Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor

BACKGROUND:

Patients with gastrointestinal stromal tumors (GISTs) resistant to both imatinib and sunitinib have a poor prognosis and few therapeutic options. In this study, the efficacy and safety of nilotinib (AMN107) as a third‐line therapy for patients with GISTs was evaluated.

METHODS:

A single‐arm, open‐label trial was conducted in 8 Japanese hospitals. The key eligibility criteria included resistance or intolerance to both imatinib and sunitinib treatment. The primary endpoint was disease control rate, defined as the percentage of patients with complete response, partial response (PR), or stable disease (SD) lasting 24 weeks or longer.

RESULTS:

Thirty‐five patients were enrolled and treated with nilotinib 400 mg twice daily, which generally was well tolerated. Disease control rate at Week 24 was 29% (90% confidence interval, 16.4%‐43.6%). The median progression‐free survival was 113 days, and the median overall survival was 310 days. The objective response rate was 3%, comprising 1 PR in a patient with a GIST possessing both a KIT exon 11 mutation, and an imatinib‐resistant and sunitinib‐resistant KIT exon 17 mutation. Twenty‐three (66%) patients had SD (≥6 weeks) as the best response.

CONCLUSIONS:

These results suggest that nilotinib is generally well tolerated and has encouraging antitumor activity in patients with GIST who failed both imatinib and sunitinib. Cancer 2011;. © 2011 American Cancer Society.     

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

BACKGROUND:

In patients with chronic‐phase chronic myeloid leukemia (CP‐CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325‐fold more potent inhibition than imatinib against unmutated Bcr‐Abl in vitro. Data with a minimum of 2 years of follow‐up were available for the current study of dasatinib and high‐dose imatinib in CP‐CML resistant to imatinib at daily doses from 400 mg to 600 mg.

METHODS:

A phase 2, open‐label study was initiated of 150 patients with imatinib‐resistant CP‐CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high‐dose imatinib 800 mg (400 mg twice daily; n = 49).

RESULTS:

At a minimum follow‐up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high‐dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high‐dose imatinib (29% vs 12%; P = .028). The estimated progression‐free survival also favored dasatinib (unstratified log‐rank test; P = .0012).

CONCLUSIONS:

After 2 years of follow‐up, dasatinib demonstrated durable responses and improved response and progression‐free survival rates relative to high‐dose imatinib. Cancer 2009. © 2009 American Cancer Society.     

Long‐term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high‐risk,high‐grade,soft tissue sarcomas of the extremities and body wall

BACKGROUND:

The use of neoadjuvant and adjuvant chemotherapy in soft tissue sarcomas is controversial. This is a report of long‐term (≥5 years) follow‐up in patients with high‐grade, high‐risk soft tissue sarcomas treated with neoadjuvant chemotherapy, preoperative radiotherapy (RT), and adjuvant chemotherapy.

METHODS:

Patients with high‐grade soft tissue sarcoma ≥8 cm in diameter of the extremities and body wall received 3 cycles of neoadjuvant chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) and preoperative RT (44 grays administered in split courses), and 3 cycles of postoperative chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine).

RESULTS:

Sixty‐four of 66 patients were analyzed. After chemotherapy and RT, 61 patients had surgery; 58 had R0 resections (5 amputations), and 3 had R1 resections. Ninety‐seven percent experienced grade 3 or higher toxicity, including 3 deaths. These toxicities were short term. With a median follow‐up of 7.7 years in surviving patients, the 5‐year rates of locoregional failure (including amputation), and distant metastasis were 22.2% (95% confidence interval [CI], 11.8‐32.6) and 28.1% (95% CI, 17.0‐39.2). The most common site of metastasis was lung. Estimated 5‐year rates of disease‐free survival, distant disease‐free survival, and overall survival were 56.1% (95% CI, 43.9‐68.3), 64.1% (95% CI, 52.3‐75.8), and 71.2% (95% CI, 60.0‐82.5), respectively.

CONCLUSIONS:

Although the toxicity was significant, it was limited in its course and for the most part resolved by 1 year. The long‐term outcome was better than might be expected in such high‐risk tumors. Cancer 2010. © 2010 American Cancer Society.     

