D. Peiffert

Prognostic implications of downstaging following preoperative radiation therapy for operable T3-T4 rectal cancer.

PURPOSE To evaluate the prognostic value of tumor downstaging after preoperative radiation for resectable rectal cancer. METHODS AND MATERIALS Eighty-eight patients with non-metastatic resectable rectal cancers (76 T3 and 12 T4) were treated with preoperative irradiation. Median dose was 40 Gy (30-46 Gy) delivered over 32 days (range 11-40). Seventeen patients received preoperative chemotherapy, two courses of 5-fluorouracil (5FU) 350 mg/m2/day and folinic acid 20 mg/m2/day; 5 days per week during the first and fifth weeks of radiotherapy. Surgery was performed with a mean delay of 46 days after completion of irradiation and included 66 abdominoperineal resections and 22 anal sphincter-preserving procedures. Postoperative chemotherapy was administered in 44 patients. RESULTS Histological tumor stages were: complete histological response in 7%, pT2N0 in 19%, pT3N0 in 46%, and pT2-3N1 in 28%. Tumor downstaging occurred in 26%. No predictive factor of downstaging was statistically significant. The median follow-up was 33 months. The 3- and 5-year cancer-specific survival rates were 100% for the pT0N0 and pT2N0, respectively, 89% and 68% for pT3N0, and 64% and 0% for pT2T3N1. After preoperative irradiation, the pathological tumor stages remained a prognostic factor. Patients with downstaging (pT0T2N0) had significantly higher cancer-specific survival rates than the group without downstaging: 100% and 80% at 3 years, and 100% and 45% at 5 years; respectively (p = 0.011). The 3- and 5-year recurrence free-survival rates were 94% for the group with downstaging and 56% and 50%, respectively, for the group without downstaging (p = 0.002). CONCLUSION Downstaging after preoperative irradiation in this retrospective study results in an improvement in local control and survival.

Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: results of the French STIC prospective study.

PURPOSE In 2005 a French multicentric non randomized prospective study was initiated to compare two groups of patients treated for cervix carcinoma according to brachytherapy (BT) method: 2D vs 3D dosimetry. The BT dosimetric planning method was chosen for each patient in each center according to the availability of the technique. This study describes the results for 705 out of 801 patients available for analysis. PATIENTS AND METHODS For the 2D arm, dosimetry was planned on orthogonal X-Rays using low dose rate (LDR) or pulsed dose rate (PDR) BT. For the 3D arm, dosimetry was planned on 3D imaging (mainly CT) and performed with PDR BT. Each center could follow the dosimetric method they were used to, according to the chosen radioelement and applicator. Manual or graphical optimization was allowed. PATIENTS AND METHODS Three treatment regimens were defined: Group 1: BT followed by surgery; 165 patients (2D arm: 76; 3D arm: 89); Group 2: EBRT (+chemotherapy), BT, then surgery; 305 patients (2D arm: 142; 3D arm: 163); Group 3: EBRT (+chemotherapy), then BT; 235 patients, (2D arm: 118; 3D arm: 117). PATIENTS AND METHODS The DVH parameters for CTVs (High Risk CTV and Intermediate Risk CTV) and organs at risk (OARs) were computed as recommended by GYN GEC ESTRO guidelines. Total doses were converted to equivalent doses in 2Gy fractions (EQD2). Side effects were prospectively assessed using the CTCAEv3.0. RESULTS The 2D and 3D arms were well balanced with regard to age, FIGO stage, histology, EBRT dose and chemotherapy. For each treatment regimen, BT doses and volumes were comparable between the 2D and 3D arms in terms of dose to point A, isodose 60 Gy volume, dose to ICRU rectal points, and TRAK. RESULTS Dosimetric data in the 3D arm showed that the dose delivered to 90% of the High Risk CTV (HR CTV D90) was respectively, 81.2Gy(α/β10), 63.2Gy(α/β10) and 73.1Gy(α/β10) for groups 1, 2 and 3. The Intermediate Risk (IR) CTV D90 was respectively, 58.5Gy(α/β10), 57.3Gy(α/β10) and 61.7Gy(α/β10) for groups 1, 2 and 3. For the OARs, doses delivered to D2cc ranged 60-70Gy(α/β3) for the bladder, 33-61Gy(α/β3) for the rectum, and 44-58Gy(α/β3) for the sigmoid according to the regimen. RESULTS At 24 months, local relapse-free survival was 91.9% and 100% in group 1, 84.7% and 93% in group 2, 73.9% and 78.5% in group 3; grade 3-4 toxicity rate was 14.6% and 8.9% in group 1, 12.5% and 8.8% in group 2, and 22.7% and 2.6% in group 3 for 2D and 3D arm. CONCLUSION This multicentric study has shown that 3D BT is feasible and safe in routine practice. It has improved local control with half the toxicity observed with 2D dosimetry. The combined treatment with radiotherapy and surgery was more toxic than definitive radiotherapy. For patients with advanced tumors, it is necessary to improve coverage of target volumes without raising toxicity.

