Independent Predictor Of Local Failure Research Articles

A Genomic Score to Predict Local Control among Patients with Brain Metastases Managed with Radiation

Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are relatively homogeneous and prescribed with a "one-size-fits-all" approach. We hypothesized that tumor-specific genomic alterations may underlie radiation sensitivity among patients with BrM and sought to develop a DNA-based signature of radiation-based efficacy in this patient population, utilizing genes that are readily testable in modern-day assays, to identify subpopulations at greater vs. lesser risk of recurrence. We identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one extracranial or intracranial tumor specimen. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency of >0.5%. Genes with a q-value<0.10 were utilized to develop a numeric "Brain-Radiation Prediction Score" ("Brain-RPS") to quantify local recurrence risk. Genomic alterations of potential biological relevance in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes (FBXW7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value<0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level Brain-RPS. On multivariable Fine/Gray's competing risks regression, Brain-RPS [1.66 (1.44-1.92, p<0.001)], metastasis-associated edema [1.89 (1.38-2.59), p<0.001], and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p<0.001] were independent predictors of local failure. Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not focused on patients with BrM and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in real-world clinical practice for this patient population. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation treatment among patients with BrM.

A genomic score to predict local control among patients with brain metastases managed with radiation.

2011 Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are prescribed with a “one-size-fits-all” approach. We sought to develop a DNA-based signature of radiation-based efficacy among patients with BrM, utilizing readily testable genes, to identify subpopulations at greater vs. lesser risk of recurrence. Methods: We retrospectively identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one tumor specimen. Local recurrence was assessed in a manner consistent with Response Assessment in Neuro-Oncology – Brain Metastases guidelines (i.e., radiographic enlargement of &gt;20% in maximal cross-sectional diameter). Enlarging lesions managed with salvage treatment prior to &gt;20% enlargement were considered to have recurred on the date of salvage therapy. Fine/Gray’s competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency &gt;0.5%. Genes with a q-value&lt;0.10 were utilized to develop a numeric “Brain-Radiation Prediction Score” (“Brain-RPS”) to quantify local recurrence risk. Results: Genomic alterations of potential biological relevance in 11 ( ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes ( FBXW 7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value&lt;0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray’s competing risks regression, RPS [1.66 (1.44-1.92, p&lt;0.001)], metastasis-associated edema [1.89 (1.38-2.59), p&lt;0.001] and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p&lt;0.001] were independent predictors of local failure. Conclusions: We developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not been BrM-specific and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in clinical practice. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genomic personalization of radiation treatment among patients with BrM.

A genomic score to predict local control among patients with brain metastases managed with radiation.

Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. We developed a DNA-based signature of radiotherapeutic efficacy among patients with BrM to better characterize recurrence risk. We identified 570 patients with 1487 BrM managed with whole-brain (WBRT) or stereotactic radiation therapy at Brigham and Women's Hospital/Dana-Farber Cancer Institute (2013-2020) for whom next-generation sequencing panel data (OncoPanel) were available. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with versus without somatic alterations of likely biological significance across 84 genes. Genes with a q-value ≤ 0.10 were utilized to develop a "Brain-Radiation Prediction Score" ("Brain-RPS"). Genomic alterations in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, and MDM4) and 2 genes (FBXW7 and AURKA) were associated with decreased or increased risk of local recurrence, respectively (q-value ≤ 0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray's competing risks regression, RPS [1.66 (1.44-1.91, P < .001)], metastasis-associated edema [1.60 (1.16-2.21), P = .004], baseline size [1.02 (1.01-1.03), P < .001] and receipt of WBRT without local therapy [4.04 (2.49-6.58), P < .001] were independent predictors of local failure. We developed a genomic score to quantify local recurrence risk following brain-directed radiation. To the best of our knowledge, this represents the first study to systematically correlate DNA-based alterations with radiotherapeutic outcomes in BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation in BrM.

Definitive radiotherapy consisting of external beam radiotherapy without central shielding and 3D image-guided brachytherapy for patients with cervical cancer: feasibility for Japanese patients and dose-response analyses for local control in the low-dose range.

