Self‐administered,subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia

BACKGROUND:

Alemtuzumab is highly effective at treating chronic lymphocytic leukemia (CLL) in bone marrow, which is the usual site of residual disease after fludarabine‐based treatment. Eliminating residual disease potentially is associated with longer remission and overall survival. The authors of this report evaluated the ability of subcutaneous alemtuzumab to treat residual disease.

METHODS:

Patients in partial remission (PR), nodular PR (nPR), or complete remission (CR) who had disease in bone marrow established by 2‐color flow cytometry analysis were enrolled and received alemtuzumab 30 mg subcutaneously 3 times weekly for 4 weeks, and patients had the option to self‐administer alemtuzumab. Responders were patients in PR who converted to an nPR or a CR, patients in nPR who converted to a CR, and patients in CR who had no evidence of disease on 2‐color flow cytometry analysis after treatment.

RESULTS:

There were 31 patients enrolled, of whom 29 were evaluable, and there were 23 responders (4 of 4 patients who achieved a CR, 8 of 9 patients who achieved an nPR, and 11 of 16 patients who achieved a PR. Nonresponders had significantly lower plasma alemtuzumab levels at the end of treatment. Furthermore, higher plasma alemtuzumab levels at the end of treatment were correlated with a longer response duration. Compared with the results from an historic group that received intravenous alemtuzumab for residual disease, there was a trend toward a higher response rate but a shorter response duration with subcutaneous alemtuzumab.

CONCLUSIONS:

The current results demonstrated that self‐administered, subcutaneous alemtuzumab was safe and active for residual disease and that plasma alemtuzumab levels and real‐time minimal residual disease evaluation are important endpoints to monitor in future alemtuzumab consolidation trials. Cancer 2011. © 2010 American Cancer Society.     

Gemcitabine and docetaxel in metastatic, castrate-resistant prostate cancer: results from a phase 2 trial

BACKGROUND:

Docetaxel is the standard of care for patients with metastatic, castrate‐resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy‐naive, metastatic CRPC.

METHODS:

Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m²) Days 1 and 8 and docetaxel (75 mg/m²) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate‐specific antigen (PSA) response was defined as a decline ≥50% in baseline PSA level.

RESULTS:

Thirty‐five patients with chemotherapy‐naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST‐defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment‐related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed.

CONCLUSIONS:

The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single‐agent docetaxel. In contrast to single‐agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve. Cancer 2011. © 2010 American Cancer Society.     

Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience

BACKGROUND:

The objective of this study was to evaluate the clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic paragangliomas by assessing reductions in tumor size and blood pressure and improvements in overall survival (OS).

METHODS:

The authors retrospectively reviewed the medical records of patients with metastatic pheochromocytomas‐sympathetic paragangliomas who had received chemotherapy at The University of Texas MD Anderson Cancer Center.

RESULTS:

Clinical benefit and OS were assessed. Of 54 patients who received chemotherapy, 52 patients were evaluable for response. Seventeen patients (33%) experienced a response, which was defined as decreased or normalized blood pressure/decreased number and dosage of antihypertensive medications and/or reduced tumor size after the first chemotherapy regimen. The median OS was 6.4 years (95% confidence interval [CI], 5.2‐16.4 years) for responders and 3.7 years (95% CI, 3.0‐7.5 years) for nonresponders. Among the patients who had synchronous metastatic disease, a positive response at 1 year after the start of chemotherapy was associated with a trend toward longer OS (log‐rank test; P = .095). In a multivariate Cox proportional hazards model, the effect of response to chemotherapy on OS was significant (hazard ratio, 0.22; 95% CI, interval: 0.05‐1.0; P = .05). All responders had received dacarbazine and cyclophosphamide. Vincristine was included for 14 responders, and doxorubicin was included for 12 responders. The clinical factors that predicted response to chemotherapy could not be identified.

CONCLUSIONS:

The current results indicted that chemotherapy may decrease tumor size and facilitate blood pressure control in approximately 33% of patients with metastatic pheochromocytoma‐sympathetic paraganglioma. These patients exhibited longer survival. Cancer 2011. © 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.     