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.

GEC-ESTRO recommendations for brachytherapy for head and neck squamous cell carcinomas.

Both primary and recurrent squamous cell carcinoma of the head and neck are classic indications for brachytherapy. A high rate of local tumor control at the cost of limited morbidity can be achieved with brachytherapy through good patient selection, meticulous source implantation and careful treatment planning. However, no randomized trials have been performed, and there is scant evidence in the literature especially regarding practical clinical recommendations for brachytherapy for head and neck subsites. The Head and Neck Working Group of the European Brachytherapy Group (Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) therefore decided to formulate the present consensus recommendations for low-dose rate, pulsed-dose rate and high-dose rate brachytherapy. The use of brachytherapy in combination with external beam radiotherapy and/or surgery is also covered as well as the use of brachytherapy in previously irradiated patients. Given the paucity of evidence in the literature, these recommendations are mainly based on clinical experience accumulated by the members of the working group over several decades and the respective publications. The recommendations cover in a general part (1) patient selection, the pre-treatment work up and patient care, (2) treatment strategy, (3) target definition, (4) implant techniques, (5) dose and dose rate prescription, (6) treatment planning and reporting, (7) treatment monitoring (8) catheter removal, and (9) post-treatment patient care and follow-up. The recommendations are then specified for the classical brachytherapy tumor sites following an analogue more focussed structure (patient selection, implant technique, target definition, dose and dose rate prescription, results): lip, oral mucosa, mobile tongue, floor of mouth, oropharynx, nasopharynx, paranasal sinuses.

Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications

UNLABELLED We analyzed in a retrospective series of patients treated by conservative irradiation for an epidermoid cancer of the anal canal (ECAC) the prognostic factors of locoregional control (LRC), survival, late severe complications (LSC), and sphincter conservation (SC). METHODS AND MATERIALS From 1976 until 1994, 118 patients presenting with an ECAC were conservatively treated (mean age, 65 years). According to the 1987 International Union Against Cancer (TNM) classification, they were: 19 T1, 70 T2, 22 T3, 7 T4, 94 N0, and 24 N1-3. The treatment started with external beam irradiation (EBI) (36 Gy in 3 weeks or 45 Gy in 5 weeks). Concomitant chemotherapy (5-fluorouracil and mitomycin C) was delivered to 31 patients. Two months later, a boost of 20 Gy was delivered by interstitial 192Ir brachytherapy to 101 patients and EBI in 5. Twelve other patients had an abdominoperineal resection (APR). The mean follow-up was 6 years. RESULTS At 5 years the overall survival was 60%, and specific survival (SS) was 75%; it was 94% for T1, 79% for T2, 53% for T3, and 19% for T4. In multivariate analysis, tumor size (> or = 4 cm), node involvement, and no response to the EBI were factors of poor prognosis for SS. Thirty-two locoregional recurrences occurred of which 21 were local recurrences in the 106 patients treated by a conservative schedule. Only tumor size and response to the EBI were prognostic factors on multivariate analysis for local and LRC. A total of 17 patients presented with LSC (Grade 3, 16 patients; and Grade 4, 1 patient), which was treated by APR in 4 patients and colostomy in 11 (of which 7 were definitive). The only significant prognostic factor for LSC in the multivariate analysis was the total extrapolated response dose of irradiation. The definitive rate of SC after conservative treatment in cured patients was 100% for T1, 82% for T2, 58% for T3, and 100% for T4. Since 1989, improvements of the technique have allowed reduction of the LSC in maintaining the same local control. CONCLUSION The results of this series are similar to those of the literature. The confirmation of pretherapeutic prognostic factors related to response to the treatment should allow us to adapt the therapeutic intensity for each case to obtain better tumor control, with as few sequelae as possible, to yield a better rate of SC.

