Adjuvant therapy for pancreatic cancer

Ductal adenocarcinoma of the pancreas is one of the leading causes of cancer death in the UK, Europe and US, with incidence closely paralleling mortality. Until recently, enthusiasm for treating these patients was limited for a number of reasons: the majority of patients undergoing surgery would relapse early, adjuvant treatment was of unproven value and systemic therapy in advanced disease had only a small chance of a short-term benefit. More recently, however, it has become recognised that specialist surgery can improve results and there is evidence that adjuvant chemotherapy has a significant advantage in terms of 5-year survival. In particular adjuvant systemic 5-fluorouracil with folinic acid can result in 5-year survival of < or = 29% (compared with 11% for controls) and adjuvant gemcitabine can improve disease-free survival to 13.4 months from a median of 6.9 months in controls, but not overall survival. In contrast the role of adjuvant chemoradiation in addition to chemotherapy remains unproven and the survival results appear to be inferior to systemic chemotherapy alone. New agents, such as capecitabine and erlotinib, are emerging with some activity in this dismal disease signalling hope for the future.     

晚期鼻咽癌放疗联合辅助性化疗的临床研究

目的 分析评价晚期（N2,N3期）鼻咽癌放疗加辅助化疗的疗效.方法 86例N2,N3期鼻咽癌患者随机分为放化组（A组,46例）和单放组（B组,40例）,均首先接受根治性放疗,其后放化组46例接受辅助化疗（LV＋5Fu＋DDP）3～4个疗程.结果 放化组5年生存率43.5%,单放组37.5%（P＞0.05）;放化组远处转移发生率19.6%,单放组45%（P＜0.05）;放化组远处转移发生时间平均放疗后18.3个月,单放组7.8个月;放疗后达到CR的放化组与单放组的5年生存率为42.9%、56.5%（P＞0.05）,非CR的放化组与单放组的5年生存率为44.4%、11.8%（P＜0.05）.结论 放疗加辅助性化疗N2,N3期鼻咽癌有助于延缓远处转移发生时间,减少远处转移;对于根治性放疗后未达CR者,辅助化疗能提高生存率.     

术后补充化疗对完整周期新辅助化疗后未获pCR的ⅡA~ⅢB期乳腺癌患者预后的影响

目的 探讨术后补充化疗对完整周期新辅助化疗后未获病理完全缓解（pCR）的ⅡA~ⅢB期乳腺癌患者预 后的影响。方法 回顾性分析行完整周期新辅助化疗后未获 pCR的 208例ⅡA~ⅢB期的乳腺癌患者,其中 81例患 者术后行补充化疗（补充化疗组）,127例未行补充化疗（未补充化疗组）。分析 2组患者 3年总生存率、3年无病生存 率及影响复发转移的因素。结果 中位随访时间 40 个月,全组无病生存率为 76.9%（160/208）,3 年总生存率为 88.9%（185/208）。补充化疗组较未补充化疗组无病生存率提高（87.7% vs. 72.4%,P＜0.05）。补充化疗组和未补充化 疗组 3年总生存率分别为 94.2%和 92.1%,差异无统计学意义（P＞0.05）。单因素分析表明雌激素受体（ER）状态、孕 激素受体（PR）状态、HER-2状态及术后补充化疗情况是无病生存的影响因素（P＜0.05）,多因素分析显示术后未补 充化疗（HR=2.044,P=0.033）和 HER-2阳性（HR=3.418,P＜0.001）是影响患者无病生存不良预后的独立危险因素。 结论 术后补充化疗可提高完整周期新辅助化疗后未获 pCR的ⅡA~ⅢB期乳腺癌患者的无病生存率,HER-2阳性 患者的预后更差。     

