Local Relapse-free Survival Research Articles

Abstract 1963: Novel small molecule inhibitor of the endonuclease function of the APE1 DNA repair and redox signaling enzyme blocks proliferation and reduces viability of glioblastoma cells

Abstract The DNA Base Excision Repair (BER) pathway repairs DNA damaged by endogenous and exogenous agents including chemotherapeutic agents. Removal of the damaged base by a DNA glycosylase creates an apurinic / apyrimidinic (AP) site. AP Endonuclease1 (APE1), a critical component in this pathway that hydrolyzes the phosphodiester backbone 5’ to the AP site. Failure to repair AP sites leads to DNA strand breaks, enhanced cytotoxicity, cell cycle arrest and increased apoptosis. In addition to APE1's role in repair, it also functions as a redox signaling factor to activate key transcription factors such as AP1 (Fos/Jun), p53, NFkB, HIF-1α, and others controlling the expression of genes important for cell survival and cancer promotion and progression. APE1 has been shown to have an altered level of expression in a variety of cancers including pancreatic, breast, prostate, gliomas, sarcomas and others. High APE1 expression has also been associated with chemoradiotherapy poor outcome, poor complete response rate, shorter local relapse-free interval, poorer survival and high angiogenesis. Due to APE1's critical role in repairing chemotherapy- and IR-induced DNA damage, we hypothesize that inhibiting APE1's DNA repair activity would not only allow us to further elucidate the role of DNA repair that elevated levels of APE1 play in tumors, but would also allow us to delineate the importance of its DNA repair and redox functions in normal cellular processes. While reducing the amount of APE1 in cancer cells using anti-sense oligonucleotide technology and RNA interference sensitizes tumor cells to chemotherapeutic agents, it may not be the most efficacious route of treatment. We have concluded a screen of small molecule compounds for their ability to inhibit APE1 AP endonuclease activity. Four families of compounds with IC50 values less than 10 μM were identified, validated and characterized. One of the most promising compounds, designated AR03 inhibited cleavage of AP sites in vivo in SF767 glioblastoma cells, in vitro in whole cell extracts and inhibits purified human APE1 in vitro. AR03 has low affinity for dsDNA and it does not affect the redox function of APE1. AR03 also potentiates the cytotoxicity of methyl methane sulfonate (MMS) and temozolomide (TMZ) in SF767 cells. AR03 is chemically distinct from all the previously reported small molecule inhibitors of APE1 which are either ineffective in vivo due to poor cellular uptake, not tested in cellular based scenarios, or lacking in specificity. Thus, AR03 is a novel small molecule inhibitor of APE1, which may have potential as an oncotherapeutic drug for treating glioblastoma and other cancers. Additional studies are needed to determine the effect of AR03 in combination with other cancer chemotherapeutic agents, in combination with other APE1 inhibitors or other emerging BER targets such as PARP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1963.

Mature Results of a Randomized Trial of Accelerated Hyperfractionated Versus Conventional Radiotherapy in Head-and-Neck Cancer

To evaluate long-term late adverse events and treatment outcome of a randomized, multicenter Phase III trial of continuous, hyperfractionated, accelerated radiotherapy (CHART) compared with conventional radiotherapy (CRT) in 918 patients with advanced squamous cell carcinomas of the head and neck. Survival estimates were obtained for locoregional relapse-free survival, local relapse-free survival, overall survival, disease-specific survival, disease-free survival and for late adverse events. The 10-year estimates (+/-1 standard error) for locoregional relapse-free survival, overall survival, disease-free survival, and disease-specific survival were 43% +/- 2% for CHART and 50% +/- 3% with CRT (log-rank p = 0.2); 26% +/- 2% and 29% +/- 3% (p = 0.4), respectively; 41% +/- 2% and 46% +/- 3% (p = 0.3), respectively; and 56% +/- 3% and 58% +/- 3% (p = 0.5), respectively. There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART (p = 0.002 to 0.05). Severe xerostomia, laryngeal edema, and mucosal necrosis were also significantly lower with CHART (p = 0.02 to 0.05). Despite the reduction in total dose from 66 Gy to 54 Gy, control of locoregional disease and survival with CHART were similar to those with CRT. These findings, together with the low incidence of long-term severe adverse events, suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withstand the toxicity of concurrent chemoradiotherapy.

Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy

Background Insulin-like growth factor (IGF) receptor is a key receptor in apoptotic protection, cell adhesion, longevity, and transformation into a cancerous cell and can induce malignant changes in the presence of the IGF ligand. Over-expression of IGF-1R has been associated with resistance to radiation. Inhibitors of IGF-1R have been shown to enhance tumor radiation sensitivity and amplify radiation therapy-induced apoptosis. The purpose of this study is to evaluate the prognostic significance of IGF-1R expression in patients with breast cancer treated with breast conserving therapy. Materials and methods Paraffin specimens from 345 women with early stage breast cancer treated with BCT were constructed into tissue microarrays and stained for IGF-1R, COX-2 and p53. The molecular profiles were correlated with clinical-pathologic factors, overall, local, and distant relapse-free survival. The association between IGF-1R, other co-variables, and outcome was assessed. Results IGF-1R over-expression was identified in 197 cases (57%). IGF-1R over-expression was found to be correlated with African-American race ( p = 0.0233), p53 status ( p = 0.0082) and COX-2 expression ( p < 0.0001). While IGF-1R over-expression was associated with lower overall survival ( p = 0.0224) in node-negative patients, there was no impact of IGF-1R expression on local control. Conclusions In node-negative patients, patients with high levels of IGF-1R were found to have a significant reduction in overall survival, but no apparent effect on local control. Given the limited published data on IGF-1R in early stage, conservatively treated patients, further studies investigating IGF-1R expression in this cohort are necessary.

Simultaneous Integrated Boost Intensity‑Modulated Radiotherapy (SIB‑IMRT) in Nasopharyngeal Cancer

To assess the efficacy and safety of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) to treat nasopharyngeal cancer (NPC) in a Caucasian cohort. Outcome was analyzed with respect to dose-volume histogram (DVH) values. Between 03/2002 and 01/2008, 39 NPC patients underwent SIB-IMRT (37 Caucasians; 31 males; mean age 53 years [16-78 years]). 41% presented with WHO (World Health Organization) type 1 unfavorable histology, 85% with stage III/IV disease. 19 patients had total gross tumor volume (GTV) 16-70 cm3 (mean 36 cm3), while 16 had GTV > 70 cm3 (73-217 cm3; mean 115 cm3). All patients with stage II-IV disease received concomitant cisplatin. The prescribed SIB dose delivered to the planning target volume (PTV) was 70 Gy (2.00 Gy/fraction) in 17, 69.6 Gy (2.11 Gy/fraction) in 19, and 66 Gy (2.20 Gy/fraction) in three patients. 3-year local relapse-free, nodal relapse-free, distant metastases-free, disease-free rates and overall survival were 86%, 89%, 85%, 72%, and 85% (median follow-up 30 months [8-71 months]). Histology was a significant prognostic factor concerning overall survival, with worst prognosis in WHO type 1 compared to type 2/3 (75% vs. 93%; p = 0.03). There was a trend in favor of WHO type 2/3 regarding local control (74% vs. 94%; p = 0.052). The PTV DVHs showed a slight left shift compared to reported series. Three patients developed grade 3 late effects (xerostomia [n = 2], dysphagia [n = 1], hearing loss [n = 1]). In comparison with predominantly Asian NPC IMRT series in the literature, chemo-IMRT in the own Caucasian cohort, characterized by less radio-responsive WHO type 1, was equally effective. Treatment tolerance was excellent.