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

BACKGROUND:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

Two-year adjuvant imatinib mesylate after complete resection of localized, high-risk GIST with KIT exon 11 mutation

Purpose

To evaluate the efficacy and safety of 2-year adjuvant imatinib for patients at high risk of recurrence after complete resection of localized gastrointestinal stromal tumor with KIT exon 11 mutation.

Methods

Imatinib 400 mg/d was administered until disease recurrence, intolerable toxicities, or for 2 years. The primary end point was recurrence-free survival.

Results

Patients (n = 47) from 4 centers in Korea were enrolled. Treatment was well tolerated. Grade 3–4 toxicities included neutropenia (27.7 %), skin rash (8.5 %), anorexia (4.3 %), and constipation (2.1 %). At a median follow-up of 56.7 months, 19 patients had recurrences. Median recurrence-free survival was 58.9 months, which was significantly longer than 22.7 months from historical data of 27 patients in the pre-imatinib era (P < 0.0001). Imatinib was rechallenged for 15 patients with recurrence after completion of adjuvant imatinib. Thirteen patients had partial response, and two had stable disease. There was only one death so far.

Conclusions

Postoperative adjuvant imatinib for 2 years was safe and could prolong the recurrence-free survival in patients with a high risk of recurrence after complete resection of localized KIT exon 11 mutated gastrointestinal stromal tumor. Reintroduction of imatinib after recurrence appears to be effective if the recurrence develops after completion of adjuvant imatinib.     

Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10‐06)

Background.

KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications.

Methods.

We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population.

Results.

Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%−28.0%) and a disease control rate of 57.1% (95% CI: 42.1%−72.1%). The median duration of response was 34 weeks (range: 5–55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only.

Conclusion.

Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations.

Implications for Practice:

KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations.     

Ixabepilone,mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

BACKGROUND:

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second‐line chemotherapy in patients with docetaxel‐refractory castration‐resistant prostate cancer. Clinical noncross‐ resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose‐limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.

METHODS:

Patients with metastatic progressive castration‐resistant prostate cancer during or after 3 or more cycles of taxane‐based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m² and mitoxantrone 12 mg/m² administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.

RESULTS:

Results are reported for the 56 evaluable patients. Twenty‐five (45%; 95% confidence interval [CI], 31%‐59%) experienced confirmed ≥50% prostate‐specific antigen (PSA) declines, 33 (59%; 95% CI, 45%‐72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%‐39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5‐5.6), and median progression‐free survival was also 4.4 months (95% CI, 3.0‐6.0). Median overall survival was 12.5 months (95% CI, 10.2‐15.9). Thirty‐two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment‐related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.

CONCLUSIONS:

These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration‐resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.     

Lack of pathologic down‐staging with neoadjuvant chemotherapy for muscle‐invasive urothelial carcinoma of the bladder

BACKGROUND:

The postcystectomy survival benefit associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) neoadjuvant chemotherapy (NC) for muscle‐invasive bladder cancer has been most evident in patients who achieve a pathologic complete response. The outcome of NC and open radical cystectomy (RC) was evaluated in a contemporary cohort of patients in a tertiary referral setting.

METHODS:

From January 2006 to November 2007, 117 patients underwent open RC at Cleveland Clinic for muscle‐invasive bladder cancer, 29 (25%) of whom received NC. Patient information was obtained from a prospective database.

RESULTS:

Clinical stage at the time of diagnosis in the NC cohort was T2 in 23 (79%) and T3‐4a in 6 (21%) patients. A total of 20 (69%) patients received the combination of gemcitabine and cisplatin (GC), 4 (14%) received MVAC, and 5 (17%) received other regimens. The median interval from the time of diagnosis of muscle‐invasive bladder cancer to RC was 208 days (interquartile range, 149 days ‐327 days) in the NC cohort. Overall, only 2 patients (7%; 95% confidence interval [95% CI], 0 patients‐17 patients) achieved a pathologic complete response, 18 (62%; 95% CI, 43 patients‐81 patients) had nonorgan‐confined residual cancer, and the overall median progression‐free survival was 10.5 months (95% CI, 7 months ‐14 months).