To assess the feasibility of external beam radiotherapy without central shielding in definitive radiotherapy for Japanese patients with cervical cancer. We retrospectively analysed the data of cervical cancer patients treated with definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy. The study included 167 patients (T1+2=108, T3+4=59) from eight Japanese institutions. For three-dimensional-image-guided brachytherapy, intra-cavitary and interstitial brachytherapy was utilized in 33 patients (20%). The median follow-up was 26.6months (interquartile range, 20-43.2). The maximum rectal D2 (75Gy)/bladder D2 (90Gy) constraints were deviated by 6%/10% and 10%/5% for T1+2 and T3+4, respectively. The 2-year incidence of ≥grade 3 proctitis/cystitis was 4%/1% for T1+2 and 10%/2% for T3+4. The 2-year local progression-free survival was 89% for T1+2 and 82% for T3+4. For T1+2, the 2-year local progression-free survival for the high-risk clinical target volume D90≥68Gy (indicated by receiver operating characteristic analysis; area under the curve=0.711) was 92% versus 67% for <68Gy (log-rank; P=0.019). Cox multivariate analysis indicated that the high-risk clinical target volume D90 was one of independent predictors of local failure (P=0.0006). For T3+4, the 2-year local progression-free survival was 87% for the high-risk clinical target volume <82cm3 (area under the curve=0.67) and 43% for ≥82cm3 (P=0.0004). Only the high-risk clinical target volume was an independent predictor of local failure (P=0.0024). Definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy was feasible for Japanese patients with cervical cancer. Dose de-escalation from the current global standards is suggested for patients with T1+2 disease.

Salvage Surgery for Locoregional Failure in Anal Squamous Cell Carcinoma.

Anal squamous cell carcinoma is a rare cancer with a high cure rate, making research into the treatment of locoregional failure difficult. The purpose of this study was to examine factors related to local treatment failure and determine the outcomes of patients undergoing local salvage resection. This was a retrospective cohort study. This study was conducted at a quaternary referral center. Patients with anal squamous cell carcinoma treated with chemoradiotherapy between January 1983 and December 2015 were included. The influence of patient-, tumor-, and treatment-related factors on the primary outcome measures of locoregional failure, overall survival, and disease-free survival were investigated. Of 467 patients with anal squamous cell carcinoma, 63 experienced locoregional failure with 41 undergoing salvage resection. Twenty-seven patients (38%) had persistent disease and 36 (62%) developed locoregional recurrence. Multivariate analysis identified tumor stage (HR, 3.16; p < 0.002) as an independent predictor of locoregional failure. Thirty abdominoperineal resections and 11 pelvic exenterations were undertaken with no surgical mortality. At a median follow-up of 20 months (range, 4-150 months), 5-year overall and disease-free survival for the salvage cohort was 51% and 47%. Margin positivity was an independent predictor for relapse post-salvage surgery on multivariate analysis (HR, 20.1; p = 0.027). Nineteen patients (48%) developed further relapse, which included all 10 patients with a positive resection margin, 3 of whom underwent re-resection. Of the 19 patients with relapse, 3 remain alive and 2 have persistent disease. Limitations include the retrospective nature of the database, the prolonged time period of the study, and episodes of incomplete data. Advanced T stage is an independent predictor of local failure in anal squamous cell carcinoma. Most patients can be salvaged, with a positive resection margin being a strong predictor of further relapse and poor outcome. See Video Abstract at http://links.lww.com/DCR/A515.

Local control dependence on consecutive vs. nonconsecutive fractionation in lung stereotactic body radiation therapy

BackgroundRecent reports demonstrate impaired tumor re-oxygenation 24–48h after stereotactic body radiation therapy (SBRT), suggesting that non-consecutive treatment delivery may be advantageous. To test this hypothesis clinically, we compared local control in patients treated in consecutive daily fractions vs. nonconsecutive fractions. MethodsWe retrospectively reviewed 107 lung SBRT patients (117 tumors) treated for T1–T2N0 NSCLC with LINAC based SBRT (50 or 60Gy/5fractions). Patients were characterized as having been treated in consecutive daily fractions vs. in non-consecutive fractions. Local control, survival and toxicity end points (CTCAE V4.0) were compared. Propensity score matching and Cox regression analyses were performed in order to determine the effect of fractionation on local control. ResultsWith a median follow up of 23.7months, 3-year local control was superior at 93.3% vs. 63.6% in the non-consecutive and consecutive group, respectively (p=0.001). Multivariate analysis and propensity score matching showed that consecutive fractionation was an independent predictor of local failure. Overall survival trended toward improvement in the non-consecutive group, but this was not statistically significant (p=0.188). Development of any grade 2 toxicity was not significantly different between the two groups (p=0.75). ConclusionFive-fraction SBRT delivered over non-consecutive days imparts superior LC and similar toxicity compared to consecutive fractionation. These results should be validated in independent datasets and in a prospective fashion.

