Phase 1 clinical trials in 83 patients with pancreatic cancer

BACKGROUND:

The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution.

METHODS:

The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics.

RESULTS:

Eighty‐three patients were identified. The median age was 62 years (range, 39‐81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow‐up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3‐6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9‐26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3‐1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005).

CONCLUSIONS:

Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer. Cancer 2011. © 2010 American Cancer Society.     

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma

BACKGROUND:

This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM‐MM).

METHODS:

In a retrospective survey in 9 cancer centers of the German Cancer Society, 692 patients were identified with BM‐MM during the period 1986 through 2007. Overall survival was analyzed using a Kaplan‐Meier estimator and compared with log‐rank analysis. Cox proportional hazards models were used to identify prognostic factors significant for survival.

RESULTS:

The median overall survival of the entire cohort was 5.0 months (95% confidence interval [95% CI], 4 months‐5 months). Significant prognostic factors in the univariate Kaplan‐Meier analysis were Karnofsky performance status (≥70% vs <70%; P < .001), number of BM‐MM (single vs multiple; P < .001), pretreatment levels of lactate dehydrogenase (LDH) (normal vs elevated; P < .001) and S‐100 (normal vs elevated; P < .001), prognostic groups according to Radiation Therapy Oncology Group (class I vs class II vs class III; P = .0485), and treatment choice (for the cohort with single BM‐MM only) (stereotactic radiotherapy or neurosurgical metastasectomy vs others; P = .036). Cox proportional hazards models revealed pretreatment elevated level of serum LDH (hazard ratio [HR], 1.6; 95% CI, 1.3‐2.0 [P = .00013]) and number of BM‐MM (HR, 1.6; 95% CI, 1.3‐2.0 [P = .00011]) to be independent prognostic variables in the entire cohort, whereas in patients with a single BM‐MM, treatment choice (HR, 1.5; 95% CI, 1.1‐1.9 [P = .0061]) was identified as a unique prognostic factor.

CONCLUSIONS:

The overall survival of patients with BM‐MM primarily depends on the number of metastases and pretreatment level of LDH. In the case of a single brain metastasis, stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival. Cancer 2011. © 2010 American Cancer Society.     

Smoking,alcohol use,obesity, and overall survival from non‐Hodgkin lymphoma

BACKGROUND:

Smoking, alcohol use, and obesity appear to increase the risk of developing non‐Hodgkin lymphoma (NHL), but to the authors' knowledge, few studies to date have assessed their impact on NHL prognosis.

METHODS:

The association between prediagnosis cigarette smoking, alcohol use, and body mass index (BMI) and overall survival was evaluated in 1286 patients enrolled through population‐based registries in the United States from 1998 through 2000. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox regression, adjusting for clinical and demographic factors.

RESULTS:

Through 2007, 442 patients had died (34%), and the median follow‐up for surviving patients was 7.7 years. Compared with never smokers, former (HR, 1.59; 95% CI, 1.12‐2.26) and current (HR, 1.50; 95% CI, 0.97‐2.29) smokers had poorer survival, and poorer survival was found to be positively associated with smoking duration, number of cigarettes smoked per day, pack‐years of smoking, and shorter time since quitting (all P <0.01). Alcohol use was associated with poorer survival (P = 0.03); compared with nonusers. Those drinking >43.1 g/week (median intake among drinkers) had poorer survival (HR, 1.55; 95% CI, 1.06‐2.27), whereas those drinkers consuming less than this amount demonstrated no survival disadvantage (HR, 1.13; 95% CI, 0.75‐1.71). Greater BMI was associated with poorer survival (P = 0.046), but the survival disadvantage was only noted among obese individuals (HR, 1.32 for BMI ≥30 vs BMI 20‐24.9; 95% CI, 1.02‐1.70). These results held for lymphoma‐specific survival and were broadly similar for diffuse large B‐cell lymphoma and follicular lymphoma.

