Neoadjuvant chemotherapy with cisplatin, ifosfamide and 5-fluorouracil in the treatment of locally advanced cervical cancer

Abstract. Etcheverry MG, Marantz A, Saine M, Litovska S, Lewi D, Cecchin G, Nuñez de Pierro A. Neoadjuvant Chemotherapy in the treatment of locally advanced cervical cancer.
The objective of this study was to evaluate clinical and histological response, resectability, and survival in patients with cervical epidermoid carcinoma stage IB2 to IIIB with the use of neoadjuvant chemotherapy followed by radical surgery and/or radiation therapy. Between September 1989 and February 1996, 53 patients were admitted to this study. They were given three cycles of cisplatin 30 mg/m²/day, 5-fluorouracil 500 mg/m²/day, ifosfamide 2000 mg/m²/day i.v., and mesna 400 mg/m²/day i.v. at hour 0 and 400 mg/m² at hours 4 and 8 during three days every 21–28 days. We evaluated 47 patients. Global clinical response obtained was 85%{95% (CI), 75–97%, CR in 14 patients (30%) and PR in 26 patients (55%)}. Twenty-three patients underwent surgery. Six patients (13%) had a complete histological response. Median follow-up was 42 months (5–96). In resected patients, with a median follow-up of 57 months (5–96), the estimated five-year disease-free survival was 78%. Global survival estimated to 60 months was 83% for stage IB2, 70% for IIB, and 20% for IIIB. This mode of therapy offers a new option to improve survival in locally advanced cervical cancer. Randomized trials are required in order to establish a definitive role for this therapeutic strategy.     

Neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer during pregnancy: a case report

Management of cervicocarcinoma during pregnancy is influenced by gestational age, stage of disease, and patient's desire to maintain her pregnancy. We report a case of a pregnant patient with locally advanced cervicocarcinoma successfully treated by neoadjuvant chemotherapy, followed by caesarean section and radical surgery.     

局部晚期宫颈癌术前化疗药物及方案的选择

局部晚期宫颈癌的治疗目前有很大的争议,美国国立综合癌症网络（NCCN）指南推荐直接行放疗,但其技术问题可能会引起不可逆的相关并发症,损伤性较大,而新辅助化疗+宫颈癌手术,是目前很多国家及地区采用的治疗方案,但目前没有统一的化疗方案、用药剂量以及强度,如何筛选出对新辅助化疗不敏感的患者以制定更加合理的治疗方案,避免治疗时机的贻误,尚需大样本、随机、多中心研究结果的支持。文章就宫颈癌新辅助化疗相关问题做一综述,旨在为临床治疗提供理论基础。     

Villoglandular papillary adenocarcinoma of the uterine cervix responding to neoadjuvant chemotherapy with docetaxel and cisplatin: a case report

Villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix is a rare neoplasm, and its treatment has rarely been reported. We report a patient with VGPA stage IIA responding to neoadjuvant chemotherapy with docetaxel (60 mg/m2 as an intravenous infusion) and cisplatin (70 mg/m2 as an intra-arterial infusion). At 3 weeks after completing one course of this regimen, the tumor size was reduced from 5.3 x 4.0 cm to 2.0 x 2.0 cm (81.1% reduction), revealed by computed tomography. Accordingly, the patient underwent radical hysterectomy, and there have been no signs of recurrence. Thus, the combination of docetaxel and cisplatin is suggested to be useful for neoadjuvant chemotherapy of cervical adenocarcinoma.     

Neoadjuvant intra-arterial infusion chemotherapy induces apoptotic cell death in locally advanced uterine cervical carcinomas. A preliminary report

Ueda M, Ueki K, Kumagai K, Terai Y, Kanemura M, Ueki M. Neoadjuvant intra-arterial infusion chemotherapy induces apoptotic cell death in locally advanced uterine cervical carcinomas. A preliminary report. Int J Gynecol Cancer 1998; 8 :144–149.
The purpose of this study was to evaluate the mechanism which leads to cell death in locally advanced uterine cervical carcinoma treated by neoadjuvant intra-arterial infusion chemotherapy (IAC). Cancer tissues surgically obtained from 11 patients (stages Ib-IIIb) receiving preoperative IAC of two courses of mitomycin-C (10 mg/m²), therarubicin (10 mg/m²) and cisplatin (100 mg/body), were examined. Biopsy specimens from the 11 patients before IAC were also used. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end-labeling (TUNEL) and immunohistochemical staining with anti-P53 and bcl-2 antibodies were performed for cancer tissues from these 11 patients before and after IAC. The evaluation of the clinical response to IAC revealed complete response (CR) in two patients, partial response (PR) in five, and stable disease (SD) in four. Careful observation of routine H. & E. sections showed some tumor cells with apoptosis, especially in patients with CR and PR. Intense TUNEL signals were observed both in ordinary, nonpyknotic nuclei of tumor cells and in nuclear fragments corresponding to apoptotic bodies. Apoptotic indices (AI) of the seven patients with CR or PR after IAC were significantly higher than those before IAC. There was no obvious correlation between apoptosis and P53 expression, but bcl-2 immunoreactivity was markedly decreased after IAC. These results suggest that the antitumor effects of neoadjuvant IAC are closely associated with apoptotic cell death in locally advanced cervical carcinomas.     

