Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design

BACKGROUND:

Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents.

METHODS:

The characteristics and outcome of refractory GCT patients enrolled in 7 single‐agent phase 2 trials conducted at Memorial Sloan‐Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all‐transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression‐free survival (PFS), and overall survival (OS).

RESULTS:

Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty‐six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8‐1.3) and 4.7 months (95% CI, 3.5‐6.4), respectively. Eighty‐six of the 90 patients have died. The 12‐ and 16‐week PFS rates were 9% (95% CI, 3‐15%) and 6% (95% CI, 1%‐11%), respectively.

CONCLUSIONS:

Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve‐week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. Cancer 2012;. © 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.     

Oxaliplatin‐based chemotherapy (dexamethasone,high‐dose cytarabine,and oxaliplatin) ± rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma

BACKGROUND:

Patients affected by relapsed or primary refractory lymphomas currently have a poor prognosis and no standard salvage treatment options. This study was carried out to assess the efficacy and safety of a dexamethasone, high‐dose cytarabine, and oxaliplatin as salvage therapy in those patients, replacing cisplatin with oxaliplatin in the standard dexamethasone, cytarabine, and cisplatin scheme.

METHODS:

Seventy patients with relapsed or refractory aggressive non‐Hodgkin or Hodgkin lymphoma were treated from September 2001 to September 2007. The median age of patients was 51 years (range, 19‐75 years). Histological subtypes were: diffuse large B‐cell lymphoma (n = 47) and Hodgkin lymphoma (n = 23). The overall response rate was 73% (51 of 70), with 30 (43%) complete remissions and 21 (30%) partial remissions. Fifty‐two patients were treated with dexamethasone, high‐dose cytarabine, and oxaliplatin as second‐line chemotherapy. Forty‐eight patients were enrolled in an autologous stem cell transplantation program; forty (83%) finally proceeded to high‐dose consolidation and autografting.

RESULTS:

No grade 3 or 4 nonhematological toxicity was demonstrated; in particular, no renal or neurotoxicity was reported. After a median follow‐up period of 21 months (range, 2‐87 months), 22 (31%) patients had died. Probabilities of 2‐year progression‐free survival (PFS) and overall survival (OS) were 44% and 71%, respectively. In the chemosensitive patients, the PFS and OS were 52% and 83%, respectively. The only factor that significantly correlated with better OS was the response to therapy.

CONCLUSIONS:

This study confirms that dexamethasone, high‐dose cytarabine, and oxaliplatin ± rituximab is an effective and feasible outpatient regimen for salvage therapy in patients affected by relapsed or refractory lymphoma. Moreover, the feasibility and efficacy of this scheme as an in vivo chemosensitive test in patients in autotransplantation programs was confirmed. Cancer 2010. © 2010 American Cancer Society.     

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials

BACKGROUND:

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

METHODS:

Individual patient data from 870 untreated extensive stage small‐cell lung cancer patients participating in 6 single‐arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient‐level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial‐level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial‐level surrogacy measures included: R² from weighted least squares regression model, Spearman correlation coefficient, and R² from bivariate survival model (Copula R²).

RESULTS:

Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1‐10.0) and 5.5 (95% CI, 5.2‐5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient‐level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35‐0.51; concordance index 0.63; P < .01), with 6‐month PFS being the strongest (HR, 0.41; 95% CI, 0.35‐0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R² = 0.79; Copula R² = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R²≤0.48).

CONCLUSIONS:

PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Cancer 2011. © 2010 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.     

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.     

Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study

BACKGROUND:

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

METHODS:

Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m² on days 1, 8, and 15 of a 28‐day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression‐free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity.

RESULTS:

Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment‐related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0‐9.4) and 16.6 months (95% CI, 12.8‐22.9), with 22 (55%) patients progression‐free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02).

CONCLUSIONS:

A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum‐resistant OC; further study is warranted. Cancer 2011;. © 2011 American Cancer Society.     

Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426)

BACKGROUND.

Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi‐institutional prospective trial.

METHODS.

Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone‐releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate‐specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration.

RESULTS.

A total of 210 eligible and evaluable patients had a median follow‐up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression‐free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12‐month or greater progression‐free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA‐only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response.

CONCLUSIONS.

These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients. Cancer 2008. © 2008 American Cancer Society.     

A randomized phase 2 trial of a preparative regimen of bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid

BACKGROUND:

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan.

METHODS:

Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m² intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m² × 3 doses (Group 2), and bortezomib 1.5 mg/m² × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90‐day treatment‐related mortality (TRM). Secondary endpoints were progression‐free survival (PFS) and overall survival (OS).

