Lynda D. Roman

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

PURPOSE A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory 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.

Clinical Activity of Pertuzumab (rhuMAb 2C4), a HER Dimerization Inhibitor, in Advanced Ovarian Cancer: Potential Predictive Relationship With Tumor HER2 Activation Status

PURPOSE Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC. PATIENTS AND METHODS Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2). RESULTS Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD > or = 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2- (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility). CONCLUSION Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.

Phase II Trial of Bevacizumab in the Treatment of Persistent or Recurrent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

PURPOSE Vascular endothelial growth factor is a key promoter of tumor progression in cervical carcinoma. The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of bevacizumab, a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody. PATIENTS AND METHODS Eligible patients had recurrent cervical cancer, measurable disease, and GOG performance status < or = 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and toxicity. RESULTS Forty-six patients were enrolled (median age, 46 years); 38 patients (82.6%) received prior radiation as well as either one (n = 34, 73.9%) or two (n = 12, 26.1%) prior cytotoxic regimens for recurrent disease. Grade 3 or 4 adverse events at least possibly related to bevacizumab included hypertension (n = 7), thrombo-embolism (n = 5), GI (n = 4), anemia (n = 2), other cardiovascular (n = 2), vaginal bleeding (n = 1), neutropenia (n = 1), and fistula (n = 1). One grade 5 infection was observed. Eleven patients (23.9%; two-sided 90% CI, 14% to 37%) survived progression free for at least 6 months, and five patients (10.9%; two-sided 90% CI, 4% to 22%) had partial responses. The median response duration was 6.21 months (range, 2.83 to 8.28 months). The median PFS and overall survival times were 3.40 months (95% CI, 2.53 to 4.53 months) and 7.29 months (95% CI, 6.11 to 10.41 months), respectively. This compared favorably with historical phase II GOG trials in this setting. CONCLUSION Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with recurrent cervical cancer and merits phase III investigation.

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 γATP-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, Fishers 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.

Radical vaginal trachelectomy and pelvic lymphadenectomy for preservation of fertility in early cervical carcinoma

OBJECTIVE The aim of this study was to examine our experience with radical vaginal trachelectomy in women with early cervical cancers who desire to maintain fertility. METHODS Women who underwent radical vaginal trachelectomy with pelvic lymphadenectomy over a 6-year period are the basis of this report. Subjects were selected for this treatment on the basis of favorable cervical tumors and a desire to maintain fertility. All subjects were informed that this therapy did not represent standard treatment for early stage cervical cancer. Obstetrical and oncologic outcomes were evaluated. RESULTS Twenty-one women underwent this procedure. The median age was 30 years (range 23-41); 14 were nulligravid and 16 were nulliparous. Mean tumor diameter was 1.1 cm (range 0.3-3.0). Mean operative time was 318 min, with a mean blood loss of 293 cc, and average hospital stay was 3 days. Three patients had transient neuropathy postoperatively. No patient required laparotomy. Two patients had completion of radical vaginal hysterectomy for an inability to clear the cancer with trachelectomy and 1 had postoperative radiation for high-risk features on final pathology. With an average follow-up of 31.5 months, there have been no recurrences. Three women have become pregnant: 1 woman delivered twins at 24 weeks, 1 woman delivered a singleton at term, and 1 patient had rupture of membranes and chorioamnionitis at 20 weeks gestation. CONCLUSIONS Radical vaginal trachelectomy with pelvic lymphadenectomy permits preservation of fertility in selected patients. To date, with more than 150 cases reported in the literature, recurrence rates are comparable to those seen with radical hysterectomy.

