Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas

BACKGROUND:

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.

METHODS:

Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4‐month progression‐free survival rate (PFSR). The hypothesis of the current study was that the 4‐month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).

RESULTS:

A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4‐month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty‐eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%‐18.6%) and 93.9% (95% CI, 85.8%‐100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months‐26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months‐23.0 months) and the 4‐month PFSR was 90.0%. Twenty‐one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months‐7.0 months) and the 4‐month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).

CONCLUSIONS:

Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas. Cancer 2012. © 2012 American Cancer Society.     

Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma

BACKGROUND.

Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5‐FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5‐FU provided any benefit in the treatment of patients with metastatic SBA.

METHODS.

The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression‐free survival (PFS), and overall survival (OS) were compared between patients who received 5‐FU and a platinum compound and patients who received other chemotherapy combinations.

RESULTS.

The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5‐FU and a platinum compound, 41 patients (51%) received 5‐FU without a platinum compound, and 10 patients (13%) received non‐5‐FU–based treatment. Compared with other chemotherapy regimens, treatment with 5‐FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P ≤ .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5‐FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3‐15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29‐0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37‐1.07; P = .08).

CONCLUSIONS.

To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5‐FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted. Cancer 2008. © 2008 American Cancer Society.     

The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy

BACKGROUND:

In men with metastatic castration‐resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation.

METHODS:

Eligible patients for this analysis included those with World Health Organization (WHO)‐defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated by using the Kaplan‐Meier method, and the prognostic relation of WHO‐defined radiologic response with OS was performed by using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and at 2, 3, 4, and 6 months after baseline.

RESULTS:

Four hundred twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty‐seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD, 24%) and 160 (38.8%) did not have a after‐baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. The authors found a significant association between ≥30% prostate‐specific antigen (PSA) declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD, and 34.4% with PD. Radiologic response remained a significant but modest post‐treatment prognostic factor for OS after adjusting for treatment, pain response, and ≥30% PSA decline (P = .009).

CONCLUSIONS:

In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS and appeared to complement PSA assessment. Cancer 2011. © 2011 American Cancer Society.     

Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma

BACKGROUND:

The addition of liposomal muramyl tripeptide phosphatidylethanolamine (MTP‐PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP‐PE to chemotherapy for patients with metastatic OS.

METHODS:

Intergroup‐0133 was a prospective randomized phase 3 trial for the treatment of newly diagnosed patients with OS. The authors compared 3‐drug chemotherapy with cisplatin, doxorubicin, and high‐dose methotrexate (Regimen A) to the same 3 drugs with the addition of ifosfamide (Regimen B). The addition of liposomal MTP‐PE to chemotherapy was evaluated.

RESULTS:

Five‐year event‐free survival (EFS) for patients who received liposomal MTP‐PE (n = 46) was 42% versus 26% for those who did not (n = 45) (relative risk for liposomal MTP‐PE, 0.72; P = .23; 95% confidence interval [CI], 0.42‐1.2). The 5‐year overall survival for patients who received MTP‐PE versus no MTP‐PE was 53% and 40%, respectively (relative risk for liposomal MTP‐PE, 0.72; P = 0.27; 95% CI, 0.40‐1.3). The comparison of Regimen A with Regimen B did not suggest a difference for EFS (35% vs 34%, respectively; relative risk for Regimen B, 1.07; P = .79; 95% CI, 0.62‐1.8) or overall survival (52% vs 43%, respectively; relative risk for Regimen B, 1.1, P = .75; 95% CI, 0.61‐2.0).

CONCLUSIONS:

When the metastatic cohort was considered in isolation, the addition of liposomal MTP‐PE to chemotherapy did not achieve a statistically significant improvement in outcome. However, the pattern of outcome is similar to the pattern in nonmetastatic patients. Cancer 2009. © 2009 American Cancer Society.     

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

BACKGROUND:

Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib‐treated and erlotinib‐treated patients with metastatic or recurrent NSCLC.

METHODS:

A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched‐pair case‐control study design, 171 pairs of gefitinib‐treated and erlotinib‐treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history.