Intraoperative Radiotherapy as a Boost During Breast-Conserving Surgery Using Low-Kilovoltage X-Rays: The First 5 Years of Experience With a Novel Approach

Intraoperative radiotherapy (IORT) during breast-conserving surgery (BCS) has been recently introduced using different devices. We report the first 5 years of a single-center experience after introduction of a novel approach to deliver IORT as a tumor bed boost during BCS for breast cancer. A total of 155 breast cancers in 154 women (median age, 63 years; range, 30-83 years; T1/T2 = 100/55; N0/N+ = 108/47) were treated between February 2002 and December 2007 at the University Medical Center Mannheim, in whom IORT as tumor bed boost was applied using 50-kV X-rays (20 Gy) followed by 46-50 Gy whole-breast external-beam radiotherapy (EBRT). Chemotherapy, if indicated, was given before EBRT. The median interval between BCS plus IORT and EBRT was 40 days. Median follow-up was 34 months (maximum 80 months, 1 patient lost to follow-up). Overall survival and local relapse-free survival were calculated at 5 years using the Kaplan-Meier method. Seventy-nine patients were evaluated at 3-year follow-up for late toxicity according to the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic system. Ten patients died, 2 had in-breast relapse, and 8 developed distant metastases (5-year overall survival = 87.0%; 5-year local relapse-free survival = 98.5%). Grade 3 fibroses of the tumor bed were detected in 5% of the patients after 3 years. Skin toxicity was mild (telangiectases and hyperpigmentations in approximately 6% each). Intraoperative radiotherapy as a tumor bed boost during BCS for breast cancer using low-kilovoltage X-rays followed by EBRT yields low recurrence and toxicity rates.

The Oncologic Safety of Skin Sparing Mastectomy with or without Conservation of the Nipple-areolar Complex: 5 Years Follow up Results

한경우, 미만성석회화를동반한경우, 유방의부피에비해종양 Purpose: Little is known about long term results of nippleareola preserving skin-sparing mastectomy (NASSM), and there are no such reports on this from South Korea. We studied 5 years follow up results of NASSM and skin sparing mastectomy (SSM) and compared clinical outcomes between NASSM and SSM. Methods: Two hundred two patients who underwent SSM (69 patients) or NASSM (133 patients) from September 1996 to December 2006 were included. Frozen section analysis of retroareolar resection margin was done to make the decision on preserving or not preserving nippleareolar complex (NAC). In the case of positive result on the frozen section, NAC was sacrificed. The local relapse (LR) rate and local relapse free survival (LFS) were analyzed for comparing between NASSM and SSM. Results: The mean age was 40.2 years (range, 24-65), the mean follow-up was 67.6 months. 52 NACs (25.7%) were involved by tumor cells. The invasion to the NAC by tumor cell was more common for invasive carcinoma with extensive intraductal component (p 0.05). Regional or distant recurrence after surgical treatment for local relapse occurred in only one SSM case. Five years LFS rate of the NASSM group was 92.1% and that of the SSM group was 95.2%. There was no significant difference for the LFS (p>0.05). Conclusion: Our long term follow up study showed that NASSM and SSM are much alike for their LR rate and LFS. Even if relapse occurs in the NAC, this recurrence cannot affect the progression of relapse after adequate local treatment. Thus, NASSM is alternative method for SSM with oncological safety and better cosmetic outcome.

Lactate Dehydrogenase 5 Expression in Squamous Cell Head and Neck Cancer Relates to Prognosis following Radical or Postoperative Radiotherapy

Objectives: We assessed the expression and the prognostic role of lactate dehydrogenase 5 (LDH5, the major LDH isoenzyme involved in anaerobic glycolysis) in patients with squamous cell head and neck cancer (SCHNC). Methods: LDH5 was assessed immunohistochemically in whole tissue sections from 141 patients with SCHNC. Of these, 102 were subjected to surgery with (90 patients) or without (12 patients) postoperative radiotherapy (group A), while 39 patients were treated with radical radiotherapy (group B). Results: Mixed nuclear/cytoplasmic LDH5 expression was detected in 72.5% of group A and 61.5% of group B patients. This was significantly related to T4-stage (p = 0.04) and hypoxia-inducible factor-1α (HIF-1α) expression (p = 0.002). In group A, high LDH5 was linked with poorer distant metastasis-free survival (p = 0.01) and disease-specific overall survival (OS; p = 0.009). In multivariate analysis, LDH5 (p = 0.002) and HIF-1α (p = 0.01) were independently linked with distant metastasis. LDH5 was also linked with death events (p = 0.005). In group B, high LDH5 expression was significantly associated with poorer local relapse-free survival (p = 0.009) and OS (p = 0.01). In multivariate analysis, only T stage was a significant predictor of death events (p = 0.04). Conclusions: LDH5 is highly expressed in SCHNC and is linked with local relapse, survival and distant metastasis, suggesting that LDH5 is a marker of radioresistance and a target for therapeutic interventions.

