卵巢癌一线治疗:PARP抑制剂研究进展

背景:多聚腺苷二磷酸核糖聚合酶(PARP)抑制剂对铂敏感复发卵巢癌的治疗带来了重大变革.最新研究表明在卵巢癌的全程治疗中早期应用PARP抑制剂可使患者获益.设计:汇总近期PARP抑制剂治疗/维持治疗新诊断卵巢癌患者的III期临床试验资料.讨论各种PARP抑制剂临床试验中的疗效和安全性,比较研究设计的优缺点,考虑后续研究...     

Phase I study of intraperitoneal carboplatin as adjuvant therapy in early ovarian cancer

Early stage poor-risk ovarian cancer patients are at considerable risk for recurrent disease. Adjuvant radio- or chemotherapy has been found to improve disease-free and overall survival. Carboplatin, a second generation platinum, is documented comparable in efficacy to cisplatin in patients with advanced ovarian cancer. The toxicity profile is different from that of cisplatin. Dose-limiting toxicity is myelosuppression. The incidence and grade of renal and neurological toxicity is much lower compared with cisplatin, as is nausea and vomiting. Carboplatin given intraperitoneally (ip) is shown to have a favorable theoretical therapeutic advantage compared with iv administration since the peak peritoneal cavity/peak plasma concentration ratio is 18. Patients with early stage ovarian cancer seem suitable for carboplatin ip treatment. The study was designed to find the maximal tolerated dose (MTD). Three new patients were given two courses at each dose level. The MTD found was confirmed with further patients. Carboplatin was given in 2 liters of glucose via a subcutaneous implantable port without removal of fluid from the cavity. The starting dose was 300 mg/m2. Dose-limiting toxicity was thrombocytopenia and leukopenia. Leukocyte and platelet counts were reconstituted within 28 days in all cases. One case of severe but transient nephrotoxicity was observed. MTD was determined to 500 mg/m2.     

The role of adjuvant therapy in Stage I ovarian cancer

Women with Stage I epithelial carcinoma of the ovary were initially treated by an extirpative operation and were subsequently randomized to either no further treatment, radiotherapy, or chemotherapy. Only two patients (6%) treated with chemotherapy developed recurrence, compared to five (17%) and seven (30%) patients in the no-treatment and radiotherapy regimens, respectively (P < 0.05). All patients, with the possible exception of those with Stage IA(1)g1, appeared to benefit from adjuvant chemotherapy compared to no treatment or radiotherapy.     

Sorafenib as a third line therapy in patients with epithelial ovarian cancer or primary peritoneal cancer: a phase II study

Purpose

New agents are required for the patients with epithelial ovarian cancer (EOC) who progress after first and second line of the treatment. Tumor vasculature targeted agents are potentially active in EOC. We aimed to assess the activity of sorafenib in patients with recurrent EOC who had received two prior therapies.

Patients and methods

A phase II non-randomized, open-label, single-arm study aimed to assess the efficacy, safety and tolerance of sorafenib monotherapy as a third line therapy in patients with EOC or primary peritoneal cancer (PPC). Sorafenib was administered as 400 mg twice daily on days 1–28 of each 4-week cycle. The primary end point of the study was to demonstrate the progression free survival (PFS).

Results

Eleven patients were enrolled. The median number of cycles was two. Among the 11 patients eligible for efficacy analysis, no patients experienced a partial response or complete response or stable disease lasting longer than 6 months according to RECIST criteria. Thus, the trial stopped at the end of the first stage of study design. The median PFS was 2.00 months (95% CI, 1,80–3,90). The median OS was 11.78 months (95% CI, 7.66 to 15.39). There were no grade 4 toxicities and few grade 3 toxicities.

Conclusion

Sorafenib fails to achieve sufficient objective response or sustained disease stabilization as third-line treatment for EOC.     