Microscopic Positive Margins in Differentiated Thyroid Cancer Is Not an Independent Predictor of Local Failure.

In contrast to other head and neck cancers, the impact of histological thyroid specimen margin status in differentiated thyroid cancer (DTC) is not well understood. The aim of this study was to investigate the prognostic value of margin status on local recurrence in DTC. The records of 3664 consecutive patients treated surgically for DTC between 1986 and 2010 were identified from an institutional database. Patients with less than total thyroidectomy, unresectable or gross residual disease, or M1 disease at presentation and those with unknown pathological margin status were excluded from analysis. In total, 2616 patients were included in the study; 2348 patients (90%) had negative margins and 268 patients (10%) had positive margins. Microscopic positive margin status was defined as tumor present at the specimen's edge on pathological analysis. Patient, tumor, and treatment characteristics were compared by Pearson's chi-squared test. Local recurrence free survival (LRFS) was calculated for each group using the Kaplan Meier method. The median age of the cohort was 48 years (range 7-91 years) and the median follow-up was 50 months (range 1-330 months). Age, sex, and histology types were similar between groups. As expected, patients who had positive margins were more likely to have larger tumors (p<0.001), extrathyroidal extension (ETE) (p<0.001), multicentric disease (p<0.001), or nodal disease (p<0.001) and were more likely to receive adjuvant radioactive iodine therapy (p<0.001) as well as external beam radiotherapy (p<0.001). The LRFS at 5 years for patients with positive margins status was slightly poorer compared with patients with negative margins (98.9% vs. 99.5%, p=0.018). Twelve patients developed local recurrence-8/2348 (0.34%) patients with negative margins and 4/263 (1.52%) patients with positive margins. Univariate predictors of LRFS were sex (p=0.006), gross ETE (<0.001), and positive margins (p=0.018). However, when controlling for presence of gross ETE on multivariate analysis, microscopic positive margin status was not an independent predictor of LRFS (p=0.193). Patients with resectable, M0 disease that undergo total thyroidectomy have an excellent five year LRFS of 99.4%. Microscopic positive margin status was not a significant predictor for local failure after adjusting for ETE or pathological tumor (pT) stage.

Predictors of Individual Tumor Local Control After Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases

To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS). Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant. Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥ 1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index. Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective setting.

1474 PT3-PROSTATE CANCER-POSITIVE SURGICAL MARGIN AT BLADDER NECK IS AN INDEPENDANT PREDICTOR OF LOCAL FAILURE AND PROSTATE CANCER MORTALITY: RESULTS OF A PROSPECTIVE SINGLE INSTITUTION SERIES

