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.     

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.     

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.     

Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer

BACKGROUND:

The role of the interaction between tumor cells and inflammatory cells in nonsmall cell lung carcinoma (NSCLC) is unclear. In this study, the authors assessed the prognostic impact of intratumoral cluster of differentiation 66b (carcinoembryonic antigen‐related cell adhesion molecule 8 [CD66b])‐positive neutrophils and of the intratumoral CD66b‐positive neutrophil‐to‐cluster of differentiation 8 (cell surface antigen T8 [CD8])‐positive lymphocytes (the CD66b‐positive neutrophil‐to‐CD8‐positive lymphocyte ratio [iNTR]) in patients with resectable NSCLC.

METHODS:

Expression levels of CD66b and CD8 were evaluated by immunohistochemistry on tissue microarrays consisting of 632 NSCLC specimens from patients who underwent curative surgery. The relation between clinicopathologic variables and patient outcome was assessed.

RESULTS:

Intratumoral CD66b‐positive neutrophils were elevated in 318 patients (50%). In univariate analysis, an increase in CD66b‐positive cells was associated with a high cumulative incidence of relapse (CIR) (median CIR, 51 months for low CD66b‐positive cell density; 36 months for high CD66b‐positive cell density; P = .002) and trended toward worse overall survival (OS) (median OS, 57 months for low CD66b‐positive cell density; 54 months for high CD66b‐positive cell density; P = .088). The iNTR was elevated in 190 patients (30%). An increased iNTR was strongly associated with both a high CIR (median CIR: 43 months for an iNTR ≤1; 34 months for an iNTR >1; P < .0001) and poor OS (median OS: 60 months for an iNTR ≤1; 46 months for an iNTR >1; P < .0001). In multivariate analysis, independent prognostic factors for a higher CIR were high iNTR (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.56‐0.90; P = .005) and tumor stage >I, (HR, 0.39; 95% CI, 0.30‐0.52; P < .0001). Independent prognostic factors for worse OS were a high iNTR (HR, 0.70; 95% CI, 0.54‐0.91; P = .007) and tumor stage >I (HR, 0.35; 95% CI, 0.26‐0.47; P < .0001).

CONCLUSIONS:

The current results indicated that the iNTR is a novel, independent prognostic factor for a high rate of disease recurrence and poor OS in patients with resectable NSCLC. Cancer 2011;. © 2011 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.     

Improved survival in patients with early stage low‐grade follicular lymphoma treated with radiation

BACKGROUND:

External beam radiation therapy (RT) is the standard treatment for stage I‐II, grade 1‐2 follicular lymphoma. Because of an indolent natural history, some advocate alternative management strategies, including watchful waiting for this disease. The relative improvement in outcomes for patients treated with and without RT has never been tested in randomized trials.

METHODS:

The Surveillance, Epidemiology, and End Results database was queried for adult patients with stage I‐II, grade 1‐2 follicular lymphoma diagnosed from 1973 to 2004. Retrievable patient data included age, sex, race, stage, extranodal disease, and treatment with RT within the first year after diagnosis. Actuarial overall survival (OS) and disease‐specific survival (DSS) were analyzed.

RESULTS:

A total of 6568 patients were identified. DSS at 5, 10, 15, and 20 years in the RT group was 90%, 79%, 68%, and 63% versus 81%, 66%, 57%, and 51% in the no RT group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.55‐0.68; P < .0001). OS at 5, 10, 15, and 20 years in the RT group was 81%, 62%, 45%, and 35% versus 71%, 48%, 34%, and 23% in patients not receiving RT (HR, 0.68; 95% CI, 0.63‐0.73; P < .0001). On multivariate analysis, upfront RT remained independently associated with improved DSS (P < .0001, Cox HR, 0.65; 95% CI, 0.57‐0.72) and OS (P < .0001; Cox HR, 0.73; 95% CI, 0.67‐0.79). Lymphoma was the most common cause of death (52%). Only 34% of patients received upfront RT.

CONCLUSIONS:

Upfront RT was associated with improved DSS and OS compared with alternate management approaches, a benefit that persisted over time. This benefit suggests that watchful waiting with administration of salvage therapies on progression/relapse do not compensate for inadequate initial definitive treatment. Although it is the standard of care for this disease, RT for early stage low‐grade follicular lymphoma is greatly underused in the US population; increased use of upfront RT could prevent thousands of deaths from lymphoma in these patients. Cancer 2010. © 2010 American Cancer Society.     

