Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are small‐molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

METHODS:

Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first‐line therapy with either sunitinib or sorafenib and subsequently receiving second‐line therapy with the other TKI agent.

RESULTS:

Twenty‐nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P = .016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P = .061).

CONCLUSIONS:

The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation. Cancer 2009. © 2008 American Cancer Society.     

A phase 2 trial of imatinib mesylate in patients with recurrent nonresectable chondrosarcomas expressing platelet-derived growth factor receptor-α or -β: An Italian Sarcoma Group study

BACKGROUND.

Chondrosarcoma (CS) is a rare and heterogeneous sarcoma in which, after failure of surgery and radiotherapy, chemotherapy plays only a marginal role. Different molecular pathways have been shown to be activated in CS; in particular, both isoforms of platelet‐derived growth factor receptor (PDGFR) are expressed and phosphorylated. These observations prompted investigation of the activity of imatinib mesylate (IM) in patients with advanced CS in a phase 2 trial.

METHODS.

Between January 2007 and June 2009, patients with metastatic, nonresectable CS were treated with 400 mg of IM administered twice daily until disease progression or unacceptable toxicity. Two criteria determined patient trial eligibility: ≥1 prior line of chemotherapy and immunohistochemical expression of either PDGFR‐α or PDGFR‐β. The primary objective of the trial was objective response. As secondary objectives, the authors selected progression‐free survival (PFS) at 4 months, overall survival, and clinical benefit (EUDRACT number 2006‐006446‐33).

RESULTS.

Twenty‐six patients were enrolled and all demonstrated PDGFR positivity and phosphorylation. No objective response was demonstrated. The 4‐month PFS rate was 31% (95% confidence interval [95% CI], 16%‐53%). The median overall survival was 11 months (95% CI, 6 months‐15 months). Neither long‐lasting freedom from disease progression nor clinical benefit was observed. The IM dose was temporarily reduced in 60% 15 of the patients because of toxicity.

CONCLUSIONS.

IM was found to be relatively well‐tolerated, but failed to demonstrate meaningful clinical activity in terms of both objective response and freedom from disease progression. Advanced CS remains an incurable disease, and effective targeted therapies are still awaited. Cancer 2011. © 2010 American Cancer Society.     

Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first‐line treatment of patients with glioblastoma multiforme

BACKGROUND:

The current study was conducted to evaluate the efficacy of sorafenib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, when added to standard radiotherapy and temozolomide in the first‐line treatment of patients with glioblastoma multiforme.

METHODS:

After initial surgical resection or biopsy, patients with newly diagnosed glioblastoma multiforme received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and temozolomide (at a dose of 75 mg/m² orally daily), followed by 6 months of maintenance therapy with temozolomide (at a dose of 150 mg/m² orally on Days 1‐5 every 28 days) and sorafenib (at a dose of 400 mg orally twice daily). Patients were re‐evaluated every 2 months; the primary endpoint of the trial was progression‐free survival (PFS).

RESULTS:

A total of 47 patients were treated; 34 had undergone previous debulking surgery. Nineteen patients withdrew from treatment before the initiation of maintenance therapy with temozolomide and sorafenib (12 because of early tumor progression). Twenty‐eight patients (60% of enrolled patients) received 4 months of maintenance therapy with temozolomide and sorafenib, and 9 patients (19%) completed the planned 6 months of maintenance therapy. The median PFS for the entire group was 6 months (95% confidence interval [95% CI], 3.7‐7 months), with a 1‐year PFS rate of 16%. The median overall survival was 12 months (95%CI, 7.2‐16 months). Maintenance therapy with temozolomide and sorafenib was found to be well tolerated by most patients, with no grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) reported to occur in >10% of patients.

CONCLUSIONS:

The addition of sorafenib did not appear to improve the efficacy of treatment when compared with the results expected with standard therapy. A substantial percentage of patients (40%) did not receive any maintenance sorafenib, most often because of early disease progression. The administration of angiogenesis inhibitors concurrently with radiotherapy and temozolomide may optimize the opportunity to improve therapy. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 open‐label study of single‐agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B–endemic Asian population

BACKGROUND:

The current study was a phase 2 open–label study to evaluate the efficacy and tolerability of single‐agent sorafenib in the treatment of advanced HCC patients in a hepatitis B–endemic Asian population.

