Results of PONDx, a prospective multicenter study of the Oncotype DX® breast cancer assay: Real-life utilization and decision impact in French clinical practice.

Adjuvant chemotherapy shows clear benefits in HER2-positive and triple-negative breast cancer (BC). Its benefits are less universal in BCs expressing hormone receptors. The 21-gene Oncotype DX® Breast Recurrence Score test was designed for HR+, HER2- early-stage BC before decision on adjuvant chemotherapy. Its validity and utility was demonstrated prospectively across multiple studies. The observational study PONDx characterized the use of Oncotype DX® Breast in routine practice in France and evaluated its decision impact. Of 882 ER-positive BC patients (67% postmenopausal), most (79%) had N0/Nmic node involvement, grade 2 tumors (68%), tumor size 1-5 cm (88%), and ductal histology (78%). BCs with histopathologically elevated recurrence risk included grade 3: 18%; N1: 21%; Ki67 > 20%: 31%. Recurrence Score results by prognostic category were: <18: 54%, 18-30: 36%; >30: 10%. Compared to recommendations before individual availability of the score, results prompted net absolute reductions in chemotherapy recommendations of 36% (total population), and 29% (grade 3 and/or Ki67 > 20% histologies). Decisions reflected prognostic implications: in the Recurrence Score <18 category, 95% of patients received recommendations of hormonal therapy only, in the >30 category, 97.5% were recommended additional chemotherapy; 95% followed the final recommendations of their physicians. The Recurrence Score provides independent predictive and prognostic information in ER + N0/N1 early BC, including high-risk subgroups. PONDx further characterizes the population where the test is beneficial in real-life use and fits current clinical needs. Oncotype DX® Breast enables relevant net reductions in chemotherapy use, sparing patients from serious toxicities. Its therapeutic implications are highly accepted by physicians and patients.

Stereotactic body radiation therapy for hepatocellular carcinoma: prognostic factors of local control, overall survival, and toxicity.

PURPOSE: Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife(®) is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment. PATIENTS AND METHODS: 75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion's movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival. RESULTS: There were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40-45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3-49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018). CONCLUSION: SBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BACKGROUND: To identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC). METHODS: In this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. RESULTS: During follow up (median: 6 [0.4-9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treatment (HR = 1.9 [1.2-3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0-3.2], p = 0.040). CONCLUSION: One EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

Image-based response assessment of liver metastases following stereotactic body radiotherapy with respiratory tracking.

OBJECTIVE: To describe post-CyberKnife® imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST). SUBJECTS AND METHODS: Imaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated. RESULTS: Complete response (CR) was 3.6% (95% CI: 0.1-18%) and 18% (95% CI: 6-37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41-78%) by RECIST and 64% (95% CI: 44%-81%) by CC. CONCLUSION: Use of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity.

Does gap-free intensity modulated chemoradiation therapy provide a greater clinical benefit than 3D conformal chemoradiation in patients with anal cancer?

BACKGROUND: Chemoradiation is the standard treatment for anal cancer. 3D conformal radiotherapy (3D-CRT) is usually split in 2 sequences with a therapeutic break (gap) in between. Intensity-modulated radiation therapy (IMRT) makes it possible to reduce treatment time by abandoning this gap. The purpose of this study was to compare outcomes and toxicities in patients treated with either IMRT or 3D-CRT. METHODS: Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6]. RESULTS: There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival, locoregional relapse-free survival and colostomy-free survival rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 acute toxicity. No grade 4 toxicity occurred. CONCLUSIONS: Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to remove the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT.

Prognostic factors affecting local control of hepatic tumors treated by Stereotactic Body Radiation Therapy.

