Incidence and Clinical Characteristic of Venous Thromboembolism in Gynecologic Oncology Patients attending King Chulalongkorn Memorial Hospital over a 10 Year Period.

BACKGROUND: Venous thromboembolisms (VTEs) constitute a group of diseases including deep vein thrombosis (DVT) and pulmonary embolism (PE). They regarded as the second leading cause of death in cancer patients and several studies have confirmed that VTEs have a negative impact on survival and recurrent rate in both ovarian and endometrial cancer cases. The incidence of VTEs differs worldwide and depends on several risk factors including race, underlying disease, lifestyle, body weight, BMI and genetic risk factors. There is heterogeneity of DVT rates between Asian and Western countries. This study was conducted in order to evaluate the character and incidence of VTEs in gynecologic oncology patients in King Chulalongkorn Memorial Hospital over a 10 year period. MATERIALS AND METHODS: A retrospective chart review was performed with VTEs defined as objective diagnosis of acute DVT or PE with typical symptoms and signs. Diagnoses were approved byan internist and/ or confirmed with imaging studies. Data from both outpatient and inpatient sessions of the affected cases from January 2004 to December 2013 were extracted. General characteristics of the patients were collected with details of the diseases, types of cancer, stage, date of diagnosis of cancer, operative data, treatment outcome, progression free survival and overall survival. RESULTS: Thirty cases of VTEs were identified in a total 2,316 gynecologic oncology cases. The incidence of symptomatic VTEs in total gynecologic oncology patients in our institution is 1.295%. The incidence of VTEs in ovarian cancer patients in our institution was 5.9%. Duration for VTE detection ranged from 13 months before diagnosis of cancer to 33 months after diagnosis of cancer. Most of the VTE cases were detected in ovarian cancer patients (60%). The most common cell type was adenocarcinoma (moderately to poorly differentiated) which accounted for 26.7% of the cases. The second most common cell type was clear cell carcinoma with 23.3% of the cases. Thirty percent of VTE cases developed before cancer was diagnosed, 20% were diagnosed at the same time as cancer detection and fifty percent developed after cancer was diagnosed. Median disease free survival of the gynecologic oncology patients with VTE was 7.5 months. Median overall survival (OS) was 12 months. Median progession free survivals of DVT and PE groups were 11.5 and 5.5 months, respectively. OS of DVT and PE was 12.0 and 11.5 months respectively. CONCLUSIONS: The incidence of VTE in Asian countries is believed to be lower than in European or Western countries. From our retrospective review, the incidence of VTEs in all types of gynecologic oncology was 1.295%, much lower than reported in the West. The reason for the lower incidence may genetic differences. Another factor is that VTE in this review was symptomatic, which is less than asymptomatic VTE. More than half of VTEs in this study developed in ovarian cancer patients. The results are compatible with earlier reports that among gynecologic malignancies, the incidence of VTE is highest in ovarian cancer.

Salvage chemotherapy in recurrent platinum-resistant or refractory epithelial ovarian cancer with Carboplatin and distearoylphosphatidylcholine pegylated liposomal Doxorubicin (lipo-dox®).

BACKGROUND: To evaluate the efficacy and safety of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum resistant or refractory epithelial ovarian cancer (EOC) or fallopian tube cancer. MATERIALS AND METHODS: A retrospective analysis of women who received DPLD with carboplatin for recurrent EOC or fallopian tube cancer in King Chulalongkorn Memorial Hospital Thailand from January 2006 to August 2011 was conducted. Patients were identified from the medical records and data on demographic factors, stage, histology, surgical findings, cytoreduction status, and prior chemotherapies were abstracted. The efficacy and toxicity of DPLD/carboplatin were evaluated. Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: A total of 65 patients, 64 with platinum resistant or refractory epithelial ovarian cancer and 1 with fallopian tube cancer, were enrolled. DPLD and carboplatin were given for an average of 4.46 cycles per patient with a total of 273 cycles. Among the 65 evaluable patients, 0% achieved CR, 7.69% PR, 15.4% SD and 76.% PD. The overall response rate was 23.1%. With a median follow-up of 27.4 months, the median progression-free and median overall survival in the 36 patients was 4.46 months and 8.76 months respectively. In the aspect of side effects, palmar-plantar erythrodysesthesia (PPE) occurred in 33.3% (Grade I 22.2%, Grade II 11.1%) and mucositis in 41.7% (Grade I 27.8%, Grade II 13.9%) of all treatment cycles, all Grade 1 or 2. Anemia, leukopenia and thrombocytopenia occurred in 58.3% (Grade I 41.7%, Grade II 16.7%), 66.7% (Grade I 47.2%, Grade II 19.4%), and 22.2% (Grade I 16.6%, Grade II 5.56%) of cycle respectively, and were mostly Grade 1 or 2. CONCLUSIONS: DPLD, the second-generation PLD drug combined with carboplatin every 4 weeks, is effective and has low toxicity for treatment of patients with recurrent platinum-resistant or refractory epithelial ovarian cancer.