Phase 2 trial of sorafenib in patients with advanced urothelial cancer

BACKGROUND:

There is no effective second‐line systemic chemotherapy for patients with disease progression after cisplatin‐based chemotherapy. A phase 2 trial of sorafenib was performed to determine the activity and toxicity of this agent in a multi‐institutional setting in patients previously treated with 1 prior chemotherapy regimen.

METHODS:

Twenty‐seven patients with advanced urothelial carcinoma were treated with sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity.

RESULTS:

There were no objective responses observed. The 4‐month progression‐free survival (PFS) rate was 9.5%; median overall survival of the group was 6.8 months. There were no therapy‐related deaths, and common grade 3 toxicities included fatigue and hand‐foot syndrome.

CONCLUSIONS:

Although sorafenib as a single agent has minimal activity in patients with advanced urothelial cancer in the second‐line setting, further investigation of tyrosine kinase inhibitors using different trial designs with PFS endpoints is warranted. Cancer 2009. © 2009 American Cancer Society.     

The role of technetium‐99m methoxyisobutyl isonitrile scintigraphy in predicting the therapeutic effect of chemotherapy against nasopharyngeal carcinoma

BACKGROUND:

The authors prospectively evaluated the correlation between technetium‐99m methoxyisobutyl isonitrile (^99mTc‐MIBI) accumulation in tumors and response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC).

METHODS:

Eighty‐six patients with locally advanced NPC underwent single‐photon emission computed tomography 15 minutes after an intravenous injection of 740 megabecquerels (20 mCi) ^99mTc‐MIBI before chemotherapy. The tumor uptake ratio (TUR) was calculated. Two weeks after the second cycle of combined chemotherapy with 5‐fluorouracil (5‐FU) and cisplatin (DDP), the tumor response rate was evaluated. The correlation between ^99mTc‐MIBI accumulation in tumors and response to chemotherapy with 5‐FU/DDP was examined.

RESULTS:

Positive accumulation of ^99mTc‐MIBI in tumors was observed in 76 patients (88.4%). The tumor response was a complete response (CR) in 8 patients, a partial response (PR) in 68 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. The response rate (CR and PR) to 5‐FU/DDP chemotherapy in patients who had positive ^99mTc‐MIBI accumulation (tumor uptake ratio [TUR] >1.1) was higher than that in patients who had negative ^99mTc‐MIBI accumulation (TUR ≤1.1; 98.7% vs 10%; P < .001).

CONCLUSIONS:

Patients with negative ^99mTc‐MIBI accumulation were resistant to 5‐FU/DDP chemotherapy. ^99mTc‐MIBI imaging in patients with NPC was capable of predicting tumor response to chemotherapy with 5‐FU/DDP and can help in the selection of patients for induction chemotherapy. Cancer 2011. © 2010 American Cancer Society.     

Docetaxel and irinotecan in recurrent or metastatic head and neck cancer

BACKGROUND:

Docetaxel and irinotecan have single‐agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN.

METHODS:

Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m² and irinotecan 60 mg/m², intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase‐2 and VEGF in baseline tumor tissue.

RESULTS:

Fifty‐two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel‐exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression‐free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085).

CONCLUSIONS:

Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum‐based regimens. Cancer 2009. © 2009 American Cancer Society.     

Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive non‐Hodgkin lymphoma

BACKGROUND:

Marqibo, a sphingosomal/cholesterol encapsulation of vincristine sulfate has targeted, increased, and sustained delivery of vincristine to tumor tissues. A phase 2, open‐label, single‐arm, and multinational study evaluated the efficacy and tolerability of Marqibo as a single agent in patients with multiply relapsed or refractory aggressive non‐Hodgkin lymphoma (NHL).

METHODS:

Eligible patients had relapsed or refractory de novo or transformed aggressive NHL and prior treatment with at least 2 multiagent chemotherapy regimens. Marqibo was administered at 2 mg/m², every 2 weeks, for a maximum of 12 cycles or until toxicity or disease progression.