对非小细胞肺癌患者左侧全肺切除后化疗效果的研究

目的研究非小细胞肺癌（以下简称NSCLC）患者左全肺切除后是否需要化疗,且化疗对哪种类型NSCLC患者有较好的疗效。方法以2007年5月至2008年6月提供的已行左全肺切除的62例NSCLC患者作为化疗组,给予TP／NP方案化疗,同时从病案库随机抽取120例单独行左侧全肺切除的NSCLC患者作对照组,对比观察两组患者的预后情况。结果化疗组化疗后3年、5年生存率分别为33．9％、36．2％,对照组分别为37．5％、24．1％。mA期NSCLC患者左肺切除后化疗组3年、5年生存率明显高于单独手术组,差异有统计学意义（P〈0．05）。结论对于ⅢA期NSCLC患者左侧全肺切除后化疗有益于提高生存率。     

乳腺癌肝转移的不同治疗方法比较

目的 比较手术治疗、全身化疗、全身化疗联合肝动脉化疗栓塞对乳腺癌肝转移的疗效.方法 回顾性分析1996年1月至2008年10月52例乳腺癌肝转移临床资料,根据治疗方法分为手术组(12例)和单纯全身化疗组(22例)和全身化疗联合肝动脉化疗栓塞组(18例),分析3组的疗效及预后,比较不同治疗方法的疗效.结果 52例乳腺癌术后肝转移患者,全组治疗有效27例(51.9%),手术组有效4例(33.3%),单纯全身化疗组有效11例(50.0%),全身化疗联合肝动脉化疗栓塞组有效12例(66.6%).1、2、3年生存率手术治疗组分别为25.0%(3例)、8.3%(11例)、0,单纯全身化疗组分别为31.8%(7例)、13.6%(3例)、9.1%(2例),全身化疗联合肝动脉化疗栓塞组分别为44.4%(8例)、33.3%(6例)、11.1%(2例),全身化疗联合肝动脉化疗栓塞组生存率明显优于手术治疗组和单纯全身化疗组(P<0.05).结论 采用全身化疗联合肝动脉化疗栓塞治疗乳腺癌术后肝转移疗效较好,值得临床进一步推广.

Abstract：

Objective To explore the efficacy of hepatectomy and chemotherapy and transcatheter arterial chemoembolization plus chemotherapy on breast cancer complicated with liver metastases. Methods Clinical features of 52 breast cancer patients with liver metastases from 1996 to 2008 were analyzed retrospectively. Fifty-two patients were divided into surgery group (group Ⅰ) , systemic chemotherapy group (group Ⅱ) and transcatheter arterial chemoembolization (TACE) plus chemotherapy group (group Ⅲ). The efficacies of different treatment approaches were compared. Results The total responsive rate was 51.9% for among all patients. TACE plus chemotherapy produced a significantly higher partial response rate 66. 6% in comparison with 50. 0% (11 cases) of systemic chemotherapy and 33.3% ( 4 cases ) of hepatectomy ( P < 0. 05 ). The median survival time was 16 months ( 2-50 months)and 1-year, 2-year, 3-year survival rate in three groups was 25.0% , 8. 3% , 0( group I ) , 31. 8% , 13.6%, 8.9%(group Ⅱ)and 44.4%, 33.3%, ll.l%(group Ⅲ), respectively. The survival time of group Ⅲ was the longest (P <0.05). Conclusion Chemotherapy plus TACE may be an effective and safe treatment for liver metastases after breast cancer.     