Neoadjuvant chemotherapy with cisplatin, aclacinomycin A, and mitomycin C for cervical adenocarcinoma – a preliminary study

Between 1989 and 2002, 28 patients with locally advanced cervical adenocarcinoma (bulky IB-IIIB) were recruited for a pilot study aimed at evaluation of the effectiveness of neoadjuvant chemotherapy with cisplatin, aclacinomycin-A, and mitomycin-C (PAM), followed by radical surgery. This regimen was administrated intra-arterially or intravenously. In addition to patients treated with PAM, we retrospectively analyzed the prognoses of 26 patients in stage I and II, who had been treated between 1975 and 1981 with radical surgery with/without radiation therapy. Twenty-eight patients received PAM therapy as neoadjuvant chemotherapy, and 75.0% of the 16 intra-arterially infused patients showed a response, as did 66.7% of the 12 intravenously infused patients. There was a significant difference in the 5-year prognosis of stage II (PAM group, 72.9%; without-PAM group, 36.4%). The results suggest that, as the free space in the parametrium is widened by neoadjuvant chemotherapy with PAM, it is possible that the tumor could be completely resected by radical hysterectomy. Thus, neoadjuvant chemotherapy with PAM is expected to improve the survival rate of patients with advanced cervical adenocarcinoma by the preliminary study. However, the survival rates of stage II with lymph node metastasis in the without-PAM group seem low, and we must also consider that the various technologies to evaluate and treat the cervical adenocarcinomas, e.g. computed tomography, magnetic resonance imaging, and surgical equipments, had improved during 1989-2002 than was the scenario during 1975-1981, and these improvements contributed to better prognosis. A prospective-randomized study is needed to assess the value of this approach compared with standard management.     

局部晚期宫颈癌术前新辅助化疗的益处

局部晚期宫颈癌的标准治疗方案目前仍存在争议,而新辅助化疗在局部晚期宫颈癌中的应用并没有在世界范围内达成共识,其临床治疗效果也不确定。多项临床试验表明术前新辅助化疗在局部晚期宫颈癌的治疗中发挥着重要作用,但我们必须明确该治疗方案的适应证和禁忌证,实施前充分考虑其利弊。术前新辅助化疗治疗局部晚期宫颈癌的疗效还有待进一步验证。     

Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells

5-Fluorouracil (5-FU) is currently being used as an anticancer drug to reduce tumor bulk in order to increase the operability rate and postoperative survival in patients with cervical cancer, which has been combined with cisplatin (CP) because of its superior activities observed in human carcinoma cells. However, the combined anticancer effect of 5-FU and CP in cervical carcinoma cells is poorly understood. Therefore, we conducted a study to investigate whether anticancer drugs 5-FU and CP may exhibit the combined antiproliferative effect in cervical carcinoma cells. Using proteomics analysis, including two-dimensional gel electrophoresis and matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS), we investigated the antiproliferative effect-related proteins after treatment with 5-FU and/or CP. Our experiments showed that the combination of 5-FU and CP engaged both the apoptotic pathways: the membrane death receptor-mediated apoptosis pathway and the mitochondrial apoptotic pathway. Moreover, the combination of 5-FU and CP resulted in remarkable increasing susceptibility to apoptosis. We suggest that the combination of 5-FU and CP suppresses the growth of cervical carcinoma cells by synergistic effect with the induction of apoptosis. In vitro synergistic effect of 5-FU and CP supports the basis of the clinical application of the combination chemotherapy to the patients with cervical cancer.     