Concurrent control study of different radiotherapy for primary nasopharyngeal carcinoma: intensity-modulated radiotherapy versus conventional radiotherapy

Intensity-modulated radiotherapy (IMRT) has recently gained popularity in the treatment of nasopharyngeal carcinoma (NPC) and improved the local-regional control rate. This study was to explore whether IMRT could improved the survival rate while reduce the radiation-related injury for primary NPC patients compared with conventional radiotherapy (CRT). From Nov. 2003 to Dec. 2005, 190 patients with NPC treated with IMRT in a single hospital were retrospectively analyzed. Another 190 patients treated with conventional radiotherapy at the same period were matched by prognostic factors respectively. The survival status and treatment-induced adverse effects were investigated. Treatment results, the occurrence and severity of adverse effects of two groups were compared. In the treatment of NPC, IMRT was superior to CRT in term of 4-year local regional control rate, relapse-free survival rate without reducing the overall survival rate. But there were no significant differences in the 4-year progress-free survival rate and distant metastasis-free survival rate between the two groups. Significant reductions of the occurrence rates and severity of acute skin reaction, neck fibrosis, trismus and xerostomia were noted in IMRT arm. But there were no differences in mucositis, hematological toxicity, hearing loss and radiation induced cranial neuropathy between IMRT arm and CRT arm. IMRT could improve the local regional control rate and relapse-free survival rate while reduce some radiation-related complications in patients with NPC. But the improvement of overall survival rate did not reach significant level.

Chordoma of the Mobile Spine and Sacrum: A Retrospective Analysis of a Series of Patients Surgically Treated at Two Referral Centers

Chordoma is a rare tumor, and its natural history is still not well known. All patients affected by localized chordoma surgically treated at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, between 1980 and 2008 were reviewed. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out. A total of 138 consecutive patients were identified (sacrum 78%, lumbar spine 15%, cervical-dorsal spine 7%). Of these, 130 underwent surgical resection. Median follow-up was 142 months. The 5- and 10-year OS, local relapse-free survival (LRFS), and distant relapse-free survival (DRFS) were, respectively, 78% and 54%, 52% and 33%, and 86% and 72%. Size was an independent prognostic factor for OS (P value < .001), LRFS (P value: .038), and DRFS (P value: .004), while surgical margins independently predicted LRFS (P value: .003) with a trend for OS. The 5- and 10-year OS, LRFS, and DRFS after the first local relapse were 50% and 26%, 47% and 31%, and 64% and 61%. The size of the recurrence and quality of surgical margins did not influence postrelapse OS. The 5-year OS after the second local relapse was 19%. 22% of patients developed distant metastases with a 5-year post-metastases OS of 33%. Tumor size and surgical margins affected outcome only on initial presentation. However, wide surgery was feasible in a minority of cases. Most patients died of local-regional disease even when metastases occurred. Indeed, long-term prognosis was such that disease-free survival at 10 years was only 26%.

Impact of pretherapy body mass index on prognosis of nasopharyngeal carcinoma

Given the limited information regarding the impact of BMI on treatment outcomes for nasopharyngeal carcinoma, we sought to examine the relationship between body mass index (BMI) and cancer control after radiotherapy. We compared clinic outcome information across BMI groups from 1,489 patients treated with radiotherapy between 1990 and 2003. Multivariate analysis was used to determine if BMI significantly predicted adverse recurrence. In comparison with normal group, there were statistical difference in age, T staging, N staging, and clinical staging (P<0.0001). In survival analysis, in comparison with under-weight group, we could found the hazard ratio was less than one, in the risk of death, cancer recurrence and local recurrence. Meanwhile, the hazard ratio gradually declined when the body weight increased. In univariate survival analysis, under-weight patient had a significant decrease in overall survival,(P<0.0001). When Cox regression model was applied to multivariate analysis, we could found age, T staging, N staging, and BMI grades could be a significant independent prognosis factors(P<0.05). Under-weight patients had a significant decrease in overall survival rate, distant metastasis failure-free survival, and local relapse-free survival. Pretherapy BMI grades could be a significant independent prognosis factors.

