Jean-Michel Hannoun-Levi

Induction Chemotherapy and Dose Intensification of the Radiation Boost in Locally Advanced Anal Canal Carcinoma: Final Analysis of the Randomized UNICANCER ACCORD 03 Trial

PURPOSE Concomitant radiochemotherapy (RCT) is the standard for locally advanced anal canal carcinoma (LAACC). Questions regarding the role of induction chemotherapy (ICT) and a higher radiation dose in LAACC are pending. Our trial was designed to determine whether dose escalation of the radiation boost or two cycles of ICT before concomitant RCT lead to an improvement in colostomy-free survival (CFS). PATIENTS AND METHODS Patients with tumors ≥ 40 mm, or < 40 mm and N1-3M0 were randomly assigned to one of four treatment arms: (A) two ICT cycles (fluorouracil 800 mg/m(2)/d intravenous [IV] infusion, days 1 through 4 and 29 to 32; and cisplatin 80 mg/m(2) IV, on days 1 and 29), RCT (45 Gy in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), and standard-dose boost (SD; 15 Gy); (B) two ICT cycles, RCT, and high-dose boost (HD; 20-25 Gy); (C): RCT and SD boost (reference arm); and (D) RCT and HD boost. RESULTS Two hundred eighty-three of 307 patients achieved full treatment. With a median follow-up period of 50 months, the 5-year CFS rates were 69.6%, 82.4%, 77.1%, and 72.7% in arms A, B, C, and D, respectively. Considering the 2 × 2 factorial analysis, the 5-year CFS was 76.5% versus 75.0% (P = .37) in groups A and B versus C and D, respectively (ICT effect), and 73.7% versus 77.8% in groups A and C versus B and D, respectively (RT-dose effect; P = .067). CONCLUSION Using CFS as our main end point, we did not find an advantage for either ICT or HD radiation boost in LAACC. Nevertheless, the results of the most treatment-intense arm B should prompt the design of further intensification studies.

Past, present, and future of radiotherapy for the benefit of patients

Radiotherapy has been driven by constant technological advances since the discovery of X-rays in 1895. Radiotherapy aims to sculpt the optimal isodose on the tumour volume while sparing normal tissues. The benefits are threefold: patient cure, organ preservation and cost-efficiency. The efficacy and tolerance of radiotherapy were demonstrated by randomized trials in many different types of cancer (including breast, prostate and rectum) with a high level of scientific evidence. Such achievements, of major importance for the quality of life of patients, have been fostered during the past decade by linear accelerators with computer-assisted technology. More recently, these developments were augmented by proton and particle beam radiotherapy, usually combined with surgery and medical treatment in a multidisciplinary and personalized strategy against cancer. This article reviews the timeline of 100 years of radiotherapy with a focus on breakthroughs in the physics of radiotherapy and technology during the past two decades, and the associated clinical benefits.

Management of prostate cancer recurrence after definitive radiation therapy

The management of prostate cancer (PC) recurrence after definitive radiation therapy (RT) is shifting and there is no consensus regarding the optimal strategy. The major challenge is determining the anatomical site of relapse. In case of biochemical relapse (BR), androgen deprivation therapy (ADT) is a non-curative option commonly used, while patients with a local PC recurrence could be managed through a curative intent. Based on a Pubmed data search, this manuscript focused on the management of post-RT local PC recurrences. In case of BR (nadir+2 ng/ml), classical imaging work-up is not contributive for PSA levels <10 ng/ml while new imaging investigations (diffusion MRI, 11C-choline PET) are more sensitive to detect local and distant recurrences at lower PSA levels. Positive prostate biopsies are the only method for confirming local recurrence, although this technique presents limitations. Primary PC presentation as well as PSA-related features (interval to failure, PSA kinetic) and patient features (life expectancy, urinary, sexual status) are important to consider. Results of curative salvage options (radical prostatectomy, cryotherapy, brachytherapy and high-intensity focused ultrasound-HIFU) are analyzed and discussed. Each of these therapies appears feasible and has its own set of experience and toxicity profile. Other therapeutic options (photodynamic therapy, ADT, observation) are discussed. Longer follow-up and mature series are needed to evaluate the optimal strategy and prospective trials are warranted. Each clinical situation should be discussed in a multidisciplinary setting. Different options should be explained to the patient and decision should be taken after balancing treatment outcomes with life expectancy.

