Terms Of Locoregional Control Research Articles

9P - Patterns of Failure in Pathologic N1 Breast Cancer Patients Treated with Mastectomy and Radiotherapy

Introduction: Pakistan has the highest rate of breast cancer of any South Asian population and the majority of patients present with locally advanced or metastatic disease. We report on patterns offailure and survival in pathologic N1 breast cancer patients treated with mastectomy, adjuvant chemotherapy/hormonal therapy and post-mastectomy radiotherapy (PMRT). Materials and methods: Between 1995 and 2009, the hospital information system identified 400 women with pathologically confirmed N1 breast cancer. Axillary nodes were clinically palpable in 75% of the patients at presentation. All patients were treated with mastectomy (including level I-II axillary dissection). Distribution of pathologic tumor size was up to 2 cm, 2.1 to 5 cm, and more than 5 cm in 16.5%, 58.5%, and 25% of the patients, respectively. Distribution of dissected lymph nodes was one to five, six to nine, and ten and above in 9%, 6% and 85% of the patients, respectively. Median number of dissected lymph nodes were 14 (range 1–37). 92% of the patients received doxorubicin-based chemotherapy either in neo-adjuvant or adjuvant setting. All patients received PMRT, to chest wall only in 12%, to chest wall and supraclavicular fossa in 81.5%, and to chest wall, supraclavicular fossa and axilla in 6.5% of the patients. All patients with positive ER/PR receptors also received hormonal modulation. Median age was 44 years (range 21–83 years). Patterns of failure and disease-free survival (DFS) were determined. Results: Median follow-up duration was 4.4 years. Patterns of failure were, isolated local (LF) in 4%, isolated regional (RF) in 0.5%, distant failure (DF) in 32%, and loco-regional along with distant failure (LRF + DF) in 2.5% of patients. Cumulative incidence of loco-regional failure for patients with a pathologic tumor size of up to 2 cm, 2.1 to 5 cm, and more than 5 cm were 2.5%, 3%, and 5.5%, respectively. These incidences for one to five, six to nine, and more than ten dissected lymph nodes were 2%, 0%, and 9.5%, respectively. The 10 years DFS for the whole group was 55%. Conclusions: The role of PMRT may have some value in terms of loco-regional control in pathologic N1 breast cancer patients. This merits further evaluation in large-scale randomized trials. Disclosure: All authors have declared no conflicts of interest.

Study of two different dose fractionation schedules of post mastectomy chest wall irradiation in carcinoma breast patients

Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women. Aim: To compare two different dose fractionation schedules in terms of overall treatment, locoregional control, acute and late toxicities and patient compliance. Materials and methods: Patients of postmastectomy non metastatic breast cancer were randomized in two arms: Arm A (45) Arm B (46) according to dose fractionation schedule of external radiation given to chest wall and draining lymphatics. Arm A was given 50 Gy in 25 fractions and Arm B was given 40Gy in 17 fractions. After completion of radiation patients were kept on follow up. Results: Median follow up was 20 months. In arm A & B the median overall treatment time was 40 and 27 days with respective ranges of 36-47 days and 22-33 days .The patients in both the arms tolerated radiation well, skin reactions were most common followed by nausea and vomiting .Grade II and III acute reactions were comparable in both arms. There was non-significant increase in both late skin and subcutaneous skin toxicities in arm B. Result of treatment of both arms are, chest wall failure 5% v/s 9% (p>.05), nodal failure 8% v/s 7%(p>.05) and distant metastasis 25% v/s 28% (p>.05). Conclusion: Both the studied dose fractionation schedules are equally efficacious in terms of locoregional control, acute and late toxicities. The shorter schedules in Arm B gives an added advantage of decreased overall treatment time giving better compliance and reduces work load of overburdened department.