Model for predicting the burden and cost of treatment in cervical cancer and HPV-related diseases in Thailand.

PURPOSE: Cervical cancer is a significant health burden in many countries. Long-term cost of care is still not well understood. We aimed to evaluate the long-term burden of illness and healthcare resource utilization associated with cervical cancer, cervical intraepithelial neoplasia (CIN) and genital warts from the care provider perspective. METHOD: We developed a health state-transition Markov model to portray the algorithm of treatment of stages of cervical cancer, CIN and genital warts by tracking a hypothetical lifetime cohort of 12-year-old girls. Costs in this study were unit cost; capital costs and labor costs were included in the unit cost for inpatients and out-patients. RESULTS: The highest incidence of CIN and genital warts was observed in women aged 20-30 years old. For cervical cancer, the highest incidence was 45-55 years. Death rate was estimated at 2%, 8%, 84% and 94% in cervical cancer Stage IA1, IA2-IIA, IIB-IVA and IVB, respectively. The estimated mean direct cost per patient with cervical cancer Stage IA1, IA2-IIA, IIB-IVA, IVB, CIN1, CIN2/3 and genital warts were 41,117 Thai Baht ($1,277 US), 97,250 Thai Baht ($3,020 US), 402,683 Thai Baht ($12,506 US), 322,619 Thai Baht ($10,019 US), 5,381 Thai Baht ($167 US), 49,933 Thai Baht ($1.551 US) and 3,585 Thai Baht ($111 US), respectively. Cost for survival or death case was indifferent. The overall lifetime costs from the provider perspective were evaluated at 859.1 million Baht ($26.7 million US) per a cohort of 100,000 women which corresponds to approximately 4,244 million Baht ($131.8 million US) for the current number of Thai 12-year-old girls. CONCLUSIONS: HPV-related diseases impose health and cost burdens in Thailand. The national immunization programme to reduce this burden as well as further research to evaluate the impact is keenly expected.

Neoadjuvant gemcitabine and cisplatin followed by radical surgery in (bulky) squamous cell carcinoma of cervix stage IB2.

OBJECTIVES: This study aimed to evaluate the efficacy and toxicity of gemcitabine in combination with cisplatin as neoadjuvant therapy in patients with cervical carcinoma stage IB2. PATIENTS AND METHODS: Chemotherapy-naive patients with histologic diagnosis of squamous cell cervical carcinoma staged as IB2 were treated with 2 cycles of cisplatin (70 mg/m(2) on day 1) and gemcitabine (1000 mg/m(2) on days 1 and 8), given every 21 days. After chemotherapy, patients underwent radical hysterectomy and pelvic lymphadenectomy. Patients judged to have a non-resectable disease were treated with standard pelvic radiation. RESULTS: Between September 2000 to March 2004, 28 patients were enrolled in the study, of which 27 were evaluable for efficacy and toxicity. The mean age was 39 years (30-55). The overall clinical response rate was 88.9% (24/27), with complete response (CR) in 9/27 patients (33.3%) and partial response in 15/27 patients (55.5%). Three patients (11.1%) did not respond and nobody progressed. A pathological CR was noted in 2 of 24 patients who underwent radical surgery. The 3 non-responding patients were subsequently treated with radiation and achieved CR. Grades 3 or 4 neutropenia, anemia, or thrombocytopenia was observed in 18.5%, 7.4%, and 3.7% patients respectively. Non-hematological toxicity was mild except grade 3 nausea/vomiting in 18.5% patients. At median follow-up time of 36.7 months (range 7-51 months), the 3-year survival was 88.9%. CONCLUSION: Neoadjuvant treatment with gemcitabine/cisplatin combination for patients with cervical cancer (stage IB2) appears encouraging, with manageable and acceptable toxicity profile.

Results of radiation therapy in stage 1B cervical carcinoma at King Chulalongkorn Memorial Hospital: fifteen-year experience.