RESULTS:

One hundred and nineteen patients were enrolled and treated on trial. Ninety‐six had histological confirmed de novo (N = 89) or transformed (N = 7) aggressive NHL. Median number of cycles was 4 (median dose/cycle 4 mg). Overall response (CR and complete response unconfirmed and PR) was 25% (95% confidence interval [CI], 17, 35), CR and complete response unconfirmed confirmed by external reviewers was 5%. Median overall survival was 6.6 months (Kaplan‐Meier estimate, 95% CI, 4.7, 9.8). Grade 3 of 4 neurotoxicity occurred in 32% of patients. All patients had prior neurotoxic agents, and 85% had baseline residual neuropathy symptoms (grades 1‐2) from prior treatment.

CONCLUSIONS:

Marqibo is an active agent in patients with heavily pretreated aggressive NHL, and tolerated at approximately twice the dose intensity of standard vincristine. Its activity supports further investigation as a substitution for vincristine in combination treatment of lymphoid disorders. Cancer 2009. © 2009 American Cancer Society.     

Phase 2 trial of mifepristone (RU‐486) in advanced or recurrent endometrioid adenocarcinoma or low‐grade endometrial stromal sarcoma

BACKGROUND:

The objective of this study was to determine the efficacy of mifepristone (RU‐486) in women with advanced or recurrent endometrioid adenocarcinoma or low‐grade endometrial stromal sarcoma (LGESS).

METHODS:

Mifepristone (RU‐486; 200 mg orally) was given daily to patients with progesterone receptor‐positive advanced or recurrent endometrioid adenocarcinoma or LGESS. Patients were evaluated every 4 weeks for toxicity and response. Quality‐of‐life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy.

RESULTS:

Twelve of 13 enrolled patients were evaluable in the first phase of accrual. Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and ≥77 weeks, respectively), and the median time to disease progression was 48 days. Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS. No partial or complete responses were observed. The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50%, 50%, and 58% of patients, respectively. The most common grade 3 toxicities were fatigue and dyspnea observed in 25% and 17% of patients, respectively. One patient experienced grade 4 dyspnea. Thirty‐three percent of patients had asymptomatic elevations of corticotropin. No serious treatment‐related adverse events occurred. There were no significant changes in quality of life.

CONCLUSIONS:

Single‐agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25%. One patient who had a biopsy‐positive disease recurrence remained stable at 77 weeks. Although mifepristone was tolerated well, as a single agent, it provided limited response as a single agent in women with progesterone receptor‐positive uterine tumors. Recently, was been recognized that biologic agents used as single agents may result only in stable disease unless they are combined with cytotoxic agents. The authors concluded that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed. Cancer 2009. © 2009 American Cancer Society.     

A phase 2 study of epothilone B analog BMS‐247550 (NSC 710428) in patients with relapsed aggressive non‐Hodgkin lymphomas

BACKGROUND:

The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS‐247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early‐phase clinical activity in drug‐resistant malignancies.

METHODS:

This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m² given intravenously weekly on days 1, 8, and 15 of a 28‐day cycle.

RESULTS:

Fifty‐one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B‐cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one‐quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months.

CONCLUSIONS:

Ixabepilone was well‐tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single‐agent activity in patients with recurrent chemosensitive aggressive lymphomas. Cancer 2013. © 2013 American Cancer Society.     

Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy

BACKGROUND:

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first‐line palliative chemotherapy. There are, however, no published studies concerning second‐line treatment of the disease. Temozolomide has shown clinical effect in well‐differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first‐line treatment.

METHODS:

Twenty‐five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.

RESULTS:

One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression‐free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.

CONCLUSIONS:

Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first‐line chemotherapy. These results indicated that temozolomide may be used as second‐line treatment in PDEC. Cancer 2011;. © 2011 American Cancer Society.     

Hypofractionated stereotactic radiotherapy for the treatment of brain metastases

BACKGROUND:

This retrospective review evaluated the efficacy and toxicity profiles of various dose fractionations using hypofractionated stereotactic radiotherapy (HSRT) in the treatment of brain metastases.