Merkel Cell Carcinoma of the Head and Neck: Challenges in Diagnosis and Therapy

Since the original description of the trabecular carcinoma of the skin, now known as Merkel cell carcinoma (MCC), by Toker in 1972, this malignancy has provided significant challenge to clinicians. With an increasing incidence and a known poor prognosis for advanced lesions, the disease continues to challenge physicians in the present time. New evidence indicates that not only the incidence is increasing in the overall population but also certain groups of patients such as those taking medications or immunosuppressed are at increased risk. Additionally, patients affected by MCC may be at risk for other malignant diseases. Therefore, it is likely that MCC will continue to challenge clinicians in the future. Current clinical questions regarding the optimal management of MCC include surgical challenges such as histologic diagnosis, sentinel lymph node biopsy, and margin control, as well as issues related to reconstruction. Radiation oncologists continue to evaluate the appropriate strategy for this rare disease in terms of locoregional control and appropriate dosing strategies. Medical oncologists continue their quest for effective treatments for this rare disease, which does not lend itself to randomized controlled trials due to the small number of eligible subjects. Recent new data regarding the analysis of MCC has resulted in a dramatic increase in our knowledge regarding this disease. The discovery of the Merkel cell polyomavirus by Feng, et al. and the subsequent work of Touze et al. which showed high antibody titers against the virus (anti-MCPyV) correlating to improved survival have provided us with new data with which to target this disease. Work in viral detection and protein expression continues to further elucidate the role of the virus in the genesis of MCC. The development of viral vaccines and targeted agents for the treatment of MCC is ongoing. The purpose of this special issue is to update the clinician on the current literature regarding Merkel cell carcinoma and provide a consolidated review of this disease for the clinician. A historical perspective as well as the current management strategies will be reviewed. Recent data will be presented regarding current diagnostic methods, and pathological evaluation as well as an evaluation of surgical, radiotherapeutic, and chemotherapeutic strategies employed in the treatment of MCC will be examined in the articles within the issue. In addition, future areas of research will be identified to allow the reader to plot the trajectory of our current understanding of this disease and where scientific and clinical research efforts are likely to yield advances in the future. Brett A. Miles

The treatment outcome and radiation-induced toxicity for patients with head and neck carcinoma in the IMRT era: a systematic review with dosimetric and clinical parameters.

A descriptive analysis was made in terms of the related radiation induced acute and late mucositis and xerostomia along with survival and tumor control rates (significance level at 0.016, bonferroni correction), for irradiation in head and neck carcinomas with either 2D Radiation Therapy (2DRT) and 3D conformal (3DCRT) or Intensity Modulated Radiation Therapy (IMRT). The mean score of grade > II xerostomia for IMRT versus 2-3D RT was 0.31 ± 0.23 and 0.56 ± 0.23, respectively (Mann Whitney, P < 0.001). The parotid-dose for IMRT versus 2-3D RT was 29.56 ± 5.45 and 50.73 ± 6.79, respectively (Mann Whitney, P = 0.016). The reported mean parotid-gland doses were significantly correlated with late xerostomia (spearman test, rho = 0.5013, P < 0.001). A trend was noted for the superiority of IMRT concerning the acute oral mucositis. The 3-year overall survival for either IMRT or 2-3DRT was 89.5% and 82.7%, respectively (P = 0.026, Kruskal-Wallis test). The mean 3-year locoregional control rate was 83.6% (range: 70–97%) and 74.4 (range: 61–82%), respectively (P = 0.025, Kruskal-Wallis). In conclusion, no significant differences in terms of locoregional control, overall survival and acute mucositis could be noted, while late xerostomia is definitely higher in 2-3D RT versus IMRT. Patients with head and neck carcinoma should be referred preferably to IMRT techniques.

Postoperative Radiotherapy for Patients With Completely Resected Pathologic N2 Non–Small-Cell Lung Cancer: A Retrospective Analysis