PURPOSE: Robotic Stereotactic Body Radiation Therapy with real-time tumor tracking has shown encouraging results for hepatic tumors with good efficacy and low toxicity. We studied the factors associated with local control of primary or secondary hepatic lesions post-SBRT. METHODS AND MATERIALS: Since 2007, 153 stereotactic liver treatments were administered to 120 patients using the CyberKnife® System. Ninety-nine liver metastases (72 patients), 48 hepatocellular carcinomas (42 patients), and six cholangiocarcinomas were treated. On average, three to four sessions were delivered over 12 days. Twenty-seven to 45 Gy was prescribed to the 80% isodose line. Margins consisted of 5 to 10 mm for clinical target volume (CTV) and 3 mm for planning target volume (PTV). RESULTS: Median size was 33 mm (range, 5-112 mm). Median gross tumor volume (GTV) was 32.38 cm3 (range, 0.2-499.5 cm3). Median total dose was 45 Gy in three fractions. Median minimum dose was 27 Gy in three fractions. With a median follow-up of 15.0 months, local control rates at one and two years were 84% and 74.6%, respectively. The factors associated with better local control were lesion size < 50 mm (p = 0.019), GTV volume (p < 0.05), PTV volume (p < 0.01) and two treatment factors: a total dose of 45 Gy and a dose-per-fraction of 15 Gy (p = 0.019). CONCLUSIONS: Dose, tumor diameter and volume are prognostic factors for local control when a stereotactic radiation therapy for hepatic lesions is considered. These results should be considered in order to obtain a maximum therapeutic efficacy.

A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases.

PURPOSE: The purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy. METHODS AND MATERIALS: Between July 2007 and June 2010, 90 patients were treated with the CyberKnife® SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity. RESULTS: A total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23-84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7-110 mm) for liver and 12.5 mm (range, 5-63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55-81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18-37%) and 10% (95% CI: 4-20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1-9.5 months). Observed toxicities included grade 1-3 acute toxicities. One grade 3 and no grade 4 toxicity were reported. CONCLUSION: High-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy. SUMMARY: Stereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients' life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens.

Salvage stereotactic reirradiation with or without cetuximab for locally recurrent head-and-neck cancer: a feasibility study.

PURPOSE: Normal tissues tolerance limits the use of reirradiation for recurrent head-and-neck cancers (HNC). Stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. Results of a feasibility study using SBRT with or without cetuximab are reported for reirradiation of recurrent primary HNC. METHODS AND MATERIALS: Patients with inoperable recurrent, or new primary tumor, in a previously irradiated area were included. Reirradiation dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the planning target volume. Patients with squamous cell carcinoma received concomitant cetuximab. RESULTS: Between June 2007 and January 2010, 40 patients were prospectively treated for 43 lesions. Median age was 60 and median tumor size was 29 mm. Fifteen patients received concomitant cetuximab and 1 received concomitant cisplatin. Median follow-up was 25.6 months with 34 patients evaluable for tumor response. Median overall survival was 13.6 months and response rate was 79.4% (15 complete and 12 partial responses). Grade 3 toxicity occurred in 4 patients. CONCLUSION: These results suggest that short SBRT with or without cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. A prospective multicenter Phase II trial of SRT and concomitant cetuximab in recurrent HNC squamous cell carcinoma is ongoing.

Delineation in thoracic oncology: a prospective study of the effect of training on contour variability and dosimetric consequences.

INTRODUCTION: As part of French residents' radiotherapy training, delineation workstations were available at a national teaching course. We report a prospective comparative study of a non small cell lung cancer (NSCLC) case delineated by 120 residents before and after a radioanatomy/radiotherapy lecture. MATERIALS AND METHODS: The case of a patient with right upper lobe non small cell lung cancer (NSCLC) was provided for delineation to 32 groups of residents before and after a radiation therapy lecture about thoracic delineation. GTV, CTV and PTV was asked to each group. In a second step, the GTV, CTV and PTV were compared with those of 9 groups of senior physicians. Finally the consequences for treatment planning between each group before and after the course were explored. RESULTS: The expert's average GTV, CTV and PTV were 89.1 cm3, 242.3 cm3 and 293.9 cm3 respectively. For residents, those volumes were 103.4 cm3, 242.3 cm3 and 457.9 cm3 before teaching, compared to 99.5 cm3, 224.2 cm3 and 412.5 cm3 after teaching. The overlap (OV) and kappa (KI) indices before and after education were respectively 0.58 and 0.73. Compared to senior physicians, OV and KI indices were lower in the residents group (p = 0.039 and p = 0.043). An increased dose to the lung is noted for the residents' dosimetry compared to the experts' (V20: 23.2% versus 36.5%) due to the larger PTV delineated. No significant difference was observed for other organs at risk. CONCLUSION: There were no significant differences for the delineation of the GTV and CTV before and after the course, although the differences tended to decrease after the course. The good initial quality of the contours could explain the lack of difference. V20 for lung was higher in the residents group compared to the experts group (23.2% vs 36.5%). No other treatment planning consequences were observed for other critical organs.