CONCLUSIONS:

Few RC patients in these investigators' recent experience achieved a pathologic complete response with NC, and most experienced rapid disease progression. These poor outcomes may be related to the use of non‐MVAC‐based regimens or excessive delay in performing RC. In the absence of supportive data for GC in the neoadjuvant setting, MVAC remained the preferred regimen. Excessive delays in performing RC may negate the benefit of NC. Cancer 2009. © 2009 American Cancer Society.     

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

BACKGROUND:

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.

METHODS:

All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme‐inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice‐a‐day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.

RESULTS:

A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice‐a‐day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.

CONCLUSIONS:

Vatalanib doses up to 1000 mg twice‐a‐day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet‐derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity. Cancer 2009. © 2009 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.     

A phase 2 pilot trial of low‐dose,continuous infusion,or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma

BACKGROUND:

Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX‐2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM.

METHODS:

Patients received paclitaxel 10 mg/m² for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6‐week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study.

RESULTS:

Twenty patients were enrolled. Twelve of 20 patients (60%) had received ≥2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment‐related grade 3/4 toxicities were limited to catheter‐related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43‐151 days), and the median overall survival was 212 days (95% confidence interval, 147‐811 days).

CONCLUSIONS:

Low‐dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. © 2010 American Cancer Society.     

Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase

BACKGROUND:

Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML‐CP). Treatment guidelines propose dose escalation based on clinical assessments of disease response.

METHODS:

Response and survival were analyzed in a cohort of patients (n = 106) with newly diagnosed CML‐CP who were enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 mg or 800 mg daily. Reasons for dose escalation were evaluated retrospectively based on 2 sets of criteria: the IRIS protocol‐defined criteria (n = 39 patients) and the European LeukemiaNet (ELN) recommendations (n = 48 patients).

RESULTS:

Among all 106 patients who underwent dose escalation, the rates of freedom from progression to accelerated phase or blast phase and overall survival were 89% and 84% at 3 years after dose increase, respectively. A cytogenetic response was obtained in 42% of patients who had their dose escalated based on protocol criteria and in 38% of patients who had their dose escalated according to the ELN recommendations.

CONCLUSIONS:

The results from this retrospective analysis supported imatinib dose escalation as an appropriate initial option for patients with CML‐CP who were experiencing suboptimal cytogenetic response or resistance. Cancer 2009. © 2008 American Cancer Society.     

Bevacizumab in association with de Gramont 5‐fluorouracil/folinic acid in patients with oxaliplatin‐, irinotecan‐, and cetuximab‐refractory colorectal cancer

BACKGROUND:

The aim of the current study was the investigation of the value of bevacizumab + 5‐fluorouracil(5–FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options.

METHODS:

The authors included 48 heavily pretreated patients (colon:rectum, 33:15; men:women, 23:25; median age, 63 years; range, 27‐79 years) whose disease had progressed during or within an oxaliplatin‐based first‐line chemotherapy, an irinotecan‐based second‐line regimen, and a third‐line treatment with cetuximab plus weekly irinotecan. Bevacizumab was given at a dose of 5 mg/kg. 5‐FU/folinic acid was administered according to the de Gramont schedule.

RESULTS:

The response rate was 6.25%, and 30.4% of patients demonstrated stable disease as the best response. The median time to disease progression was 3.5 months (95% confidence interval [95% CI], 2.3‐6.9 months), and the median survival time was 7.7 months (95% CI, 3.9‐11.9 months). The most common grade 3 to 4 side toxicities (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) were: diarrhea (20.8%), fatigue (14.5%), and stomatitis (12.5%). Grade 3 to 4 hemorrhage occurred in 8 patients (16.6%), including 4 cases of bleeding in the gastrointestinal tract. Other relatively common adverse events such as hypertension, thrombosis, and bowel perforation were reported in 50%, 18.7%, and 4.16%, of patients respectively.

CONCLUSIONS:

The data from the current study suggest a modest but significant clinical benefit of bevacizumab + de Gramont schedule in heavily pretreated colorectal cancer patients. Cancer 2009. © 2009 American Cancer Society.     

The effects of paclitaxel,dose density,and trastuzumab on treatment‐related amenorrhea in premenopausal women with breast cancer

BACKGROUND:

Little information is available regarding the effects of new adjuvant treatment regimens on menstrual functioning in premenopausal women with early breast cancer.