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 20111474 PT3-PROSTATE CANCER-POSITIVE SURGICAL MARGIN AT BLADDER NECK IS AN INDEPENDANT PREDICTOR OF LOCAL FAILURE AND PROSTATE CANCER MORTALITY: RESULTS OF A PROSPECTIVE SINGLE INSTITUTION SERIES Martin Spahn, Alberto Briganti, Umberto Capitanio, Paolo Gontero, Burkhard Kneitz, Pia Bader, Hein Van Poppel, Detlef Frohneberg, and Steven Joniau Martin SpahnMartin Spahn Würzburg, Germany More articles by this author , Alberto BrigantiAlberto Briganti Milan, Italy More articles by this author , Umberto CapitanioUmberto Capitanio Milan, Italy More articles by this author , Paolo GonteroPaolo Gontero Turin, Italy More articles by this author , Burkhard KneitzBurkhard Kneitz Würzburg, Germany More articles by this author , Pia BaderPia Bader Karlsruhe, Germany More articles by this author , Hein Van PoppelHein Van Poppel Leuven, Belgium More articles by this author , Detlef FrohnebergDetlef Frohneberg Karlsruhe, Germany More articles by this author , and Steven JoniauSteven Joniau Leuven, Belgium More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1409AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous studies have shown a positive correlation between presence of positive surgical margin (SM) and cancer recurrence and mortality. Only few addressed the importance of the location of positive SM.We hypothesized that the outcome of pts. with positive SMs (PSM) varies significantly according to their location in a large pT3 PCa series. METHODS The study included 550 consecutive pts. with high risk pPCa (PSA>20 ng/ml, cT3/cT4, bx Gleason 8–10) treated with RP+ PLND at a single institution. Of these,187 (34%) had pT3a/b disease and did not receive adjuvant radiation therapy.These pts. represented the study cohort. All pts.had detailed pathological data (presence and number of PSM (namely 1,2 or 3) that were collected prospectively. Location of PSM was recorded for all pts. and categorized as apical, posterolateral, urethral,posterior,seminal and bladder. A PSM was defined as presence of tumor cells at the inked margin of resection. Kaplan-Meier curves assessed the time to local failure and cancer specific survival (CSS) according to the number and location of PSM.The association between location of PSM was confirmed at multivariable Cox regression analyses after accounting for pathol. Gleason sum,PSA and use of adjuvant hormonal therapy. RESULTS Overall, 5,8 and 10-year CSS rates were 88, 86 and 86%, respectively, while local recurrence free rate was 82, 80 and 71% at 5–8 and 10-year follow-up, respectively. At Kaplan Meier analysis, only the presence of PSM at bladder neck was associated with both local failure and CSS (all p< 0.001). At 5 and 10 year follow-up, patients with PSM at bladder neck had significantly worse local failure (63 and 63% vs 87 and 74%; all p=0.001) and CSS rate (68 and 68% vs 94 and 91%; p<0.001) as compared to patients with negative margin at bladder neck. Conversely, no association was association between all other PSM location and CSS locations (all p=0.3). These results were confirmed at multivariable Cox regression analysis where the presence of PSM at bladder neck was the only independent predictor of both local failure (p=0.001; HR3.94) 0 and CSS (p=0.001; HR 5.61) even after accounting for all predictors. CONCLUSIONS Our study demonstrated that PSM at bladder neck is a significant predictor of local recurrence and cancer specific mortality in patients with pT3 disease even after accounting for pathological characteristics and use of adjuvant hormonal therapy. Patients with PSM at bladder neck should be thus considered for a combined, multimodal approach. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e591 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Martin Spahn Würzburg, Germany More articles by this author Alberto Briganti Milan, Italy More articles by this author Umberto Capitanio Milan, Italy More articles by this author Paolo Gontero Turin, Italy More articles by this author Burkhard Kneitz Würzburg, Germany More articles by this author Pia Bader Karlsruhe, Germany More articles by this author Hein Van Poppel Leuven, Belgium More articles by this author Detlef Frohneberg Karlsruhe, Germany More articles by this author Steven Joniau Leuven, Belgium More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Tumour budding correlates with local recurrence of rectal cancer

Predictive tools for local recurrence (LR) of rectal cancer are needed. This study assessed the predictive value of tumour budding detected by MNF-116 and laminin-5 γ2 chain (Ln-5 γ2). In a case-control study, the surgical specimens of 48 patients with LR after from primary resection of rectal carcinoma and 82 control patients matched for gender and preoperative radiation from a population of 1180 patients operated with total mesorectal excision were studied. The presence of budding was examined using immunohistochemistry with Ln-5 γ2 and pan-cytokeratin staining with MNF-116. Tumour budding counts ranged from 0 to 106 buds (mean 43, median 38) for all patients. Significantly more tumours with more than 35 buds were seen in the LR than in the control group (67 vs 44%; P = 0.02). The spread of budding was also more extensive in the LR than in the control group (63 vs 49%, P = 0.03). In a multivariate analysis with tumour, node, metastasis stage, MNF-116-stained budding was an independent predictor of local failure (P = 0.02). The budding frequency was higher in irradiated tumours in comparison with tumours that had not received irradiation (mean 53 vs 38, P = 0.03). For Ln-5 γ2, more tumours with ≥ 10 buds were seen in the group with LR than among the control patients, but this difference was not statistically significant (73 vs 57%; P = 0.09). No additive value was found in the multivariate logistic regression model when Ln-5 γ2-stained budding frequency was added to MNF-116 and tumour, node, metastasis stage. The agreement between budding frequency determined by MNF-116 and Ln-5 γ2 was moderate, with a κ-coefficient of 0.34 (0.16-0.51). Tumour budding determined by MNF-116 staining may serve as a predictive marker for LR in rectal cancer.