Robotic image-guided reirradiation of lateral pelvic recurrences: preliminary results.

BACKGROUND: The first-line treatment of a pelvic recurrence in a previously irradiated area is surgery. Unfortunately, few patients are deemed operable, often due to the location of the recurrence, usually too close to the iliac vessels, or the associated surgical morbidity. The objective of this study is to test the viability of robotic image-guided radiotherapy as an alternative treatment in inoperable cases. METHODS: Sixteen patients previously treated with radiotherapy were reirradiated with CyberKnife® for lateral pelvic lesions. Recurrences of primary rectal cancer (4 patients), anal canal (6), uterine cervix cancer (4), endometrial cancer (1), and bladder carcinoma (1) were treated. The median dose of the previous treatment was 45 Gy (EqD2 range: 20 to 96 Gy). A total dose of 36 Gy in six fractions was delivered with the CyberKnife over three weeks. The responses were evaluated according to RECIST criteria. RESULTS: Median follow-up was 10.6 months (1.9 to 20.5 months). The actuarial local control rate was 51.4% at one year. Median disease-free survival was 8.3 months after CyberKnife treatment. The actuarial one-year survival rate was 46%. Acute tolerance was limited to digestive grade 1 and 2 toxicities. CONCLUSIONS: Robotic stereotactic radiotherapy can offer a short and well-tolerated treatment for lateral pelvic recurrences in previously irradiated areas in patients otherwise not treatable. Efficacy and toxicity need to be evaluated over the long term, but initial results are encouraging.

Image-guided robotic stereotactic body radiation therapy for liver metastases: is there a dose response relationship?

PURPOSE: To evaluate the outcome, tolerance, and toxicity of stereotactic body radiotherapy, using image-guided robotic radiation delivery, for the treatment of patients with unresectable liver metastases. METHODS AND MATERIAL: Patients were treated with real-time respiratory tracking between July 2007 and April 2009. Their records were retrospectively reviewed. Metastases from colorectal carcinoma and other primaries were not necessarily confined to liver. Toxicity was evaluated using National Cancer Institute Common Criteria for Adverse Events version 3.0. RESULTS: Forty-two patients with 62 metastases were treated with two dose levels of 40 Gy in four Dose per Fraction (23) and 45 Gy in three Dose per Fraction (13). Median follow-up was 14.3 months (range, 3-23 months). Actuarial local control for 1 and 2 years was 90% and 86%, respectively. At last follow-up, 41 (66%) complete responses and eight (13%) partial responses were observed. Five lesions were stable. Nine lesions (13%) were locally progressed. Overall survival was 94% at 1 year and 48% at 2 years. The most common toxicity was Grade 1 or 2 nausea. One patient experienced Grade 3 epidermitis. The dose level did not significantly contribute to the outcome, toxicity, or survival. CONCLUSION: Image-guided robotic stereotactic body radiation therapy is feasible, safe, and effective, with encouraging local control. It provides a strong alternative for patients who cannot undergo surgery.

Adjuvant radiation therapy in metastatic lymph nodes from melanoma.