RESULTS:

The median age of all patients was 58 years (range, 20‐85 years), and the median ECOG performance status was 1 (range, 0‐3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second‐line or third‐line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow‐up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66‐14.14 months), and the median progression‐free survival (PFS) was 3.2 months (95% CI, 2.65‐3.75 months). The overall response rates and disease control rates in the gefitinib‐treated and erlotinib‐treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (median, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib‐treated and erlotinib‐treated groups.

CONCLUSIONS:

This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib‐ and erlotinib‐treated patients. Cancer 2010. © 2010 American Cancer Society.     

A single‐arm,multicenter, open‐label phase 2 study of lapatinib as the second‐line treatment of patients with locally advanced or metastatic transitional cell carcinoma

BACKGROUND:

The treatment of recurrent transitional cell carcinoma (TCC) remains an unmet clinical need. This study assessed lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER‐2, as second‐line therapy in patients with locally advanced or metastatic TCC.

METHODS:

This was a single‐arm, multicenter, open‐label, prospective phase 2 study. Patients with TCC whose disease progressed on prior platinum‐based chemotherapy received lapatinib until disease progression or unacceptable toxicity, with evaluations for response by Response Evaluation Criteria In Solid Tumors criteria performed every 8 weeks. The primary endpoint of the current study was objective tumor response rate. Secondary endpoints included safety, time to disease progression, and overall survival.

RESULTS:

Fifty‐nine patients were enrolled in the study, 25 of whom (42%) could not be evaluated for response. The primary endpoint of an objective response rate (ORR) >10% was observed in 1.7% (95% confidence interval [95% CI], 0.0%‐9.1%) of patients; however, 18 (31%; 95% CI, 19%‐44%) patients achieved stable disease (SD). The median time to disease progression and overall survival (OS) were 8.6 weeks (95% CI, 8.0 weeks‐11.3 weeks) and 17.9 weeks (95% CI, 13.1 weeks‐30.3 weeks), respectively. Clinical benefit (ORR and SD) was found to be correlated with EGFR overexpression (P = .029), and, to some extent, HER‐2 overexpression. The median OS was significantly prolonged in patients with tumors that overexpressed EGFR and/or HER‐2 (P = .0001). Lapatinib was well tolerated.

CONCLUSIONS:

The study was considered to be negative because it did not meet its primary endpoint; however, further analysis demonstrated an improvement in OS in a subset of patients with tumors overexpressing EGFR and/or HER‐2, which is encouraging and warrants further investigation. Cancer 2009. © 2009 American Cancer Society.     

Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies

BACKGROUND:

Antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved.

METHODS:

A literature‐based meta‐analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression‐free survival (PFS) and overall survival (OS); the event‐based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed.

RESULTS:

Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti‐EGFR MoAb to first‐line chemotherapy increased PFS in the KRAS wild‐type population (HR, 0.91; 95% confidence interval [CI], 0.84‐0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03‐1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild‐type patients (relative risk, 1.17; 95% CI, 1.04‐1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan‐containing regimens (P = .01), and at meta‐regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit.

CONCLUSIONS:

The addition of an anti‐EGFR MoAb to first‐line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild‐type patients and translates into a small benefit in PFS. At present, irinotecan‐based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti‐EGFR MoAbs might be more suitable for patients needing tumoral shrinkage. Cancer 2011;. © 2011 American Cancer Society.     

Trends in survival for patients with metastatic soft-tissue sarcoma

BACKGROUND:

The objective of this study was to determine whether the overall survival of patients with metastatic soft tissue sarcoma (STS) has improved over the last 20 years.

METHODS:

In total, 1024 patients who had synchronous metastatic (SM) STS or metachronous metastatic (MM) STS diagnosed between 1987 and 2006 were included prospectively in the French Sarcoma Group database after central histologic review. Four periods of diagnosis of metastatic disease were defined: P1, from 1987 to 1991 (n = 208); P2, from 1992 to 1996 (n = 287); P3, from 1997 to 2001 (n = 285); and P4, from 2002 to 2006 (n = 244). Patient characteristics were analyzed as prognostic factors by using a Cox model.