A clinical verification of the Chinese 2008 staging system for nasopharyngeal carcinoma

The Chinese 2008 staging system for nasopharyngeal carcinoma (NPC) was a common set of recommendations by initial revision of the previous'92 staging system. This study was to verify the Chinese 2008 staging system and to provide evidence for its further revision. Between January 2003 and December 2004, 924 consecutive patients with newly diagnosed, nondisseminated biopsy-proven NPC, presented at the Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, were entered into our study. All patients received magnetic resonance imaging examination of the neck and nasopharynx before treatment. According to the principle of the staging system, the indices of hazard consistency, hazard discrimination, prognostic value, and distribution were used to evaluate the Chinese 2008 staging system. According to the Chinese 2008 staging system, the distribution of stage group for the whole series was 4.9% for the stage I, 22.6% stage II, 38.0% stage III, and 34.5% stage IVA. As for hazard discrimination, the 4-year local relapse-free survival (LRFS) rates for T1-T4 patients were 95.4%, 93.7%, 90.5% and 79.1%, respectively. Although the separation of LRFS for all subclassifications of T-stage showed reasonable, the differences among the subgroups T1, T2, and T3 were still lack of significant statistically. The 4-year distant metastasis failure-free survival (DMFS) rates for N0-N3 patients were 89.4%, 84.3%, 73.6, and 59.2%, respectively. The 4-year overall survival (OS) rates for stage I-IV patients were 96.7%, 94.1%, 82.6% and 67.1%, respectively. As for hazard consistency, the distinctions between T3 with skull base involvement and T3 with medial pterygoid muscle in the hazard ratios of local failure (1.628 vs. 3.905) and disease failure (1.630 vs. 3.288) were large. Multivariate analyses showed that cervical nodal level, extranodal neoplastic spread, and laterality were independent prognostic factors for OS and DMFS, but maximal axial diameter was not. Using the Chinese 2008 staging system for NPC produces an acceptable distribution of patient numbers. Stage group, T classification, and N classification represent independent prognosis factors for major endpoints. However, our study reveals several deficiencies in the current system yet.

How to deal with prognostic factors and radiotherapy results in uterine neoplasms with a sarcomatous component?

Uterine tumours with a sarcomatous component are rare neoplasms with a wide pathologic heterogeneity in which the stage is the main prognostic factor. These aspects and their aggressiveness make the analysis of prognostic factors and radiotherapy difficult. The aim of this study was to evaluate the prognostic factors by stages and to assess the impact of prognostic factors and the effect of radiotherapy on the outcome of the disease. Eighty-one patients diagnosed and treated for uterine tumours with a sarcomatous component at the Hospital Clinic in Barcelona between 1975 and 2003 were retrospectively studied; 76/81 patients underwent surgery (total hysterectomy plus bilateral salpingo-oophorectomy, and in 13/76 of these patients an additional pelvic lymphadenectomy was performed). All 76 patients were staged after pathological evaluation of the surgical specimen by FIGO classification with 54 patients being stages I-II and 27 patients stages III-IVA. Only 5 patients were clinically staged as III-IVA. Radiotherapy was administered in 21 women with early-stage tumours and in 16 with advanced neoplasms. 5/81 patients received complementary chemotherapy to the surgery and 5 patients received chemotherapy as treatment of local and distant relapse (All the patients were treated with a different chemotherapy schedule). The impact of pathologic prognostic factors and radiotherapy on specific overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) were analysed by Log Rank test and Cox proportional risk models. The effect of each risk factor was studied by the hazard ratio and 95% confidence interval. An increased frequency of several adverse prognostic factors was observed in tumours with advanced stages compared to early neoplasms in deep myometrial invasion (83% vs. 27%), VLSI (75% vs. 29%), tumour size >8 cm (50% vs. 30%) and multicentricity (36% vs. 10%), and similar values were found for necrosis (79% vs. 78%) and high mitotic index (78% vs. 80%). For pathological type the frequency by advanced vs. early stages was 54% vs. 52% for carcinosarcomas, 33.5% vs. 17.5% for leiomyosarcoma, and 30.5% and 12.5% for adenosarcoma and endometrial stromal sarcoma, respectively. Univariate analysis showed that the stage was the only independent prognostic factor. Stratification by early (I-II) and advanced stages (III, IV) revealed tumour size >8 cm was the only prognostic factor significantly associated with OS, DFS, LRFS and DMFS on univariate analysis for early stages (HR: OS 2.52, DFS 3.10, LRFS 3.10 and DMFS 2.63). For advanced stages, radiotherapy was the only prognostic factor associated with OS, DFS, LRFS and DMFS on multivariate analysis (HR: OS 4.26, DFS 3.14, LRFS 3.25 and DMFS 3.66). Uterine tumours with a sarcomatous component have a poor outcome in spite of treatment in comparison to endometrial carcinoma, probably due to the higher frequency of adverse prognostic factors. In early stages tumour size was the most determining factor for OS, DFS, LRFS and DMFS. Radiotherapy significantly improved these survivals in advanced cases.

Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation Therapy

To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy. Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre-radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid-radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival. Median pre-radiation therapy and mid-radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, -1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre-radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reduction of interstitial fluid pressure was noted only in patients with complete responses (P = 0.002), and mid-radiation therapy interstitial fluid pressure was significantly lower in patients with complete responses (P = 0.036). In the multivariate analysis including interstitial fluid pressures and clinical variables, pre-radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively). Mid-radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre-radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy.

Intra-Arterial Infusion Chemotherapy Using Cisplatin With Radiotherapy for Stage III Squamous Cell Carcinoma of the Cervix

To examine the effectiveness of concomitant intra-arterial infusion chemotherapy (IAIC) using cisplatin (CDDP) with radiotherapy for Stage III squamous cell carcinoma of the cervix. We analyzed 29 cases of Stage III squamous cell carcinoma of the uterine cervix treated with radiotherapy and IAIC of CDDP from 1991 to 2006. External-beam therapy was given to the whole pelvis using four opposing parallel fields with an 18-MV linear accelerator unit. A central shield was used after 30-40 Gy with external whole-pelvic irradiation, and the total dose was 50 Gy. High-dose-rate brachytherapy was given with (192)Ir microSelectron. The dose at Point A was 6 Gy per fraction, 2 fractions per week, and the total number of fractions was either 3 or 4. Two or three courses of IAIC were given concomitantly with CDDP 120 mg or carboplatin 300 mg. We confirmed excellent medicine distribution directly by using computed tomographic angiography. The 5-year overall survival rate for Stage III patients was 62%, the cause-specific survival rate was 70%, and the local relapse-free survival rate was 89%. Local recurrence, distant metastasis, and occurrences of both were 7%, 38%, and 3%, respectively. The incidence of severe acute hematologic adverse reactions (Grade > or =3) was 27% for all patients; however, all recovered without interruption of radiotherapy. Severe nonhematologic effects (Grade > or =3) were 3%, including nausea and ileus. Only 1 patient's radiotherapy was interrupted for a period of 1 week because of ileus. Severe late complication rates (Grade > or =3) for the bladder, rectum, and intestine were 3%, 3%, and 10%, respectively. A combination of IAIC and systemic chemotherapy should be considered to improve the prognosis of patients with Stage III squamous cell carcinoma of the cervix.

The impact of margin status in breast-conserving therapy for lobular carcinoma is age related

Purpose The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). Methods This manuscript describes an analysis on 330 BCT in 318 patients with ILC. Results The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age > 50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women ≤ 50 years. The 12-year disease-specific survival (DSS) was 85%. In multivariate Cox regression analysis grade 3 compared to grade 2 (HR 7.2), and a tumour size of pT2 (HR 2.5) were significant independent predictors of disease-specific survival (DFS). These factors were also relevant for distant metastasis-free survival (DMFS) and disease-free survival (DFS). Conclusions Positive margins for invasive carcinoma seem to be a strong predictor for local recurrence in particular for women ≤ 50-years. Our study showed grade 3 and tumour size to be strong predictors of DMFS, DFS, and DSS. Margin status was not.