RESULTS:

The median follow‐up of all surviving patients was 36 months (range, 20‐43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high‐risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group.

CONCLUSIONS:

Adding bortezomib to a preparative regimen of ATO, AA, and high‐dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups. Cancer 2012;. © 2011 American Cancer Society.     

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

BACKGROUND:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

Upfront observation versus radiation for adult pilocytic astrocytoma

BACKGROUND:

Although pilocytic astrocytoma accounts for up to 40% of all childhood brain tumors, it is a rare disease in adults. Consequently, there are few mature data on the impact of up‐front treatment options after surgery that include observation or adjuvant radiotherapy.

METHODS:

Ten women and 20 men were identified who were diagnosed with pilocytic astrocytoma from 1971 to 2007 and were retrospectively reviewed. The median patient age was 30 years (range, 18‐64 years), and the median follow‐up was 87 months (range, 16‐420 months). Initial surgery included biopsy (10% of patients), subtotal resection (57% of patients), or gross‐total resection (33% of patients). Nineteen patients were observed postoperatively, whereas 11 patients received up‐front postoperative adjuvant radiotherapy (50 grays in 25 fractions). No patient received adjuvant or concurrent chemotherapy. Progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan‐Meier method. Differences between survival curves were analyzed with the log‐rank test.

RESULTS:

For the entire cohort, the 5‐year and 10‐year OS rates were 95% and 85%, respectively, and the 5‐year and 10‐year PFS rates were 63% and 35%, respectively. The median PFS was 8.4 years. Initial radiation, compared with observation, did not have an impact on OS but significantly improved PFS. The 5‐year PFS rate for patients who were observed versus those who received radiation was 42% versus 91%, respectively; and, at 10 years, the PFS rate was 17% versus 60%, respectively (P = .005). Patients who progressed after observation (11 of 19 patients) received various salvage therapies, resulting in a 2‐year PFS rate of 68% compared with 33% for patients who progressed after initial radiation (3 of 11 patients) and were salvaged with either chemotherapy or surgery (P = .1).

CONCLUSIONS:

Adjuvant radiotherapy for pilocytic astrocytoma significantly prolonged PFS at both 5 years and 10 years compared with observation. However, equivalent OS was observed, which reflected the efficacy of salvage therapies. Cancer 2011;. © 2011 American Cancer Society.     

Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma

BACKGROUND:

Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination.

METHODS:

Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme‐inducing anticonvulsants were enrolled. Treatment was in 6‐week cycles with irinotecan at 125 mg/m² weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression‐free survival rate at 6 months (PFS‐6), and the secondary endpoints were overall survival (OS) and response rate (RR).

RESULTS:

In 39 eligible patients, PFS‐6 for the intent‐to‐treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment‐related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment‐related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis.

CONCLUSIONS:

The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing. Cancer 2012;3599–3606. © 2011 American Cancer Society.     

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto‐HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto‐HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post‐HCT VGPR and in 2 of 12 patients with post‐HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto‐HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post‐HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.     

A retrospective analysis of early CA19-9 change in salvage chemotherapy for refractory pancreatic cancer

Purpose

In salvage chemotherapy for refractory pancreatic cancer, early assessment is important to avoid unnecessary toxicities from ineffective chemotherapy. Early CA19-9 change after the first course as a prognostic factor was evaluated in this setting.

Methods

Patients receiving salvage chemotherapy were retrospectively studied. CA19-9 was measured prior to and after the first course. Cox regression analysis was performed for prognostic factors for progression-free survival (PFS) and overall survival (OS), using the landmark method defined as a day of CA19-9 measurement after the first course.

Results

A total of 239 salvage regimens were given in 167 patients. Median PFS and OS were 2.7 and 6.1 months, respectively. Median pretreatment CA19-9 was 2,362 U/mL, and median CA19-9 change after the first course was 17.8 % increase. CA19-9 change was associated with tumor response, and PFS was 1.7 versus 3.5 months and OS was 3.9 and 8.6 months in patients with ≥50 % versus <50 % increase. In the multivariate analyses, CA19-9 increase ≥50 % was prognostic of both PFS and OS (HR 2.28 and 2.50, p < 0.001, respectively).

Conclusion

CA19-9 change after the first course was prognostic of PFS and OS in refractory pancreatic cancer. Early discontinuation should be considered given the palliative setting.     

Bortezomib,thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

BACKGROUND:

This single‐center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3‐week cycles of bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte‐colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front‐line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front‐line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34‐positive stem cell collection was 10.67 × 10⁶/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression‐free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow‐up of 25 months, and the 2‐year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2‐year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long‐term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.     

Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients

BACKGROUND:

Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported.