METHODS:

Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4‐week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria.

RESULTS:

Fifty‐one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28‐79 years). Approximately 90% had hepatitis B virus–related HCC. Thirty‐six (71%) patients had underlying Child‐Pugh A cirrhosis, 13 (26%) Child‐Pugh B, and 2 (3%) Child‐Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4‐17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand‐foot‐skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment‐related toxicity profile with sorafenib treatment.

CONCLUSIONS:

Single‐agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B–endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients. 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.     

Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma

BACKGROUND:

Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting.

METHODS:

Patients with recurrent and/or metastatic HNSCC after platinum‐based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12‐week progression‐free survival (PFS) and objective response rate with a 2‐stage design and early withdrawal if the 12‐week PFS rate was ≤20% and no patients had an objective response (OR). Forty‐nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients.

RESULTS:

Of the 15 patients enrolled, 12 were evaluable for response, and all patients were evaluable for toxicity. No OR was observed and 2 patients (16.7%) had stable disease (SD) at 8 weeks. The median treatment duration was 59 days, the median time to disease progression was 3.9 weeks, and the median survival was 26 weeks. One patient required a dose reduction, 3 patients required dose interruptions, and 4 patients were hospitalized for toxicity. Dasatinib inhibited c‐Src both when administered orally and via PFG. Greater mean drug exposure, decreased half‐life, and greater maximum concentration were observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and 1 CAF, macrophage migration inhibitory factor, was found to be differentially modulated in correlation with SD versus disease progression.

CONCLUSIONS:

Single‐agent dasatinib failed to demonstrate significant activity in patients with advanced HNSCC, despite c‐Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube. Cancer 2011. © 2010 American Cancer Society.     

Bevacizumab for recurrent alkylator‐refractory anaplastic oligodendroglioma

BACKGROUND:

A retrospective evaluation of single agent bevacizumab was carried out in adults with recurrent alkylator‐refractory 1p19q codeleted anaplastic oligodendrogliomas (AO) with an objective of determining progression‐free survival (PFS). There is no standard therapy for alkylator‐resistant AO, and hence a need exists for new therapies.

METHODS:

Twenty‐two patients aged 24 to 60 years with recurrent AO were treated. All patients had previously been treated with surgery, radiotherapy, adjuvant chemotherapy (temozolomide, 17; carmustine wafers, 4; carmustine, 1), and 1 salvage regimen (procarbazine, lomustine, and vincristine, 15; temozolomide, 6; carmustine wafers, 1). Eleven patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks, and neuroradiographic assessment was made after the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab.

RESULTS:

A total of 391 cycles of bevacizumab (median, 14.5 cycles; range, 2‐39 cycles) were administered. Bevacizumab‐related toxicity included fatigue (14 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (5; 1 grade 3), deep vein thrombosis (4; 1 grade 3), and wound dehiscence (2; 1 grade 3). Fifteen (68%) patients demonstrated a partial radiographic response, 1 (5.0%) demonstrated stable disease, and 6 (27%) demonstrated progressive disease after 2 cycles of bevacizumab. Time to tumor progression ranged from 1 to 18 months (median, 6.75 months). Survival ranged from 3 to 19 months (median, 8.5 months). Six‐month and 12‐month PFS were 68% and 23%, respectively.

CONCLUSIONS:

Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent 1p19q codeleted alkylator‐refractory AO. Cancer 2009. © 2009 American Cancer Society.     

Vinflunine in platinum‐pretreated patients with locally advanced or metastatic urothelial carcinoma

BACKGROUND:

The activity and safety of vinflunine was evaluated in patients with locally advanced or metastatic urothelial carcinoma (UC) who developed disease progression within 12 months of platinum‐containing chemotherapy.