CONCLUSIONS:

NHL patients who smoked, consumed alcohol, or were obese before diagnosis were found to have a poorer overall and lymphoma‐specific survival. Cancer 2010. © 2010 American Cancer Society.     

Expression patterns of Bmi-1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma

BACKGROUND:

The objective of this study was to link expression patterns of B‐cell–specific Moloney murine leukemia virus integration site 1 (Bmi‐1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC).

METHODS:

Expression levels of Bmi‐1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease‐specific, and recurrence‐free survival.

RESULTS:

The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi‐1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi‐1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167‐2.838); this correlation was also observed for atypical cytoplasmic Bmi‐1 expression (P = .001; HR, 2.164; 95% CI, 1.389‐3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178‐0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237‐16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146‐2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869‐13.635) were correlated with overall survival, disease‐specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477‐5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850‐15.679), and the combined markers also were correlated with recurrence‐free survival (P = .001; HR, 8.943; 95% CI, 2.562‐31.220).

CONCLUSIONS:

Cytoplasmic Bmi‐1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease‐specific and recurrence‐free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow‐up. Cancer 2011;. © 2011 American Cancer Society.     

Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer

BACKGROUND:

Recent observational studies have shown that metformin use in diabetic patients decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. In the current study, the authors explored the association between metformin use and survival outcomes in patients with triple receptor‐negative breast cancer (TNBC) who were receiving adjuvant chemotherapy.

METHODS:

The Breast Cancer Management System database of The University of Texas MD Anderson Cancer Center identified 1448 women who received adjuvant chemotherapy for TNBC between 1995 and 2007. Patients were categorized by diabetes status and metformin use. The Kaplan‐Meier product‐limit method was used to calculate distant metastasis‐free survival (DMFS), recurrence‐free survival (RFS), and overall survival (OS). Cox proportional hazards models were fit to determine the association between metformin use and survival outcomes.

RESULTS:

The study cohort was comprised of 63 diabetic patients receiving treatment with metformin, 67 diabetic patients not receiving metformin, and 1318 nondiabetic patients. Patients in the diabetic groups tended to be older (P = .005); more diabetic patients were postmenopausal (P = .0007), black (P = .0001), and obese (P < .0001). At a median follow‐up of 62 months, there were no significant differences with regard to 5‐year DMFS (P = .23), RFS (P = .38), and OS (P = .58) between the 3 groups. Compared with the metformin group, patients who did not receive metformin (hazard ratio [HR], 1.63; 95% confidence interval [95% CI], 0.87‐3.06 [P = .13]) and nondiabetic patients (HR, 1.62; 95% CI, 0.97‐2.71 [P = .06]) tended to have a higher risk of distant metastases.

CONCLUSIONS:

The findings of the current study suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC. Cancer 2012;. © 2011 American Cancer Society.     

Stage IV breast cancer in the era of targeted therapy

BACKGROUND:

Multiple studies have suggested that resection of the primary tumor improves survival in patients with stage IV breast cancer, yet in the era of targeted therapy, the relation between surgery and tumor molecular subtype is unknown. The objective of the current study was to identify subsets of patients who may benefit from primary tumor treatment and assess the frequency of local disease progression.

METHODS:

Patients presenting with stage IV breast cancer and intact primary tumors (n = 186) were identified from a prospectively maintained clinical database (2000‐2004) and clinical data were abstracted (grading determined according to the American Joint Committee on Cancer staging system).