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

The study of tumoral, radiobiological, and general health factors that influence results and complications in a series of 448 oral tongue carcinomas treated exclusively by irradiation

PURPOSE Our aim was to study the different factors that influence the results and complications in a series of 448 carcinomas of the oral tongue treated from January 31, 1972 to December 31, 1986, by brachytherapy (Br) +/- neck dissection (181 cases) or combination of external beam irradiation and brachytherapy (EBI + Br) (267 cases). METHODS AND MATERIALS The patients distribution (TNM classification 1979) was: 125 T1, 186 T2, 128 T3, 9 T4Tx, 78% N0, and 22% N+. We used guide gutter or plastic tubes technique (Paris system dosimetry). Results at 5 and 10 years are: local control 68% and 64%, locoregional control 58% and 53%, specific survival 45% and 39%, and overall survival 44% and 27%. RESULTS In the univariate analysis for local control (LC) and overall survival (OS), we considered the tumoral factors. At 5 years, the LC for T1, T2, T3 are 93%, 65%, and 49%, and the OS 69%, 41%, and 25%, respectively (p < 0.002). The lesions of the undersurface of the tongue have a better LC (77%) than other localizations (64%) (p = 0.02). For general factors, the index of general health condition, age, and sex were not significant for LC, but proved significant for OS (p = 0.01). Significant radiobiological factors: the safety margin (expressed by the ratio treated surface on tumoral surface > or = 1.2) is significant for LC and OS. This is the same if the interval between EBI and Br is < or = 20 days. Neither the dose rate, the spacing between the sources, the total dose, nor Br dose were significant, but the last two were adapted according to the infiltration. In the univariate study for grade 2 and 3 complications (tissue and bone), the surface treated (> 12 cm2), and the dose rate > 0.7 Gy/h were significant. CONCLUSION The multivariate study showed that the small size of the lesion is the most important factor for local control, with brachytherapy alone for T1T2N0 and the number of days between EBI and brachytherapy < or = 20 days. For the complications, the most important factors are the total dose > 80 Gy and a treated surface > 12 cm2.

Quality of life in long-term survivors of oropharynx carcinoma

PURPOSE To collect data on the health-related quality of life (QOL) of long-term survivors and to determine to what extent QOL might be an appropriate end point in the comparison of treatment options in oropharyngeal carcinoma. METHODS AND MATERIALS All patients treated between 1992 and 1998, in two French comprehensive cancer centers, by brachytherapy (BT) +/- external beam radiotherapy (EBRT) or surgery plus RT, or exclusive EBRT for T1-T3 (International Union Against Cancer staging system) oropharynx squamous cell carcinoma, were included. QOL was measured once in disease-free patients at least 2 years after treatment initiation. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the specific H&N35 module were self-administered by all participating patients. Sociodemographic data were collected using a questionnaire specifically designed for the study. The association between the QOL scores of the various treatment-, disease-, and patient-related variables was performed through bivariate analysis and then by multivariate analysis. The mean QOL scores of the EORTC QLQ-C30 questionnaire were compared with the mean scores in the general population. RESULTS Of the 159 eligible patients, 113 agreed to participate (97 men and 16 women, median age 61 years, range 41-83). The initial treatment was EBRT plus BT in 49 patients, surgery plus RT in 27, and EBRT alone in 37. The median follow-up time was 62 months (range 24-110). Compared with the general population, the three scores indicating the most impaired QOL were emotional and social functioning and fatigue. The clinical significance of global QOL impairment was borderline. The physical functioning, role functioning, and pain scores did not significantly differ from those of the general population. In multivariate analysis, the initial treatment had no significant influence on any dimension of QOL, except global QOL and emotional functioning. Surprisingly, surgery plus RT, as the initial treatment, favorably influenced the emotional functioning score and EBRT plus BT negatively influenced the global QOL score. None of these treatment modalities influenced any symptom scales. Patient selection was, at least partially, responsible for these paradoxical results. CONCLUSION The results of this study bring original and useful data about the QOL of long-term survivors of oropharynx carcinoma. In these patients, the QOL was significantly impaired, particularly in its psychosocial dimensions. The level of symptoms and functioning (except global QOL and emotional) was similar whatever the initial treatment. These results suggest the importance of coping processes. In a trial comparing treatment options from a long-term perspective, survival remains the most relevant end point, and a QOL evaluation should be a secondary end point. More prospective studies on QOL in head-and-neck cancer patients are needed to determine new strategies for rehabilitation management.