METHODS:

We collected clinical and biological data of patients presenting with an osteo‐dural or primary dural multiple myeloma (OD‐DMM) or a central nervous system myelomatosis (CNS‐MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA).

RESULTS:

A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty‐five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS‐MM was 6 months, for OD‐DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression‐free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. β2‐Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with β2‐microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR.

CONCLUSIONS:

The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials. Cancer 2011;. © 2011 American Cancer Society.     

Correlation of pretransplant and early post‐transplant response assessment with outcomes after reduced‐intensity allogeneic hematopoietic stem cell transplantation for non‐Hodgkin's lymphoma

BACKGROUND:

Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non‐Hodgkin lymphoma (NHL) patients undergoing reduced‐intensity allogeneic hematopoietic stem cell transplantation (allo‐HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post‐transplant outcomes.

METHODS:

The impact of pretransplant and early (28 days) post‐transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced‐intensity allo‐HCT.

RESULTS:

The 3‐year event‐free survival (EFS) and overall survival (OS) (median potential follow‐up after reduced‐intensity allo‐HCT = 58 months) for all patients was 37% and 47%, respectively. The 3‐year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3‐year follow‐up. The 3‐year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3‐year EFS based on post‐transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post‐transplant reached 3‐year follow‐up. The 3‐year OS based on post‐transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS.

CONCLUSIONS:

These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced‐intensity allo‐HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy

BACKGROUND.

The purpose of the current study was to examine overall survival (OS) and time to local failure (LF) in patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases (BM) after initial management that included whole‐brain radiation therapy (WBRT).

METHODS.

The records of 1789 BM patients from August 1989 to November 2004 were reviewed. Of these, 111 underwent WBRT as part of their initial management and SRS as salvage. Patients were stratified by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class, primary disease, dimension of the largest metastases and number of BM at initial diagnosis, and time to first brain recurrence after WBRT. Overall survival, survival after SRS, and time to local and distant failure were analyzed.

RESULTS.

The median OS from the initial diagnosis of BM was 17.7 months. Median survival after salvage SRS for the entire cohort was 9.9 months. Median survival after salvage SRS was 12.3 months in patients who had their first recurrence >6 months after WBRT versus 6.8 months for those who developed disease recurrence ≤6 months after (P = .0061). Primary tumor site did not appear to affect survival after SRS. Twenty‐eight patients (25%) developed local recurrence after their first SRS with a median time of 5.2 months. A dose <22 grays and lesion size >2 cm were found to be predictive of local failure.

CONCLUSIONS.

In this study, patients who recurred after WBRT and were treated with salvage SRS were found to have good local control and survival after SRS. WBRT provided good initial control, as 45% of these patients failed >6 months after WBRT. Those with a longer time to failure after WBRT had significantly longer survival after SRS. Cancer 2008. © 2008 American Cancer Society.     

Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy

BACKGROUND.

The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression‐free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown.

METHODS.

Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead‐time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS.

RESULTS.

In total, 1158 patients were included. The median follow‐up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log‐rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42‐3.84) and 2.96 (95% confidence interval, 2.39‐3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation.

CONCLUSIONS.

PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. Cancer 2011;. © 2010 American Cancer Society.     

Therapeutic efficacy of combination therapy with intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma with portal venous invasion

BACKGROUND:

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly among patients with portal vein tumor thrombosis (PVTT). This study evaluated the efficacy of combined 5‐fluorouracil and pegylated interferon (PEG‐IFN) α‐2b in patients with advanced HCC.

METHODS:

Subjects comprised 59 HCC patients with PVTT treated using subcutaneous administration of PEG‐IFNα‐2b (50‐100 μg on day 1 of each week for 4 weeks) and intra‐arterial infusion of 5‐fluorouracil (250 mg/d for 5 hours on days 1‐5 of each week for 4 weeks). One treatment cycle lasted 4 weeks. The current therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. The primary efficacy endpoint was the objective early response rate. Secondary efficacy endpoints were progression‐free survival (PFS) and overall survival.

RESULTS:

Objective early response rate was 73.0%. Cumulative PFS rates were 67.4% at 6 months, 30.2% at 12 months, 25.9% at 18 months, and 20.7% at 24 months. Median PFS was 9.7 months. Cumulative survival rates were 82.4% at 6 months, 73.6% at 12 months, 52.8% at 24 months, and 44.0% at 36 months. Median survival time was 29.9 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment‐related deaths were not observed.

CONCLUSIONS:

Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5‐fluorouracil and PEG‐IFNα‐2b, this new combination therapy may be useful for patients with advanced HCC. Cancer 2011. © 2011 American Cancer Society.