RESULTS:

Surgery was performed in 69 (37%) patients: 34 (49%) patients with unknown metastatic disease at the time of surgery, 15 (22%) patients for local control, 14 (20%) patients for palliation, and in 6 (9%) patients to obtain tissue. Surgical patients were more likely to be HER‐2/neu negative (P = .001), and to have smaller tumors (P = .05) and solitary metastasis (P <.001). Local therapy included axillary lymph node clearance in 33 (48%) patients and postoperative radiotherapy in 9 (13%) patients. The median survival was 35 months. Cox regression analysis identified estrogen receptor (ER) positivity (hazard ratio [HR], 0.47; 95% confidence interval [95% CI], 0.29‐0.76), progesterone receptor (PR) positivity (HR, 0.57; 95% CI, 0.36‐0.90), and HER‐2/neu amplification (HR, 0.51; 95% CI, 0.34‐0.77) as being predictive of improved survival. There was a trend toward improved survival with surgery (HR, 0.71; 95% CI, 0.47‐1.06). On exploratory analyses, surgery was found to be associated with improved survival in patients with ER/PR positive or HER‐2/neu?amplified disease (P = .004). No survival benefit was observed in patients with triple‐negative disease.

CONCLUSIONS:

Although a trend toward improved survival with surgery was observed, it was noted most strongly in patients with ER/PR positive and/or HER‐2/neu?amplified disease. This suggests that the impact of local control is greatest in the presence of effective targeted therapy, and supports the need for further study to define patient subsets that will benefit most. Cancer 2010. © 2010 American Cancer Society.     

Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma

BACKGROUND:

A history of multiple primary melanomas (PMs) has been associated with improved survival in patients with early stage melanoma, but whether it also is correlated with survival in patients with metastatic melanoma is unknown. The authors sought to address the latter question in the current study.

METHODS:

Patients with metastatic melanoma diagnosed at the Melanoma Institute Australia between 1983 and 2008 were identified. Overall survival (OS) was calculated from date of first distant metastasis. Survival analysis was performed using the Kaplan‐Meier method, log‐rank tests, and multivariate Cox proportional hazards models.

RESULTS:

Of 2942 patients with metastatic melanoma, 2634 (89.5%) had 1 PM and 308 (10.5%) had >1 PM. Factors that were associated independently with shorter OS were site of metastasis, including the brain (hazard ratio [HR], 2.41; 95% confidence interval [CI], 2.07‐2.81; P < .001) and nonlung viscera (HR, 1.92; 95% CI, 1.67‐2.22; P < .001, vs lymph node/subcutaneous/soft tissue), age >60 years (HR, 1.23; 95% CI, 1.12‐1.36; P < .001), shorter disease‐free interval from PM to first distant metastasis (≤12 months vs >36 months: HR, 1.62; 95% CI, 1.39‐1.89; P < .001), and fewer PMs (1 vs >1; HR, 1.26; 95% CI, 1.08‐1.47; P = .004).

CONCLUSIONS:

A history of multiple PM was an independent predictor of improved survival for patients with metastatic melanoma. The results indicate that a history of multiple PMs should be incorporated into multivariate analyses of prognostic factors and treatment outcomes. Cancer 2012. © 2012 American Cancer Society.     

Prognostic model to predict outcomes in nonsmall cell lung cancer patients treated with gefitinib as a salvage treatment

BACKGROUND:

A prognostic model based on clinical parameters for nonsmall cell lung cancer (NSCLC) patients treated with gefitinib (250 mg/day) as a salvage therapy was devised.

METHODS:

Clinical data regarding a total of 316 metastatic or recurrent NSCLC patients who were treated with gefitinib were analyzed.

RESULTS:

Poor prognostic factors for overall survival (OS) by multivariate analysis were an Eastern Cooperative Oncology Group (ECOG) performance status of 2 to 3 (hazards ratio [HR] of 2.07; 95% confidence interval [CI], 1.57‐2.73 [P < .001]), the presence of intra‐abdominal metastasis (HR of 1.76; 95% CI, 1.33‐2.34 [P < .001]), elevated serum alkaline phosphatase (HR of 1.50; 95% CI, 1.13‐2.00 [P = .005]), time interval from diagnosis to gefitinib therapy of ≤12 months (HR of 1.48; 95% CI, 1.12‐1.95 [P = .005]), low serum albumin (HR of 1.45; 95% CI, 1.09‐1.92 [P = .009]), progression‐free interval for previous chemotherapy of ≤12 weeks (HR of 1.40; 95% CI, 1.0‐1.84 [P = .015]), white blood cell >10,000/μL (HR of 1.38; 95% CI, 1.02‐1.85 [P = .032]), and ever‐smoker (HR of 1.33; 95% CI, 1.02‐1.75 [P = .033]). Of the 272 patients applicable to this prognostic model, 41 patients (15%) were categorized as a good prognosis group (0‐1 risk factors), 100 patients (37%) as an intermediate prognosis group (2‐3 risk factors), 81 patients (30%) as a poor prognosis group (4‐5 risk factors), and 50 patients (16%) as a very poor prognosis group (≥6 risk factors). The median OS from the time of gefitinib treatment for the good, intermediate, poor, and very poor prognosis groups were 18.0 months, 11.2 months, 4.0 months, and 1.3 months, respectively (P < .001).

CONCLUSIONS:

This prognostic model based on easily available clinical variables would be useful to identify patients who might derive more benefit from gefitinib treatment and to make decisions in clinical practice. Cancer 2009. © 2009 American Cancer Society.     

Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns

BACKGROUND:

Primary cardiac lymphoma (PCL) represents a rare subset of non‐Hodgkin lymphoma, characterized by poor outcomes. The authors aimed to construct a framework of known clinical presentations, diagnostic features, disease complications, treatment, and outcomes to improve prognostication.

METHODS:

Individual patient data were obtained from defined cases of PCL (1949‐2009) and systematically analyzed.

RESULTS:

The authors report results of a review of 197 cases of PCL, with half of all cases reported since 1995. Survival was affected by 4 factors: immune status, left ventricular involvement, presence of extra‐cardiac disease, and arrhythmia. Median overall survival (OS) for immunocompromised and immunocompetent was 3.5 months (m) and not reached, respectively (HR 0.29, 95% CI, 0.13‐0.68; P = .004). LV involvement was uncommon (26%) and associated with an OS of only 1m, whereas patients free of LV involvement had a median OS of 22m (HR 0.28, 95% CI, 0.12‐0.64; P = .002). Patients with extracardiac disease had shorter median OS compared with those without (6m vs 22m, HR 0.49, 95% CI, 0.26‐0.91; P = .02). Those patients with an arrhythmia of any type had a median OS that was not reached (n = 55), whereas those without rhythm disturbances (n = 41) had median OS of 6m (HR 0.51, 95% CI, 0.29‐0.91; P = .024). Overall response rate to therapy was 84%, with long‐term OS over 40%.

CONCLUSIONS:

The current study presents the largest analysis of PCL to date. The data demonstrate that PCL is now more frequently diagnosed premortem and appears to have reasonable response rates. Lack of LV involvement and the presence of arrhythmias are associated with improved survival. Cancer 2011. © 2010 American Cancer Society.     

Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma

BACKGROUND:

Gemcitabine (2′,2′‐difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease‐free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate‐limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine‐based chemoradiation regimen.

METHODS:

Forty‐five patients with resected pancreatic adenocarcinoma received adjuvant gemcitabine based‐therapy in the context of multicenter phase 2 studies. Their tumors were evaluated retrospectively for dCK protein expression by immunohistochemistry. A composite score based on the percentage of dCK‐positive cancer cells and the intensity of staining was generated, and the results were dichotomized at the median values.

RESULTS:

The median follow‐up was 19.95 months (95% confident interval [CI], 3.3‐107.4 months). The lymph node (LN) ratio and dCK protein expression were significant predictors of DFS and OS in univariate analysis. On multivariate analysis, dCK protein expression was the only independent prognostic variable (DFS: hazard ratio [HR], 3.48; 95% CI, 1.66‐7.31; P = .001; OS: HR, 3.2; 95% CI,1.44‐7.13; P = .004).