Recurrent salivary gland carcinomas treated by surgery with or without intraoperative radiation therapy

The optimal treatment for patients with locally recurrent carcinomas of the salivary glands is unclear. Ninety-nine patients underwent salvage surgery for locally recurrent salivary gland carcinomas. Eighty-one (82%) had previously received radiation. Thirty-seven patients (37%) received intraoperative radiation therapy (IORT) to a median dose of 15 Gy (range, 12-18 Gy) at the time of salvage. The 1-, 3-, and 5-year estimates of local control after salvage surgery were 88%, 75%, and 69%, respectively. A Cox proportional hazard model identified positive margins (0.01) and the omission of IORT (p = .001) as independent predictors of local failure. The 5-year overall survival was 34%. Distant metastasis was the most common site of subsequent failure, occurring in 42% of patients. IORT significantly improves disease control for patients with locally recurrent carcinomas of the salivary glands. The high rate of distant metastasis emphasizes the need for effective systemic therapies.

Patterns of local disease failure and outcome after salvage surgery in patients with anal cancer

Salvage surgery for anal cancer is usually reserved for local disease failure, but issues relating to the prediction of local failure and surgical outcome are ill defined. Between 1988 and 2000, 254 patients with non-metastatic anal epidermoid carcinoma were treated at a regional cancer centre with radiotherapy (n = 127) or chemoradiotherapy (n = 127). There were 99 local disease failures (39.0 per cent), all but five occurring within 3 years of initial treatment. Increasing age (P < 0.001, Cox model), total radiation dose (P = 0.004) and tumour stage (P = 0.010) were independent predictors of local failure. The overall 3- and 5-year survival rates after local disease failure were 46 and 29 per cent; the corresponding rates after salvage surgery (73 patients) were 55 and 40 per cent. A positive resection margin was the strongest negative predictor of survival after salvage surgery (P = 0.008, log rank test). Of 52 patients treated before the routine consideration of primary plastic reconstruction, delayed perineal wound healing occurred in 22 (42 per cent). In the management of anal cancer, local disease failure is a major clinical problem requiring early detection followed by radical surgery, often accompanied by plastic reconstruction. By implication, these factors favour the centralization of treatment for this uncommon cancer to a multidisciplinary oncology team.

Obesity at diagnosis confers worse outcome in patients with early stage breast cancer treated with breast conservation therapy

Obesity has been shown to be a risk factor for the development of primary breast cancer. Prior studies have reported contradictory results regarding the influence of obesity on outcome in breast cancer patients. Therefore, the prognostic influence of obesity remains uncertain, especially in early stage breast cancer patients. This study analyses the impact of obesity on outcome in women with early stage I/II breast cancer treated with conservative surgery and radiation therapy. From 1978 to 2003, 2010 women with Stage I/II breast cancer underwent lumpectomy, axillary dissection and radiation therapy with or without systemic therapy. The median age was 58 years (range 20–89). Obesity was defined by using the Quetelet’s Index (also called the body mass index or BMI), which is the patient’s weight divided by the height squared. Patients were categorized into three groups according to their Quetelet’s Index (QI), which was calculated at the time of diagnosis. The groups were defined as the normal weight group (QI range >0 ≤ 3.2), the overweight group (QI range >3.2 ≤ 4), and the obese group (QI range >4). 701 patients (35%) were considered obese, 857 patients (43%) were overweight, and 452 patients (22%) were in the normal weight group. The median follow-up was 61 months. The three groups were compared for differences in the clinical factors of age, race, tumor size, family history, menopausal status; the pathologic factors of histology, extensive intraductal component (EIC), lymphovascular invasion (LVI), final margin status, nodal status, receptor status; and treatment-related factors of regions treated with radiation therapy and systemic therapy. Cox multivariate regression models were used to determine the independent predictors of local failure (LF), distant metastases (DM), cause-specific survival (CSS), and overall survival (OS). Five-year rates were estimated using Kaplan-Meier methodology and comparisons were made using the log-rank test. Statistically significant differences between the three weight groups were observed for age (p < 0.0001) and menopausal status (p < 0.0001), with the obese weight group being comprised of older and more post-menopausal women. There was no statistically significant difference observed for tumor size or number of involved lymph nodes between the three weight groups. The actuarial five-year rates of DM were 7%, 6% and 10% for the normal weight, overweight and obese weight groups, respectively (p = 0.06). The actuarial five-year rates of CSS were 96%, 95% and 93% for the normal weight, overweight and obese groups, respectively (p = 0.05). The actuarial five-year rates of OS were 92%, 92% and 88% for the normal weight, overweight and obese groups, respectively (p = 0.0035). Using a Cox multivariate proportional hazards regression model, obesity was found to be a statistically significant independent predictor of increased distant metastases (p = 0.0145), and worse cause-specific survival (p = 0.0060). Obesity was not found to be a significant predictor of local failure. Obesity at the time of diagnosis of early stage breast cancer is a significant predictor for poorer outcome. Women who are obese are at greater risk for breast cancer death and distant metastases, although they do not present with more advanced stage disease compared with normal weight patients. We have demonstrated a significant association between obesity and adverse breast cancer outcome in patients with early stage breast cancer. Because the prevalence of obesity increases with age, as does the risk for breast cancer, interventions that enhance weight control may have a substantial effect on breast cancer outcome

Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy

Purpose To investigate the value of CT-determined tumor perfusion as a predictive factor of local and regional failure and cause-specific survival in head-and-neck cancer treated by radiotherapy. Methods and materials In 105 patients, the perfusion of a primary head-and-neck squamous cell carcinoma was estimated using dynamic CT. A contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumor surface. The perfusion in the selected tumor region of interest was calculated by dividing the slope of the tumor–time density curve by the maximal value in arterial density. Primary and nodal tumor volume was calculated from the CT images. All patients were treated by radiotherapy with curative intent; in 15 patients, adjuvant concomitant chemotherapy was administered. Mean follow-up time was 2.2 years. Actuarial (life-table) statistical analysis was done; multivariate analysis was performed using the Cox proportional hazards model. Results When the patients were stratified according to the median perfusion value (83.5 mL/min/100 g), those with the lower perfusion rate had a significantly higher local failure rate ( p < 0.05). In the multivariate analysis, perfusion rate ( p = 0.01) and T category ( p = 0.03) were found to be the independent predictors of local failure. Perfusion rate had predictive value regarding neither regional control nor cause-specific survival. Conclusion CT-determined tumor perfusion rate was found to be an independent predictor of local outcome in irradiated head-and-neck cancer. The results of this study confirm the hypothesis that less-perfused tumors respond poorly to radiotherapy.

P53 and Ki-67 as markers of radioresistance in head and neck carcinoma.

p53 and Ki-67 are regarded as potential interesting predictors of radioresistance, although their exact influence awaits confirmation on a large cohort of uniformly treated patients. In a retrospective cohort of 304 patients with squamous cell carcinoma of the head and neck who were treated with radical radiotherapy, the expression levels of p53 and Ki-67 were assessed by immunohistochemistry. Local control and survival curves were generated for p53 and Ki-67 using the Kaplan-Meier method. The difference between curves was calculated in univariate and multivariate analyses. The overexpression of p53 was associated with local treatment failure (P = 0.01) but not with survival (P = 0.09). In a Cox analysis, p53 overexpression remained an independent predictor of local failure, with a relative risk of local failure of 1.5 (P = 0.05). Low proliferation (Ki-67 < 20%) was a significant factor in local failure for patients with tumors of the oral cavity only (P = 0.01). Patients with both unfavorable immunohistochemical markers (p53 overexpression and low proliferation) had a 45% rate of local control compared with a 67% rate for all other combinations (P = 0.002). This association was even more significant in patients with T1-T2 lesions (45% vs. 77%; P = 0.0002). The results support the role of p53 as an independent predictor of local failure in patients with squamous cell carcinoma of the head and neck who are treated by radical radiotherapy, suggesting that it may predict radioresistance. Combined with p53, Ki-67 may help in the better selection of patients for radiotherapy, especially for patients with early-stage tumors. Prospective studies are now needed to confirm these results and to define better the role of these markers in the management of patients with head and neck carcinoma.

FAMILIAL PROSTATE CANCER: A DIFFERENT DISEASE?