MET Y1253D-activating point mutation and development of distant metastasis in advanced head and neck cancers

We investigated if the MET-activating point mutation Y1253D influences clinical outcomes in patients with advanced squamous cell carcinoma of the head and neck (HNSCC). The study population consisted of 152 HNSCC patients treated by hyperfractionated radiotherapy alone or concomitant with chemotherapy between September 1994 and July 2000. Tumors were screened for the presence of the MET-activating point mutation Y1253D. Seventy-eight patients (51%) received radiotherapy alone, 74 patients (49%) underwent radiotherapy concomitant with chemotherapy. Median patient age was 54 years and median follow-up was 5.5 years. Distant metastasis-free survival, local relapse-free survival and overall survival were compared with MET Y1253D status. During follow-up, 29 (19%) patients developed distant metastasis. MET Y1253D was detected in tumors of 21 out of 152 patients (14%). Distant metastasis-free survival (P = 0.008) was associated with MET Y1253D. In a multivariate Cox regression model, adjusted for T-category, only presence of MET Y1253D was associated with decreased distant metastasis-free survival: hazard ratio = 2.5 (95% confidence interval: 1.1, 5.8). The observed association between MET Y1253D-activating point mutation and decreased distant metastasis-free survival in advanced HNSCC suggests that MET may be a potential target for specific treatment interventions.

DVH parameters and outcome for patients with early-stage cervical cancer treated with preoperative MRI-based low dose rate brachytherapy followed by surgery

Background To our knowledge no DVH data have so far been reported for MRI-guided BT in the preoperative setting of early-stage cervical cancer. We assessed DVH parameters and clinical outcome using 3D MRI-guided preoperative intracavitary LDR BT. Patients and methods Thirty-nine patients with primary early cervical carcinoma (IB1 37, IIA 1 and IIB 1) were treated with preoperative MRI-based LDR BT, consisting of uterovaginal BT to a total dose of 60 Gy to the intermediate-risk CTV, followed 6 weeks later by bilateral salpingo-oophorectomy and extrafascial hysterectomy plus pelvic node dissection. Adjuvant chemoradiation was delivered to patients with pelvic lymph node involvement. Results With a median follow-up of 4.4 years (range 2.6–6.6 years), local recurrence occurred in 1 patient (a lateropelvic relapse) (2.6%). The 4-year actuarial overall survival and disease-free survival were 94% (95% CI, 82–98), and 86% (95% CI, 67–95), respectively. The 2- and 4-year actuarial local relapse-free survival were 94 (95% CI, 86–100) and 91% (95% CI, 81–100), respectively. For intermediate-risk CTV, median D 100 and D 90 were 43 Gy α / β 10 (range 2–74 Gy α / β 10) and 75 Gy α/β 10, respectively (range 29–129 Gy α/β 10). For high-risk CTV, the median D 100 and D 90 were 69 Gy α/β 10 (range 24–137 Gy α/β 10) and 109 Gy α/β 10 (range 37–198 Gy α/β 10), respectively. Twenty grade 1–2 late complications were observed in 13 patients (33.3%): 10 bladder, 3 ureteral, 1 rectal, 1 small bowel, 1 vaginal, 1 pelvic fibrosis, 1 peripheral nerve, and 2 others. No grade 3 or 4 complication occurred. Conclusion MRI-guided brachytherapy with adaptation of the time duration and/or the length of each radioactive source allows both high local control and low toxicity in the preoperative settings of early-stage cervical cancers.

Oncologic Outcome of Intersphincteric Resection for Very Low Rectal Cancer

In 2000 we launched a prospective program of intersphincteric resection (ISR) for very low rectal cancer. In this study we compared the oncologic outcome of patients who underwent ISR with the outcome of patients who underwent abdominoperineal resection (APR). The data of 202 patients with very low rectal cancer who underwent curative ISR (n = 132) or curative APR (n = 70) between 1995 and 2006 were analyzed. Patients were divided into ISR and APR groups. Survival and local recurrence were investigated in both groups. The median follow-up was 40 months in the ISR group and 57 months in the APR group. The 5-year local relapse-free survival rate was 83% in the ISR group and 80% in the APR group (p = 0.364), and the 5-year disease-free survival rate was 69% in the ISR group and 63% in the APR group (p = 0.714). For very low rectal cancers, ISR appears to be oncologically acceptable and can reduce the number of APRs.

