C. Massabeau

Basic Fibroblast Growth Factor-2/β3 Integrin Expression Profile: Signature of Local Progression After Chemoradiotherapy for Patients With Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome. METHODS AND MATERIALS FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis. RESULTS Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3(+)), 43% FGF-2 (FGF-2(+)), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2(+)/beta3(+) tumors compared with FGF-2(-)/beta3(-) tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival. CONCLUSION The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced NSCLC.

Potential benefits of using cardiac gated images to reduce the dose to the left anterior descending coronary during radiotherapy of left breast and internal mammary nodes.

PURPOSE To assess the benefits of using cardiac gated images for treatment planning of breast and internal mammary nodes. PATIENTS AND METHODS Inspiration breath hold computed tomography (CT) series acquired at prospectively gated diastolic phase were used for planning. Three different techniques were compared. Technique A used tangents and an internal mammary nodes field covering the three first inter-rib spaces; technique B used an extended internal mammary nodes including part of the medial breast in junction with tangential fields; the 3(rd) technique used helical tomotherapy. For each technique, two treatment plans were performed: one plan (plan-01) where mean dose and V(25) to the heart were considered for plan evaluation and a second plan (plan-02) where the irradiation of the left anterior descending artery was minimized. RESULTS V(25) to the heart was found to be less than 5% for all six plans. Mean doses to the heart were within 4.8 to 7.2 Gy. By attempting to lower the dose to the left anterior descending artery, heart D(mean) was decreased by 20-30% for the two techniques A and B while being unchanged for tomotherapy. Regarding target coverage, there was no marked difference between plans where only heart dose was considered (plans-01) and plans where the left anterior descending artery dose was minimized (plans-02). When the left anterior descending artery dose was part of plan evaluation, D(mean) to the left anterior descending artery could be decreased by 24, 19 and 9% for techniques A, B and tomotherapy respectively. The three techniques exposed segments of the left coronary to different levels of dose. CONCLUSION This study showed that evaluation of the dose to the left anterior descending artery coronary may change the treatment strategy. Cardiac gated images without IV contrast permitted a good visualization of the coronaries in order to optimize the dose on these structures. In addition to heart V(25,) the dose to the coronaries should be included in prospective studies on radiotherapy related heart toxicity in association with all additional risk factors.

Implant breast reconstruction followed by radiotherapy: Can helical tomotherapy become a standard irradiation treatment?

To evaluate the benefits and limitations of helical tomotherapy (HT) for loco-regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 and 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received ≥20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies.

Heart, coronaries and breast cancer radiotherapy

0960-9776/

The Prognostic Significance of Lymphovascular Invasion on Biopsy Specimens in Lung Cancer Treated With Definitive Chemoradiotherapy

– see front matter 2010 Elsevier Ltd. doi:10.1016/j.breast.2010.12.002 Radiation therapy (RT) has demonstrated strong clinical benefit in patients with breast conservative surgery or with radical mastectomy and who are at high risk for relapse. This benefit was counterbalanced by an increased risk for death from cardiac events.1,2 Unfortunately, most trials did not consider cardiac toxicity in its entirety. When focussing on heart disease, most available studies split the two different parts of the adjuvant treatment, that is, systemic therapies and RT. Consequently, their design does not allow obtaining exhaustive information, including all parts of

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non–Small-cell Lung Cancer: A Phase I Study

PURPOSE This study aims to determine prognostic factors for patients who have non-small-cell lung cancer (NSCLC) that is treated with definitive chemoradiation therapy. MATERIALS AND METHODS Seventy-eight patients has been treated with radiation therapy and concomitant or sequential chemotherapy between 2000 and 2005. Paraffin-embedded biopsy specimens were obtained before treatment from 73 patients and reviewed by two independent pathologists. Complete follow-up data were collected. The impact of clinical and pathological factors and treatment modality on survival was studied using the χ(2) and Fisher exact tests. A multivariate analysis was performed using the Cox proportional hazard model. RESULTS Seventy-three patients were evaluated, 58 men and 15 women. Median age was 62 years. Most had locally advanced disease (42 stage IIIB and 24 stage IIIA), whereas 7 were medically inoperable stage I-II patients. Lymphovascular invasion (LVI) was identified in 20 biopsy specimens (27.4 %). Radiotherapy delivered a median dose of 66 Gy (range, 60 to 70 Gy). The median overall survival was 20.5 months. Relapse-free and overall survival were significantly higher in the concomitant arm than in the sequential arm (P = .025 and P = .031, respectively). We found an independent association between the presence of LVI and both the risk of death with an adjusted hazard ratio (HR) of 2.69 (95% confidence interval [CI] 1.50-4.83) and the risk of metastatic progression (adjusted HR = 3.01; 95% CI 1.58-5.72). CONCLUSION The presence of LVI on stage III NSCLC biopsy specimens was the only independent prognostic factor for poor outcome and may, therefore, be helpful in identifying patients at high risk of metastatic disease.