First-line chemotherapy with weekly paclitaxel and carboplatin for advanced ovarian cancer: a phase I study

OBJECTIVE: The presence of nodal metastases is the most important prognostic factor in cervical cancer. To adjust our therapy based on the true extent of the patient's disease, we performed an extraperitoneal lymph node dissection (EPLND) in all patients with cervical cancer prior to radiotherapy (RT) or radical hysterectomy. METHODS: Thirty-three patients with carcinoma of the cervix underwent EPLND. The value of this procedure as a diagnostic tool for monitoring the extension of the disease was determined. Additionally, EPLND/RT-associated treatment complications were monitored. RESULTS: The combined treatment approach of EPLND with RT or chemotherapy/RT was without major complications. Nineteen patients showed a temperature elevation, but only one patient had a fever of greater than 39.0 degrees C. Fourteen (48.3%) of 29 patients experienced some degree of proctitis or diarrhea and 3 (10.3%) experienced cystitis during the course of RT. No grade 3 or 4 acute or late genitourinary or gastrointestinal toxicities were noted. EPLND changed the clinical management for 6 patients from a radical hysterectomy to RT and for 7 patients from standard-field RT to extended-field RT. Without EPLND these 7 patients would have received RT with standard pelvic fields that would not have treated involved lymph node areas at high risk for subsequent failure. CONCLUSION: Thirteen (44.8%) of 29 patients received a different treatment than would otherwise have been administered with standard treatment planning. Therefore, we suggest that EPLND should be performed in all patients with cervical cancer prior to radical surgery or RT.     

Analysis of failures in patients with stage I ovarian cancer: an Italian multicenter study

Gadducci A, Sartori E, Maggino T, Zola P, Landoni F, Fanucchi A, Stegher C, Alessi C, Buttitta F, Bergamino C. Analysis of failures in patients with stage I ovarian cancer: An Italian multicenter study. Int J GynecolCancer 1997; 7: 445–450.
The objective of this retrospective multicenter study was to assess the rates, times, sites, and risk factors for recurrences in 224 patients with surgical stage I ovarian cancer. Postoperative adjuvant treatment was given to 153 of these patients. One hundred and eighty-two (81.3%) patients are currently alive with no clinical evidence of disease after a median time of 84 months (range, 4–191 months) from surgery, whereas 39 (17.4%) developed recurrent disease after a median time of 29 months (range, 5–112 months). The relapse involved the pelvis in 21 (53.8%) cases, abdomen in 19 (48.7%), pelvic and/or para-aortic lymph nodes in 5 (12.8%), and distant sites in 5 (12.8%). The risk of recurrence was significantly related to FIGO substage ( P < 0.0001) and tumor grade ( P < 0.0001), but not to histological subtype. However, the recurrence rate was lower in mucinous carcinomas (6/52, 11.5%) and higher in clear cell carcinomas (5/14,35.7%). By log-rank test the disease-free survival was significantly related to FIGO substage ( P = 0.0006) and grade ( P = 0.0001). Cox proportional hazard model showed that grade was the only independent prognostic variable for disease-free survival, with a risk ratio for relapse of 2.831 (95% CI, 1.120–6.624) for grade 2 and 7.725 (95% CI, 3.290–18.140) for grade 3, compared to grade 1. In conclusion, tumor grade is the strongest predictor of recurrence in stage I ovarian cancer.     

化疗对卵巢癌患者NK细胞活性的影响

目的 观察化疗对NK细胞活性的损伤程度。方法 收集1999～2001年32例上皮性卵巢癌，观察化疗前后NK细胞活性的变化。然后与IL-2共培养，观察其活性恢复情况．结果 化疗后与化疗前比较，NK细胞活性下降明显，差异有统计学意义。应用IL-2共培养后，化疗前NK细胞活性明显升高；化疗后第1～3疗程细胞活性升高有显著性，第4～6疗程活性无显著性变化。结论 化疗损伤了NK细胞的活性，早期损伤程度较轻，能恢复；晚期损伤程度较重，短期内不能恢复。     