CONCLUSIONS:

dCK protein expression was identified as an independent and strong prognostic factor in patients with resected pancreatic adenocarcinoma who received adjuvant gemcitabine therapy. The authors concluded that it deserves prospective evaluation as a predictive biomarker for patient selection. Cancer 2010. © 2010 American Cancer Society.     

Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first‐line palliative chemotherapy

BACKGROUND:

Advanced biliary tract adenocarcinoma (BTA) has been a rare but fatal cancer. If unresectable, palliative chemotherapy improved the quality and length of life, but to the authors' knowledge, prognostic factors in such patients have not been well established to date. In the current study, prognostic factors were investigated in patients with advanced BTA receiving first‐line palliative chemotherapy.

METHODS:

Data from 213 patients with advanced BTA who were in prospective phase 2 or retrospective studies from September 2000 through October 2007 were used.

RESULTS:

With a median follow‐up duration of 29.7 months, the median overall survival (OS) was 7.3 months (95% confidence interval [95% CI], 6.3 months‐8.3 months). A Cox proportional hazards model indicated that metastatic disease (hazards ratio [HR], 1.521; P = .011), intrahepatic cholangiocellular carcinoma (HR, 1.368; P = .045), liver metastasis (HR, 1.845; P < .001), Eastern Cooperative Oncology Group performance status (HR, 1.707; P < .001), and alkaline phosphatase level (IU/L) (HR, 1.001; P < .001) were statistically significant independent predictors of poor prognosis. Patients were classified into 3 risk groups based on the prognostic index (PI), which was constructed using the regression coefficients of each variable. The median OS was 11.5 months (95% CI, 9.6 months‐13.5 months) for the low‐risk group (PI ≤ 1.5; n = 67), 7.3 months (95% CI, 5.7 months‐8.9 months) for the intermediate‐risk group (PI > 1.5 but ≤ 2.2; n = 75), and 3.6 months (95% CI, 2.9 months‐4.1 months) for the high‐risk group (PI > 2.2; n = 70 [P < .001]).

CONCLUSIONS:

Five prognostic factors in patients with advanced BTA were identified. The predictive model based on PI appears to be promising and may be used for the management of individual patients and to guide the design of future clinical trials, although external validation is needed. Cancer 2009. © 2009 American Cancer Society.     

Salvage stereotactic radiosurgery for breast cancer brain metastases: outcomes and prognostic factors

BACKGROUND:

Salvage stereotactic radiosurgery (SRS) is often considered in breast cancer patients previously treated for brain metastases. The goal of this study was to analyze clinical outcomes and prognostic factors for survival in the salvage setting.

METHODS:

The authors retrospectively examined 79 consecutive breast cancer patients who received salvage SRS (interval of >3 months after initial therapy), 76 of whom (96%) received prior whole‐brain radiation therapy. Overall survival (OS) and central nervous system (CNS) progression‐free survival rates were calculated from the date of SRS using the Kaplan‐Meier method. Prognostic factors were evaluated using the Cox proportional hazards model.

RESULTS:

Median age was 50.5 years. Fifty‐eight percent of this population was estrogen receptor positive, 62% was HER2 positive, and 10% was triple negative. At the time of SRS, 95% had extracranial metastases, with 81% of extracranial metastases at other visceral sites (lung/pleura/liver). Forty‐eight percent had stable extracranial disease. Median interval from initial brain metastases therapy to SRS was 8.4 months. Median CNS progression‐free survival after SRS was 5.7 months (interquartile range [IQR], 3.6‐11 months), and median OS was 9.8 months (IQR, 3.8‐18 months). Eighty‐two percent of evaluable patients received further systemic therapy after SRS. HER2 status (adjusted hazard ratio [HR], 2.4; P = .008) and extracranial disease status (adjusted HR, 2.7; P = .004) were significant prognostic factors for survival on multivariate analysis.

