Performance characteristics of a polymerase chain reaction-based assay for the detection of EGFR mutations in plasma cell-free DNA from patients with non-small cell lung cancer using cell-free DNA collection tubes.

Survival rates in non-small cell lung cancer (NSCLC) are low. Detection of circulating tumor DNA in liquid biopsy (plasma) is increasingly used to identify targeted therapies for clinically actionable mutations, including EGFR mutations in NSCLC. The cobas® EGFR Mutation Test v2 (cobas EGFR test) is FDA-approved for EGFR mutation detection in tissue or liquid biopsy from NSCLC. Standard K2EDTA tubes require plasma separation from blood within 4 to 8 hours; however, Roche Cell-Free DNA (cfDNA) Collection Tubes (Roche cfDNA tube) enable whole blood stability for up to 7 days prior to plasma separation. This analysis assessed performance of Roche cfDNA tubes with the cobas EGFR test for the detection of EGFR mutations in plasma from healthy donors or patients with NSCLC. Overall, test performance was equally robust with either blood collection tube, eg, regarding limit of detection, linearity, and reproducibility, making Roche cfDNA tubes suitable for routine clinical laboratory use in this setting. Importantly, the Roche cfDNA tubes provided more flexibility for specimen handling versus K2EDTA tubes, eg, in terms of tube mixing, plasma separation, and sample stability, and do not require processing of blood within 8 hours thereby increasing the reach of plasma biopsies in NSCLC.

Efficacy of liquid biopsy for disease monitoring and early prediction of tumor progression in EGFR mutation-positive non-small cell lung cancer.

15-40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations.

Budget Impact Analysis of EGFR Mutation Liquid Biopsy for First- and Second-Line Treatment of Metastatic Non-Small Cell Lung Cancer in Greece.

Within the European Union, Greece has the highest incidence of lung cancer among people under 45 years of age. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are indicated for the treatment of patients with EGFR mutation-positive metastatic non-small cell lung cancer (mNSCLC). Tumor tissue biopsy is the standard method for EGFR mutation detection but is invasive, is resource-intensive, and has risks of complications. The objective of this analysis was to estimate the financial impact on the Greek National Health System of adopting plasma biopsy and to identify the cost-optimal approach for EGFR mutation testing of patients with mNSCLC. We developed a budget impact model to estimate total costs for three EGFR mutation testing approaches: (1) plasma test, (2) combined testing (tissue and plasma test), and (3) reflex testing, compared to the current scenario of tissue biopsy only. One-way sensitivity and scenario analyses were conducted to evaluate the impact of uncertainty and variance of different input parameters on the results. In the first-line (1L) setting, base-case results showed that adopting plasma testing in a combined testing approach identified more EGFR mutation-positive patients and yielded cost savings (-€17 per correctly classified patient) relative to tissue testing alone. The reflex testing approach was the cost-optimal strategy in the second-line (2L) setting as it identified the most EGFR mutation-positive patients with cost savings of -€42 per correctly classified patient relative to tissue testing alone. This analysis suggests that access to both EGFR mutation tissue and plasma testing are important for optimizing mNSCLC treatment decisions in Greece. Inclusion of plasma testing in either a combined or reflex testing approach may be cost optimal for EGFR mutation plasma test implementation.

Clinical utility of a blood-based EGFR mutation test in patients receiving first-line erlotinib therapy in the ENSURE, FASTACT-2, and ASPIRATION studies.

OBJECTIVE: Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas®EGFR Mutation Test v2. MATERIALS AND METHODS: Two EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden. RESULTS: Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8-76.1) and a specificity of 97.9% (95% CI 96.0-99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors. CONCLUSIONS: Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations.

Detection of EGFR Variants in Plasma: A Multilaboratory Comparison of a Real-Time PCR EGFR Mutation Test in Europe.