Evidences and opinions for adjuvant therapy in pancreatic cancer

Pancreatic adenocarcinoma is a rare tumor with a very poor outcome. Even with surgery, 5-year overall survival is less than 10%, due to the propensity of the disease for local and systemic recurrence. Adjuvant chemoradiotherapy and systemic chemotherapy were assessed in prospective trials in order to improve disease control and patients' prognosis. However, due to the difficulty of performing prospective trials in a rare disease; to the progress in surgical and radiotherapic techniques; and to the availability of novel anti-cancer agents, the existing information on the best possible management of patients with resectable disease is limited and becomes rapidly obsolete. Accordingly and also due to some contradictory findings from randomized trials, the topic of optimal adjuvant therapy for this disease encompasses several areas of controversy. The present review reports the main opinions on the role of adjuvant chemoradiotherapy, adjuvant chemotherapy, best single agent, and combination chemotherapy. Data from randomized trials are presented and critically analyzed to identify the available evidence supporting the different therapeutic choices and the main methodological drawbacks hampering the proper interpretation of results. Single agent chemotherapy yields a clinically significant, albeit modest, improvement in overall survival and may represent a standard option. The role of combination chemotherapy warrants further investigation and the impact of adjuvant chemoradiation both on local control and on the final outcome is uncertain. The need for more active and effective systemic treatments, for a better knowledge of the disease biology, for new therapeutic agents and predictors of pattern of recurrence is evident.     

基因检测指导Ⅱ、ⅢA期非小细胞肺癌术后辅助化疗的临床研究

目的 探讨以基因检测为指导的非小细胞肺癌 （NSCLC） 术后个体化治疗的效果。方法 将接受全胸腔镜肺癌根治术的Ⅱ、 ⅢA 期 NSCLC 患者 56 例随机分为个体化治疗组 26 例和非个体化治疗组 30 例, 取个体化治疗组患者新鲜肿瘤组织进行基因检测, 检测靶标包括切除修复交叉互补复合体 1(ERCC1)、 核苷酸还原酶亚单位 1 (RRM1)、 β微管蛋白Ⅲ、 胸苷酸合成酶(TS)、 表皮生长因子受体(EGFR)、 乳腺癌敏感蛋白 1 （BRCA1） 等。个体化治疗组根据检测结果制定化疗方案, 非个体化治疗组采用 “吉西他滨+顺铂” 方案, 比较 2 组 1 年、 2 年无疾病生存率 （DFS）、疾病无进展生存期(PFS)和总生存期(OS)。结果 个体化治疗组 2 年 DFS （57.69%）、 PFS （月： 22.1±5.0） 和 OS （月： 24.1±3.2） 均高于非个体化治疗组 （分别是 30.00%、 18.9±6.2、 21.9±4.3, 均 P < 0.05）; 2 组 1 年 DFS （88.46% vs 83.33%）差异无统计学意义。结论 基于基因检测的个体化治疗可以提高 NSCLC 术后的 2 年 DFS、 PFS 和 OS, 提高化疗的有效率。     

The role of adjuvant therapy for pancreatic cancer

Patients with pancreatic cancer have a very poor outlook. There have been major advances in the standard surgical treatment of this disease, resulting in decreased post-operative mortality and morbidity. The use of chemotherapy and radiotherapy has been developed to increase long-term patient survival following potentially curative resection. The standard chemotherapeutic agent is 5-fluorouracil (5-FU), although newer cytotoxic agents are in clinical trials for advanced cancer. Initial studies of adjuvant therapy have been based on small numbers of patients, but recently two large European randomised controlled trials of adjuvant therapy (EORTC and ESPAC-1) have been completed. These suggest that adjuvant chemotherapy has a significant survival advantage over resection alone but chemoradiotherapy does not. Promising new agents are being developed and tested mainly in clinical trials of advanced pancreatic cancer. The results of large-scale randomised controlled trials to assess adjuvant therapies for pancreatic cancer demonstrate the great surgical and oncological progress that has been made over the past decade.     