RESULTS:

The proportion of patients with SM, the interval between diagnosis and MM, and the clinical characteristics of the patients were similar across the 4 periods. Although there was no significant difference in the median overall survival (OS) from P1 through P2 (P1, 12.3 months; 95% confidence interval [CI], 9.9‐14.7 months; P2, 11.4 months; 95% CI, 9‐13.9 months), significant improvements were observed in the later periods (P3, 15 months; 95% CI, 11.8‐18.2 months; P4, 18 months; 95% CI, 15.3‐20.7 months; P = .029; log‐rank test). The 2‐year OS rate also increased throughout the study period from 28.1% during P1 to 38.7% during P4. On multivariate analysis, period of diagnosis, age, histologic subtype, time to metastatic recurrence, French Federation of Cancer Centers Sarcoma Group grade, and the number of metastatic sites were independent prognostic factors for OS.

CONCLUSIONS:

The current analysis revealed that the median OS of patients with metastatic STS had improved by 50% during the last 20 years. These data should be considered in the interpretation of results from ongoing and future STS trials. Cancer 2011. © 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.     

Circulating endothelial progenitors and CXCR4-positive circulating endothelial cells are predictive markers for bevacizumab

BACKGROUND:

Bevacizumab plus chemotherapy is a standard option in the treatment of metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential of circulating endothelial cell progenitors (CEPs) and phenotypical circulating endothelial cells (CECs) as surrogate markers of clinical outcome in mCRC patients to identify responders to bevacizumab in combination with chemotherapy.

METHODS:

A total of 69 patients with measurable mCRC were enrolled in this prospective study. Whole blood samples were analyzed before initiation of treatment and on days 4 and 14. Phenotypical CECs and CEPs were then isolated and enumerated by using flow cytometry.

RESULTS:

CEP levels of less than 0.04% on day 4 were significantly associated with longer progression‐free survival (PFS) and overall survival (OS) (P < .001, P = .002, respectively) as compared with levels of 0.04% or more. In addition, CXCR4‐positive CEC levels of less than 20% at baseline were significantly associated with longer PFS and OS as compared other indicators investigated (P < .001, P = .002, respectively).

CONCLUSIONS:

Levels of CEPs on day 4 and proportion of CXCR4‐positive CECs at baseline were correlated with the prognosis of bevacizumab combination chemotherapy, suggesting that these surrogate markers may play a core role in the selection of candidates for bevacizumab treatment. Cancer 2011;. © 2011 American Cancer Society.     

Stage migration and increasing proportion of favorable‐prognosis metastatic renal cell carcinoma patients

BACKGROUND:

The Memorial Sloan‐Kettering Cancer Center risk model classifies patients with metastatic renal cell carcinoma (RCC) by 5 pretreatment features as favorable, intermediate, and poor risk. The number of Memorial Sloan‐Kettering Cancer Center patients in each risk group was examined by year of treatment to analyze stage migration.

METHODS:

The distribution of risk groups was examined retrospectively in 789 Memorial Sloan‐Kettering Cancer Center patients with metastatic RCC treated in a first‐line therapy clinical trial from 1975 to 2007. Date of treatment onset was divided into 6 cohorts between 1975 and 2007 (1975‐1980, 1981‐1985, 1986‐1990, 1991‐1995, 1996‐2001, and 2001‐2007).

RESULTS:

The median age of the first‐line metastatic RCC clinical trial patients was 59 years (range, 20‐82 years). Most patients received cytokine therapy (55%), 37% received chemotherapy/other, and 8% received vascular endothelial growth factor‐targeted therapies. Overall survival increased with each consecutive cohort year group (P < .001). Median survival was 0.43 years (95% confidence interval [CI], 0.27‐0.68) in the 1973‐1980 cohort and 1.5 years in the 2001‐2007 cohort (95% CI, 1.15‐2.11). Memorial Sloan‐Kettering Cancer Center risk‐group distribution shifted between 1975 and 2007 (P < .0001). The poor‐risk group proportion became smaller (from 44% in 1975‐1980 to 13% in 2001‐2007), whereas the favorable‐risk group increased (from 0% in 1975‐1980 to 49% in 2001‐2007). The intermediate‐risk group remained stable at 50%. After adjusting for type of therapy, the shifts continue to be significant (P < .0001).