In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer

OBJECTIVE: The purpose of this study was to evaluate the potential of dendritic cells pulsed with whole-tumor extracts derived from autologous ovarian cancer cells in eliciting a tumor-specific cytotoxic T-cell response in vitro from patients with advanced ovarian cancer. STUDY DESIGN: CD8(+) T lymphocytes stimulated in vitro with autologous ovarian tumor lysate-pulsed dendritic cells were tested for their ability to induce a human leukocyte antigen class I-restricted cytotoxic T-lymphocyte response able to specifically kill autologous tumor cells in standard 6-hour chromium 51 cytotoxicity assays. In addition, to correlate cytotoxic activity by cytotoxic T-lymphocytes with a particular lymphoid subset, 2-color flow cytometric analysis of intracellular cytokine expression (interferon gamma and interleukin 4) at the single-cell level was performed. RESULTS: Cytotoxic T lymphocytes specific for autologous ovarian tumor cells were elicited from 3 patients with advanced ovarian cancer. Although cytotoxic T-lymphocyte populations expressed strong cytolytic activity against autologous tumor cells, they did not lyse concanavalin A-stimulated autologous lymphocytes or autologous Epstein-Barr virus-transformed lymphoblastoid cell lines and showed negligible cytotoxicity against the natural killer cell-sensitive cell line K-562. Cytotoxic effect against the autologous tumor cells was inhibited by an anti-human leukocyte antigen class I monoclonal antibody (W6/32). It is interesting that CD8(+) cytotoxic T lymphocytes expressed variable levels of CD56, a marker that may be associated with high cytotoxic activity. Finally, most of the tumor-specific CD8(+) T cells exhibited a T(H)1 cytokine bias, and a high percentage of interferon gamma expressors among cytotoxic T lymphocytes was correlated with higher cytotoxic activity. CONCLUSION: These data show that tumor lysate-pulsed dendritic cells can consistently induce in vitro specific CD8(+) cytotoxic T lymphocytes able to kill autologous tumor cells from patients with advanced stage ovarian cancer. This novel approach may have important implications for the treatment of residual or resistant disease with active or adoptive immunotherapy after standard surgical and cytotoxic treatment.     

Olaparib: a promising PARP inhibitor in ovarian cancer therapy

Background

Ovarian cancer (OC) is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at advanced stage with poor prognosis. Currently, surgical tumor debulking followed by chemotherapy based on platinum and taxane is the standard treatment for advanced OC. However, these patients remain at great risk for recurrence and developing drug resistance. Therefore, new treatment strategies are needed to improve outcomes for patients with advanced and recurrent OC. Olaparib (AZD2281, KU-0059436), as one of the best understood Poly-(ADP-ribose) polymerase (PARP) inhibitor targeting DNA repair mechanisms, caused more and more attention. Clinical trial data of Olaparib had been cumulated, which applied as the single-agent in relapsed OC monotherapy, especially for BRCA mutation associated OC.

Methods

In this review, we demonstrated the mechanism of PARP inhibitors and summarized clinical trial data and clinical development of Olaparib targeted OC in order to address a new promising therapy strategy for advanced relapsed OC.

Conclusion

Given the unprecedented clinical potential of Olaparib, the further research on Olaparib will have great significance in selection of OC patient populations that will respond to treatment.     

Oncogene expression in ovarian cancer: a pilot study of c-myc oncoprotein in serous papillary ovarian cancer

The nuclear-associated protein product of the c-myc gene, p62c-myc, was assayed simultaneously with total DNA using flow cytometry in nuclei extracted from archival biopsies of serous papillary carcinoma of the ovary. The oncoprotein was probed with a synthetic peptide-induced mouse monoclonal antibody which was subsequently labeled with a fluorescent rabbit anti-mouse immunoglobulin and DNA was assayed using the nucleic acid fluorochrome propidium iodide. Serous papillary ovarian carcinoma expressed significantly higher p62c-myc levels compared with normal ovary (P less than 0.00003 Mann-Whitney U test). Biopsies classified as "borderline" low-potential malignancy exhibited levels between normal ovary and carcinoma. The difference between normal and "borderline" was significant at P less than 0.003, but no difference between "borderline" and frankly invasive biopsies was observed, P = 0.149. There was no difference among the histological grades of carcinomas. All normal ovaries had diploid DNA content as did 5/6 cases of "borderline" malignancy. The majority of cases of carcinoma, 28/36, were aneuploid. There was a statistically significant difference in the distribution of aneuploidy, P less than 0.005, between invasive carcinomas and those classified as "borderline" low-potential malignancy.     