Contact X-ray Therapy for Rectal Cancer: Experience in Centre Antoine-Lacassagne, Nice, 2002–2006

PURPOSE To report the results of using contact X-ray (CXR), which has been used in the Centre-Lacassagne since 2002 for rectal cancer. METHODS AND MATERIALS A total of 44 patients were treated between 2002 and 2006 using four distinct clinical approaches. Patients with Stage T1N0 tumors were treated with transanal local excision (TLE) and adjuvant CXR (45 Gy in three fractions) (n = 7). The 11 inoperable (or who had refused surgery) patients with Stage T2-T3 disease were treated with CXR plus external beam radiotherapy (EBRT). Those with Stage T3N0-N2 tumors were treated with preoperative CXR plus EBRT (with or without concurrent chemotherapy) followed by surgery (n = 21). Finally, the patients with Stage T2 disease were treated with CXR plus EBRT followed by TLE (n = 5). RESULTS The median follow-up was 25 months. In the 7 patients who underwent TLE first, no local failure was observed, and their anorectal function was good. Of the 11 inoperable patients who underwent CXR plus EBRT alone, 10 achieved local control. In the third group (preoperative CXR plus EBRT), anterior resection was performed in 16 of 21 patients. Complete sterilization of the operative specimen was seen in 4 cases (19%). No local recurrence occurred. Finally, of the 5 patients treated with CXR plus EBRT followed by TLE, a complete or near complete clinical response was observed in all. TLE with a R0 resection margin was performed in all cases. The rectum was preserved with good function in all 5 patients. CONCLUSION These early results have confirmed that CXR combined with surgery (or alone with EBRT) can play a major role in the conservative and curative treatment of rectal cancer.

Renaissance of contact x-ray therapy for treating rectal cancer

Contact x-ray therapy (CXRT) with 50 kV has proven to be an efficient radiation therapy technique to achieve local control and rectal preservation for early rectal adenocarcinoma. Despite these results, CXRT has not been used due to the shortage of the no longer manufactured Philips RT 50™ unit. Recently, a new CXRT machine (Papillon 50™) became available on the market. This machine delivers a beam of 50 kV with a dose rate close to 15 Gy/min and has a percentage depth dose of 50% at 6–7 mm. The applicator size varies from 2–3 cm in diameter. Due to the original design of the main tube, treatment delivery is quick and more comfortable for the patients. An online viewing system incorporated in the tube allows a good visualization of the tumor with improved accuracy of radiation delivery. An international collaborative trial (Contact Endoscopic Microsurgery [CONTEM]) was set up to accrue approximately 300 cases of rectal adenocarcinoma staged T1, T2 or early T3 tumors in the UK, France, Denmark and Sweden. This trial should confirm the role of CXRT in curative treatment with organ preservation for early rectal cancers.

Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in node-negative breast cancer patients