METHODS:

Patients with UC were eligible if they received a prior platinum‐based regimen in the neoadjuvant/adjuvant setting or as first‐line treatment for advanced/metastatic disease and had developed disease progression within 12 months. Vinflunine was administered intravenously every 3 weeks. Patients with Karnofsky performance status of 80 or 90, impaired renal function, prior pelvic irradiation, or age ≥75 years received an initial dose of 280 mg/m², which was escalated to 320 mg/m² in Cycle 2 if well tolerated. All other patients received an initial dose of 320 mg/m². The primary endpoint was response rate defined by an independent response review committee (IRRC).

RESULTS:

Per the IRRC, 22 patients achieved a partial response, with a response rate of 15% (95% confidence interval, 9%‐21%) with a median duration of response of 6.0 months. Sixty‐four (42%) patients had stable disease. The median progression‐free survival was 2.8 months, and the median overall survival was 8.2 months. Myelosuppression was the most frequent adverse event, with grade 3 of 4 (adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria [version 2.0] guidelines) neutropenia reported in 58% of the patients. Grade 3 of 4 febrile neutropenia occurred in 10 (7%) patients. Nonhematologic treatment‐related events (grade 3 of 4) were generally manageable and included constipation (17%), asthenia/fatigue (13%), ileus (5%), and abdominal pain (5%). No cumulative toxicity was observed.

CONCLUSIONS:

Vinflunine demonstrates moderate activity in patients with platinum‐pretreated UC. Toxicity is manageable and noncumulative. Cancer 2009. © 2009 American Cancer Society.     

The prognostic value of pretreatment CA 125 in patients with advanced ovarian carcinoma

BACKGROUND:

The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen.

METHODS:

Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression‐free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype.

RESULTS:

In total, 1299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (≤35 U/mL). The lowest median CA 125 level was observed in the group with mucinous tumors; however, 69% of women who had mucinous tumors had abnormal CA 125 levels. Shorter PFS was observed with increasing CA 125 and persisted in multivariate analysis. Overall and in the serous subgroup, a 1‐fold increase in CA 125 level was associated with a 7% increase in the hazard of disease progression (P < .001). This association was even more pronounced in patients who had stage III disease that was debulked to microscopic disease (15%; P = .003) and in patients who had endometrioid tumors (17%; P = .001).

CONCLUSIONS:

A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. Cancer 2009. © 2009 American Cancer Society.     

CA‐125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers

BACKGROUND:

There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA‐125 antigen levels and prognosis.

METHODS:

A retrospective review of 7 previously reported Gynecologic Oncology Group phase 3 trials in patients with stage III/IV EOC was conducted. A variety of clinical parameters were examined, including the impact of baseline and changes in the CA‐125 level after treatment of CC and MU EOC on progression‐free (PFS) and overall survival (OS).

RESULTS:

Clinical outcomes among patients with advanced CC and MU EOC were significantly worse when compared with other cell types (median PFS, 9.7 vs 7.0 vs 16.7 months, respectively, P < .001; median OS, 19.4 vs 11.3 vs 40.5 months, respectively, P < .001). Suboptimal debulking was associated with significantly decreased PFS and OS among both. Although baseline CA‐125 values were lower in CC (median, 154 μ/mL) and MU (100 μ/mL), compared with other cell types (275 μ/mL), this level did not appear to influence outcome among these 2 specific subtypes of EOC. However, an elevated level of CA‐125 at the end of chemotherapy was significantly associated with decreased PFS and OS (P < .01 for all).

CONCLUSIONS:

Surgical debulking status is the most important variable at prechemotherapy predictive of prognosis among advanced CC and MU EOC patients. Changes in the CA‐125 levels at the end treatment as compared with baseline can serve as valid indicators of PFS and OS, and likely the degree of inherent chemosensitivity. Cancer 2009. © 2009 American Cancer Society.     

Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas

BACKGROUND:

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.

METHODS:

Seventy‐seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty‐five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine‐based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure.

RESULTS:

The median follow‐up was 6 months (range, 3‐31 months) and, among surviving patients, it was 12 months (range, 3‐31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6‐ and 12‐month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12‐month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression‐free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade ≥2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade ≥3 late toxicity. At 6 months and 12 months, the rates of grade ≥2 late toxicity were 11% and 25%, respectively.