Interval to biochemical failure as a biomarker for cause-specific and overall survival after dose-escalated external beam radiation therapy for prostate cancer

BACKGROUND:

After external beam radiation therapy (EBRT) for prostate cancer, a short interval to biochemical failure of <18 months has been proposed as a surrogate for cause‐specific survival. Because EBRT dose influences biochemical failure, the authors investigated the interval to biochemical failure in a cohort of patients treated with dose‐escalated EBRT.

METHODS:

From 1998 to 2008, 710 patients were treated with EBRT (≥75 grays) ± androgen deprivation therapy (ADT) at the University of Michigan. Biochemical failure was defined using the Phoenix consensus definition (nadir + 2 ng/mL). A short interval to biochemical failure was defined as <18 months after completing radiotherapy and/or ADT. The associations between biochemical failure, the interval to biochemical failure, and clinical factors with cause‐specific survival (CSS) and overall survival (OS) were evaluated.

RESULTS:

There were 149 biochemical failures (21%), and short interval to biochemical failure accounted for 14% and 40% of biochemical failures in those with intermediate‐risk or high‐risk disease, respectively. Biochemical failure impacted CSS (P < .0001) but not OS (P = .36). However, a short interval to biochemical failure predicted decreased CSS (P < .0001; hazard ratio [HR], 5.6; 95% confidence interval [CI], 2.4‐13.0) and OS (P < .0001; HR, 4.8; 95% CI, 2.3‐10.3) when compared with a long interval to biochemical failure. The 8‐year OS was 78% without biochemical failure, compared with 87% with a long interval to biochemical failure (P = .1; HR, 0.7; 95% CI, 0.4‐1.1) and 38% with a short interval to biochemical failure (P < .0001; HR, 3.7; 95% CI, 2.3‐5.9). On multivariate analysis, a short interval to biochemical failure increased the risk of prostate cancer death (P < .0001; HR, 18.1; 95% CI, 8.4‐39) and all cause mortality (P = .0027; HR, 1.5; 95% CI, 1.2‐2.1), whereas a long interval to biochemical failure did not.

CONCLUSIONS:

The relation between the interval to biochemical failure, CSS, and OS was independently validated in patients treated with dose‐escalated EBRT. Further evaluation of the interval to biochemical failure as a surrogate endpoint is warranted. Cancer 2012. © 2011 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.     

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.     

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: Final results of a randomized, double-blind, placebo-controlled, phase 3 study

BACKGROUND:

Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum‐based chemotherapy is often a first‐line treatment. Pemetrexed has shown single‐agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed‐cisplatin for SCCHN.

METHODS:

In a double‐blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²; n = 398) or placebo plus cisplatin (75 mg/m²; n = 397) to assess overall survival (OS) and secondary endpoints.

RESULTS:

Median OS was 7.3 months in the pemetrexed‐cisplatin arm and 6.3 months in the placebo‐cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75‐1.02; P = .082). Median progression‐free survival (PFS, months) was similar in both treatment arms (pemetrexed‐cisplatin, 3.6; placebo‐cisplatin, 2.8; HR, 0.88; 95% CI, 0.76‐1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed‐cisplatin (n = 347) led to longer OS and PFS than placebo‐cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed‐cisplatin (n = 86) resulted in longer OS and PFS than placebo‐cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed‐cisplatin toxicity was consistent with studies in other tumors.

CONCLUSIONS:

Pemetrexed‐cisplatin compared with placebo‐cisplatin did not significantly improve survival for the intent‐to‐treat population. However, in a prespecified subgroup analysis, pemetrexed‐cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. © 2012 American Cancer Society.     

Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma

BACKGROUND:

Low‐grade serous carcinoma (LGSC) of the ovary is a rare tumor that is distinct from its high‐grade counterpart. The objective of this study was to determine whether patient demographic factors and clinical treatment histories affected survival in a population of women with LGSC.

METHODS:

A review of patients who had pathologically confirmed LGSC of the ovary diagnosed between 1977 and 2009 was performed. Abstracted data included medical and social histories, anthropometric measurements, and details about diagnosis, treatment, and follow‐up. Statistical analyses included Fisher exact tests, Cox proportional hazards models, and the Kaplan‐Meier method.