Cyclooxygenase inhibition and hyperthermia for the potentiation of the cytotoxic response in ovarian cancer cells

OBJECTIVES: The progression of chemotherapy-resistant cancer confers poor prognosis and decreases overall survival in ovarian cancer patients. Adjuvants to traditional chemotherapy regimens have become attractive modalities for the clinical treatment of refractory or resistant ovarian cancer. We evaluated whether the addition of NSAID to hyperthermic chemotherapy would increase cytotoxicity in cisplatin- and taxane-treated ovarian cancer cells. METHODS: Western blot analysis was utilized to determine COX-2 protein expression levels in the 2008, cisplatin-sensitive, and C13*, cisplatin-resistant, cell lines. PGE2 levels were determined and analyzed as a function of cyclooxygenase activity by LC/MS/MS. Cells were treated with cisplatin, docetaxel or paclitaxel in combination with either NS-398 or sulindac sulfide at 37 degrees C, 41 degrees C or 43 degrees C. Cell viability was determined by a MTS cell proliferation assay. RESULTS: Both cell lines expressed COX-2 protein, and NS-398 and sulindac sulfide effectively blocked PGE2 production. The addition of a NSAID to cisplatin treatment in 2008 and C13* cells offered enhanced cytotoxicity and this effect was further enhanced at 41 degrees C. In docetaxel-treated 2008 cells, both NS-398 and sulindac sulfide offered enhanced cell kill; however, this result was not observed in paclitaxel-treated cells. Hyperthermia appeared to play no additional role in taxane cytotoxicity enhancement, however no antagonism was detected. CONCLUSIONS: Our results suggest that the combination treatment (cisplatin or docetaxel in combination with NSAID) cause a dose-dependent enhancement of cytotoxicity. Hyperthermia may improve the results of intraperitoneal cisplatin therapy, thus warranting further evaluation in clinical studies.     

The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p?=?0.001 and p?=?0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p?p?=?0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.     

Four-dimensional computed tomography-based respiratory-gated whole-abdominal intensity-modulated radiation therapy for ovarian cancer: a feasibility study

This study assesses the feasibility and implementation of respiratory-gated whole-abdominal intensity-modulated radiation therapy (RG-WAIMRT). Three patients were treated with RG-WAIMRT. The planning target volume (PTV1) included the entire peritoneal cavity and a pelvic boost field was created (PTV2). The dose prescribed was 30 Gy to PTV1 and 14.4 Gy to PTV2. For comparison, a conventional three-dimensional (3D) plan was generated for each patient. In the WAIMRT plan, an average of 90% of PTV1 received 30 Gy compared to 70% for the conventional 3D plan. The percent volume receiving 30 Gy (V(30)) for liver averaged 54% (WAIMRT) vs 43% (3D). The percent volume receiving 20 Gy (V(20)) for kidneys averaged 19% vs 0%, and the mean V(20) for bone marrow was 74% vs 83%, respectively. Major acute toxicities were anemia (grade 2: 1/3), leukopenia (grade 3: 2/3 patients), and thrombocytopenia (grade 2: 1/3 patients, grade 3: 1/3 patients). One patient could not complete the whole-abdomen field after 19.5 Gy because of persistent nausea. No major subacute toxicity has been reported. WAIMRT demonstrated superior target coverage and reduced dose to bone marrow, with a slightly increased dose to liver and kidneys. WAIMRT is a novel and feasible technique for ovarian cancer treatment.