METHODS:

Between 2004 and 2007, 36 patients with 66 brain metastases were treated with HSRT. Nine of these subjects were excluded because of the absence of post‐treatment magnetic resonance imaging scans, resulting in 27 patients with a total of 52 lesions. Of these 52 lesions, 45 lesions were treated with whole‐brain radiotherapy plus a HSRT boost and 7 lesions were treated with HSRT as the primary treatment. The median prescribed dose was 25 grays (Gy) (range, 20 Gy‐36 Gy) with a median of 5 fractions (range, 4 fractions‐6 fractions) to a median 85% isodose line (range, 50%‐100%). The median follow‐up interval was 6.6 months (range, 0.9 months‐26.8 months).

RESULTS:

The median overall survival time was 10.8 months, and 66.7% of patients died of disease progression. After HSRT treatment of 52 brain lesions, 13 lesions demonstrated complete responses, 12 lesions demonstrated partial responses, 22 lesions demonstrated stable disease, and 5 lesions demonstrated progressive disease. Actuarial local tumor control rates at 6 months and 1 year were 93.9% and 68.2%, respectively. Maximum tumor dimension, concurrent chemotherapy, and a tumor volume <1 cc were found to be statistically significant factors for local tumor control. One patient had a grade 3 toxicity (according to National Cancer Institute Common Terminology Criteria for Adverse Events).

CONCLUSIONS:

HSRT provides a high level of tumor control with minimal toxicity comparable to single‐fraction stereotactic radiosurgery (SRS). The results of the current study warrant a prospective randomized study comparing single‐fraction SRS with HSRT in this patient population. Cancer 2009. © 2009 American Cancer Society.     

Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study

BACKGROUND:

Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. First‐line platinum‐based chemotherapy is active in patients with advanced SBA, but data regarding second‐line chemotherapy are lacking. The aim of this study was to evaluate the efficacy and tolerability of fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) as second‐line chemotherapy in patients with advanced SBA.

METHODS:

We analyzed all consecutive patients who received second‐line chemotherapy with FOLFIRI among 93 patients with advanced SBA included from 1996 to 2008 in a previous retrospective multicenter study. Progression‐free survival (PFS) and overall survival (OS) were estimated from the start of second‐line chemotherapy using the Kaplan‐Meier method. Cox models were applied for multivariate analyses.

RESULTS:

Among 51 patients who received second‐line chemotherapy, 28 patients (male, 57%; median age, 54 years; metastatic disease, 96%) were treated with FOLFIRI after progression (n = 24) or limiting toxicity (n = 4) to first‐line FOLFOX (n = 19) or LV5FU2‐cisplatin (n = 9). Grade 3‐4 toxicity was observed in 48% of patients (grade 3‐4 neutropenia, 37%). After a median follow‐up of 21.5 months, all patients had tumor progression, and 22 patients died. Objective response rate was 20%, and disease control rate was 52%. Median PFS and OS were 3.2 and 10.5 months, respectively. No clinical, biological, or tumor characteristics were associated with PFS or OS by multivariate analysis.

CONCLUSIONS:

Second‐line chemotherapy with FOLFIRI produced disease control in half of patients with advanced SBA after failure with first‐line platinum‐based chemotherapy. Nevertheless, the short median PFS warrants the evaluation of other treatments including targeted therapies. Cancer 2011. © 2010 American Cancer Society.     

Reactivation of hepatitis B virus after rituximab‐containing treatment in patients with CD20‐positive B‐cell lymphoma

BACKGROUND:

Reactivation of hepatitis B virus (HBV) after rituximab‐containing chemotherapy in patients with B‐cell lymphoma has been recognized as a potentially serious complication in HBV immune patients.

METHODS:

To determine the HBV reactivation in patients treated with rituximab, a retrospective study of HBV‐related markers was performed before and after rituximab‐containing treatment in 261 consecutive patients with CD20‐positive B‐cell lymphoma.

RESULTS:

Of the 261 patients, 230 patients were tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti‐HBc) before treatment. Fifty‐six (24.3%) of 230 patients were anti‐HBc positive, and the remaining 174 (75.6%) patients were anti‐HBc negative. Among the 56 anti‐HBc–positive patients, 5 (8.9%) became HBsAg positive (HBV reactivation), whereas none of the 174 anti‐HBc–negative patients became HBsAg positive with a median follow‐up of 24 months (P = .001). Among the 5 patients with HBV reactivation, 4 were negative for antibody to HBsAg (anti‐HBs), and 1 patient was positive for anti‐HBs. All 5 of these patients were treated successfully with entecavir on detection of HBsAg, although 4 of the 5 patients exhibited mild to moderate elevation of alanine aminotransferase. Among 56 anti‐HBc–positive patients, those negative for anti‐HBs had a higher probability of developing HBV reactivation compared with those positive for anti‐HBs (4 of 19; 21.1% vs 1 of 37; 2.7%, P = .014).