Purpose We analyzed the outcome after radical prostatectomy of patients with familial prostate cancer versus patients with sporadic prostate cancer. Materials and Methods The study included 720 patients with prostate carcinoma who were treated with prostatectomy between 1987 and 1996. Patients were excluded from the study if they had received adjuvant or neoadjuvant treatment, or had no available pretreatment prostatic specific antigen (PSA) level, no available biopsy Gleason score, incomplete pathological information or no available followup PSA levels. The analysis was performed on 529 cases. Patients were considered to have a positive family history for prostate cancer when the index patient confirmed the diagnosis of prostate cancer in a first degree relative (brother or father). The outcomes of interest were biochemical relapse-free survival, local failure and distant metastases. Proportional hazards were used to analyze the effect of family history and confounding variables (that is age, stage, biopsy Gleason score, initial PSA levels, surgical specimen Gleason score, extracapsular extension, lymph node metastasis, seminal vesicle invasion and surgical margin involvement) on treatment outcome. Results Median followup was 30 months. Of all cases 12% had a positive family history. Younger age was the only factor associated with positive family history, with 18% of patients younger than 65 years having a positive family history versus 6% of older patients (chi-square p <0.001). The 5-year biochemical relapse-free survival rate for the entire group was 64%. The 5-year biochemical relapse-free survival rates for patients with negative family history versus positive history were 66% and 46%, respectively (p = 0.001). A multivariate time-to-failure analysis using the proportional hazards model was performed based on family history, age (less than 65 versus 65 to 69 versus 70 or greater, initial PSA (10 or less versus greater than 10), biopsy Gleason score (6 or less versus 7 or greater), clinical T stage (T1-T2 versus T2B-C), prostatectomy specimen Gleason score (6 or less versus 7 or greater), extracapsular extension, seminal vesicle involvement, surgical margin involvement and lymph node involvement. After adjusting for the potential confounding factors, positive family history remained strongly associated with biochemical failure. The clinical failure rate for the entire group was 14%. The 5-year local failure rate was 7%, with positive surgical margins being the only independent predictor of local failure. The 5-year distant metastasis rate was 8%, with family history and initial PSA levels being independent predictors of distant relapse. Conclusions Our study suggests that patients with a familial prostate cancer have a higher likelihood of biochemical failure after radical prostatectomy than patients with sporadic cancer. This effect is independent of pretreatment or pathological factors. Our results suggest that the higher failure rates associated with familial prostate cancer are mainly secondary to higher distant relapse rates, and that familial prostate cancer may be more biologically aggressive than sporadic cancers.

State T1–2 prostate cancer: A multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy

Prostate-specific antigen (PSA) is extensively used in case selection and outcome evaluation after treatment of clinically localized prostate cancer. Careful case selection can have a profound impact on pathologic findings and ultimate outcome. In addition, salvage treatment is frequently initiated at the time of biochemical relapse rather than clinical recurrence. Consequently, patterns of failure can be significantly altered compared to previous times when PSA was not available. To better understand the impact of PSA on pathologic findings, outcome, and salvage treatment, we reviewed our experience in the PSA era with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. Between 1987 and 1993, 423 cases could be identified with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. The distribution of cases by pretreatment PSA levels was as follows: < or = 4 ng/ml (18%), 4-10 ng/ml (42%), 10-20 ng/ml (21%), > 20 ng/ml (14%), and unknown (5%). The median pretreatment PSA level for the entire group was 8.0 ng/ml. Sixteen patients received adjuvant or neoadjuvant androgen suppression and 13 received postoperative radiotherapy. Only 31 patients (7%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 46%. Fifty-three percent of patients had surgical Gleason scores > or = 7, and 65% had extracapsular extension. The median follow-up time was 41 months. The projected overall survival at 7 years after surgery was 90%. The 5-year clinical relapse-free survival rate was 84%. At 5 years, the local control and distant failure rates were 92% and 91%, respectively. Biochemical relapse was defined as a detectable or rising PSA level after prostatectomy. The 5-year biochemical relapse-free survival (bRFS) rate was 59%. The 5-year RFS was 88% in patients with preoperative PSA levels < or = 4, 62% for 4-10, 48% for 10-20, and 31% for > 20. Combining the two independent preoperative variables, iPSA and biopsy GS (bGS), two risks groups were defined: low risk [initial PSA (iPSA) levels < or = 10.0 and bGS < or = 6] and high risk (iPSA levels > 10.0 ng/ml or bGS > or = 7). The 5-year bRFS rate for the low-risk cases was 81% vs. 40% for high-risk cases (p < 0.001). On multivariate analysis, three factors independently predicted biochemical relapse: iPSA levels (p = 0.005), Gleason score from the surgical specimen (sGS) (p = 0.002), and positive surgical margins (p < or = 0.001). The 5-year bRFS rates for margin positive vs. margin negative patients were 37% vs. 78%, respectively. The 5-year bRFS rates for GS > or = 7 vs. GS > or = 6 were 42% vs. 80%, respectively. All clinical relapses were accompanied by a rise in PSA. In patients who manifested biochemical failure followed by a clinical failure, the median interval between the PSA rise and clinical failure was 19 months (range 7-71). Margin involvement was the only independent predictor of local failure (p = 0.019). The 5-year local failure-free survival for negative margin cases was 96% vs. 87% for positive margin cases (p = 0.012). Lymph node (LN) involvement and high-risk group were the two independent predictors of distant failure. The 5-year distant failure-free survival for negative LN cases was 94% vs. 67% for positive LN cases (p < 0.001). The 5-year distant failure-free survival for low-risk cases was 97% vs. 85% for high-risk cases (p = 0.005). For the 124 patients failing biochemically, 85 were observed and 39 were treated either with radiation or androgen deprivation. With a median follow-up of 32 months, the clinical disease relapse-free survival was 79% for the treated patients vs. only 32% for the patients observed (p < 0.001). Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse, thereby allowing markedly better case selection. Achieving negative margins, even in relatively advanced disease, provides excellent lon