Cervical lymph node metastasis from an unknown primary: is a tonsillectomy necessary?

PURPOSE The detection of an infraclinical primary by tonsillectomy in case of cervical lymph node of an epidermoid carcinoma with unknown primary after a radical neck dissection, allows avoiding irradiation of the normal larynx. The aim of this study is to quantify the rate of tonsil primary to justify this procedure. METHODS AND MATERIALS From 1969 to 1992, 87 patients had a tonsillectomy as part of the workup for cervical nodal metastasis of an epidermoid carcinoma with unknown primary. The mean age was 57 years (range: 39-75 years) and the sex ratio was 8.6. Sixty-seven patients had a single cervical adenopathy (17 N1, 30 N2a, 5 N3, 15 Nx), and 20 patients multiple cervical adenopathies (17 N2b, 3 N2c). The treatments included always an irradiation to the node areas (50 Gy), and to the pharyngolarynx in case of normal tonsil (50 Gy), or to the tonsil if it was the primary (50 Gy with a brachytherapy boost of 20-25 Gy). In this last case, the larynx could be protected. RESULTS Tonsillectomy never induced specific complication. Out of 87 patients, 26% had a tonsil primary. There was not specific histological differentiation in this group. In the 67 patients with a single cervical adenopathy, 31% had a tonsil primary (6 N1, 7 N2, 1 N3, 7 Nx). It was a subdigastric adenopathy in 38%, a submandibular in 28% and a midjugulocarotidian in 23%. Among the 17 patients N2b, none had a tonsil primary. In the three patients N2c, two presented a tonsil carcinoma (two subdigastric nodes). CONCLUSION Tonsillectomy allows avoiding irradiation of normal larynx in 26% of patients who have a cervical lymph node with unknown primary. It should be performed in case of a single node of the subdigastric, midjugulocarotidian or submandibular area or bilateral subdigastric adenopathies.

Salvage irradiation by brachytherapy of velotonsillar squamous cell carcinoma in a previously irradiated field: Results in 73 cases

PURPOSE The salvage brachytherapy performed in patients presenting velotonsillar carcinoma in a previously irradiated field is evaluated in terms of local control, complications and survival. METHODS AND MATERIALS Between 1976 and 1990, 73 patients presenting with velotonsillar squamous cell carcinoma in a previously irradiated area were treated at Center Alexis Vautrin with brachytherapy along using an 192Ir implant (afterloading technique) with curative intent. According to the UICC 1987 TNM classification, there were 45 T1 N0, 20 T2 N0, one T3 NO, one T3 N2 and six Tx Nx. RESULTS The 5-year actuarial local control for T1 N0 and T2 N0 are 80% and 67% respectively. The regional relapse rate was 10% in both groups. Grade 2 complications occurred in 13% of patients and these were neither related to the volume treated nor the dose rate. There were no Grade 3 or 4 complications. The 5-year specific survival is 64%, with a plateau after the 5th year, but the 5-year overall survival is only 30%. Fourty-two percent of the patients in this series died from another carcinoma. All but two of these were related to continued alcohol and tobacco intoxication. CONCLUSION We conclude that brachytherapy alone (60 Gy) is optimal treatment for patients presenting with velontonsillar carcinoma in a previously irradiated field. The greatest challenge is the screening of these patients and the prevention of subsequent head and neck cancers. Recognizing the fact that these patients are at high risk for subsequent malignancies of upper aerodigestive tract, lung and esophagus, close surveillance is necessary for: (a) early diagnosis and prompt treatment; and (b) development of prevention strategies of field cancerization.