CONCLUSIONS:

SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease‐related mortality. Cancer 2009. © 2008 American Cancer Society.     

Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab

BACKGROUND:

Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab‐ or sunitinib‐refractory mRCC have not been prospectively investigated.

METHODS:

Metastatic RCC patients with Response Evaluation Criteria in Solid Tumors (RECIST)‐defined disease progression (PD) after treatment with either bevacizumab or sunitinib received twice daily 400 mg of sorafenib in a multicenter, prospective phase 2 study. Dose escalation was permitted in the absence of significant toxicity. The primary endpoint was tumor burden reduction rate, defined as the proportion of patients with ≥5% reduction in the sum of RECIST‐defined target lesions without other PD. Secondary endpoints included progression‐free survival (PFS), duration of response, overall survival, and safety. A 2‐stage accrual design was used to test the alternative hypothesis that the tumor burden reduction rate was >20% versus <5%.

RESULTS:

Forty‐eight patients were enrolled. The tumor burden reduction rate was 30% (95% confidence interval [CI], 17%‐45%). One unconfirmed objective partial response was observed. The median PFS was 4.4 months (95% CI, 3.6‐5.9). There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment‐related adverse events were of mild‐to‐moderate intensity, and included fatigue, hypertension, diarrhea, and palmoplantar erythrodysesthesia (PPE). Patients previously treated with bevacizumab tended to develop more PPE (P = .03) and mucositis (P = .06), whereas sunitinib‐treated patients tended to develop more skin rash (P = .06).

CONCLUSIONS:

Administration of sorafenib is safe and feasible in patients with mRCC refractory to either bevacizumab or sunitinib. Modest clinical activity was observed supporting current practice patterns of sequential vascular endothelial growth factor‐targeted therapy in mRCC. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 Southwest Oncology Group-directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas

BACKGROUND:

Patients with advanced soft tissue sarcomas (STS) have limited therapeutic options. Sorafenib (BAY 43‐9006) is a multitargeted tyrosine kinase inhibitor of raf, vascular endothelial growth factor receptors 1 (VEGFR1) through 3, platelet‐derived growth factor B, fms‐like tyrosine kinase 3, and c‐kit, and some of these may be relevant in STS.

METHODS:

The authors tested sorafenib at a dose of 400 mg twice daily in patients with advanced vascular sarcoma (VS), high‐grade liposarcomas, and leiomyosarcomas who had received 0 or 1 previous regimens for advanced disease.

RESULTS:

Fifty‐one patients were accrued to the study, and 37 were evaluable for toxicity and response. There were no unexpected side effects and no confirmed responses. The median progression‐free survival was 3 months, and the median overall survival was 17 months. Six of 8 patients in the VS cohort had prolonged clinical benefit (stable disease or better), resulting in a median progression‐free survival of 5 months compared with 2 to 3 months for the patients who had liposarcoma and leiomyosarcomas.

CONCLUSIONS:

Sorafenib at the dose and schedule studied did not result in any responses in the VS, liposarcoma, or leiomyosarcoma cohort according to Response Evaluation Criteria in Solid Tumors. Cancer 2012;. © 2011 American Cancer Society.     

Patterns of disease progression in metastatic renal cell carcinoma patients treated with antivascular agents and interferon

BACKGROUND:

The standard of care for patients with advanced renal cell carcinoma (RCC) has changed to favor targeted therapy over immunotherapy. Differences in patterns of progression between patients treated with these 2 modalities, and the impact of disease stabilization on outcome, were investigated.

METHODS:

Patients who progressed on first line antivascular therapy (AVT) or interferon were identified, and their medical records reviewed.

RESULTS:

A total of 162 patients met inclusion criteria for this analysis. Patients in the AVT group had better baseline performance status, fewer liver metastases, and more responses (CR + PR) compared with the interferon group. Both groups were equally likely to develop distant metastases; however, for patients in the AVT group, these new metastases were more likely to arise in the setting of controlled disease at baseline sites (18% vs 4%, P = .012). There was no difference in anatomic sites of progression between the 2 groups. Patients responding (CR + PR) to AVT trended toward longer progression‐free survival (PFS) compared with patients with stable disease (SD) (P = .06). No difference between responders and SD was seen in the interferon group.