Chordoma of the mobile spine: A retrospective analysis on 146 patients from two reference centers

10517 Background: The natural history of chordoma is still poorly known. Methods: We reviewed a large series of patients (pts) from two major reference centers for chordoma. All pts presenting at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, over 25 years, were reviewed. Clinical and pathologic characteristics were recorded. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out. PDGFR and brachyury expression analysis is ongoing. Results: One hundred forty-six consecutive pts were identified (sacrum 79%, lumbar spine 15%, cervical-dorsal spine 6%; extension at diagnosis: localized 90%, locally-advanced 5%, metastatic 5%; median size 10 cm, IQ range: 6–14). Median follow-up was 140 months (IQ range: 80–205). The 5/10-year OS, local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) were respectively: 76/52%, 51/32%, 86/72%. For pts with primary disease, size independently predicted OS (p-value: 0.004), LRFS (p-value: 0.006) and DRFS (p-value: 0.02), while surgical margins independently predicted only LRFS (p-value: 0.0001) with a trend for OS (p-value 0.1007). Radiotherapy performed in 44 pts did not influence LRFS nor OS, but only 9 pts received &gt;60 Gy. The 5/10-year OS, LRFS, DRFS after the first local relapse were 54/24%, 50/45%, 64/61%. Size of the recurrence and quality of surgical margins did not influence post-relapse OS. The 5/10-year OS after the second local relapse were 20/0%. The overall incidence of metastases was 32% (commonest site: lung). The 5/10-year post-metastases OS was 35/0% (median 3 years). Results on PDGFR and brachyury expression will be provided. Conclusions: Tumor size and surgical margins affected outcome only on initial presentation. Incidence of distant metastases was higher than expected, although with a more indolent course than generally supposed. In spite of its indolent behavior, long-term prognosis was poor, with 26% of pts being continuously disease-free at 10 years. This series may provide an external control for studies on novel targeted agents, which are proving effective in such a rare tumor. No significant financial relationships to disclose.

Solitary fibrous tumor: A retrospective analysis on 65 patients from a reference center

10572 Background: Solitary fibrous tumors (SFT) are very rare mesenchymal tumors with an unpredictable malignant potential. We retrospectively reviewed the long-term outcome of patients operated on at the Istituto Nazionale Tumori (INT), Milan, in a 18-year time span. Methods: All patients who underwent surgery at INT from 1990 to 2008 for primary SFT or first local relapse were retrospectively reviewed. Clinical and pathologic data were recorded. Local recurrence, distant metastases and overall survival were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. Biomolecular studies are ongoing for those cases whose frozen material is available. Results: 65 patients were identified (M/F: 33/32 - age: mean 54 yrs, range 19–85 yrs - site: peritoneum 45%, pleura 21%, lower-limb 17%, other 18% - extension at diagnosis: localized 94%, locally-advanced/unresectable 3%, metastatic 3% - size: median 11 cm, range 2–40 cm). The median follow-up was 54 months (range 0–185 months). The overall 5/10-year survival (OS), local relapse-free survival (LRFS) and metastasis-free survival (DRFS) were, respectively, 92/91%, 89/86%, 94/89%. The 5-year OS, LRFS, DMRFS after the first local relapse were, respectively, 100%, 67%, 89%. The overall incidence of metastases was 17% (lung was the commonest site). The 5-year post-metastasis OS was 45%. Multivariate analysis on clinical and pathologic/molecular prognostic factors is ongoing. Conclusions: SFT arise from a variety of anatomic sites. Surgery is curative in most patients, and local relapse has a limited impact on prognosis. Pathologic prognostic factors are under investigation to help identify the minority of patients with a poor clinical outcome. No significant financial relationships to disclose.