METHODS:

The authors conducted a retrospective review of data from premenopausal women who received treatment for early breast cancer to evaluate the rates of amenorrhea in follow‐up. The women who were included received treatment with either doxorubicin and cyclophosphamide (AC) or combined AC and paclitaxel (T) (AC‐T) given either every 3 weeks, or as a dose‐dense (DD) regimen, or as AC followed by weekly T with trastuzumab or followed by trastuzumab (AC‐T+trastuzumab). A multivariate logistic regression analysis was conducted to evaluate amenorrhea during follow‐up.

RESULTS:

Of 431 patients who were eligible for analysis, the average age at diagnosis was 13 years (range, 25‐55 years), 61% of women received AC only, and 39% received AC‐T. Of the 39% who received AC‐T, 49% of women received DD therapy, 14% received AC‐T+trastuzumab, and 71% of all patients received tamoxifen (TAM). The median follow‐up was 33 months (range, 6‐114 months). After adjusting for age, weight, gravidity, parity, age at menarche, smoking, alcohol use, TAM use, type and regimen of chemotherapy, and use of trastuzumab, the likelihood of remaining amenorrheic was not statistically different in patients who received AC‐T versus AC (odds ratio [OR], 1.59; 95% confidence interval [CI], 0.8‐3.2), DD treatment versus treatment every 3 weeks (OR, 0.56; 95% CI, 0.25‐1.3), or AC‐T + trastuzumab (OR, 0.6; 95% CI, 0.22‐1.61). Amenorrhea was associated significantly with TAM use and age at diagnosis.

CONCLUSIONS:

Recent advances in the adjuvant treatment of early breast cancer do not appear to have increased the risk of amenorrhea in premenopausal women. Cancer 2010. © 2010 American Cancer Society.     

Nonsteroidal anti‐inflammatory drugs

BACKGROUND:

Nonsteroidal anti‐inflammatory drug (NSAID) use has been associated with a decreased colorectal cancer (CRC) risk. However, to the best of the authors' knowledge, the effects of NSAID on clinical outcomes after CRC diagnosis are not well defined. The authors investigated the association between prediagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study cohort.

METHODS:

Women aged <85 years participating in the California Teachers Study, without a prior CRC diagnosis at baseline (1995‐1996), and who were diagnosed with CRC during follow‐up through December 2005, were eligible for analysis of the association between prediagnosis NSAID use and mortality. NSAID use (including aspirin and ibuprofen) was collected through a self‐administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariate Cox proportional hazards regression models were used to estimate hazards ratios (HR) for death and 95% confidence intervals (95% CIs).

RESULTS:

Among 621 CRC patients who were identified, 64% reported no prediagnosis regular NSAID use, 17% reported use of 1 to 6 days/week, and 20% reported daily use. A duration of NSAID use <5 years was reported by 17% of patients and a use of ≥5 years was reported by 18%. Regular prediagnosis NSAID use (1‐3 days/week, 4‐6 days/week, and daily) versus none was associated with improved overall survival (OS) (HR, 0.71; 95% CI, 0.53‐0.95) and CRC‐specific survival (HR, 0.58; 95% CI 0.40‐0.84) after adjustment for clinically relevant factors. Prediagnosis NSAID use ≥5 years (vs none) was found to be associated with improved OS (HR, 0.55; 95% CI, 0.37‐0.84) and CRC‐specific survival (HR, 0.40; 95% CI, 0.23‐0.71) in adjusted analyses.

CONCLUSIONS:

When used regularly or over a prolonged duration before CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC patients. Cancer 2009. © 2009 American Cancer Society.     

A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma

BackgroundTargeting platelet-derived growth factor receptor-β (PDGFR-β) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-β inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC).Patients and methodsUsing a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m² (DL4)] and oxaliplatin [day 2, 85 (DL1–4) and 100 mg/m² (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2–5) each cycle.ResultsTwenty-seven patients received 168 cycles in total. Median age was 61 years (44–74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1–7.0) and 5.6 months (95% CI 2.5–8.7), respectively.ConclusionIn gemcitabine-refractory PC, gemcitabine (1000 mg/m²) and oxaliplatin (85 mg/m²) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.     