A retrospective study was performed on 131 patients with stage 1B cervical carcinoma who were referred and treated with external beam radiation and intracavitary brachytherapy at the Division of Radiation Therapy, Department of Radiology, King Chulalongkorn Memorial Hospital between February 1985 and February 2000. Primary outcomes were overall survival rate, progression free survival rate, recurrence, and treatment-related complications. The treatment results from different sources of intracavitary radiation therapy were secondary endpoints. The number of patients treated with Ra-226, Cs-137, and Ir-192 intracavitary irradiation were 12, 84, and 35 patients respectively. The median follow-up times were 69, 59, and 21 months for Ra-226, Cs-137, and Ir-192, respectively. Actuarial 5-year overall survival rate was 89 per cent. The 5-year progression free survival rate was 80 per cent. Actuarial 5-year survival and progression free survival rate were comparable among different sources of intracavitary brachytherapy (p = 0.553 and p=0.793, respectively). The overall recurrent rate was 16.8 per cent. Of the recurrence; 40.9 per cent was locoregional, 54.6 per cent was distant failure, and 4.5 per cent was combined locoregional and distant failure. The overall complication rate was 25.95 per cent. The severe complication rates (Grade III-V) from treatment occurred in the urinary bladder (0.76%) and in the small bowel (0.76%.) These results suggest that radiation therapy alone is an effective treatment for stage 1B cervical carcinoma. Additionally, all types of intracavitary brachytherapy provide comparable clinical results.

Human papillomavirus DNA in plasma of patients with cervical cancer.

BACKGROUND: Human papillomavirus (HPV) is a crucial etiological factor for cervical cancer (CC) development. From a diagnostic view-point, the consistent presence of HPV in CC allows the viral DNA to be used as a genetic marker. The aims of this study were to evaluate the presence, physical status and clinical significant of HPV DNA in circulation of CC patients. RESULTS: Whereas 6 out of 50 (12%) HPV positive CC patients revealed plasma HPV DNA, it was detected in none of 20 normal controls or 13 HPV negative CC cases. The plasma DNA exhibited an HPV type identical to the HPV in the primary tumors and the DNA from both sources was integrated into host genome. Interestingly, several findings suggested an association between plasma HPV DNA and metastasis. First, three of the HPV DNA positive cases were CC patients with clinical stage IVB or recurrence with distance metastases (P = 0.001, RR = 15.67). Second, the amount of plasma HPV DNA from metastatic patients to be three times more than three other patients without metastases. Finally, the later cases had tendency to develop recurrence distant metastases within one year after complete treatment when compared with other HPV associated CC patients with the same stage but without the present of plasma HPV DNA. CONCLUSIONS: The plasma HPV DNA originated from the CC, was associated with metastasis and could be used as a marker representing the circulating free CC DNA.

Phase II study of high-dose paclitaxel in platinum-refractory epithelial ovarian cancer.

The purposes of this study were to determine the efficacy of paclitaxel, using a dose of 200 mg/m2 intravenous continuous infusion over 24 hours every three weeks in the treatement of platinum-refractory epithelial ovarian cancer (EOC) and to evaluate the toxicities. Eligibility criteria included: histologically proven EOC, platinum resistance, measurable disease, Zubrod performance status grade 0-2, expected survival of > 3 months and adequate hematological function. Response was assessed at three-cycle intervals or earlier if required. Twenty-one patients were recruited in this study. The response rate was 52% (2 CR, 9 PR) with a median duration of response of six months. The median progression-free interval was eight months and the median survival was 12 months. Leukopenia was the predominant toxic effect. Eighty-six percent of patients required granulocyte-colony stimulation factor (G-CSF). All patients had alopecia grade 3. In conclusion, high-dose paclitaxel is active in platinum-refractory EOC with manageable toxicities.

13-cis-retinoic acid and interferon-alpha 2a therapy in locally advanced squamous cell carcinoma of the cervix: p53 alteration, proliferating cell nuclear antigen expression and angiogenesis response.

OBJECTIVE: To evaluate prognostic importance of p53, PCNA and vascularization alteration in patients with locally advanced cervical squamous cell carcinoma (SCC) after combination therapy with 13-cis-retinoic acid (13cRA) and interferon-alpha 2a (IFN-alpha 2a). METHODS: 13cRA and IFN-alpha 2a were administered to patients with locally advanced cervical SCC. Formalin fixed, paraffin embedded tissues sections obtained at pre- and post-therapy, respectively, were stained immunohistochemically with anti-p53, anti-PCNA and anti CD31. RESULTS: p53 alteration was demonstrated in 5/10 patients and 3/10 patients pre- and post-therapy, respectively. There was no correlation between p53 alteration and prognosis. After therapy, two patients with complete response had lower PCNA expression whereas the non-responders demonstrated the opposite result. The vascularization showed a correlation with PCNA and prognosis. In the response group, patients had lower microvessel count while the metastatic group exhibited higher count. CONCLUSIONS: The present study suggests that p53 alteration is neither related to the prognosis of cervical SCC nor is it influenced by the combination therapy while PCNA expression and vascularization might be constitute potential markers for tumorigenesis, prognosis and responsiveness to this novel regimen.