BackgroundAdjuvant radiotherapy in non–small-cell lung cancer (NSCLC) is still controversial. The purpose of this retrospective study was to evaluate the role of postoperative radiotherapy (PORT) in terms of local control and survival in pathologic N2 NSCLC. Patients and MethodsFrom January 2003 to December 2008, 66 patients with pathologic N2 NSCLC received PORT. Mediastinal lymph node metastases were classified into single (12 patients) or multiple (54 patients) stations. All patients received conformal radiation therapy, with a median total dose of 50.4 Gy. Target volumes included the bronchial stump, ipsilateral hilum, all pathologically involved lymph node regions, and all the lymph nodes between 2 noncontiguous pathologic nodal stations. The pattern of failure was considered as locoregional or systemic, or a combination of both. Locoregional failure was defined as in field or out of field. ResultsMedian follow-up time was 34.9 months (range 3.5-62.8 months). Local control was 80% at 12 months, 77.2% at both 24 and 36 months, and 72.1% at 60 months. The pattern of failure was locoregional in 3 patients (1 out of field and 2 in field) and systemic in 25 patients, with 12 patients presenting both locoregional and distant disease. Overall survival at 12, 36, and 60 months was 77%, 44%, and 37%, respectively. Median survival time was 34 months. The number of pathologically involved lymph node stations was a prognostic factor for local control (P = .05), cancer-specific survival (CSS) (P = .04), and disease-free survival (DFS) (P = .04). ConclusionDespite the limitations of the present study, mainly represented by its retrospective nature, our data support the role of PORT in terms of locoregional control and overall survival benefit; the number of involved mediastinal lymph nodes represents a significant prognostic factor in patients with pathologic N2 NSCLC.

A novel low dose fractionation regimen for adjuvant vaginal brachytherapy in early stage endometrioid endometrial cancer

PurposeTo evaluate local control, survival and toxicity in patients with early-stage endometrioid adenocarcinoma of the uterus treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) alone using a novel low dose regimen. MethodsWe reviewed records of 414 patients with stage IA to stage II endometrial adenocarcinoma treated with VB alone from 2005 to 2011. Of these, 157 patients with endometrioid histology received 24Gy in 6 fractions of HDR vaginal cylinder brachytherapy and constitute the study population. Dose was prescribed at the cylinder surface and delivered twice weekly in the post-operative setting. Local control and survival rates were calculated by the Kaplan–Meier method. ResultsAll 157 patients completed the prescribed course of VB. Median follow-up time was 22.8months (range, 1.5–76.5). Two patients developed vaginal recurrence, one in the periurethral region below the field and one in the fornix after treatment with a 2.5-cm cylinder. Three patients developed regional recurrence in the para-aortic region. Two patients developed distant metastasis (lung and carcinomatosis). The 2-year rate of vaginal control was 98.6%, locoregional control was 97.9% and disease-free survival was 96.8%. The 2-year overall survival rate was 98.7%. No Grade 2 or higher vaginal, gastrointestinal, genitourinary or skin long-term toxicity was reported for any patient. ConclusionVaginal brachytherapy alone in early-stage endometrial cancer provides excellent results in terms of locoregional control and disease-free survival. The fractionation scheme of 24Gy in 6 fractions prescribed to the cylinder surface was well-tolerated with minimal late toxicity.

Impact of Pretreatment Body Mass Index on Patients With Head-and-Neck Cancer Treated With Radiation

To investigate the association of pretreatment body mass index (preT BMI) with outcomes of head-and-neck cancer in patients treated with radiotherapy (RT). All 1,562 patients diagnosed with head-and-neck cancer and treated with curative-intent RT to a dose of 60 Gy or higher were retrospectively studied. Body weight was measured both at entry and at the end of RT. Cancer-specific survival (CSS), overall survival (OS), locoregional control (LRC), and distant metastasis (DM) were analyzed by preT BMI (<25 kg/m(2) vs. ≥25 kg/m(2)). The median follow-up was 8.6 years. Patients with lower preT BMI were statistically significantly associated with poorer CSS and OS than those with higher preT BMI. There was no significant difference between preT BMI groups in terms of LRC and DM. Body weight loss (BWL) during radiation did not influence survival outcomes. However, in the group with higher preT BMI, CSS, OS, and DM-free survival of patients with less BWL during radiation were statistically longer when compared with greater BWL. This study demonstrates that higher preT BMI positively influenced survival outcomes for patients with head-and-neck cancer. Patients with higher preT BMI who were able to maintain their weight during radiation had significantly better survival than patients with greater BWL.