RESULTS:

The study sample included 194 patients who had a median follow‐up of 60.9 months (range, 1‐383 months). In multivariate analyses, smoking had a negative association with both overall survival (OS) (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03‐2.92; P = .04) and progression‐free survival (PFS) (HR, 1.72; 95% CI, 1.00‐2.96; P = .05). The median OS was shorter in current smokers than in former/never smokers (48.0 months vs 79.9 months; P = .002). PFS also was predicted by year of diagnosis >1994 (HR, 1.74; P = .01). Although the difference was not statistically significant, hormone consolidation appeared to be associated with better OS (HR, 0.15; P = .06) and better PFS (HR, 0.44; P = .07). A smaller proportion of the patients who received hormone consolidation experienced disease recurrence compared with the patients who did not receive hormone consolidation (66.7% vs 87.6%; P = .07).

CONCLUSIONS:

Smoking was associated negatively with survival outcomes in women with LGSC of the ovary, whereas consolidation treatment with hormone antagonists demonstrated a protective associative trend with survival. Both lifestyle modification and innovative treatment plans should be considered in this group of patients. Cancer 2011. © 2011 American Cancer Society.     

Pathologic complete response in breast cancer patients receiving anthracycline‐ and taxane‐based neoadjuvant chemotherapy

BACKGROUND:

The current study was conducted to evaluate the influence of race/ethnicity and tumor subtype in pathologic complete response (pCR) following treatment with neoadjuvant chemotherapy.

METHODS:

A total of 2074 patients diagnosed with breast cancer between 1994 and 2008 who were treated with neoadjuvant anthracycline‐ and taxane‐based chemotherapy were included. pCR was defined as no residual invasive cancer in the breast and axilla. The Kaplan‐Meier product‐limit was used to calculate survival outcomes. Cox proportional hazards models were fitted to determine the relationship of patient and tumor variables with outcome.

RESULTS:

The median patient age was 50 years; 14.6% of patients were black, were 15.2% Hispanic, 64.3% were white, and 5.9% were of other race. There were no differences in pCR rates among race/ethnicity (12.3% in black, 14.2% in Hispanics, 12.3% in whites, and 11.5% in others, P = .788). Lack of pCR, breast cancer subtype, grade 3 tumors, and lymphovascular invasion were associated with worse recurrence‐free survival (RFS) and overall survival (OS) (P ≤ .0001). Differences in RFS by race/ethnicity were noted in the patients with hormone receptor‐positive disease (P = .007). On multivariate analysis, Hispanics had improved RFS (hazard ratio [HR], 0.69; 95% confidence interval [95% CI], 0.49‐0.97) and OS (HR, 0.63; 95% CI, 0.41‐0.97); blacks had a trend toward worse outcomes (RFS: HR, 1.28 [95% CI, 0.97‐1.68] and OS: HR, 1.32 [95% CI, 0.97‐1.81]) when compared with whites.

CONCLUSIONS:

In this cohort of patients, race/ethnicity was not found to be significantly associated with pCR rates. On a multivariate analysis, improved outcomes were observed in Hispanics and a trend toward worse outcomes in black patients, when compared with white patients. Further research was needed to explore the potential differences in biology and outcomes. Cancer 2010. © 2010 American Cancer Society.     

Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer

BACKGROUND:

Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow‐up.

METHODS:

Seventy consecutive patients with unresectable (n = 46) or borderline resectable (n = 24) locally advanced pancreatic cancer were treated with CRT from 2005 to 2009. Patients typically received 50.4 grays in 28 fractions (91%) with concurrent 5‐fluorouracil (84%) or capecitabine (14%). Forty patients received CRT alone, and 30 patients received neoadjuvant chemotherapy before CRT for a median of 4 months, typically gemcitabine (93%). All patients without progression after neoadjuvant chemotherapy were offered CRT.

RESULTS:

Median follow‐up was 14.2 months (range, 3‐57 months). Fifty‐three percent of patients in the CRT group versus 83% in the neoadjuvant chemotherapy before CRT group had unresectable tumors at diagnosis; after completion of CRT, 20% of patients in both groups underwent resection. Compared with CRT alone, the neoadjuvant chemotherapy before CRT group demonstrated improved median overall survival (OS; 18.7 vs 12.4 months; P = .02) and progression‐free survival (11.4 vs 6.7 months; P = .02). On multivariate analysis, receipt of neoadjuvant chemotherapy (adjusted hazard ratio [HR], 0.49; 95% CI, 0.28‐0.87; P = .02) and surgical resection (adjusted HR, 0.38; 95% CI, 0.17‐0.85; P = .02) were associated with increased OS.

CONCLUSIONS:

Gemcitabine‐based neoadjuvant chemotherapy confers a significant OS advantage by allowing the selection of patients who will derive greatest benefit from CRT. Median survival with this approach was similar to that seen with surgical resection. Cancer 2012;118: 3026–35. © 2011 American Cancer Society.     