Gynecologic cancer in the elderly.

Ovarian and endometrial cancers are diseases of the aging process. The complications of treatment are those of comorbid illness and the extent of cancer rather than of advanced age. Elderly patients are diagnosed initially with more advanced disease.

Complete remission of refractory gestational trophoblastic disease with brain metastases treated with multicycle ifosfamide, carboplatin, and etoposide (ICE) and stem cell rescue.

Patients with chemotherapy-refractory gestational trophoblastic disease and brain metastasis are considered to have a very poor prognosis. We present the case of a patient who had failed several chemotherapeutic regimens. Despite transient responses to chemotherapy, she had not achieved a complete remission in 3 years, and had developed systemic disease and recurrent brain metastasis. She was treated with four cycles of high-dose ifosfamide, carboplatin, and etoposide with blood progenitor cell support. She tolerated this regimen well and has obtained a complete remission that is ongoing for 12 months.

Prolonged oral etoposide for advanced uterine leiomyosarcoma with pulmonary metastases: case report.

A patient who had a high grade uterine leiomyosarcoma with intraabdominal and pulmonary metastases at the time of diagnosis underwent supracervical hysterectomy, bilateral salpingo-oophorectomy and tumor reductive surgery. Induction chemotherapy achieved a partial response with small amount of residual disease. On achieving a plateau in the response to her induction chemotherapy, she was switched to prolonged oral etoposide at a dose of 50 mg/m2/day 21 days with a 7-day rest period between cycles. Follow up imaging revealed stable disease with a slight decrease in the size of the paraaortic lymphnodes. Prolonged oral etoposide may be considered in patients with advanced high grade leiomyosarcoma of the uterus.

Remission of refractory gestational trophoblastic disease in the brain with ifosfamide, carboplatin, and etoposide (ICE): first report and review of literature.

Gestational trophoblastic disease (GTD) metastatic to the brain has a very poor prognosis with a survival rate of less than 25%, especially for patients in whom brain metastases develop while on or after chemotherapy. Cure can be achieved by chemotherapy alone. The regimen of etoposide, methotrexate, actinomycin-D, vincristine, and cyclophosphamide has shown encouraging results and is considered to be standard first-line treatment for high risk patients. For patients in whom this regimen fails, a salvage chemotherapy regimen is used. The combination of ifosfamide, carboplatin, and etoposide (ICE) has synergistic activity in preclinical studies. This regimen has shown activity in metastatic breast cancer and non-small-cell lung cancer as well as platinum-resistant germ-cell tumors and metastatic GTD. This is the first report of a patient with a highly refractory GTD in whom brain metastasis developed while on chemotherapy, and whose brain metastasis went into remission with a low dose ICE regimen. Accordingly, ICE may be considered for patients with chemotherapy refractory GTD metastatic to the brain.

A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.

Remission of advanced uterine leiomyosarcoma with pulmonary metastases with carboplatin and paclitaxel.

A patient who had a high-grade uterine leiomyosarcoma (LMS) with extensive intra-abdominal and pulmonary metastases at the time of diagnosis underwent supracervical hysterectomy, bilateral salpingo-oophorectomy and tumor reductive surgery. She then received induction chemotherapy with paclitaxel 135 mg/m2 over 24 h and carboplatin (target AUC = 7.5 mg.ml/min) monthly for seven courses, achieving remission with a small amount of residual disease. The treatment was well tolerated except for peripheral neuropathy. Accordingly, the combination of carboplatin and paclitaxel may be considered in patients with advanced high-grade LMS of the uterus, and this regimen warrants further study in this disease.

Prolonged stabilization of progressive squamous cell cancer of the cervix with interferon-alpha and 13-cis-retinoic acid: report of two cases and review of the literature.