Adjuvant chemotherapy of colon cancer: lymph node involvement without metastases

(1) The standard treatment for colon cancer is surgical excision, but without additional treatment nearly 50% of surgically treated patients die from relapse and metastatic disease progression. Adjuvant chemotherapy is designed to reduce the risk of post-surgical relapse. (2) The standard adjuvant chemotherapy is a combination of fluorouracil + folinic acid administered intravenously for 6 months (de Gramont protocol). (3) In patients with stage III disease (corresponding to Dukes stage C: lymph node involvement but no metastases), the 5-year survival rate after a 6-month course of fluorouracil + folinic acid is significantly higher than with placebo (63% versus 51%). The efficacy of this treatment has not been established in patients with stage II disease (no lymph node involvement or metastases), for whom the overall 5-year survival rate is about 80%. (4) In one trial a combination of oxaliplatin + fluorouracil + folinic acid (FOLFOX 4 protocol) failed to increase the overall 3-year survival rate more than the fluorouracil + folinic acid combination. It increased the event-free survival rate (72.2% versus 65.3%) but had more severe adverse effects, including: neuropathies (in about 12% of patients), neutropenia (41%), and gastrointestinal disturbances (5% to 10% of patients had nausea, vomiting and diarrhoea). (5) Capecitabine, a fluorouracil precursor, does not appear to be more effective than fluorouracil, but it does provide an alternative oral treatment with a slightly different profile of adverse effects (more frequent erythrodysesthesia, etc.). (6) In practice, adjuvant treatment with fluorouracil + folinic acid should be offered to patients with surgically treated stage-III colonic cancer.     

Resectable non-small cell lung cancer in the elderly: is there a role for adjuvant treatment?

Over the past 2 years, systemic chemotherapy has emerged as the standard adjuvant approach for resectable non-small cell lung cancer (NSCLC). In aggregate, a 5.3% improvement in 5-year survival has been observed with platinum-based combination chemotherapy in patients with NSCLC, with benefits being most pronounced in stage II and IIIa disease. Recent data suggest that the elderly (up to age 75 years) derive benefits from such therapy similar to those seen in younger patients. Unfortunately, although patients aged >or=70 years constitute 50% of those with newly diagnosed NSCLC, <10% of enrollees in clinical trials are in this age group. To help offset the spectre of increased risk in this age group, two potential strategies exist: (i) substitution of carboplatin for cisplatin; and (ii) increased use of neoadjuvant treatment to avoid perioperative co-morbidities and difficulties with compliance that can hamper appropriate administration of adjuvant treatment. To date, there have been no elderly-specific adjuvant trials in NSCLC. Over time, this omission is likely to be corrected.     

结肠癌的辅助化疗

在可接受根治性手术的结肠癌患者中,约1/3存在区域淋巴结转移(Ⅲ期),1/4患者的肿瘤侵透肌层但不伴有区域淋巴结转移(Ⅱ期),辅助化疗的目的是消灭微小转移灶,提高患者的无病生存期和总生存期。临床研究的结果显示辅助化疗能够显著降低Ⅲ期结肠癌患者的复发和死亡风险;但是对于Ⅱ期患者,辅助化疗的作用还不完全明确,亚组分析表明辅助化疗对于具有临床病理高危因素的Ⅱ期患者有益,而分子标志物有助于低危患者的危险分层和治疗选择。     

Recent and ongoing clinical trials for treating colorectal cancer

Colorectal cancer is one of the most common cancers worldwide. Through well-designed clinical trials, advances have been made in the treatment of localised and advanced colorectal cancer. It has been established that 6 months of 5-fluorouracil-based chemotherapy will improve overall survival in patients with stage III colon cancer. The role of adjuvant chemotherapy in stage II colon cancer remains an unresolved issue. Recent studies have demonstrated an improved survival with the addition of irinotecan to 5-fluorouracil and leucovorin for the treatment of advanced colorectal cancer. Immunotherapy, molecular targeted therapy and liver-directed therapy, in addition to new chemotherapy combinations, are all being evaluated for the treatment of localised and advanced colorectal cancer. Ongoing and proposed studies are incorporating the identification of genetic and molecular abnormalities, which may provide prognostic information as well as direct treatment decisions.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only approximately 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil-folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of approximately 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