BACKGROUND AND PURPOSE There is no general consensus concerning irradiation (RT) of internal mammary nodes (IMN) in axillary node-negative breast cancer. Based on a large series of patients treated in a single institute and followed up for a long period of time, we looked at the influence of IMN RT on late outcome of these patients as well as the development of contralateral breast cancer (CBC). PATIENTS AND METHODS The study was based on 1630 node-negative breast cancer patients treated in our institution between 1975 and 2008 with primary conservative surgery and axillary dissection or sentinel node examination. All patients received post-operative breast RT. IMN RT was more frequent in inner or central tumours. Kaplan-Meier (K-M) overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) according to IMN RT were calculated for all patients and for patients with inner/central tumours. The K-M rate of contralateral breast cancer (CBC) was also analysed and correlated with IMN RT. RESULTS Prognostic variables such as tumour size, histological grade, and hormone receptors were not significantly different in the groups having received IMN RT or not. Considering all patients, OS was strictly comparable in the 2 groups: 10-year values were 85% (IMN RT) and 86% (no IMN RT), respective values at 20 years were 66.6% and 61.0% (p=0.95). However, in patients presenting with inner/central tumours, OS was significantly improved in the IMN RT group with respective values of 92.5% and 87.2% at 10 years, and 80.2% and 63.3% at 20 years: Hazard ratio (HR)=0.56 (0.37-0.85); p=0.0052. Again, CSS was improved in patients with inner/central tumours having received IMN RT, with 20-year rates of 89.5% versus 79.1% in patients not receiving IMN RT (p=0.047). No difference in DFS was noticed. The actuarial rate of CBC development was comparable between patients having received IMN RT and other patients. However, considering only patients alive 10 years after primary breast surgery, the K-M rate of CBC at 20 years was 5.3% in patients without IMN RT and 7.2% in patients with such RT; HR=2.47 (1.23-4.95); p=0.008. CONCLUSIONS IMN RT in node-negative tumours was associated with increase in OS and CSS in patients with inner or centrally located lesions. An increase in CBC development was also noticed in long-survivors of IMN RT patients; however, these findings have to be interpreted with caution because of the difference in follow-up between the 2 groups. Further studies are warranted to investigate the potential role of IMN irradiation in the development of CBC.

Second conservative treatment for ipsilateral breast cancer recurrence using high-dose rate interstitial brachytherapy: Preliminary clinical results and evaluation of patient satisfaction

PURPOSE To assess early clinical results and evaluate patient satisfaction in case of second conservative treatment (2nd CT) combining lumpectomy plus high-dose rate (HDR) interstitial brachytherapy for patients (pts) presenting with ipsilateral breast cancer recurrence (IBCR). METHODS AND MATERIALS From June 2005 to July 2009, 42 pts presenting with an IBCR underwent a second lumpectomy with intraoperative implantation of plastic tubes in the tumor bed. After performing the dose distribution analysis on the postimplant CT scan, a total dose of 34 Gy in 10 fractions over 5 consecutive days was delivered. Toxicity evaluation was based on the Common Terminology Criteria for Adverse Events v3.0 criteria. Applying a visual analogic scale (VAS) analysis, patient satisfaction regarding cosmetic result and 2nd CT possibility was performed after the end of brachytherapy. RESULTS Median followup was 21 months (range, 6-50 months) and median age at the time of local recurrence was 65 years (range, 30-85 years). Median delay between primary and recurrence was 11 years (range, 1-35 years). Median recurrence tumor size was 12 mm (range, 2-30 mm). Median number of plastic tubes and planes were nine (range, 5-12) and two (range, 1-3), respectively. Median clinical target volume was 68 cc (range, 31.2-146 cc). Second local control rate was 97%. Twenty-two pts (60%) developed complications. Cutaneous and subcutaneous fibrosis was the most frequent side effect. Median VAS satisfaction score regarding cosmetic result was 7 of 10 (range, 4-9), whereas median VAS satisfaction score for 2nd CT was 10 of 10 (range, 8-10). CONCLUSION A 2nd CT for IBCR using high-dose rate brachytherapy seems feasible with encouraging results in terms of second local control with an acceptable toxicity. Patient satisfaction regarding the possibility of second breast preservation should be considered.