Localized operable soft tissue sarcoma of the upper extremity. Presentation, management, and factors affecting local recurrence in 108 patients.

Radical ablative surgery for upper extremity sarcoma often results in significant loss of function. With the recent emphasis on limb preservation, function-sparing excision has been combined with adjuvant radiation and chemotherapy in an increasing number of patients. To assess the effect of changing management on local recurrence rates and identify factors governing local failure, the records of 108 patients with operable, nonmetastatic soft tissue sarcoma of the upper extremity, treated at the Memorial Sloan-Kettering Cancer Center between 1968 and 1978, were reviewed. Median follow-up care was 8.2 years. One third of the patients presented with locally recurrent tumors after initial treatment elsewhere. Over half of the lesions were above the elbow and 62% were high grade. Seventy-three patients (68%) had limb-sparing surgery (LSS), but margins were considered adequate in less than half. Local recurrence was directly related to the adequacy of the surgical margins and was significantly higher in the LSS patients (p = 0.008). Other factors associated with an increased risk of local failure included: presentation with local recurrence, superficial location, and invasion of vital structures (LSS only). Local failure varied significantly with histologic type and was highest in patients with embryonal rhabdomyosarcoma and angiosarcoma. When the data were subjected to multivariate analysis, the following variables emerged as independent predictors of local failure: presentation with local recurrence, surgery by LSS, inadequate margins, angiosarcoma, and invasion of vital structures. These risk factors should be carefully weighed when selecting local treatment for patients with upper extremity soft tissue sarcomas.

Localized, operable soft tissue sarcoma of the lower extremity.

Recent developments in adjuvant treatment of soft tissue sarcomas of the extremities have altered the surgical approach to this disease. To assess the effects of changing management on local recurrence rates and to examine factors governing local failure, we reviewed the records of 315 adults with operable, nonmetastatic soft tissue sarcoma of the lower extremity who were treated at one institution over a ten-year period. The median follow-up was 8.2 years. One third of our patients presented with locally recurrent tumors after initial treatment elsewhere. Sixty-six percent of the lesions were above the knee, and 60% were high grade. Two thirds of the patients underwent limb-sparing surgery (LSS), which in the latter half of the study period outnumbered amputations by four to one. Local recurrence was directly related to the adequacy of the surgical margins. Adjuvant radiotherapy and chemotherapy did not significantly decrease local recurrence in patients who underwent LSS, although favorable trends were observed. A significantly increased risk of local failure was associated with age greater than 53 years, presentation with local recurrence, high tumor grade, deep location, positive nodes, and less than adequate surgical margins. Local failure also varied significantly with histologic type and was highest in patients with embryonal rhabdomyosarcoma and neurofibrosarcoma. Improved local control, particularly in patients with high-grade tumors, was observed in the latter half of the study period despite the increased use of LSS. When the data were subjected to multivariate analysis, the following variables emerged as independent predictors of local failure: age greater than 53 years, presentation with local recurrence, high grade, less than adequate margins, embryonal rhabdomyosarcoma, and neurofibrosarcoma. The key to local control of sarcomas of the extremities is resection of the tumor with adequate margins. The role of adjuvant treatment, particularly following LSS, is still being evaluated. The risk factor profile should be considered when selecting a treatment program for patients with lower extremity sarcomas.