Molecular testing of EGFR is required to predict the response likelihood to targeted therapy in non-small cell lung cancer. Analysis of circulating tumor DNA in plasma may complement limitations of tumor tissue. This study evaluated the interlaboratory performance and reproducibility of a real-time PCR EGFR mutation test (cobas EGFR Mutation Test v2) to detect EGFR variants in plasma. Fourteen laboratories received two identical panels of 27 single-blinded plasma samples. Samples were wild type or spiked with plasmid DNA to contain seven common EGFR variants at six predefined concentrations from 50 to 5000 copies per milliliter. The circulating tumor DNA was extracted by a cell-free circulating DNA sample preparation kit (cobas cfDNA Sample Preparation Kit), followed by duplicate analysis with the real-time PCR EGFR mutation test (Roche Molecular Systems, Pleasanton, CA). Lowest sensitivities were obtained for the c.2156G>C p.(Gly719Ala) and c.2573T>G p.(Leu858Arg) variants for the lowest target copies. For all other variants, sensitivities varied between 96.3% and 100.0%. All specificities were 98.8% to 100.0%. Coefficients of variation indicated good intralaboratory and interlaboratory repeatability and reproducibility but increased for decreasing concentrations. Prediction models revealed a significant correlation for all variants between the predefined copy number and the observed semiquantitative index values, which reflect the samples' plasma mutation load. This study demonstrates an overall robust performance of the real-time PCR EGFR mutation test kit in plasma. Prediction models may be applied to estimate the plasma mutation load for diagnostic or research purposes.

The Clinical and Economic Impact of Inaccurate EGFR Mutation Tests in the Treatment of Metastatic Non-Small Cell Lung Cancer.

Advances in personalized medicine are supported by companion diagnostic molecular tests. Testing accuracy is critical for selecting patients for optimal therapy and reducing treatment-related toxicity. We assessed the clinical and economic impact of inaccurate test results between laboratory developed tests (LDTs) and a US Food and Drug Administration (FDA)-approved test for detection of epidermal growth factor receptor (EGFR) mutations. Using a hypothetical US cohort of newly diagnosed metastatic non-small cell lung cancer (NSCLC) patients and EURTAC (erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer) clinical trial data, we developed a decision analytic model to estimate the probability of misclassification with LDTs compared to a FDA-approved test. We estimated the clinical and economic impact of inaccurate test results by quantifying progression-free and quality-adjusted progression-free life years (PFLYs, QAPFLYs) lost, and costs due to incorrect treatment. The base-case analysis estimated 2.3% (n = 1422) of 60,502 newly diagnosed metastatic NSCLC patients would be misclassified with LDTs compared to 1% (n = 577) with a FDA-approved test. An average of 477 and 194 PFLYs were lost among the misclassified patients tested with LDTs compared to the FDA-approved test, respectively. Aggregate treatment costs for patients tested with LDTs were approximately $7.3 million more than with the FDA-approved test, due to higher drug and adverse event costs among patients incorrectly treated with targeted therapy or chemotherapy, respectively. Invalid tests contributed to greater probability of patient misclassification and incorrect therapy. In conclusion, risks associated with inaccurate EGFR mutation tests pose marked clinical and economic consequences to society. Utilization of molecular diagnostic tests with demonstrated accuracy could help to maximize the potential of personalized medicine.

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

OBJECTIVE: To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. METHODS: In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). RESULTS: 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS: Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. METHODS: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. RESULTS: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status >or=90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. CONCLUSIONS: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

PURPOSE: This study was designed to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in ovarian cancer patients treated with low-dose cyclophosphamide and bevacizumab. EXPERIMENTAL DESIGN: Seventy recurrent/metastatic epithelial ovarian cancer patients were enrolled in a phase II clinical trial. Genomic DNA was available from 53 blood samples. Polymorphisms were analyzed using the PCR-RFLP protocol. A 5' end 33P gammaATP-labeled PCR protocol was used to analyze dinucleotide repeats. RESULTS: Patients genotyped A/A or A/T for the IL-8 T-251A gene polymorphism had a statistically significant lower response rate (19%; 0%) than those homozygous T/T (50%; P = 0.006, Fisher's exact test). Patients carrying a minimum one C allele (C/C; C/T) of the CXCR2 C+785T polymorphism showed a median progression-free survival (PFS) of 7.4 months compared with the PFS of 3.7 months for those homozygous T/T (P = 0.026, log-rank test). Patients with the VEGF C+936T polymorphism C/T genotype had a longer median PFS of 11.8 months, compared with those with the C/C and T/T genotype, which had median PFS of 5.5 months and 3.2 months, respectively (P = 0.061, log-rank test). Patients carrying both AM 3'end alleles < 14 CA repeats had the shortest median PFS of 3.4 months; patients with at least one allele > 14 repeats or both alleles > 14 repeats showed a median PFS of 6.4 months and 7.2 months, respectively (P = 0.008, log-rank test). CONCLUSION: Our data suggest that the IL-8 A-251T polymorphism may be a molecular predictor of response to bevacizumab-based chemotherapy. The CXCR2 C+785T, VEGF C+936T single nucleotide polymorphisms and the AM 3' dinucleotide repeat polymorphisms may be molecular markers for PFS in ovarian cancer patients.

Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.

PURPOSE: Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC. PATIENTS AND METHODS: Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially. RESULTS: Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (+/- 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome. CONCLUSION: The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.

Long-term results of maximally aggressive trimodality therapy in a high-risk subset of early-stage cervical cancer patients.

OBJECTIVE: To evaluate the long-term survival and treatment-related morbidity associated with treating patients who have early-stage cervical carcinoma metastatic to the paraaortic lymph nodes with radical hysterectomy, pelvic and paraaortic lymphadenectomy, and adjuvant, extended field chemoradiation with cisplatin and 5-fluorouracil (5-FU). STUDY DESIGN: From 1988 to 1997, 14 consecutive patients referred to Radiological Associates of Sacramento following radical hysterectomy and pelvic and paraaortic lymphadenectomy with findings of clinical stage IB or IIA cervical cancer and histologically confirmed lymph node metastasis to the common iliac or paraaortic distributions were treated with adjuvant, extended field chemoradiation utilizing prolonged infusion 5-FU and bolus cisplatin. Retrospective chart review was performed, and survival and morbidity information were analyzed. Recurrence was assessed among patients based on age, race, total number of nodes involved, gross vs. microscopic nodal involvement, squamous vs. nonsquamous tumor histology, time to initiation of adjuvant treatment and time required to complete that treatment. Calculated 5-year survival, mean survival, morbidity type and incidence are reported for the group as a whole. RESULTS: Calculated 5-year survival of patients in this series was 38% by life table analysis. Median survival was 4.4 years; 50% of patients had a recurrence. None of the examined parameters were significant predictors of recurrence. There was 1 treatment-related death and a second case of severe treatment-related morbidity (radiation enteritis requiring colostomy and bilateral ureteral stenosis requiring bilateral nephrostomies). There were 6 cases of minor treatment-related toxicity occurring in 5 of 14 (36%) treated patients. CONCLUSION: In general, survival in the current series of patients was akin to that in clinically similar patients treated with chemoradiation alone. Morbidity among our patients was significant. In the presence of positive paraaortic lymph nodes there were no independent predictors of recurrence among the pathologic or treatment parameters examined.

Low-dose warfarin does not decrease the rate of thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy, radiation, and erythropoeitin.

OBJECTIVES: We had previously reported an association between the use of recombinant human erythropoietin (rHuEPO) and thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy and radiation. We hypothesized that low-dose warfarin would be effective prevention for thromboembolic events in this setting. METHODS: A retrospective analysis of patients with cervical or vulvo-vaginal carcinoma receiving chemoradiation and rHuEpo was performed. Thirty-two patients received rHuEpo alone, and 24 received warfarin (1-2 mg) and rHuEpo. The primary endpoint was objectively proven symptomatic venous thrombosis. RESULTS: There was no difference in the baseline characteristics (e.g. age, stage, body mass index, mean and peak hemoglobin, WBC and platelet counts, and number of transfusions) between these two groups. The rate of thrombosis also was not statistically different (P = 0.62). Nine of 24 patients had a symptomatic deep vein thrombosis (DVT) while receiving warfarin compared to 10 of 32 patients not on warfarin. There was no difference between the two groups in the percentage of patients with upper extremity DVT (P = 0.83) or lower extremity DVT (P = 0.64). CONCLUSION: Daily low-dose warfarin did not alter the incidence of symptomatic DVT in patients with cervical or vulvo-vaginal cancer who received rHuEpo in conjunction with chemoradiation.

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group.

OBJECTIVES: To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. METHODS: Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. CONCLUSION: The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.

An evaluation of barriers to accrual in the era of legislation requiring insurance coverage of cancer clinical trial costs in California.