Carcinoma of the cervical stump: Retrospective analysis of 77 cases

BACKGROUND AND PURPOSE Although supracervical hysterectomy is becoming a rare procedure, there are still many women with retained cervical stump. The purpose of this retrospective study was to assess the results of treatment in patients with carcinoma of the cervical stump. MATERIALS AND METHODS From 1974 to 1990, 77 patients were treated for an infiltrating carcinoma of the cervical stump. This group accounted for 6.6% of the cervical carcinoma diagnosed during the same period. The pathological examination showed, 91% of squamous cell carcinomas and 9% of adenocarcinomas. FIGO stage distribution was: I (35%), II (45%), III (18%), IV (2%). According to the stages, the treatment used a combination of external beam radiation therapy (EBRT) with plesiobrachytherapy (PBT), and in a few cases, patients underwent surgery or interstitial brachytherapy (IBT). In patients with bulky tumour or advanced stage and/or lymphatic node involvement, EBRT was first delivered. Most of Stage I and Stage II patients, began their treatment with PBT. All stages included, 95% of the patients were treated by exclusive radiation therapy. Complications were classified according to the recommendations of late effects normal tissues (LENT) scoring system described by the EORTC/RTOG. RESULTS Three-year pelvic control was achieved in 59 of 77 patients (76.6%) in the whole series. Three-year pelvic control probabilities were 77% (95% CI: 66-85%), and 89% (95% CI: 72-96%), 73.7% (95% CI: 65-88%) and 56% (95% CI: 28-80%) in the whole series and in Stage I-III tumour patients, respectively. The 5-year and 10-year overall survival probabilities in the whole series, were 66.4% (95% CI: 55-76%) and 61.2% (95% CI: 50-72%), respectively. Ten patients (12.8%) developed 17 late complications distributed as follows: G1, nine patients (11.7%); G2, five patients (6.5%); G3, one patient (1.3%); and G4, two patients (2.6%). CONCLUSIONS Treatment results are similar both in patients with carcinoma of the cervical stump and in patients with carcinoma of the intact uterus. Indeed, it is sometimes difficult to perform a correct PBT application because of the pelvic anatomic modifications induced by the subtotal hysterectomy and its consequences on the new organisation of critical organs into the treated volume.

Proton beams in cancer treatments: Clinical outcomes and dosimetric comparisons with photon therapy

PURPOSE To review current evidence of the role of proton therapy (PT) in other tumors than skull base, sinusal/parasinusal, spinal and pediatric tumors; to determine medico-economic aspects raised by PT. MATERIAL AND METHODS A systematic review on Medline was performed with the following keywords: proton therapy, proton beam, protontherapy, cancer; publications with comparison between PT and photon-therapy were also selected. RESULTS In silico studies have shown superiority (better dose delivery to the target and/or to organs at risk) of PT toward photon-therapy in most of thoracic and abdominal malignant tumors. Potential benefits of PT could be: reduction of toxicities (including radiation-induced cancer), increase of tumor control through a dose-escalation approach, hypofractionation. Cost of treatment is always cited as an issue which actually can be managed by a precise patient selection making PT a cost-effective procedure. Comparison plan with photon therapy may be useful to determine the dosimetric and clinical advantages of PT (Normal Tissue Complications Probability). CONCLUSION PT may be associated with a great advantage compared to the best photon-therapies in various types of cancers. Accumulation of clinical data is on-going and will challenge the in silico data analysis. Some indications are associated with strong superiority of PT and may be discussed as a new standard within prospective observational studies.

Local treatment options for ipsilateral breast tumour recurrence

PURPOSE In case of ipsilateral breast tumour recurrence (IBTR), radical mastectomy represents the treatment option frequently proposed. A second conservative treatment (2ndCT) has been proposed using either lumpectomy alone or associated with a re-irradiation of the tumor bed. However, in both clinical situations, the proof level of such therapeutic approaches remains low, based on cased-series or retrospective studies (level C). MATERIAL AND METHODS In order to assess the different strategies of local treatment proposed in case of IBTR, a PubMed literature review was performed using the following keywords: breast cancer, ipsilateral recurrence, mastectomy, radiation therapy, brachytherapy. Four different salvage options were analyzed: (a) salvage mastectomy alone; (b) salvage mastectomy with postoperative re-irradiation; (c) 2ndCT with surgery alone; (d) 2ndCT with re-irradiation. RESULTS The rate of second local recurrence is about 10% [3-32%], about 25% [7-36%] and about 10% [2-26%], after salvage mastectomy, salvage lumpectomy alone or combined with a re-irradiation of the tumor bed respectively. However, the 5-year overall survival rates after salvage mastectomy and 2ndCT seem to be equivalent (≈75%) mainly influenced by distant metastatic progression. CONCLUSION In terms of Evidence Based Medicine, different options can be discussed such as Phase III or II randomized trials comparing salvage mastectomy versus 2ndCT, retrospective studies based on a matched-pair analysis or observatory studies. Those study designs need to be carefully analyzed to be able to propose new treatment options for women who experience an IBCR.