POSTOPERATIVE RADIOCHEMOTHERAPY WITH WEEKLY CISPLATIN IN PATIENTS WITH HEAD AND NECK CANCER SINGLE-INSTITUTION OUTCOME ANALYSIS

The objective of this study was to evaluate the feasibility, toxicity and efficacy of postoperative radiochemotherapy with weekly cisplatin in locoregionally advanced or high risk head and neck cancer in a single institutional setting. Patients with head and neck cancer of stage III/IV or patients with insufficient margins of resection were included in the study. Radiotherapy consisted of 70 Gy/ 7 weeks/ 35 fraction after R1/2 resection and 60-64 Gy/ 6-6,5 weeks/ 30-32 fraction after R0 resection, respectively. All patients received concurrent cisplatin 40 mg/m2 weekly. Between 7/2002 and 12/2008, 100 consecutive patients [WHO ≤ 2, male to female ratio 84/16, median age 54 years] were treated. Tumors of the oropharynx were the most frequent (49%) and stage IV was predominant (86%). 96% patients received the full radiation treatment as planned, median total tumor dose was 66 Gy. Omission of weekly cisplatin had been occurring frequently, the most frequent reason for its early cessation were hematological toxicities (34%). Grade 3/4 mucosal toxicity developed in 32%. No death was observed during the treatment. The late toxicities were acceptable, predominantly subcutaneous fibrosis and xerostomia in most of the cases. We recorded six cases of osteonecrosis. Two and half year overall survival, locoregional control, time to progression and disease free survival were 64%, 88%, 79% and 59%, respectively. Postoperative radiochemotherapy with weekly cisplatin is toxic, but tolerable and highly effective in terms of locoregional control and survival. Multivariete analysis revealed that the only prognostic factor for survival was primary surgery at the University centre.

Postoperative chemoradiotherapy in high risk locally advanced gastric cancer

PurposeTo evaluate treatment outcome of patients with high risk locally advanced gastric cancer after postoperative chemoradiotherapy.Materials and MethodsBetween May 2003 and May 2012, thirteen patients who underwent postoperative chemoradiotherapy for gastric cancer with resection margin involvement or adjacent structure invasion were retrospectively analyzed. Concurrent chemotherapy was administered in 10 patients. Median dose of radiation was 50.4 Gy (range, 45 to 55.8 Gy).ResultsThe median follow-up duration for surviving patients was 48 months (range, 5 to 108 months). The 5-year overall survival rate was 42% and the 5-year disease-free survival rate was 28%. Major pattern of failure was peritoneal seeding with 46%. Locoregional recurrence was reported in only one patient. Grade 2 or higher gastrointestinal toxicity occurred in 54% of the patients. However, there was only one patient with higher than grade 3 toxicity.ConclusionDespite reported suggested role of adjuvant radiotherapy with combination chemotherapy in gastric cancer, only very small portion of the patients underwent the treatment. Results from this study show that postoperative chemoradiotherapy provided excellent locoregional control with acceptable and manageable treatment related toxicity in patients with high risk locally advanced gastric cancer. Thus, postoperative chemoradiotherapy may improve treatment result in terms of locoregional control in these high risk patients. However, as these findings are based on small series, validation with larger cohort is suggested.

Intensity-modulated radiotherapy (IMRT)/Tomotherapy following neoadjuvant chemotherapy in stage IIB–IVA/B undifferentiated nasopharyngeal carcinomas (UCNT): A mono-institutional experience

To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3-64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a-2b and T3-T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach.

Sequential or concomitant chemotherapy in limited stage small-cell lung cancer

Chemotherapy (CT) combined with radiation therapy (RT) is the standard treatment for limited disease small-cell lung cancer (LDSCLC). Many questions including RT dose, fractionation, and sequence of RT/CT administration remain controversial. In this paper, we retrospectively assessed the outcome of patients with LDSCLC treated with radiation of at least 50 Gy. From December 1997 to January 2006, 69 consecutive patients with LDSCLC were treated at our institutions. Treatment consisted of at least 4 cycles of CT, and 3D conformal thoracic RT. The median age was 61 years (range, 37-78 years). Sequential or concomitant CT/RT was given in 47 (68%) and 22 (32%) of the patients, respectively. The median RT dose was 60 Gy. Prophylactic cranial irradiation (PCI) was administered in 47 (68%) patients. With a median follow-up of 36 months (range, 6-107), 16 patients were alive without disease. The median overall survival time was 24 months, with a 3-year survival rate of 29%. The 3-year disease-free survival (DFS) and loco-regional control (LRC) rates were 23% and 60%, respectively. A better DFS was significantly associated with performance status (PS) 0 (p = 0.004), complete response to treatment (p = 0.03), and PCI group (p = 0.03). A trend towards improved overall survival (OS) was observed for patients who underwent PCI (p = 0.07). Patients treated with sequential CT/RT had a better outcome than those treated with concomitant treatment (3-year DFS rate 27% vs. 13%; p = 0.04). However, PCI was delivered more frequently for the sequential group. No significant dose-response relationship was found in terms of LRC. The multivariate analysis showed that complete response to treatment was the only significant factor for OS. Complete response to treatment was the most important factor for OS. A better DFS was significantly associated with the PCI group. We did not find a significant difference in outcome between patients receiving doses of 60 Gy or more and patients receiving 60 Gy or less.

