Damrong Tresukosol

Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma.

PURPOSE To determine the efficacy and toxicity of topotecan administered as a 5-day intravenous infusion in patients with advanced ovarian cancer refractory to cisplatin-based chemotherapy. PATIENTS AND METHODS Thirty patients with advanced epithelial ovarian cancer refractory to cisplatin-based chemotherapy received intravenous infusions of topotecan 1.5 mg/m2 delivered over 30 minutes each day for 5 days. A course was repeated every 21 days. The patient eligibility requirements included age > or = 18 years, Zubrod score < or = 2, measurable disease, adequate hepatic and renal function, neutrophil count > or = 1,500/microL, platelet count > or = 100,000/microL, and anticipated survival > or = 3 months. RESULTS Twenty eight patients were assessable for response and toxicity. All patients were assessable for survival. The major toxicity from administration of topotecan at this dose schedule was myelosuppression; 21 patients required dose reductions. Four patients had neutropenic fever that required hospitalization, and seven patients required platelet transfusions. Maculopapular pruritic exanthema occurred in 20% of patients; gastrointestinal side effects were mild. No deaths were reported on the study. At dose levels of 1.5, 1.25, and 1.0 mg/m2, 61%, 31%, and 25% of patients, respectively, required dose reductions. Of 28 assessable patients, four (14%; 95% confidence interval [CI], 4% to 34%) achieved a partial response (PR) at a median of 1.4 months and lasting 8.9 months, and 17 had stable disease (SD). The overall median survival time was 10.0 months (95% CI, 8.1 to 13.5). CONCLUSION Topotecan shows modest clinical activity against cisplatin-refractory ovarian cancer, although the dose-intensity is compromised by the depth of the granulocyte nadir and the duration of granulocytopenia. Further studies of topotecan may necessitate a reevaluation of optimal dose schedule, with the possible incorporation of multilineage cytokines, and its activity in taxane-resistant tumors.

Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer.

PURPOSE To determine the activity of carboplatin in patients with ovarian cancer who progressed on taxane (paclitaxel or docetaxel) therapy. PATIENTS AND METHODS Thirty-three patients with ovarian cancers refractory to platinum and taxane therapy were treated with single-agent carboplatin reinduction once the disease progressed on a taxane. The starting dose of carboplatin was 300 mg/m2 at 28-day intervals. RESULTS Patients were a median age of 56 years (range, 31 to 80), had a median Zubrod performance status of 1 (range, 0 to 2) and had received a median of three prior chemotherapy regimens (range, two to eight) and one pretaxane platinum regimen (range, one to three). Twenty-six patients had a platinum-free interval of at least 12 months at the time of posttaxane re-treatment with carboplatin. There were seven of 33 (21%) partial responses, with a median duration of 7+ months (range, 2+ to 12+). Responses were noted only in patients with at least a 12-month platinum-free interval and an initial sensitivity to a taxane. The therapy was well tolerated and neurotoxicity was absent. CONCLUSION A subset of patients with platinum-refractory disease that initially responded to a taxane and who eventually have a platinum-free interval of at least 1 year may respond to carboplatin reinduction. This finding may be secondary to paclitaxel or docetaxel therapy that leads to the reversal of platinum resistance, or the prolonged platinum-free interval permits the loss of resistance to platinum by the tumor. Carboplatin reinduction should be considered in the treatment of patients whose ovarian cancer progresses after an initial sensitivity to a taxane and who had a prolonged platinum-free interval.

Cyclin A1 promoter hypermethylation in human papillomavirus-associated cervical cancer

BackgroundThe aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirus-associated cervical cancer. Y. Tokumaru et al., Cancer Res64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development.MethodsIn this study, we performed duplex methylation-specific PCR and reverse transcriptase PCR on several cervical cancer cell lines and microdissected cervical cancers. Furthermore, the incidence of cyclin A1 methylation was studied in 43 samples of white blood cells, 25 normal cervices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively.ResultsWe demonstrated cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with its physiological role being to decrease gene expression. More important, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation.ConclusionThis methylation study indicated that cyclin A1 is a potential tumor marker for early diagnosis of invasive cervical cancer.

Telomerase activity and human papillomavirus in malignant, premalignant and benign cervical lesions.

The purpose of this study was to define a correlation between telomerase activity and human papillomavirus (HPV) in normal control tissue and in benign, premalignant and malignant cervical lesions. Telomerase activity was detectable in 33 out of 34 cases of squamous-cell carcinoma, five out of six cases of microinvasive carcinoma, 8 out of 20 cases and two out of six cases of high- and low-grade squamous intraepithelial lesions (SILs) respectively. The higher frequency of positive telomerase in invasive carcinoma compared with SILs was observed in both HPV-associated and non-associated groups. Whereas 92.6% of HPV-positive and 100% of HPV-negative invasive lesions expressed telomerase, only 50% of HPV-positive and 25% of HPV-negative SILs did. Interestingly, telomerase activity was also detectable in 13 out of 28 cases of benign lesions regardless of the presence of HPV. In conclusion, there may be two roles of telomerase in the cervix. The first one would present in benign lesions; the second is associated with cancer development and activated during the late stage of multistep carcinogenesis in both HPV-positive and -negative groups.

Recurrent ovarian granulosa cell tumor: a case report of a dramatic response to Taxol

A case is described of a granulosa cell tumor (GCT) of the ovary that recurred 2 years after cessation of platin-based chemotherapy. In view of the extent and volume of the disease at recurrence, and because of the reported poor response rates to second-line chemotherapy, Taxol was given. There was a dramatic response and tumor shrinkage to single-agent therapy with Taxol.