CONCLUSIONS:

In patients with good Karnofsky performance status, salvage SRS for breast cancer brain metastases is a reasonable treatment option, given an associated median survival in excess of 9 months. Furthermore, patients with HER2‐positive tumors at diagnosis or stable extracranial disease at the time of SRS have an improved clinical course, with median survival of >1 year. Cancer 2012. © 2011 American Cancer Society.     

Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in mantle cell lymphoma patients treated with R-HyperCVAD

BACKGROUND:

Although convincing data exist regarding the prognostic utility of positron emission tomographic (PET)‐computed tomographic (CT) imaging in Hodgkin lymphoma and diffuse large B‐cell lymphoma, its prognostic utility both during treatment and immediately after treatment have not been systematically evaluated in a large mantle cell lymphoma (MCL) patient cohort to support its use in clinical practice.

METHODS:

The authors conducted a retrospective cohort study to examine the prognostic utility of PET‐CT imaging in a uniform MCL patient cohort undergoing dose‐intensive chemotherapy (R‐HyCVAD) in the frontline setting. The primary study endpoints were progression‐free survival (PFS) and overall survival (OS). PET‐CT images were centrally reviewed for the purposes of this study using standardized response criteria.

RESULTS:

Fifty‐three patients with advanced stage MCL with PET‐CT data were identified. With median follow‐up of 32 months, 3‐year PFS and OS estimates were 76% (95% confidence interval [CI], 64%‐84%) and 84% (95% CI, 72%‐90%), respectively. Interim PET‐CT status was not associated with PFS (hazard ratio [HR], 0.9; 95% CI, 0.3‐2.7; P = .8) or OS (HR, 0.6; 95% CI, 0.1‐2.9; P = .5). Post‐treatment PET‐CT status was statistically significantly associated with PFS (HR, 5.2; 95% CI, 2.0‐13.6; P = .001) and trended toward significant for OS (HR, 2.8; 95% CI, 0.8‐9.6; P = .07).

CONCLUSIONS:

These data do not support the prognostic utility of PET‐CT in pretreatment and interim treatment settings. A positive PET‐CT after the completion of therapy identifies a patient subset with an inferior PFS and a trend toward inferior OS. Cancer 2012;3565–3570. © 2011 American Cancer Society.     

Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy

BACKGROUND:

Although obesity is an established risk factor for developing colon cancer, its prognostic impact and relation to patient sex in colon cancer survivors remains unclear.

METHODS:

The authors examined the prognostic and predictive impact of the body mass index (BMI) in patients with stage II and III colon carcinoma (N = 25,291) within the Adjuvant Colon Cancer Endpoints (ACCENT) database. BMI was measured at enrollment in randomized trials of 5‐fluorouracil–based adjuvant chemotherapy. Association of BMI with the time to recurrence (TTR), disease‐free survival (DFS), and overall survival (OS) were determined using Cox regression models. Statistical tests were 2‐sided.

RESULTS:

During a median follow‐up of 7.8 years, obese and underweight patients had significantly poorer survival compared with overweight and normal‐weight patients. In a multivariable analysis, the adverse prognostic impact of BMI was observed among men but not among women (P_interaction = .0129). Men with class 2 and 3 obesity (BMI ≥35.0 kg/m²) had a statistically significant reduction in DFS (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.01‐1.33; P = .0297) compared with normal‐weight patients. Underweight patients had a significantly shorter TTR and reduced DFS (HR, 1.18; 95% CI, 1.09‐1.28; P < .0001) that was more significant among men (HR, 1.31; 95% CI, 1.15‐1.50; P < .0001) than among women (HR, 1.11; 95% CI, 1.01‐1.23; P = .0362; P_interaction = .0340). BMI was not predictive of a benefit from adjuvant treatment.

CONCLUSIONS:

Obesity and underweight status were associated independently with inferior outcomes in patients with colon cancer who received treatment in adjuvant chemotherapy trials. Cancer 2013. © 2013 American Cancer Society.     