Role of chemoradiotherapy alone in the management of unfit patients with nonmetastatic locally advanced squamous cell carcinoma of the esophagus.

138 Background: Surgery is considered the best treatment for patients (pts) with non-metastatic locally advanced squamous cell carcinoma of the esophagus who have responded to neoadjuvant chemoradiotherapy (CRT) in terms of locoregional control. However, in these pts PFS and OS have not been proved superior to those achieved by CRT alone. Besides, the addition of surgery to CRT increases treatment-related morbidity and mortality. Unfit pts are usually declined for surgical procedures and included in definitive CRT programs. The aim of this study was to define the role of non-surgical strategies (CRT, CT or RT) in unfit pts considered non-optimal for surgical procedures. Methods: We retrospectively reviewed 90 pts with squamous cell carcinoma of the esophagus who had been diagnosed and treated at our institution from January 2004 to December 2009. Fifty-one pts were non-metastatic among which 19 underwent surgery and 32 a non-surgical procedure (CRT, CT, RT or BSC). Our aim was to identify OS, PFS, RR, data on comorbidity and toxicity in these 32 pts. Results: Thirty out of the 32 pts were men with a median age of 62 years (range 41-90). Comorbidity was detected in 17 pts (53%) as means of respiratory disorders (21.9%), cardiopathy (12.5%), hepatopathy (21.9%), synchronic tumors (25%) and metachronic tumors (25%). Seventeen pts received CRT, 7 received CT, 1 received RT and 7 received BSC alone (53%, 22%, 3% and 22% respectively). Grade 3 and 4 toxicities were observed in 15 pts (46.9%) as means of mucositis (18.8%), oesophagitis (15.6%), diarrhoea (12.5%) and neutropaenia (12.5%). One patient in the CRT group died of toxicity. RR was 43.8% (70.6% for CRT, 14.3% for CT alone). Median follow-up was 17.2 months. Median PFS was 11.3 ± 6.12 months (17.9 for CRT, 5.1 for CT alone). Median OS was 15.6 ± 7.6 months (6.9 for CT alone). Conclusions: Our experience with CRT alone in unfit pts with locally advanced squamous cell carcinoma of the oesophagus supports its use with a median PFS of 17.9 months and controllable toxicity. Data on median OS are lacking due to pending long-term follow-up. No significant financial relationships to disclose.

Radical surgery and postoperative radiotherapy in patients with advanced squamous cell carcinoma of the larynx

Background: The aim of this study is to analyze the results of radical surgery followed by postoperative radiotherapy in patients with advanced laryngeal cancer. Methods: Seventy-seven patients with advanced laryngeal cancer were treated with postoperative radiotherapy following total laryngectomy with or without neck dissection. Median age of patients at the diagnosis was 57 years (range, 43-76). The median follow-up was 41 months (range, 11-70). Radiotherapy was performed using three-dimensional conformal technique. Results: Median duration of overall radiation treatment time was 5.9 weeks (range, 5.4-7.6). Median total dose delivered was 60 Gy (range, 50-66). Locoregional relapse was the most frequent pattern of failure. A 5-year locoregional control (LRC) and overall survival (OS) rates were 72.3% and 66.2%, respectively. A 5-year LRC and OS rates were significantly higher in patients without nodal disease (N0) as compared to patients with metastatic involvement of the neck lymph nodes (N+) (p=0.009 and p=0.002, respectively). Confluent mucositis was developed in 16 patients (20.8%). Late toxicity most frequently occurred in the skin as well as in the mucous membrane and in the subcutaneous tissue and was grade 1 reaction (74.0%, 67.5%, and 72.7%, respectively). Conclusion: In order to improve treatment results in terms of LRC and OS and following evidence-based treatment recommendations for patients with advanced laryngeal cancer whose initial treatment was radical surgery, we strongly advocate the acceptance of postoperative concurrent chemoradiotherapy in cases with surgical specimen demonstrating high-risk pathological features.