Dasatinib in imatinib‐resistant or imatinib‐intolerant chronic myeloid leukemia in blast phase after 2 years of follow‐up in a phase 3 study

BACKGROUND:

In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome‐positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow‐up are reported.

METHODS:

Patients were stratified according to whether they had CML in myeloid blast phase (MBP‐CML) or in lymphoid blast phase (LBP‐CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily.

RESULTS:

In patients with MBP‐CML, the major hematologic response rate was 28% for both regimens; and, in patients with LBP‐CML, the major hematologic response rate was 42% for once‐daily dasatinib and 32% for twice‐daily dasatinib. The major cytogenetic response rates were 25% for once‐daily dasatinib and 28% for twice‐daily dasatinib in patients with MBP‐CML, and the respective rates in patients with LBP‐CML were 50% and 40%. The overall survival rate at 24 months was 24% for once‐daily dasatinib and 28% for twice‐daily dasatinib in patients with MBP‐CML, and the respective values in patients with LBP‐CML were 21% and 16%. Adverse events indicated a trend toward improved tolerability for the once‐daily regimen.

CONCLUSIONS:

The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70‐mg twice‐daily regimen in patients with imatinib‐resistant, blast phase CML. Cancer 2010. © 2010 American Cancer Society.     

Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate

BACKGROUND:

The authors sought to determine the incidence and severity of cardiovascular toxicity caused by imatinib mesylate in gastrointestinal stromal tumor (GIST) and other sarcoma patients, and to explore cardiotoxicity caused by imatinib mesylate using cell culture and in vitro models.

METHODS:

To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving imatinib mesylate, the authors performed a retrospective analysis of 219 consecutive patients treated with imatinib mesylate. In vitro studies of imatinib mesylate on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with imatinib mesylate were performed to define the potential cardiotoxic effects of imatinib mesylate.

RESULTS:

Grade 3 or 4 potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of imatinib mesylate. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in <1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response.

CONCLUSIONS:

The authors concluded that imatinib is an uncommon cause of cardiotoxicity, and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our preclinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore, the cardiac consequences of long‐term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib‐treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure. Cancer 2010. © 2010 American Cancer Society.     

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high‐dose imatinib or switch to second‐line sunitinib in the event of disease progression and appropriately managing treatment‐associated side effects. Imatinib is the standard first‐line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high‐dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high‐dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes.     

Multicenter phase 2 study of belotecan,a new camptothecin analog,and cisplatin for chemotherapy‐naive patients with extensive‐disease small cell lung cancer

BACKGROUND:

The objective of this study was to investigate the efficacy of belotecan, a new camptothecin analog, combined with cisplatin for the treatment of chemotherapy‐naive patients with extensive‐disease small cell lung cancer (ED SCLC).

METHODS:

Treatment consisted of belotecan 0.5 mg/m² daily on Days 1 through 4 and cisplatin 60 mg/m² on Day 1 of a 3‐week cycle for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient refusal. Response assessment was done every 2 cycles using the Response Evaluation Criteria in Solid Tumors, and toxicity assessment was done every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

RESULTS:

Between September 2006 and March 2008, 30 patients participated in the study. Among them, 21 patients achieved a partial response, and the response rate was 70% (95% confidence interval [CI], 50.6%‐85.3%); and, after a median follow‐up of 20.2 months, the median progression‐free survival was 6.9 months (95% CI, 6.3‐7.5 months), and the overall survival was 19.2 months (95% CI, 13.3‐25.2 months). Grade 3 and 4 adverse events included neutropenia in 23 patients, thrombocytopenia in 8 patients, febrile neutropenia in 9 patients, nausea in 3 patients, and pneumonia in 3 patients. There was 1 treatment‐related death from pneumonia. However, nonhematologic toxicity generally was mild and manageable.

CONCLUSIONS:

The belotecan and cisplatin combination that was studied demonstrated promising response rates and survival outcomes with a manageable toxicity profile for chemotherapy‐naive patients who had ED SCLC. The authors concluded that the combination warrants further randomized trials. Cancer 2010. © 2010 American Cancer Society.