CONCLUSIONS:

Patients with RCC treated with antivascular therapy were more likely to progress at new sites in the setting of stable disease at baseline sites, suggesting that AVT may be more effective at controlling existing sites of disease than it is at preventing new metastases. Patients with SD on AVT had shorter PFS compared with responders (CR + PR). Whether this relationship extends to overall survival requires further study. Cancer 2009. © 2009 American Cancer Society.     

Sunitinib rechallenge in metastatic renal cell carcinoma patients

BACKGROUND:

Sunitinib was a standard initial therapy in metastatic renal cell carcinoma (mRCC). Given the fact that many patients progressed through many available therapies and antitumor activity had been demonstrated with sequential vascular endothelial growth factor‐targeting approaches, a retrospective review was performed of the experience of rechallenge with sunitinib in sunitinib‐refractory mRCC.

METHODS:

mRCC patients who received sunitinib therapy after disease progression on prior sunitinib and other therapy were retrospectively identified. Patient characteristics, toxicity, clinical outcome, Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate, and progression‐free survival (PFS) were recorded.

RESULTS:

Twenty‐three mRCC patients who were rechallenged with sunitinib were identified. Upon rechallenge, 5 patients (22%) achieved an objective partial response. The median PFS with initial treatment was 13.7 months and 7.2 months with rechallenge. Patients with >6‐month interval between sunitinib treatments had a longer PFS with rechallenge than patients who started the rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P = .03). There was no significant difference in outcome to sunitinib rechallenge based on number or mechanism of intervening treatments. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort.

CONCLUSIONS:

Sunitinib rechallenge had potential benefits and was tolerated in select metastatic RCC patients. Additional prospective investigation was warranted. Cancer 2010. © 2010 American Cancer Society.     

Carboplatin‐based primary chemotherapy for infants and young children with CNS tumors

BACKGROUND:

A carboplatin‐based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure.

METHODS:

Fifty‐three patients aged <age 3 years with embryonal CNS tumor medulloblastoma (n = 20), ependymoma (EP, n = 21), choroid plexus carcinoma (CPCA, n = 5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n = 7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was used only for residual disease at the end of chemotherapy or disease progression.

RESULTS:

The response rate after 2 cycles of chemotherapy was 34% (complete response, 13.8%; partial response, 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The 5‐year overall survival (OS) was 49% ± 7%, and the progression‐free survival (PFS) was 31% ± 7%, with a median follow‐up of 11.4 years (range, 5.2‐15.0 years). For medulloblastoma, the 5‐year PFS was 26% ± 9%; for EP it was 33% ± 10%; for CPCA it was 80% ± 18%; and for primitive neuroectodermal and atypical teratoid rhabdoid tumors it was 0%. Localized EP patients with gross total resection who did not undergo radiotherapy had a 5‐year PFS of 57% ± 17% and OS of 71% ± 16%. Two patients developed late second malignancies; 1 was associated with germline p53 mutation.

CONCLUSIONS:

The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five‐year survival data are comparable to those reported in other recent studies, including high‐dose chemotherapy studies. Of note is the marked activity in CPCA and gross totally resected EP. Cancer 2009. © 2009 American Cancer Society.     

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

Impact of disease progression date determination on progression‐free survival estimates in advanced lung cancer

BACKGROUND:

In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression‐free survival (PFS)‐based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates.

METHODS:

Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression‐free scan; M3, midpoint between the last progression‐free scan and the RPD; and M4, an interval‐censoring approach. PFS was estimated using Kaplan‐Meier (M1‐M3), and maximum‐likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression‐free scan and the PD on time‐to‐progression estimates.

RESULTS:

PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time‐to‐progression, <1.5%) compared with M1 (11% to 30%) and M2 (?8% to ?29%). The overall study conclusion was unaffected by the method used for randomized trials.

CONCLUSIONS:

The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS‐based endpoints. Cancer 2012. © 2012 American Cancer Society.     

Multicenter Phase 2 Trial of Gemcitabine,Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Background

Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma.

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.