[90Yttrium‐DOTA]‐TOC response is associated with survival benefit in iodine‐refractory thyroid cancer

BACKGROUND:

The authors aimed to explore the efficacy of ⁹⁰Yttrium‐1,4,7,10‐tetra‐azacyclododecane N,N′,N″,N?‐tetraacetic acid [⁹⁰Y‐DOTA]‐Tyr³‐octreotide (TOC) in advanced iodine‐refractory thyroid cancer.

METHODS:

In a phase 2 trial, the authors investigated biochemical response (assessed by serum thyroglobulin levels), survival, and the long‐term safety profile of systemic [⁹⁰Y‐DOTA]‐TOC treatment in metastasized iodine‐refractory thyroid cancer. Adverse events were assessed according to the National Cancer Institute criteria. Survival analyses were performed by using multiple regression models.

RESULTS:

A total of 24 patients were enrolled. A median cumulative activity of 13.0 GBq (range, 1.7‐30.3 GBq) was administered. Response was found in 7 (29.2%) patients. Eight (33.3%) patients developed hematologic toxicity grade 1‐3, and 4 (16.7%) patients developed renal toxicity grade 1‐4. The median survival was 33.4 months (range, 3.6‐126.8 months) from time of diagnosis and 16.8 months (range, 1.8‐99.1 months) from time of first [⁹⁰Y‐DOTA]‐TOC treatment. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.03‐0.92; P = .04) and from time of first [⁹⁰Y‐DOTA]‐TOC therapy (HR, 0.20; 95% CI, 0.04‐0.94; P = .04). The visual grade of scintigraphic tumor uptake was not associated with treatment response (odds ratio [OR], 0.98; 95% CI, 0.26‐3.14; P = 1.00).

CONCLUSIONS:

Response to [⁹⁰Y‐DOTA]‐TOC in metastasized iodine‐refractory thyroid cancer was associated with longer survival. Upcoming trials should aim to increase the number of treatment cycles. Cancer 2009. © 2009 American Cancer Society.     

Prognostic factors for recurrent breast cancer patients with an isolated,limited number of lung metastases and implications for pulmonary metastasectomy

BACKGROUND:

The aim of this study was to evaluate the clinical treatment outcomes of recurrent breast cancer with a limited number of isolated lung metastases, and to evaluate the role of pulmonary metastasectomy.

METHODS:

The authors consecutively enrolled 140 recurrent breast cancer patients with isolated lung metastasis from 1997 to 2007 in Seoul National University Hospital and retrospectively analyzed 45 patients who had <4 metastatic lesions.

RESULTS:

Fifteen patients had pulmonary metastasectomy followed by systemic treatment (pulmonary metastasectomy group), and 30 received systemic treatment alone (nonpulmonary metastasectomy group). The 3‐year progression‐free survival (PFS) and 4‐year overall survival (OS) was significantly longer in the pulmonary metastasectomy group than in the nonpulmonary metastasectomy group (3‐year PFS, 55.0% vs 4.5%, P < .001; 4‐year OS, 82.1% vs 31.6%, P = .001). In multivariate analysis, a disease‐free interval (DFI) of <24 months (hazard ratio [HR], 4.53; 95% CI, 1.72‐11.90), no pulmonary metastasectomy (HR, 9.52; 95% CI, 3.34‐27.18) and biologic subtypes such as human epithelial growth factor receptor‐2 positive (HR, 3.00; 95% CI, 1.04‐8.64) and triple negative (HR, 3.92; 95% CI, 1.32‐11.59) were independent prognostic factors for shorter PFS.

CONCLUSIONS:

The authors' results demonstrated that DFI and biologic subtypes of tumor are firm, independent, prognostic factors for survival, and pulmonary metastasectomy can be a reasonable treatment option in this population. Further prospective studies are warranted to evaluate the role of pulmonary metastasectomy. Cancer 2010. © 2010 American Cancer Society.     

Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers

PURPOSE:

To evaluate the impact of low estrogen/progesterone receptor (ER/PR) expression and effect of endocrine therapy on survival outcomes in human epidermal growth factor receptor 2 (HER2)‐negative tumors with ER/PR <10%, previously labeled as triple negative.

METHODS:

In a retrospective review, 1257 patients were categorized according their ER/PR percentages into 3 groups, ER/PR <1% (group A), ER/PR 1% to 5% (group B), and ER/PR 6% to 10% (group C). Kaplan‐Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics.

RESULTS

Groups A, B, and C had 897 (71.4%), 241 (19.2%), and 119 (9.4%) patients, respectively. After a median follow‐up of 40 months there was no significant difference in 3‐year recurrence‐free survival (RFS): 64%, 67%, and 77% (P = .34) or overall survival (OS): 79%, 81%, and 88% (P = .33) for groups A, B, and C, respectively. ER/PR expression was not an independent predictor for RFS (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.86‐1.39; P = .46 for group B, and HR, 0.96; 95% CI, 0.66‐1.38; P = .81 for group C, compared with group A), or OS (HR, 1.11; 95% CI, 0.84‐1.46; P = .46 for group B, and HR, 0.94; 95% CI, 0.63‐1.42; P = .78 for group C, compared with group A). Endocrine therapy had no impact on survival outcomes (RFS: P = .10; OS: P = .45) among groups.

CONCLUSIONS:

In this cohort, a low ER/PR level (1%‐5%) does not appear to have any significant impact on survival outcomes. There was a tendency for survival advantages in the ER/PR 6% to 10% is seen. Benefit of endocrine therapy in these patients is unclear. Cancer 2011;. © 2011 American Cancer Society.     

Nodal yield and survival in oral squamous cancer: Defining the standard of care

BACKGROUND:

Elective neck dissection (END) is commonly used as a staging and therapeutic procedure for oral squamous cell carcinoma (SCC) at high risk of nodal metastases. The authors aimed to determine whether the extent of lymphadenectomy, as defined by nodal yield, is a prognostic factor in this setting.

METHODS:

A retrospective database review identified 225 patients undergoing END with curative intent for oral SCC between 1987 and 2009. Nodal yield was studied as a categorical variable for association with overall, disease‐specific, and disease‐free survival in univariate and multivariate analyses.

RESULTS:

Nodal yield <18 was associated with 5‐year overall survival of 51% compared with 74% in those with nodal yield ≥18 (P = .009). Five‐year disease‐specific survival rates were 69% in those with <18 nodes and 87% in patients with ≥18 nodes (P = .022). Similar results were obtained for disease‐free survival, with 5‐year rates of 44% with <18 nodes versus 71% with ≥18 nodes (P = .043). After adjusting for the effect of age, nodal status, T stage, and adjuvant radiotherapy on multivariate analysis, nodal yield <18 was associated with reduced overall (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1‐3.6; P = .020), disease‐specific (HR, 2.2; 95% CI, 1.1‐4.5; P = .043), and disease‐free survival (HR, 1.7; 95% CI, 1.1‐2.8; P = .040). In the pathologically lymph node‐negative subgroup (n = 148), similar results were obtained.

CONCLUSIONS:

Nodal yield is an independent prognostic factor in patients undergoing END for oral SCC. These results suggest that an adequate lymphadenectomy in this setting should include at least 18 nodes. Cancer 2011. © 2011 American Cancer Society.     

A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer

BACKGROUND:

Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5‐fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC).

METHODS:

Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first‐line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5‐fluorouracil/leucovorin (leucovorin 400 mg/m² intravenously [IV], 5‐fluorouracil 400‐mg/m² bolus, 5‐fluorouracil 2400 mg/m² IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression‐free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first‐line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events.

RESULTS:

Fifty‐eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84‐2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first‐line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86‐2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin‐related death occurred because of arrhythmia.

CONCLUSIONS:

Enzastaurin combined with bevacizumab‐based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab‐based therapy alone. Cancer 2012. © 2011 American Cancer Society.