Hypofractionated Radiotherapy in the Treatment of Early Glottic Carcinoma

ABSTRACTIntroductionGiven the high probability of cure, the aims of treatment are cure, laryngeal preservation and good voice quality while making effective use of available resources. In this study we analyze locoregional control (LRC) and survival following hypofractionated radiotherapy in early stage glottic squamous cell carcinoma treated at Shaukat Khanum Memorial Cancer Hospital and Research Center.Materials and methodsBetween October 2003 and June 2009, 87 patients with early glottic squamous cell carcinoma were treated with hypofractionated radiotherapy. All patients were included in the study (M: 94%; F:6%). Median age was 60 years (range: 21-81 years). Sixty-six percent of patients were smokers. AJCC stage was T1 in 95% and T2 in 5% of the patients. Radiotherapy dose was 55 Gy in 20 fractions over 4 weeks. All patients were treated on cobalt-60. Median radiotherapy treatment time was 28 days (range: 23-35 days).ResultsThe LRC rate after primary radiotherapy at 5 years was 91% (95% CI: 88-94%). The 5 years overall and disease-specific survival was 86% (95% CI: 81 and 91%) and 97% (CI 95%: 95 and 99%) respectively. Patients with T1a and T1b disease had LRC rates of 95 and 88% (p = 0.32). The LRC rates for patients with and without anterior commissure involvement at 5 years were 80 and 96% (p = 0.02) respectively.ConclusionHypofractionated radiotherapy 55 Gy in 20 fractions is comparable to conventional fractionation schedules in terms of locoregional control and survival while offering potential for optimizing resources usage.

Postoperative accelerated radiotherapy (POPART) versus conventional postoperative radiotherapy (CPORT) in squamous cell head and neck cancer: A multicenter prospective randomized study of the Dutch Head and Neck Cooperative Study Group.

5508 Background: In head and neck squamous cell carcinoma (HNSCC), the overall treatment time of radiation (OTT) is significantly associated with locoregional control (LRC), which is consistent with rapid repopulation of cancer clonogens during radiotherapy. However, the importance of the OTT in the postoperative setting is less clear. Therefore, the main objective of this phase III study was to determine the value of reduction of the OTT of postoperative radiotherapy in high risk patients primarily treated with surgery. Methods: Patients with HNSCC treated with curative surgery and with high risk factors for locoregional recurrence (i.e., positive surgical margins and/or extranodal spread) were randomly assigned to receive either standard postoperative radiotherapy (SPORT) at 2 Gy/fraction/day, 5 days/week to 66 Gy/33 fractions/7 weeks or postoperative accelerated radiotherapy (POPART) with 2 Gy/fraction/day, 5 days per week, to 20 Gy followed by 1.8 Gy/fraction/day and 1.3 Gy/fraction per day to a boost field as a second daily treatment to 66.5 Gy/40 fractions/5 weeks.The primary endpoint was locoregional tumor control (LRC). Secondary endpoints were overall survival, acute and late toxicity and quality of life. Results: From December 2004 to October 2008, 148 patients were enrolled in the study (74 pts for SPORT and 74 pts for POPART). The two study-arms were well balanced with regard to the most important prognostic factors. No significant differences were noted with regard to acute and late toxicity, although there was a trend towards more use of pain medication among patients treated with POPART. At 3 years, the locoregional control rate was 77% after POPART compared to 76% with SPORT (HR: 0.86, CI 0.42-1.76; p=0.68). The 3-year overall survival rate was 71% with POPART compared to 63% with SPORT (HR:0.93, CI 0.54-1.61; p=0.81). Conclusions: A reduction in the OTT of postoperative radiotherapy in patients with HNSCC with adverse factors for locoregional failure does not improve outcome in terms of locoregional control and overall survival. No significant financial relationships to disclose.