NSCLC辅助化疗的分子标志物研究进展

作为一种全身性疾病,非小细胞肺癌（NSCLC）的治疗需要多学科的综合性治疗,越来越多的证据显示,术后辅助化疗能在不同程度上提高部分NSCLC患者的术后生存期,但大多数肺癌患者的术后生存期并没有根本性的提高.近年来随着肿瘤分子生物学的发展,我们发现非小细胞肺癌可能是一组在遗传学上完全不同的疾病,这导致了细胞学类型、细胞分化程度和病理分期均相同的患者,对同种化疗方案的疗效存在不同甚至相反的结果.基因组学和蛋白质组学研究针对NSCLC患者的一些具有疗效预测性的分子标志物,通过这些分子标志物,笔者成功地将相同组织学类型的NSCLC分成不同的亚型,从而实现肺癌的个体化治疗,最终改善患者预后.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only ～ 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil–folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of ～ 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Combination adjuvant chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin after liver transplantation for hepatocellular carcinoma: a preliminary open-label study

The purpose of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy with FOLFOX regimen on the outcome after LT for HCC patients who did not meet the Milan criteria. Ninety-five consecutive HCC patients with liver cirrhosis undergoing LT were enrolled. Fifty-eight who did not meet the Milan criteria were randomized to open-label treatment with or without adjuvant chemotherapy after LT (n = 29/group). The FOLFOX chemotherapy protocol comprised 3-week cycles of oxaliplatin 100 mg/m² on day 1, leucovorin (calcium folinate, CF) 200 mg/m² on day 1 followed by 3-day, and 5-fluorouracil (5-FU) 2000 mg/m² as a 48-h continuous infusion, for up to six courses in the 1st year after transplantation. Median survival was extended by 4.57 months by combination chemotherapy. The 1- and 3-year survival rates were 89.7% and 79.3% with chemotherapy versus 69.0% and 62.1% without chemotherapy. The cumulative 1-year survival was significantly increased by chemotherapy (log-rank test, P = 0.043). The 6-month tumor-free survival rate was 24.1% higher with chemotherapy than without. The recurrence rate after LT was significantly different between the two groups at 6 months (P = 0.036), but not at 3 years (P = 0.102). The chemotherapy regimen was generally well tolerated. Post-LT adjuvant chemotherapy with oxaliplatin/5-FU/CF could not prevent tumor recurrence post-LT but may contribute to improve the survival of HCC patients who do not meet the Milan criteria. These results should be verified in a larger sample with a longer follow-up period.     

Adjuvant chemotherapy for localised colon cancer. Fluorouracil + folinic acid for node-positive, non-metastatic disease

The standard treatment for colon cancer is surgical excision. Adjuvant chemotherapy is intended to reduce the risk of relapse, which is responsible for the death of nearly half of all patients treated surgically for localised disease. After surgery for stage III disease (node involvement without metastases), the 5-year survival rate is about 63% with adjuvant chemotherapy combining fluorouracil and folinic acid, versus 51% with placebo, a statistically significant difference. After surgery for stage II disease (tumour spread beyond the intestinal wall but no node involvement), a meta-analysis updated in 2008 showed no impact of adjuvant chemotherapy on the overall survival rate. Fluorouracil + folinic acid administration according to the de Gramont protocol is the standard adjuvant treatment. The addition of regional fluorouracil chemotherapy did not further improve outcome in a trial in 1501 patients with stage II or stage III disease. The fluorouracil precursors, capecitabine and tegafur, provide no advantages in terms of efficacy or tolerability. These oral drugs have not been compared with the de Gramont protocol. A trial comparing raltitrexed versus fluorouracil + folinic acid was stopped because of an excess of deaths in the raltitrexed arm. In two large trials, each including more than 2000 patients, the addition of oxaliplatin to the fluorouracil + folinic acid combination (Folfox 4 protocol) in patients with stage III disease appeared to slightly improve overall survival in patients under 65 years of age, but severe neuropathy, diarrhoea, nausea and vomiting were more frequent. In three trials in a total of more than 3000 patients with stage III disease, the addition of irinotecan did not improve the efficacy of the fluorouracil + folinic acid combination, while serious adverse effects were more frequent. No new drugs intended for the treatment of colon cancer have been introduced since 2006, but better evaluation of existing drugs means that patients with stage III colorectal cancer can now be offered a choice between standard intravenous fluorouracil and oral capecitabine or tegafur. Oxaliplatin adjunction is another option for patients under 65. The adverse effect profile is an important factor in the choice of treatment.     