CONCLUSIONS:

Patients with isolated anti‐HBc are at high risk of HBV reactivation and should be monitored closely for HBsAg, anti‐HBs, HBV‐DNA, and transaminase levels during and after rituximab‐containing treatment. Although preemptive use of entecavir enabled successful management of HBV reactivation, mild to moderate hepatic flare was still observed. These approaches should be further evaluated in a prospective study with regard to clinical usefulness, safety, and cost‐effectiveness. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

BACKGROUND:

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

METHODS:

Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed.

RESULTS:

Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome.

CONCLUSIONS:

Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 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.     

Human immunodeficiency virus‐associated plasmablastic lymphoma

BACKGROUND:

Plasmablastic lymphoma (PBL) is a rare and aggressive B‐cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi‐institutional, retrospective study to describe characteristics and determine prognostic factors in HIV‐associated PBL.

METHODS:

For this study, the investigators included consecutive, HIV‐positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)‐negative, and expressed markers of plasmacytic differentiation.

RESULTS:

Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T‐helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm³. At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v‐myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty‐five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome.

CONCLUSIONS:

The prognosis of PBL in HIV‐infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV‐associated PBL. Cancer 2012. © 2012 American Cancer Society.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Long‐term results (>25 years) of a randomized,prospective clinical trial evaluating chemotherapy in patients with high‐grade,operable osteosarcoma

BACKGROUND:

The authors present the long‐term follow‐up (>25 years) data from 1 of the original prospective, randomized trials that compared adjuvant chemotherapy with expectant management in patients with high‐grade, localized osteosarcoma. In addition, the value of pathologic necrosis induced by a single cycle of neoadjuvant chemotherapy was analyzed as a predictive marker of disease‐free and overall survival.

METHODS:

Fifty‐nine patients with high‐grade, localized osteosarcoma were enrolled in a prospective trial that was performed between 1981 and 1984 at the University of California‐Los Angeles (UCLA). Patients were randomized to receive either adjuvant chemotherapy or observation after surgical resection. Long‐term outcomes, follow‐up, and pathologic review of all available histologic sections were performed.

RESULTS:

The 25‐year disease‐free survival rate was 28% for patients who received adjuvant chemotherapy compared with 15% for the untreated patients (P = .02). The overall survival rate at 25 years was also significantly higher for treated patients versus untreated patients (38% vs 15%; P = .02). Tumor necrosis >90% after a single round of chemotherapy was a statistically significant predictor of overall survival and disease‐free survival for patients who received adjuvant therapy (164 months vs 65 months [P = .04] and 141 months vs 14 months [P < .01], respectively).

CONCLUSIONS:

Patients with high‐grade, localized osteosarcoma who received adjuvant chemotherapy after undergoing definitive surgical resection had a statistically significant benefit in disease‐free and overall survival that was maintained through 25 years. Tumor necrosis after just 1 cycle of neoadjuvant chemotherapy and radiation was predictive of overall survival and disease‐free survival in patients who received adjuvant chemotherapy. Cancer 2012. © 2012 American Cancer Society.     

An open-label, phase 2 trial of RPI.4610 (Angiozyme) in the treatment of metastatic breast cancer

BACKGROUND:

Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR‐1 and VEGFR‐2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR‐1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well‐tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC.

METHODS:

This phase 2, multicenter, single‐arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m² for 12 weeks.

RESULTS:

Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow‐up was 2.76 months (range, 0.89‐36.6 months). No partial responses nor complete responses were found. Median progression‐free survival was 1.41 months (95% confidence interval [CI], 1.35‐1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11‐23.66). Treatment‐related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever.

CONCLUSIONS:

Although RPI.4610 demonstrated a well‐tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012.© 2012 American Cancer Society.