Recurrent and metastatic cervical carcinoma has very poor prognosis, mainly because there is no effective systemic therapy which would increase the duration of survival. Biologic agents have recently been found to have activity in cervical carcinoma. The combination of interferon (IFN)-alpha and 13-cis-retinoic acid had additive and synergistic antitumor activity. Both have antiviral, immunoregulatory and antiangiogenic properties, and are known to modulate malignant cell differentiation and proliferation. We report two patients with recurrent squamous cell carcinoma (SCC) of the cervix who had small-volume progressive metastatic disease, and were treated with a combination of IFN-alpha and 13-cis-retinoic acid. The first patient had pelvic lymph node metastases and the other had lung metastases. The previously progressive diseases remained stable for a prolonged period of time, 3 and 4 years, with a good quality of life. These cases suggest the possibility of using IFN-alpha and 13-cis-retinoic acid as a treatment for small-volume residual disease or as postinduction therapy in patients at high risk for disease recurrence.

Effects of interleukin-1 alpha on ovarian carcinoma in patients with recurrent disease.

The aim of this study was to evaluate the safety and the biological effects of interleukin (IL-1 alpha) in patients' with recurrent ovarian carcinoma treated with carboplatin. In this phase I study, IL-1 alpha was administered by a continuous intravenous infusion at doses ranging 0.1-10 micrograms/m2 every 24 h for 4 days (96 h) 3 weeks before the first dose of carboplatin (400 mg/m2) in patients with potentially platinum-sensitive ovarian cancer. The maximum tolerated dose was 3 microgram/m2/day. Dose-limiting effects at 10 micrograms/m2/day were fever, chills, hypotension and fluid retention. Minor but objective antitumour effects were observed in 2 of 18 patients. 4 patients (including 1 with a minor response) had a decrease of the CA-125 serum level ranging from 33 to 39%. The trial design precluded evaluation of the duration of response to single-agent IL-1 alpha. Based on this trial design, there is evidence of minor antitumour effect to a single course of IL-1 alpha dose given prior to chemotherapy.

Remission of refractory gestational trophoblastic disease with high-dose paclitaxel.

High-risk metastatic gestational trophoblastic disease (GTD) in patients who have failed primary chemotherapy has a very poor prognosis. About 25% of women with high-risk metastatic disease become refractory to EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine) and fall to achieve a complete remission. Currently, there is no standard salvage chemotherapeutic regime for EMA-CO failure. Paclitaxel, a taxane analog extracted from the bark of the western yew (Taxus brevlfolla), has shown antitumor activity in a variety of cancer cell lines. High in vivo efficacy was confirmed in phase II trials, especially for breast and epithelial ovarian cancer patients. Recently, two in vitro studies have shown that paclitaxel is a highly effective antineoplastic agent in choriocarcinoma cell lines. We present the first clinical report of a serologic remission with high-dose paclitaxel (250 mg/m2 i.v. infusion over 24 h every 3 weeks) of a highly refractory GTD in a patient who developed brain metastasis after multiple combined chemotherapeutic regimens. The patient tolerated paclitaxel with granulocyte colony stimulating factor support very well. The remission with paclitaxel in this patient confirms its preclinical activity in high-risk, refractory GTD.

Paclitaxel in patients with platinum-resistant ovarian cancer: a selected review of literature and clinical experience.

Single-agent paclitaxel infused over 24 hours produces response rates of 10 per cent to 20 per cent and 48 per cent respectively, for doses of 135 mg/m2 and 250 mg/m2. This suggests a dose response relationship. However, only a randomized trial comparing the 135 mg/m2 and 250 mg/m2 doses can confirm this result. Unfortunately, the median survival is comparable despite the difference in response rates. This may be secondary to a low CR noted at all doses. The apparent lack of benefit in terms of increased survival for the high dose group, with its attendant increase in incidence of toxic effects and cost (owing to both the paclitaxel and the G-CSF), suggest that the role of higher doses remains to be proven. It may be most useful in alleviating the severe cancer induced symptoms of some patients with advanced platinum resistant ovarian cancer(19). Despite the extensive international experience with paclitaxel in the ovarian cancer clinic its role still needs to be better defined both for salvage therapy and in combination with platinum as a front-line treatment.

Remission of recurrent cervical cancer with paclitaxel and carboplatin: a case report and review of literature.

We report the case of a patient with recurrent squamous cell carcinoma of the cervix, that metastasized to the paraaortic and supraclavicular lymph nodes and the lungs after primary radiotherapy for stage IIB. The tumor was refractory to multiple drug regimens. A combination of paclitaxel (135 mg/m2 intravenous infusion over 24) hours and carboplatin with a target area under the curve of 7.5 mg-min/mL were then administered and repeated every 4 weeks. The patient tolerated the chemotherapy well with myeloprotection from granulocyte colony-stimulating factor and the disease went into remission. Thus, the combination of paclitaxel and carboplatin may have antitumor activity in advanced or recurrent squamous cell carcinoma of the cervix.