Concurrent carboplatin/5-FU and radiotherapy for locally advanced cervical carcinoma

Landoni F, Maneo A, Colombo A, Cormio G, Placa F, Nava S, Rossi R,Mangioni C. Concurrent carboplatin/5-FU and radiotherapy for locally advancedcervical carcinoma. Int J Gynecol Cancer 1997; 7 :471–476.
Despite innovative techniques in radiotherapy delivery no significant improvement in survival rates for cervical carcinoma has been achieved during the last few decades. Concurrent chemoradiation (CR) is one of the several avenues being explored to improve these results.
Forty-seven women with locally advanced (IB2-IVA) squamous cell carcinoma of the uterine cervix were treated with CR, comprising a combination of external and intracavitary radiation along with three cycles of 5-FU and carboplatin.
Treatment was well tolerated with 81% of the patients completing the CR protocol as planned. Acute toxicity was severe but manageable: 16 patients (34%) experienced grade 3–4 acute toxicity. Late morbidity occurred in 15% of the patients. Overall response rate was 88%. At a median follow-up time of 19 months (range 12–59) 62% of the patients are alive without disease and 18% are dead of disease. Actuarial two-year survival rate for the whole group of patients is 64%.
Concomitant carboplatin/5-FU and radiotherapy is a safe and tolerable mean of treatment for locally advanced cervical cancer. The true advantage for survival, however, can be demonstrated only after completion of randomized trials comparing CR with conventional radiation therapy.     

局部晚期宫颈癌术前动静脉化疗利弊

根据我国国情,局部晚期宫颈癌术前新辅助化疗的实施有存在的必要,但是化疗方式的选择却存在较大的争议。术前静脉化疗仅仅是在近10年来由于新的有效的抗癌药物的出现而占尽了优势,但是宫颈癌动脉化疗的历史较静脉化疗更为悠久,动脉化疗能在较短时间之内通过提高癌灶内的药物剂量而有效缩小肿瘤体积,为后续治疗奠定手术基础。文章就两种化疗方式的利弊问题,从动脉化疗的历史、机制、与静脉化疗的疗效对比、经济效益比较等方面进行讨论,供临床医生参考。     

单次大剂量顺铂术前不同给药途径在局部晚期子宫颈癌中的疗效分析

目的 探讨局部晚期子宫颈癌术前单次大剂量顺铂不同途径给药的临床疗效、手术率、化疗毒副反应以及术后生存率.方法 分析丽水市中心医院2013年1 月1 日至2019年12月31 日收治局部晚期子宫颈癌Ⅰ B2～ⅡA2期患者207例,根据化疗途径不同分为两组:超选择子宫动脉插管灌注单次大剂量顺铂+栓塞术(简称动脉化疗组)10...     

Neoadjuvant high-dose intraarterial infusion chemotherapy under percutaneous pelvic perfusion with extracorporeal chemofiltration in patients with stages IIIa-IVa cervical cancer

OBJECTIVE: The objective of this study was to evaluate the response rate and survival of patients with locally advanced uterine cervical cancer who were treated with intraarterial infusion chemotherapy under percutaneous pelvic perfusion with extracorporeal chemofiltration (PPPEC). METHODS: Twenty-three untreated patients with stages IIIa-IVa cervical cancer were enrolled in the study. PPPEC was administered twice at 2 weeks interval using high-dose cisplatin alone (140-250 mg/m(2)) or high-dose cisplatin plus mitomycin C (7 mg/m(2)), pepleomycin (7 mg/m(2)) and 5-fluorouracil (700 mg/m(2)). Eighteen patients in whom the tumor downstaging was confirmed underwent radical surgery following PPPEC, whereas in the remaining five patients, radiotherapy was administered. RESULTS: Two weeks after the second PPPEC, the median volumetric tumor reduction and tumor response were 76% and 87%, respectively. Histologic response was 96%, while the tumor downstaging reached 83%. The curative surgery rate achieved was 89%. Five-year progression-free survival was 47% and 5-year survival rate was 74%. CONCLUSION: High-dose intraarterial infusion chemotherapy under PPPEC effectively achieved tumor downstaging and resulted in the favorable performance of the subsequent radical surgery and improved the 5-year survival rate of patients with locally advanced uterine cervical cancer.     

Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: report of a case and review of the literature

Although cervical carcinoma is among the most frequently encountered malignancies during pregnancy, only four cases of neoadjuvant chemotherapy during pregnancy have been reported. A 28-year-old A0P1G2M0 was diagnosed at 15 weeks with stage Ib1 invasive squamous cervical cancer. Because she strongly desired the continuation of this pregnancy, after extensive counseling she was treated with 75 mg/m(2) cisplatin every 10 days starting at 17 weeks. After six cycles, clinically and radiologically stable disease with normalization of the squamous cell carcinoma tumor marker was obtained. An elective cesarean delivery followed by radical hysterectomy and lymphadenectomy was performed at 32 weeks gestation. The pathology report revealed a moderately differentiated squamous cell carcinoma of 3.5 cm, and all 33 lymph nodes were free of disease. Neonatal examination of the baby could not reveal any abnormalities, and this was confirmed at 6 months. The use of neoadjuvant chemotherapy enabled us to continue this pregnancy until the fetus was viable. Cisplatin did not influence the short-term outcome, but only a long-term follow-up will inform us on its safety during pregnancy.     

Combined radio-chemotherapy in advanced cervical cancer: a phase-II trial with weekly applied carboplatin, 5-fluorouracil and folinic acid

The 5-year survival of patients with advanced cervical cancer is poor. Major problems are the high frequency of pelvic recurrences and distant metastases. To prevent both, various efforts have been made to combine local radiotherapy with systemic chemotherapy. In this prospective study, 28 previously untreated patients with advanced cervical cancer (FIGO IIB-IVB) were treated with a newly designed therapy consisting of fractionated external beam irradiation (54 Gy) followed by two intracavitary cesium (Cs) applications (2 × 15 Gy), combined with carboplatin (70 mg m⁻²), 5-fluorouracil (5-FU) (400 mg m⁻²) and folinic acid (400 mg m⁻²). Cytotoxic agents were given intravenously on days 1, 8, 15, 22 and 29 as 1-day courses during external irradiation followed by three 3-day courses with carboplatin (100 mg m⁻² i.v. daily), 5-FU (400 mg m⁻² i.v. daily) and folinic acid (400 mg m⁻² i.v. daily) after 8, 12 and 16 weeks of treatment.
Acute toxicities ( WHO grade 2) were leucopenia (27 of 28 patients), diarrhea (23/28), abdominal pain (19/28), nausea (14/28) and skin desquamation (12/28). Clinically diagnosed pelvic response was achieved in 88.5% (23/26) with a complete response of 34.5% (9/26). As yet, 19 of 26 patients (73.1%) are alive and well (persistent complete/partial remission), two patients (7.7%) are alive with local progression, four (15.4%) have died from pelvic and/or distal recurrence and one (3.8%) died some weeks after the start of therapy. The combined modality treatment concept has to be considered for the therapy of advanced cervical cancer and a prospective and randomized trial with a greater number of patients is warranted.     

Neoadjuvant intraarterial infusion chemotherapy with a combination of mitomycin-C, vincristine, and cisplatin for locally advanced cervical cancer: a preliminary report.

Combination chemotherapy including cisplatin was administered intraarterially from the internal iliac artery as neoadjuvant chemotherapy to six patients with locally advanced uterine cervical cancer (stage higher than IIIB of FIGO). The drugs and doses were mitomycin-C 10 mg/m2, vincristine 1 mg/m2, and cisplatin 50 mg/m2. Two or three courses were repeated at intervals of 3 weeks. In three patients, dose reductions were undertaken for decreased renal function and thrombocytopenia. Partial response was, however, observed in all patients (response rate 100%), and five of six patients were able to undergo a radical hysterectomy. The major toxic effects were leukocytopenia, nausea, and vomiting. Our preliminary experience suggests that pelvic intraarterial infusion of combination chemotherapy is effective against primary and advanced uterine cervical cancer, and this preoperative treatment can lead to easier radical hysterectomy. However, further studies are warranted.     

增殖细胞核抗原对局部晚期宫颈癌新辅助化疗敏感性的预测价值

目的探讨增殖细胞核抗原作为评价局部晚期宫颈癌新辅助化疗敏感性指标的可行性。方法收集2007年1月至2007年9月南华大学第一附属医院妇产科收治的49例局部晚期宫颈癌患者新辅助化疗前后标本组织,采用免疫组织化学技术检测癌组织中增殖细胞核抗原的表达。结果49例局部晚期宫颈癌患者经新辅助化疗治疗2周后评价临床疗效,临床有效(CR+PR)率为79.6%(39/49)。新辅助化疗有效组化疗前宫颈癌组织中PCNA阳性细胞数比率明显高于无效组(P0.05)。结论增殖细胞核抗原(PCNA)是判定局部晚期宫颈癌化疗敏感性的重要指标。