低位直肠癌术后化学治疗辅助使用参术益中汤近远期疗效研究

目的探讨低位直肠癌术后化学治疗(简称化疗)辅助使用参术益中汤的近远期疗效。方法选取医院2013年1月至2014年12月收治并行直肠癌根治术的低位直肠癌患者82例,按随机数字表法分为观察组和对照组,各41例。两组患者术后均予FOLFOX化疗方案,观察组患者加用参术益中汤辅助治疗。结果治疗后,两组患者的CD3^+,CD4^+水平和CD4^+/CD8均明显升高,CD8^+明显降低,且观察组明显优于对照组(P<0.05);治疗后,两组患者的生活质量(包括生理功能、心理功能、日常活动、社交功能)评分均明显升高,且观察组明显高于对照组(P<0.05);观察组不良反应发生率与对照组相当(34.15%比24.39%,P>0.05);门诊随访5年,观察组患者的肿瘤复发率、远端转移率均明显低于对照组,而5年生存率明显高于对照组(P<0.05)。结论低位直肠癌术后化疗辅助使用参术益中汤,可提高免疫功能和生活质量,且远期疗效更好。     

乳腺癌治疗中TE方案新辅助化疗的应用效果及机制

目的观察并研究乳腺癌治疗中TE方案新辅助化疗的应用效果及机制。方法选取2010年1月～2012年1月在笔者所在医院治疗的40例乳腺癌患者,采取TE方案新辅助进行化疗,并观察其疗效。结果 40例患者,完全缓解11例,部分缓解为21例,病情稳定为8例,疾病进展为0例,总的有效率为80%。本研究中的患者均能对其出现的不良反应耐受,且在化疗的过程中未发现腹泻、肝肾功能或心电图出现异常的患者。结论 TE方案新辅助化疗对治疗乳腺癌有良好的应用效果,能大幅度地提高乳腺癌的化疗有效率,值得临床上运用于治疗乳腺癌。     

Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study

The aim of the present trial was to investigate the protective effects on ovarian function, and the efficacy and tolerability of goserelin added to adjuvant chemotherapy for early breast cancer. Following surgical treatment, 64 premenopausal patients with early breast cancer received goserelin 3.6 mg (every 28 days for 1 year) and an adjuvant treatment which was chosen according to the patient's prognosis. Median age was 42 years (range 27-50). ECOG performance status was 0-1 in all patients. Twenty-eight patients (44%) had estrogen receptor (ER)+ tumors and 36 (56%) patients had ER- tumors. Fifty-two (81%) patients had stage II disease and 12 (19%) had stage III disease. Eighteen patients received cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, 46 patients received an anthracycline-based regimen, and nine of them received high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation. Fifty-one patients (80%) were irradiated. ER+ patients also received tamoxifen for 5 years. Serum estradiol was suppressed to values below 40 pg/ml in all patients. After a median follow-up of 55 months, 86% of patients had resumed normal menses, 84% of patients were disease-free and 94% were alive. The 1-, 3- and 5-year projected recurrence-free survival rates were 100, 81 and 75%, respectively. Five years after treatment one patient had a pregnancy that ended with a normal childbirth. No unexpected adverse events were reported. These data show that the addition of goserelin to adjuvant therapy of premenopausal patients with early breast cancer is well tolerated and protects long-term ovarian function.