PURPOSE: To analyze the outcome after adjuvant radiation therapy with standard fractionation regimen in metastatic lymph nodes (LN) from cutaneous melanoma. PATIENTS AND METHODS: 86 successive patients (57 men) were treated for locally advanced melanoma in our institution. 60 patients (69%) underwent LN dissection followed by radiation therapy (RT), while 26 patients (31%) had no radiotherapy. RESULTS: The median number of resected LN was 12 (1 to 36) with 2 metastases (1 to 28). Median survival after the first relapse was 31.8 months. Extracapsular extension was a significant prognostic factor for regional control (p = 0.019). Median total dose was 50 Gy (30 to 70 Gy). A standard fractionation regimen was used (2 Gy/fraction). Median number of fractions was 25 (10 to 44 fractions). Patients were treated with five fractions/week. Patients with extracapsular extension treated with surgery followed by RT (total dose ≥50 Gy) had a better regional control than patients treated by surgery followed by RT with a total dose <50 Gy (80% vs. 35% at 5-year follow-up; p = 0.004). CONCLUSION: Adjuvant radiotherapy was able to increase regional control in targeted sub-population (LN with extracapsular extension).

Use of conventional fractionation with cyberknife in children: a report of 5 cases.

SUMMARY: The use of stereotactic radiotherapy with CyberKnife (Accuray Incorporated, Sunnyvale, CA) in adults is becoming more and more established. For children, there is no such consensus and the appropriate approach to this type of treatment is still debated. In the meantime, there seems to be a number of certain pediatric cases in which the use of CyberKnife within very strict limits is potentially justified. Here, we report the feasibility of and acute tolerance to radiotherapy with CyberKnife using conventional fractionation in 5 children.

Cancer-associated hypercalcemia: validation of a bedside prognostic score.

INTRODUCTION: Until now, there was no validated and reliable tool to estimate life expectancy among patients with cancer-associated hypercalcemia (CAH). This study aimed to validate a prognostic score previously published. METHODS: We studied a new cohort of 252 patients with CAH. Our prognostic score based on the four poor-prognosis factors (liver metastasis, squamous cell carcinoma, hypoalbuminemia, and calcemia >2.83 mmol) was implemented to this cohort. The accuracy of this score for the prediction of 90-day mortality was estimated with area under the curve of the receiver operator curve (AUC-ROC). RESULTS: Among this validation cohort, patients with score = 0 experienced a median overall survival of 797 days; whereas, patients with score >/=1 (at least one poor-prognosis factor) had median overall survival of 49 days (p < 0.0001). The AUC-ROC for the prediction of 90-day mortality were 0.88 (0.76-0.86) and 0.67 (0.61-0.74) in the development cohort and in the validation cohort, respectively. CONCLUSION: We have validated a reliable bedside prognostic score for CAH.

Cancer-associated hypercalcemia treated with intravenous diphosphonates: a survival and prognostic factor analysis.

BACKGROUND: Cancer-associated hypercalcemia (CAH) is the most frequent metabolic disorder in cancer patients. We retrospectively reviewed the outcome and prognostic factors for patients with CAH being treated with standard intravenous disphosphonates. MATERIALS AND METHODS: Two hundred sixty patients were reviewed. Overall survival and prognostic factors were analyzed. Relative risks (RR) for early death (within 60 days) were assessed (Fischer exact test and logistic regression model). RESULTS: Median survival was 64 days (range, 12-1,955+). Multivariate analysis identified the following factors as poor survival predictors: serum corrected calcium >2.83 mmol/l [hazard ratio (HR) = HR 2.21], albuminemia <35.5 (HR 2.41), squamous cell carcinoma (HR 2.64), bone metastasis (HR 1.44), and liver metastasis (HR 2..22). One hundred twenty-one patients died within 60 days. For those patients, the logistic regression model identified four independent predicting factors for early death: calcemia >2.83 mmol/l (RR 5.07), hypoalbuminemia (RR 7.42), liver metastasis (RR 4.34), and squamous cell carcinomas (RR 2.21). DISCUSSION: Despite intravenous diphosphonate, CAH is still associated with poor outcome. Simple bedside parameters may estimate the risk of early deaths.