Outcome of pN0 Triple-Negative Breast Cancer with or without Lymph Node Irradiation: A Single Institution Experience

INTRODUCTION Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

1208PCONTINUOUS INFUSION OF CILENGITIDE WITH RADIO-CHEMOTHERAPY IN STAGE III NSCLC: A PHASE I STUDY

The optimal management of patients with pathologically node‐negative triple‐negative breast cancer (pN0 TNBC) remains unclear. We hypothesized that lymph node irradiation (LNI; internal mammary chain/periclavicular irradiation) had an impact on outcomes of pN0 TNBC. A cohort of 126 consecutive patients with pN0 TNBC treated between 2007 and 2010 at a single institute were included. All radiotherapy (breast/chest wall, ±LNI) was delivered adjuvantly, following completion of surgery ± chemotherapy. Tumors were reviewed and histologic features were described. Tissue microarrays were constructed and tumors were assessed by immunohistochemistry using antibodies against ER, PR, HER2, Ki‐67, cytokeratins 5/6, 14, epidermal growth factor receptor and androgen receptor. Patients were divided into two groups for statistical analysis: LNI (LNI+) or no LNI (LNI−). We focused on disease‐free survival (DFS), metastasis‐free survival (MFS), and overall survival (OS). Fifty‐seven and 69 patients received or not LNI, respectively. Median age was 52 (range [25–76]) and 55 (range [29–79]) in LNI+ and LNI− group (p = 0.23). LNI was associated with larger tumors (p = 0.033), central/internal tumors (33 versus 4, p < 0.01) and more chemotherapy (86% versus 59.4% p < 0.01). The median follow‐up was 53.5 months. The rate of first regional relapse (associated or not with distant relapse) was low in both groups. There was no difference in 4‐year DFS (82.2% versus 89.9%; p = 0.266), MFS (87.0% versus 91.1%; p = 0.286) and OS (85.8% versus 89.9%; p = 0.322) between LNI+ and LNI− group, respectively. In univariate analysis, only clinical size (T >10 mm versus ≤10 mm), histologic size (pT >10 mm versus ≤10 mm) and grade 3 (versus grade 2) were found to be significantly associated with shorter DFS. Omission of LNI in patients with pN0 TNBC does not seem to result in poorer outcome. Further studies are needed to specifically evaluate LNI in pN0 TNBC with histologic grade 3 and/or (p)T >10 mm.

Early Experience of Helical Tomotherapy for Hepatobiliary Radiotherapy

ABSTRACT Aim: We have shown that avb3 integrins control radioresistance, hypoxia and angiogenesis and that co-expression of FGF-2 and avb3 integrins in the tumors of patients treated with exclusive radio-chemotherapy for stage III non-small lung carcinoma (NSCLC), was associated with a worse local control, suggesting that inhibition of avb3 integrin could induce a radiosensitization of such tumours. We designed a phase I trial associating the specific avb3/avb5 integrin inhibitor cilengitide with radio-chemotherapy in patients with stage III NSCLC. Methods: A standard 3 + 3 dose escalation design was used. Cilengitide was given in continuous infusion starting 2 weeks before and then during the whole course of the radio-chemotherapy (66 Gy combined with a Platine-Navelbine regimen), and then at a dose of 2000 mg twice a week in association with chemotherapy. Planed Cilengitide continuous infusion dose levels were 12, 18, 27 and 40 mg/h. PET-FDG and CT scan were performed before and then after the first two weeks of Cilengitide administration and then 2 months after the end of radio-chemotherapy. Patients were followed by CT scan. Toxicity for DLT was assessed during combined treatment and until 1 month after. Clinical response on CT scan and TEP was evaluated according to RECIST and PERCIST criteria. Results: Fourteen patients were included between March 2010 and July 2013. Eleven patients were evaluable for DLT. No DLT was observed at level 0, 1 and 2. One DLT, a tracheo-bronchial fistula was reported at the 40 mg/h dose. No relevant adverse event related to Cilengitide (7 grade 1 and one grade 2) was observed on the whole population. Among 11 patients evaluable for efficacy, 9 patients presented a partial response and 2 a stable disease. At 6 months after the end of radio-chemotherapy, 2 patients presented a progressive disease. At PET evaluation 2 months after radio-chemotherapy, 4 patients had a complete response and 4 patients had a partial response. Conclusions: Cilengitide given continuously with radio-chemotherapy was well tolerated and shows encouraging clinical results, suggesting that targeting avb3 integrin continuously during radio-chemotherapy in NSCLC is a promising approach to treat this disease. Disclosure: E.L. Cohen-Jonathan Moyal: E Moyal has been member of an advisory board for Merck KGaA and received a funding grant from Merck KGaA for research. All other authors have declared no conflicts of interest.

The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer?

Helical tomotherapy (HT), an image-guided, intensity-modulated, radiation therapy technique, allows for precise targeting while sparing normal tissues. We retrospectively assessed the feasibility and tolerance of the hepatobiliary HT in 9 patients. A total dose of 54 to 60 Gy was prescribed (1.8 or 2 Gy per fraction) with concurrent capecitabine for 7 patients. There were 1 hepatocarcinoma, 3 cholangiocarcinoma, 4 liver metastatic patients, and 1 pancreatic adenocarcinoma. All but one patient received previous therapies (chemotherapy, liver radiofrequency, and/or surgery). The median doses delivered to the normal liver and to the right kidney were 15.7 Gy and 4.4 Gy, respectively, below the recommended limits for all patients. Most of the treatment-related adverse events were transient and mild in severity. With a median followup of 12 months, no significant late toxicity was noted. Our results suggested that HT could be safely incorporated into the multidisciplinary treatment of hepatobiliary or pancreatic malignant disease.