CONCLUSIONS:

The risk‐group distribution for metastatic RCC patients in clinical trials shifted from 1975 to 2007. These shifts have direct implications for data analysis, interpretation of metastatic RCC trends, and drug development. Cancer 2010. © 2010 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.     

Outcome for adolescent and young adult patients with osteosarcoma: A report from the Children's Oncology Group

BACKGROUND:

There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials.

METHODS:

Patients with high‐grade osteosarcoma of any site enrolled on North American cooperative group trials CCG‐7943, POG‐9754, INT‐0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event‐free survival (EFS).

RESULTS:

A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10‐year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049).

CONCLUSIONS:

In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation. Cancer 2012. © 2012 American Cancer Society.     

Noninvasive imaging with thallium‐201 scintigraphy may not correlate with survival in patients with osteosarcoma

BACKGROUND:

Histologic response to preoperative chemotherapy is a strong prognostic factor for osteosarcoma (OS). Thallium‐201 (Tl‐201) scintigraphic response to initial chemotherapy has previously been described as a predictor of histologic response. In the current study, the authors re‐examined a series of patients studied using Tl‐201 scintigraphy to determine the correlation between changes observed on Tl‐201 scintigraphy and event‐free survival (EFS).

METHODS:

A total of 22 patients with biopsy‐proven OS of the extremity underwent Tl‐201 imaging before and immediately after preoperative chemotherapy. The maximum pixel counts taken over the tumor divided by those taken of a background region yielded a tumor‐to‐background ratio (TBR). The percentage of change in the TBR before and after adjuvant chemotherapy, defined as the alteration ratio (AR), was correlated with EFS.

RESULTS:

The median AR was 85% (range, 28‐100%). The 3‐year EFS was 0.72 (95% confidence interval [95% CI], 0.48‐0.86) and the 5‐year EFS was 0.67 (95% CI, 0.43‐0.86). There was no association between AR and EFS detected in this cohort (hazard ratio, 0.99; 95% CI, 0.95‐1.02 [Somers rank correlation coefficient, 0.15]).

CONCLUSIONS:

Although Tl‐201 scintigraphy was used as a tool for the assessment of response to chemotherapy in patients with OS, the AR did not appear to be predictive of EFS in this small group of patients. It is necessary to use the outcome variables of ultimate interest–EFS and overall survival– and not rely on surrogates for outcome to evaluate potential prognostic factors. 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.     

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas

BACKGROUND:

Data regarding the role of anthracyclines and taxanes as first‐line treatments of metastatic angiosarcoma are limited.

METHODS:

Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.

RESULTS:

Seventy‐five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single‐agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression‐free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9‐6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4‐10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.

CONCLUSIONS:

First‐line single‐agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS. Cancer 2011. © 2011 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.     

A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C)

BACKGROUND:

The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI‐779), a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS).

METHODS:

Patients ≥18 years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant chemotherapy allowed), adequate organ function, and performance status of ≤2 were eligible. After premedication with an antihistamine, CCI‐779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors.

RESULTS:

Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40 patients are evaluable for response and adverse events. The median age was 62 years (range, 28‐72 years) with 56% women. Eighty percent had high‐grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%; 95% confidence interval [CI], 1‐17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a confirmed partial response lasting 3 and 17 months, respectively. Thirty‐nine (95%) patients have progressed, with a median time to progression of 2.0 months (95% CI, 1.8‐3.5). The median overall survival was 7.6 months (95% CI, 6.1‐15.9). Forty‐three percent experienced grade 3+ adverse events that were possibly related to therapy.

CONCLUSIONS:

Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxicities. Cancer 2011. © 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.     

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.