Impact of residual normal metaphases in core binding factor acute myeloid leukemia

BACKGROUND:

Karyotype allows for stratification of outcomes in acute myeloid leukemia (AML) patients. Previous data suggested that the presence of residual normal cells improved the prognosis in patients with monosomy 7. The Southwest Oncology Group (SWOG) reported the impact of residual normal metaphases in AML patients with monosomal karyotype (MK) and found a similar relationship. We determined the influence of residual normal metaphases in patients with core binding factor (CBF) AML.

METHODS:

The presence and total number of normal and abnormal metaphases were tallied for patients with CBF AML treated in 10 consecutive SWOG trials and used as a variable to determine the effect on complete remission, refractory disease, and overall survival (OS) rates.

RESULTS:

Among 113 CBF AML patients, median age of diagnosis was 45 years (range, 18‐77 years), and median OS was 4 years (CI—2 years—not reached). Patients with inv(16) and no normal metaphases had improved OS compared with those with 1+ normal metaphases (P = .00005), whereas no difference was noted for patients with t(8;21). Multivariate analysis demonstrated that having cells with a normal karyotype had a negative impact on survival (HR, 2.11; 95% CI, 1.09‐4.08; P = .026). This shorter survival was a consequence of a higher rate of refractory disease in older patients (OR, 1.03; 95% CI, 0.9998‐1.06; P = .05) and in those with normal metaphases (HR, 1.26 95% CI, 1.04‐1.51; P = .02).

CONCLUSIONS:

In patients with CBF AML, the presence of cells with normal metaphases and increasing age negatively affect the prognosis, especially in patients with inv(16). Cancer 2012;. © 2011 American Cancer Society.     

Survival after second primary lung cancer: a population-based study of 187 Hodgkin lymphoma patients

BACKGROUND:

Lung cancer accounts for the largest absolute risk of second malignancies among Hodgkin lymphoma (HL) survivors. However, no population‐based studies have compared overall survival (OS) between HL survivors who developed nonsmall cell lung cancer (HL‐NSCLC) versus patients with first primary NSCLC (NSCLC‐1).

METHODS:

The authors compared the OS of 178,431 patients who had NSCLC‐1 and 187 patients who had HL‐NSCLC (among 22,648 HL survivors), accounting for sex, race, sociodemographic status, calendar year, and age at NSCLC diagnosis, and NSCLC histology and stage. All patients were reported to the population‐based Surveillance, Epidemiology, and End Results Program. Hazard ratios (HRs) were derived from a Cox proportional hazards model.

RESULTS:

Although the NSCLC stage distribution was similar in both groups (20% localized, 30% regional, and 50% distant), HL survivors experienced significantly inferior stage‐specific OS. For patients with localized, regional, and distant stage NSCLC, the HRs (95% confidence interval [CI]) for death among HL survivors were 1.60 (95% CI, 1.08‐2.37; P < .0001), 1.67 (95% CI, 1.26‐2.22; P = .0004), and 1.31 (95% CI, 1.06‐1.61; P = .013), respectively. Among HL‐NSCLC patients, significant associations were observed between more advanced NSCLC stage and the following variables: younger age at HL diagnosis (P = .003), younger age at NSCLC diagnosis (P = .048), and longer latency between HL and NSCLC diagnoses (P = .015).

CONCLUSIONS:

Compared with patients who had de novo NSCLC, HL survivors experienced a significant 30% to 60% decrease in OS after an NSCLC diagnosis. Further research is needed to not only elucidate the clinical‐biologic underpinnings of NSCLC after HL, including the influence of previous HL treatment, but also to define the role of lung cancer screening in selected patients. Cancer 2011;. © 2011 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.     

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.     

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.     

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.     

Upfront,randomized, phase 2 trial of sorafenib versus sorafenib and low‐dose interferon alfa in patients with advanced renal cell carcinoma

BACKGROUND:

The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low‐dose interferon‐alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC).

METHODS:

Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression‐free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers.

RESULTS:

Eighty patients were enrolled. The median follow‐up was 19.7 months (range, 0‐34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%‐46.5%) in the sorafenib arm and 25% (95% CI, 12.7%‐41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib‐alone arm (95% CI, 5.52‐9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19‐11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00‐1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02‐1.29; P = .0173).

CONCLUSIONS:

The addition of low‐dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required. Cancer 2010. © 2010 American Cancer Society.