Leuprolide acetate and intravascular leiomyomatosis

Background Intravascular leiomyomatosis is an uncommon uterine tumor characterized by grossly visible intravascular proliferation of benign smooth muscle. Based on its role in reducing the size of leiomyomas, leuprolide acetate was given as induction therapy for extensive inoperable intravascular leiomyomatosis. Case A 44-year-old woman, gravida 1, para 1-0-0-1, presented in July 1992 with abnormal uterine bleeding. Pelvic examination and ultrasonography revealed the presence of a large irregular pelvic mass. At laparotomy, uterine and bilateral adnexal masses were noted extending up to the pelvic inlet and into the broad and infundibulopelvic ligaments. This tumor was not resectable. Based on histologic and immunoperoxidase studies, the lesion was interpreted as a plexiform epithelioid smooth-muscle tumor of uncertain malignant potential. Leuprolide acetate depot therapy (7.5 mg every 4 weeks) was begun in September 1992 and continued for a total of 20 months. Maximal tumor regression was achieved after 9 months. Subsequent reexploration at 20 months revealed a resectable tumor. Resection was accomplished successfully, leaving no apparent residual disease. Conclusion Leuprolide acetate induced tumor regression and rendered debulking surgery feasible in a patient with previously unresectable, widespread, retroperitoneal intravascular leiomyomatosis. Primary hormone therapy may provide alternative therapeutic options for certain cases of intravascular leiomyomatosis.

Posterior leukoencephalopathy following cisplatin, bleomycin and vinblastine therapy for germ cell tumor of the ovary

A 31‐year‐old female developed multiple episodes of grand mal seizures after combination chemotherapy with cisplatin, vinblastine and bleomycin for germ cell ovarian cancer stage Ic. The clinicoradiologic fea‐tures in this patient were consistent with posterior leukoencephalopathy, which is a rare complication of chemotherapy. Seizures were controlled by the anticonvulsive agent Dilantin (Pfizer, Khet Klongtoey, Bangkok) and she returned home without any permanent neurologic deficits. Follow‐up magnetic resonance imaging 2 weeks later showed complete resolution of the abnormalities. This syndrome has been previously reported following cisplatin‐based chemotherapy. Physicians should remain alert to the potential hazards of chemotherapy to the central nervous system. Risks and benefits should be seriously considered before starting treatment.

Phase II study of prolonged oral etoposide in refractory ovarian cancer.

A phase II study of prolonged oral etoposide at 50 mg m−2 was performed in patients with refractory ovarian cancer. A dose schedule algorithm was used to generate a calendar with the number of capsules to be administered each day and the date of blood tests. Fourteen of 15 patients were evaluable for response. Among the evaluable patients, 12 (86%) had poorly differentiated tumors, 13 (93%) had primary or secondary platin-resistant tumors, and 12 (86%) had progressed on a prior taxoid therapy. The median number of prior regimens was four (1–7). Despite the use of a 50-mg capsule of etoposide, the algorithm permitted the delivery of a median of 94% (89–107.5%) of the ideal calculated dose. The dose-limiting toxicity was myelosuppression with a grade 3 or 4 neutropenia in two-thirds of the patients. There were no deaths on the study and no significant neurologic or cardiovascular toxicity noted. There were no objective responses. The median survival of evaluable patients was 8.1 (95% CI 5.6–13.2) months.

Is complete surgical staging necessary in clinically early-stage endometrial carcinoma?

The purpose of this study was to evaluate the incidence of pelvic/para-aortic node metastases and the other pathological characteristics from medical records of patients with endometrial carcinoma treated at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between1996 and 2005. The records of 213 patients with endometrial carcinoma who had complete surgical staging were reviewed. A particular focus was on clinically early-stage disease. Clinical staging could be determined in 206 patients. Of the 206 patients, 182 (88.3%) presented with clinical stage I disease. However, only 142 (78%) of these patients were confirmed as surgical stage I and 22% were upstaged. Preoperative histologic grade was diagnosed inaccurately in 15.9% of patients and 7.7% were upgraded. Of patients with preoperative histologic grade 1, 33% had deep myometrial invasion, 8.2% had pelvic node metastasis, and 3.3% had para-aortic node metastasis. Even in clinical stage IaG1, pelvic node metastasis occurred in 5.6% and para-aortic node metastasis in 1.3%. It has been suggested that complete surgical staging may not be necessary in patients with low-risk endometrial carcinoma who have disease limited to the uterus without grade 3 or deep myometrial invasion. However, proper selection of such low-risk patients remains problematic. In situations where there is limited preoperative and intraoperative assessment of high-risk factors, particularly radiographic imaging and frozen section assessment, the role of complete surgical staging is beneficial.

Entire genome characterization of human papillomavirus type 16 from infected Thai women with different cytological findings

Global prevalence of human papillomavirus type 16 (HPV16) exceeds that of other types. This project has been aimed at attaining basic molecular knowledge of HPV16 by sequencing the whole genome of HPV16 isolated from Thai women at various clinical stages of disease progression. Our group analyzed seven samples of HPV16 in infected women ranging from normal to cervical cancer and discovered two critical non-synonymous changes within the coding region converting the E2-219P prototype to E2-219T in cervical cancer and the L2-269S prototype to L2-269D in CIN III, respectively. Phylogenetic analysis based on the whole genome with special emphasis on the genes E2, E6, L1, and L2 showed the Thai samples to be more closely related to the European than the non-European strains. The vaccine strain’s L1 polypeptides showed close relationship to our samples. The results provide basic data for future research on cervical cancer pathogenesis and representative data of HPV16 genome in Southeast Asia.