy and he finally received the boost by external RT (18Gy). Median followup was 26 months. Looking at acute G3 toxicities (RTOG score), proctitis occurred in 2 of 6 patients in the “RT group” and in 1 of 7 patients in the “RT-CT group,” with 1 of the 2 G3 rectal reactions of RT group recorded in a patient who already received 70Gy of contact-therapy before external RT. In the RT-CT group, G2-3 leukopenia was observed in 1 of 7 patients (0 of 6 in RT group). After BRT, 1 G3 (RT group) and 1 G4 (RT-CT group, bleeding described above) acute rectal toxicities were recorded. Late toxicities were evaluated in 7 of 13 patients with at least 12 months of follow–up; 1 patient in RT group and 1 patient in RT-CT group showed G3 rectal toxicities. An 8-mm rectal necrosis was found in the patient that received contact therapy. One patient showed a G2 gynecologic toxicity (symptomatic vulvar necrosis of 0.5 cm of diameter), which was medically treated. Others patients did not showed major late toxicities. We also verified whether a difference existed between the 2 groups in terms of toxicities. Using a nonparametric statistical test to take in account the small number of patients (Wilcoxon–Mann–Whitney test), we did not find differences in toxicity between the 2 groups (P=0.6). The reduction of toxicities of exclusive or concomitant treatments is a major issue in elderly patients, particularly if standard treatments are delivered. Intensity-modulated radiation therapy (IMRT) is increasingly used Conflict of interest disclosure and funding declaration: No conflicts of interest exist. Authors did not receive funds for this research. LETTERS TO THE EDITOR

Qualité des dossiers de cancérologie : résultats d'une démarche qualité aux Hospices civils de Lyon

The objective of this study was to assess the quality of information contained in the medical files of patients in an oncology unit of the Lyons Civil Hospices. Prior to the audit, the health care teams established a set of consensus standards to compare with observed procedures. The analysis of the results led to propositions for guidelines designed to improve points where significant deviations were observed. In the first audit, 80 medical files from patients cared for in four oncology units were retrospectively analysed to determine information quality. Seven items of this audit were retained for a second audit on 127 medical files of patients in a cancerology unit; those items were: postal code of birth place, weight, codified evaluation of general status, TNM classification, pTNM classification, presence of pathology report, localisation of metastasis. Significant deviations were observed for pTNM classification and postal code of birth. During the second audit, a manual of procedures was distributed in the unit, and a new evaluation will be done in one year to assess the impact of guidelines.