Cervical cancer in pregnancy : reporting on planned delay in therapy

Objective:To report our experience with invasive carcinoma of the cervix during pregnancy, assessing maternal morbidity due to treatment delay and reporting maternal and fetal outcome.Methods:Twenty-seven patients with invasive cervical cancer, who were pregnant at the time of diagnosis or treatment

Cold-knife conization versus conization by the loop electrosurgical excision procedure: A randomized, prospective study

Abstract Objective: Our purpose was to compare the diagnostic ability and treatment efficacy of conization by the loop electrosurgical excision procedure with cold-knife conization. Study Design: One hundred eighty women who required conization for diagnosis and treatment of cervical dysplasia or microinvasive cervical carcinoma were prospectively enrolled in a randomized clinical trial to receive either cold-knife conization or conization by the loop electrosurgical excision procedure. Conization complications, rate of lesion clearance, and therapeutic outcome were assessed for the 2 study groups. Results: There were no statistically significant differences in the complication rate ( P = 1.00), the rate of lesion clearance ( P = .18), or the rate of disease recurrence ( P = .13) between the 2 study groups. The mean follow-up was 11.2 months in the cold-knife conization group and 10.4 months in the loop-excision conization group. Conclusion: Cold-knife conization and loop-excision conization yield similar diagnostic and therapeutic results. (Am J Obstet Gynecol 1999;180:276-82.)

Pelvic examination, tumor marker level, and gray-scale and Doppler sonography in the prediction of pelvic cancer.

Objective To determine the ability of pelvic examination, tumor marker assessment, and transvaginal ultrasonography, with selected use of Doppler ultrasonography, to predict pelvic malignancy. Methods Two hundred twenty-six women scheduled for operative removal of a pelvic mass were entered in the study prospectively. Each woman underwent pelvic examination, tumor marker assessment, and transvaginal ultrasonography preoperatively. Women whose gray-scale findings were suspicious for malignancy underwent Doppler ultrasonography. Suspicious findings included masses that were fixed or irregular on pelvic examination; CA 125 level greater than 35 U/mL; elevations in serum lactic dehydrogenase, alphafetoprotein, or hCG; and the presence of a substantial solid component on gray-scale ultrasonography. Suspicious Doppler findings included intratumoral color flow, pulsatility index less than 1.0, or resistance index 0.4 or lower. The findings were correlated with the presence of malignancy. Results If all three indicators (examination, tumor marker assessment, and gray-scale ultrasound findings) were nonsuspicious, 99% of premenopausal women and 100% of postmenopausal women had benign masses. If all three indicators were suspicious, 77% of premenopausal women and 83% of postmenopausal women had malignant tumors. Logistic regression identified ultrasound impression and tumor size to be significant predictors of malignancy in premenopausal women, whereas CA 125 level and ultrasound impression were significant in postmenopausal women. In patients with suspicious gray-scale findings, recategorization based on Doppler findings resulted in inferior diagnostic indices. Conclusions Ultrasonographic tumor size and appearance are the best predictors of pelvic malignancy in premenopausal women, whereas CA 125 level and ultrasonographic appearance are the best predictors in postmenopausal women. Neither color nor spectral Doppler is useful in this setting.

Overcoming platinum resistance in ovarian carcinoma

Importance of the field: Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy, including platinum. Because response rates for current treatment regimens are relatively similar and unfortunately low, no standard chemotherapy for platinum-resistant ovarian cancer exists. Areas covered in this review: A systematic literature review of clinical studies published between January 2005 and March 2010 was conducted using search engines, PubMed and MEDLINE with the entry keywords ‘ovarian cancer’ and ‘platinum resistance’. This search revealed 40 clinical trials (1793 patients). What the reader will gain: Gemcitabine was the most common drug used in clinical trials reporting higher response rates, ≥ +1 SD of overall response rate (5 out of 8). Gemcitabine-based combination therapy showed an average response rate of 27.2% (95% CI, 22.4 – 32.0). Combination of gemcitabine and pegylated liposomal doxorubicin (PLD) was the most common regimen (n = 3) and was associated with possible additive effects in platinum-resistant ovarian cancer patients: response rate, gemcitabine alone 6.1%, PLD alone 19.8%, and gemcitabine with PLD 28.7% (95% CI, 20.4 – 37.0), respectively. Take home message: Analysis of recent clinical trials showed that gemcitabine-based combination chemotherapy was associated with the highest antitumor effects in platinum-resistant ovarian cancer patients during the study period.