Long-term treatment outcome of nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT).

5582 Background: A number of centers have reported promising early results of treating NPC patients using IMRT, in terms of locoregional control and parotid sparing. This study evaluated the sustainability of early favorable results, and late events. Methods: 231 consecutive NPC patients were treated with IMRT between 2000 and 2005. The proportion of stage I, IIA, IIB, III, IVA, and IVB disease was 8%, 5%, 14%, 32%, 28%, and 13% respectively. The prescribed dose was 66 Gy over 33 daily fractions to the gross tumor, 60 Gy to the planning target volume, and 54–60 Gy to the clinically negative neck. Majority of T1-2a patients received brachytherapy boost (12 Gy/ 4 fractions), and T2b-T4 patients received conformal or IMRT boost (6-8 Gy/ 3-4 fractions). Stage III–IVB patients also received concurrent chemotherapy, with or without neoadjuvant chemotherapy. Results: The median follow-up period was 59 months. The overall 6-year local failure-free survival (LFFS), regional failure-free survival (RFFS), distant metastasis-free survival (DMFS), and overall survival (OS) was 82%, 91%, 75%, and 66% respectively. Between 3 to 6 years there was a drop in LFFS, RFFS, and OS, while DMFS plateaued. Local failure was dominated by within-field failure (85%). 68% of local failure involved the skull base and intracranial region (rT3/4). Only two patients developed visual impairment despite a proportion of T3/4 patients had received > 54Gy to the optic nerves or chiasm. Radiation-induced malignancy occurred in 3 patients (2 in oral tongue, 1 in nasal cavity). The 5-year cumulative incidence of radiation-induced tongue cancer was 1.43%, higher than that seen after 2-dimensional radiotherapy. Conclusions: Although IMRT at a dose between 66-74 Gy achieves good early response and promising late toxicity profile, further locoregional recurrence can be seen on longer follow-up, especially at or above skull-base region. More vigorous use of adaptive and image-guidance radiotherapy may be needed to overcome potential setup error and volumetric changes during treatment course. The incidence of radiation-induced oral tongue cancer warrants further assessment. No significant financial relationships to disclose.

Postoperative adjuvant chemoradiotherapy versus radiotherapy alone for head and neck squamous cell carcinoma: A meta-analysis evaluating the role of chemotherapy schedules.

5583 Background: To compare concurrent post-operative chemoradiotherapy (POCRT) with post operative radiotherapy alone (PORT) for head and neck squamous cell carcinoma (HNSCC), evaluating different chemotherapy regimens used. Methods: A meta-analysis of RCT was performed comparing POCRT to PORT for HNSCC. The MEDLINE, EMBASE, and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment. Results: Pooled results from 8 randomized trials (1,808 patients) evaluating POCRT (3 trials using cisplatin alone, 2 mitomycin –c, 2 carboplatin and 1 cisplatin + 5-FU) in HNSCC showed significant decreased of mortality (OR=0.68, CI95%-0.52, 0.86, p<0.0001) as compared to PORT. In the subgroup analysis cisplatin alone was the only chemotherapy schedule that showed a reduction in overall mortality rate when compared to PORT (OR=0.62, CI95%-0.47, 0.82, p=0.0008). There was significant difference for local recurrence among those patients receiving PORCT and PORT (OR=0.46, CI 95% 0.37-0.58, p<0.0001). In the subgroup analysis the carboplatin schedule was the only subgroup that there was not any difference for local recurrence rates when compared to PORT (OR=0.72, CI 95% 0.46-1.13, p=0.25). Conclusions: Our data demonstrate that adjuvant cisplatin-enhanced radiation therapy is more effective than PORT for high-risk tumors in terms of locoregional control and survival, when compared to other regimens. Results of the present study failed to demonstrate that the addition of carboplatin to PORT provides a statistically significant benefit in terms of local control and survival rate. No significant financial relationships to disclose.

Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary

Purpose To compare the impact of an unilateral post-operative irradiation or a bilateral irradiation in terms of loco-regional control and survival in patients with cervical lymph node of squamous cell carcinoma from an unknown primary (CUP). Methods and materials Ninety five patients with epidermoid carcinoma involving unilateral cervical lymph nodes from an unknown primary were treated in two institutions from 1990 to 2007. Post-operative radiation therapy was delivered to one side of the neck in 59 cases, to both sides of the neck in 36 cases. There were 11 women and 84 men ranging in age from 38 to 80 years (median 59 years). Neck dissection was performed in 79 patients while 16 patients underwent single lymph node sampling only. Results After a median follow-up of 3.3 years, the nodal relapse rate was 34% after unilateral neck irradiation and 25% after bilateral radiotherapy ( p = 0.21). Six contralateral lymph node relapses occurred after unilateral irradiation (10%). The 5-year overall survival rate of the entire group was 24%. The 5-year OS rates were 22% after unilateral irradiation and 23%, after bilateral radiotherapy ( p = 0.944). The occult primary occurred in 12% after unilateral irradiation and 6% after bilateral radiotherapy. The radiation technique (3D-CRT or IMRT vs. 2D: p = 0.026) was prognostic on loco-regional control. Independent prognostic determinants on overall survival were the WHO status ( p = 0.013) and the radiation technique (2D vs. 3D-CRT or IMRT; p = 0.029). There was no difference in loco-regional control ( p = 0.639) and no difference in survival ( p = 0.493) when chemotherapy was associated. Conclusions Retrospective comparisons between bilateral and unilateral neck radiotherapies did not show differences in terms of loco-regional control and survival. However, patient’s local regional control and survival are significantly improved after 3D-CRT or IMRT.

Promoter methylation of TIMP3 and CDH1 predicts better outcome in head and neck squamous cell carcinoma treated by radiotherapy only

As with other solid tumor types, head and neck squamous cell carcinoma (HNSCC) has been identified as an epigenetic, as well as genetic, disease. Consequently, promoter hypermethylation, being the most important aberrant epigenetic characteristic, has been intensively investigated for its biomarker potential in this cancer type. As many of these evaluations are obscured by a heterogeneity of treatments, the current study aimed to evaluate the incidence and prognostic value of the promoter hypermethylation of TIMP3, CDH1, DAPK, RASSF1A, p16INK4A and MGMT in HNSCC treated solely by radiotherapy. In 46 patients with advanced HNSCC treated with a hybrid accelerated fractionation radiotherapy schedule, DNA extracted from pretreatment paraffin-embedded tumor biopsies was used to determine the methylation status of the genes of interest by methylation-specific PCR (MSP). The detected epigenetic silencing was related with outcome in terms of locoregional control (LRC), and overall (OS), disease-free (DFS) and disease-specific survival (DSS). Tumor biopsies revealed the epigenetic silencing of MGMT in 42.5% (17 of 40) of patients and of TIMP3 in 40.5% (17 of 42) of cases. For the remaining investigated genes, a lower methylation percentage was detected: 13.2% (5 of 38) for CDH1, 11.4% (4 of 44) for DAPK, 4.8% (2 of 42) for p16INK4A and 2.4% (1 of 41) for RASSF1A. The promoter hypermethylation of TIMP3 and CDH1 was significantly related with better LRC (p=0.009 and p=0.02, respectively), OS (p=0.005 and p=0.002, respectively), DFS (p=0.02 and p=0.004, respectively) and DSS (p=0.12 and p=0.007, respectively). In conclusion, in this representative group of 46 patients with advanced HNSCC treated by radiotherapy only, the epigenetic silencing of TIMP3 and CDH1 predicted a better outcome.

The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor alpha (TNFalpha), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble alpha chain of IL-15 receptor (sIL-15Ralpha), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15Ralpha was performed with a newly developed RIA. Increased serum sIL-15Ralpha concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15Ralpha was mainly produced by tumor cells via proteolytic cleavage of IL-15Ralpha mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Ralpha concentrations. Surprisingly, sIL-15Ralpha did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15-induced proinflammatory cytokines (IL-6, TNFalpha, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15Ralpha. Overall, these results support for the first time an original protumor role of sIL-15Ralpha in cancer.