Judith K. Wolf

Rankings and symptom assessments of side effects from chemotherapy: Insights from experienced patients with ovarian cancer

Goals of workAlthough many patients with ovarian cancer achieve favorable responses to primary chemotherapy, the majority of women will experience recurrence of their cancer. Selection of second- or third-line chemotherapy ultimately depends on patient preferences for different side effects. To better understand this process, we evaluated preferences and symptom distress in patients with ovarian cancer.Patients and methodsA total of 70 women with ovarian cancer who had previously received at least three cycles of platinum-based chemotherapy and currently undergoing chemotherapy for newly diagnosed or recurrent disease were interviewed in an outpatient chemotherapy clinic. The patients were asked to rank order 27 health states using a modified visual analog scale and to complete the Memorial Symptom Assessment Scale (MSAS).Main resultsMost favorable health states included perfect health, clinical remission and complete control of chemotherapy-induced nausea and vomiting (CINV). Least favorable health states included more severe CINV health states and death. Patients on first-line chemotherapy had less symptom distress, and rated sexual dysfunction, fatigue and memory loss more favorably than patients on second- or third-line chemotherapy (P<0.05). Married patients generally had less symptom distress compared to patients who were not married, but married patients indicated more distress with sexual dysfunction (P=0.04). Married patients rated alopecia less favorably than unmarried patients (P=0.03), but married patients viewed certain CINV health states more favorably (P=0.02–0.04).ConclusionsCINV remains one of the most dreaded side effects of chemotherapy. Separate preference profiles exist for patients with newly diagnosed and recurrent disease, as well as for married versus unmarried patients. While MSAS scores and VAS rankings showed consistency across some health states, this was not true for CINV, suggesting that current symptom status may only influence patient preferences for selected side effects.

Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects : a phase I clinical trial

PURPOSE Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

Ovarian and extraovarian endometriosis-associated cancer

OBJECTIVE To determine clinical characteristics of women with endometriosis‐associated intraperitoneal cancers, to assess differences based on the relationship of the cancer to the endometriosis, and to assess factors associated with survival. METHODS A search of medical records at The University of Texas M. D. Anderson Cancer Center from 1970 to 1999 identified patients who had synchronous endometriosis and intraperitoneal cancer. Demographic and clinicopathologic characteristics were evaluated for differences based on the relationship of the cancer to the endometriosis and for correlation with survival. RESULTS One hundred fifteen patients were identified: 25 patients with ovarian cancer arising in endometriosis, 21 with an extraovarian cancer arising in endometriosis, 33 patients with endometriosis and ovarian cancer in the same location but without a definite transition point, and 36 patients with ovarian cancer and incidental endometriosis. Women with extraovarian cancers arising in endometriosis were more likely to be postmenopausal (P < .001) and use hormone replacement (P < .001). The median age was 47 years, the most common histological tumor types were clear cell and endometrioid (23% each), and the most common stage was stage I (31%). The median survival was 35 months. Univariate survival analysis revealed that gravidity (P < .038), grade (P < .001), stage (P < .001), histology (P < .01), and type of chemotherapy (P < .011) correlated with survival. Multivariable analysis revealed that stage and gravidity independently predicted survival. CONCLUSION Women with endometriosis‐associated cancers are typically premenopausal, have a high incidence of endometrioid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival.

A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma

Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol‐3‐kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up‐regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR.

BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas.

Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.

Adenocarcinoma in situ of the cervix: Significance of cone biopsy margins

Objective To evaluate the treatment and outcome of patients with adenocarcinoma in situ of the cervix, with special emphasis on cone biopsy margins. Methods Sixty-one women with adenocarcinoma in situ of the cervix treated between April 1984 and December 1993 were identified. Medical records and histologic material were reviewed. Mixed lesions with both adenocarcinoma in situ and squamous cervical intraepithelial neoplasia (CIN) were included. Results The mean age of the patients was 35.9 years. Fifty-five of the 61 (90%) patients had cone biopsies, and 44 of these 55 (80%) subsequently had hysterectomies. Eight women (13%) had associated invasive cancer. Among 50 patients in whom the status of the margins was confirmed, 23 (46%) had positive margins and 27 (54%) had negative margins. Of 23 women with positive margins, 19 had hysterectomies and ten of the 19 (53%) had residual disease in the uterus. Of 27 patients with negative cone margins, 21 had hysterectomies, and seven of the 21 (33%) had residual disease in the uterus. Two women with negative margins who did not have hysterectomies developed recurrent disease. Fifty-five of the total series of 61 patients followed-up for a median of 57 months (range 17–132) had no evidence of disease at last follow-up. Conclusion Women with adenocarcinoma in situ of the cervix often have residual disease in the uterus, regardless of whether the margins on cone biopsy are positive or negative.

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

Sequential treatment with azacitidine can induce re‐expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b‐2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum‐resistant or platinum‐refractory epithelial ovarian cancer.

Phase II Trial of Irinotecan in Patients With Metastatic Epithelial Ovarian Cancer or Peritoneal Cancer

PURPOSE To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer. PATIENTS AND METHODS Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m2 intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m2 because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response. RESULTS The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred. CONCLUSION Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer.

Therapeutic Targeting of ATP7B in Ovarian Carcinoma

Purpose: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models. Experimental Design: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). Results:ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC50 levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH2-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis. Conclusion: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance.

Dosing chemotherapy in obese patients : Actual versus assigned body surface area (BSA)

Obesity is a chronic disease that has increased dramatically in the past few decades worldwide. More concerning, obesity is linked to many other disease states including cancer and has been shown to increase mortality. Unfortunately, oncology drug development and most clinical trials fail to address the problem of appropriate chemotherapy dosing in obese patients. This can potentially lead to either increased toxicity or decreased efficacy. Although dosing schemas may vary among practices and institutions, many oncologists tend to remain conservative and empirically dose-reduce obese patients despite data suggesting otherwise. The goals of this review were to consider the various aspects of pharmacokinetics in obese patients, to examine the existing literature regarding chemotherapy dosing in obese patients, and to determine the most appropriate weight estimation for body surface area (BSA) dose calculations. Based upon the current clinical data of obesity and chemotherapy dosing it can be concluded there is very limited if any data to support the perception that capping the doses of obese patients is beneficial and more likely this practice may have negative implications on survival outcomes. Under dosing patients with treatable or even curable disease to prevent toxicities could be costing the obese oncology patient population months to years of overall survival.