PURPOSE: Clinical trials are essential to improve cancer therapy, but only 3% of newly diagnosed adult cancer patients enroll annually. We previously conducted a prospective analysis of factors affecting trial accrual at the UC Davis Cancer Center between 1997 and 2000. It was found that the accrual rate was 14% and that patients with private insurance were significantly less likely than patients with government insurance to enroll, suggesting that fear of insurance denial was a barrier. In 2002, a new California law (SB37) required insurers to reimburse routine costs of care for cancer trials. METHODS: To assess the impact of SB37 on accrual, we repeated our study using the same sur vey instrument. Oncologists seeing new patients at the UC Davis Cancer Center from August to November 2002 completed questionnaires that inquired about patient characteristics and eligibility, protocol availability, and patient willingness to participate. RESULTS: Physicians considered clinical trials for 55% (118/216) of patients, but trials were available for only 53% (62/118). Eligibility criteria were met by 82% (51/62). Of these, 69% (35/51) agreed to participate (vs 51% previously). No patient declined to participate because of insurance limitations (vs 8% previously). Furthermore, insurance type was no longer a significant factor in determining whether patients would enroll. This suggests that although the overall rate of accrual is only slightly increased after passage of SB37, patients may be more willing to enroll. Efforts to increase participation must include enhancing physician and patient awareness of SB37.

Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: a Southwest Oncology Group study.

OBJECTIVES: To evaluate response rates, progression-free survival (PFS), overall survival (OS), and toxicity of two high-dose chemotherapy regimens with stem cell rescue used to treat patients with recurrent or persistent stage III/IV ovarian cancer, with the goal of taking one forward into a Phase III comparison with conventional therapy. METHODS: Patients under 65 with clinically or pathologically persistent disease after initial chemotherapy or those relapsing >6 months after a complete remission (CR) were randomized to CMC carboplatin (1500 mg/m(2)), mitoxantrone (75 mg/m(2)), and cyclophosphamide (120 mg/kg)], or CTC: [cisplatin (165 mg/m(2)), thiotepa (600 mg/m(2)), and cyclophosphamide (5625 mg/m(2))] with stem cell rescue. RESULTS: Of 67 randomized, the 32 and 26 eligible in the CMC and CTC arms were matched including age (median 49), maximum tumor diameter, and disease status at transplant. Low-risk disease (maximum diameter disease

Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer.

PURPOSE: To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA. EXPERIMENTAL DESIGN: To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients. RESULTS: Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean +/- SD end-of-infusion CSA level (HPLC assay) was 1253 +/- 400 microg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC. CONCLUSIONS: Steady-state levels of >1 microg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics.

Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin.

BACKGROUND: Because studies have suggested that anemia has an adverse effect on outcome for patients with cervical carcinoma who are treated with radiation, recombinant human erythropoietin (rHuEpo) has been used increasingly to maintain hemoglobin levels in these patients. Erythropoietin may increase the risk of thrombosis. The authors performed a retrospective analysis to determine whether there was an increased rate of symptomatic venous thrombosis associated with the use of rHuEpo in patients with carcinoma of the uterine cervix and vagina. METHODS: A retrospective, case-control study was performed on consecutive patients with localized carcinoma of the uterine cervix or vagina who were treated with chemotherapy and radiation (chemoradiotherapy). The primary outcome was symptomatic venous thrombosis. RESULTS: One hundred forty-seven patients were reviewed. When they were divided into women who received rHuEpo (n = 75 patients) and women who did not receive rHuEpo (n = 72 patients), there were no significant differences in age, height, weight, disease stage, or body mass index. Fewer patients in the rHuEpo group required transfusions. In the rHuEpo group, 17 of 75 patients had either an upper extremity thrombosis (n = 12 patients) or a lower extremity thrombosis (n = 7 patients): 2 patients had both, and 2 patients had more than 1 event. Two of 72 patients who did not receive rHuEpo had symptomatic thrombosis. Patients who received rHuEpo had an odds ratio (OR) of developing thrombosis of 10.3 (95% confidence interval [95% CI], 2.3-46.2). Multiple logistic regression revealed that only the use of rHuEpo was associated with an increased risk of thrombosis (OR, 15.3; 95% CI, 3.1-76.7). CONCLUSIONS: Patients with cervical carcinoma who received chemoradiotherapy and rHuEpo had an increased risk of symptomatic venous thrombosis.