Current approaches of neoadjuvant chemotherapy in cervical cancer

Despite remarkable improvement in clinical management, the survival of cervical cancer patients has shown only minor progress in the last decade, particularly in patients with advanced and high-risk disease. Multimodal treatment option has been investigated, such as the concurrent use of chemotherapy and radiation, neoadjuvant chemotherapy and radical hysterectomy, or neoadjuvant chemotherapy followed by radiotherapy. Recently, a flow of randomized clinical trials have demonstrated a benefit from the concurrent chemoradiation for the treatment of the cancer of the cervix. This review will summarize the role and benefit of neoadjuvant chemotherapy in combination with sequential or concurrent radiotherapy and radical surgery for treatment of cervical cancer.     

Concurrent chemotherapy and radiation therapy as the standard of care for cervical cancer

From 1999-2000, each of five randomized trials demonstrated improved rates of survival and local control when concurrent cisplatin-based chemotherapy was added to radiation therapy in patients with loco-regionally advanced cervical cancer. These studies demonstrated that addition of chemotherapy to radiation therapy improved the outcome of patients treated with radiation therapy and hysterectomy or radiation therapy alone. Although concurrent chemotherapy increases the severity of acute side effects, it does not appear to increase the risk of late side effects of radiation therapy. A sixth randomized trial, published in 2002, failed to demonstrate improved outcome with concurrent weekly cisplatin over radiation therapy alone; however, the earlier trials demonstrated benefit with this chemoradiation regimen. In addition, three of the earlier randomized trials demonstrated improved outcome with combinations of cisplatin and 5-fluorouracil compared with radiation therapy alone. Although cisplatin-based chemoradiation is the most accepted standard, individual trials have suggested that other drugs, including mitomycin and epirubicin, might be beneficial. Randomized trials that investigated the administration of neoadjuvant chemotherapy before radiation therapy have failed to demonstrate a benefit of this approach. Although the evidence for benefit of concurrent chemotherapy is strong for otherwise healthy patients with newly diagnosed, loco-regionally advanced cervical cancers confined to the pelvis, the relative benefits and risks are not well understood for patients who are infirm or who require larger fields of radiation therapy. In such patients, the theoretical benefits and potential risks should be considered carefully before a treatment plan is prescribed.     

Treatment of stage IB2 (bulky) cervical carcinoma

Tumour size is an important prognostic factor in patients with stage IB cervical cancer. The patient with stage IB2 (bulky) cervical cancer represents a therapeutic challenge. Neither radical hysterectomy nor primary radiation therapy are sufficiently effective and are associated with significant treatment-related complications including ovarian failure and psychosexual deficits. A number of phase III studies have explored alternative management approaches in this patient population. It appears that extrafascial hysterectomy following radiation therapy does not improve overall survival relative to radiation therapy alone. Consistent with results seen in locally advanced cervical carcinoma, chemoradiation therapy is superior to radiation therapy alone as primary treatment for stage IB2 cervical cancer and as adjuvant therapy for surgically treated patients with high-risk factors for recurrence. Neoadjuvant chemotherapy has resulted in high clinical response rates and operability rates. There are two phase III trials suggesting an improvement in survival with neoadjuvant chemotherapy followed by radical hysterectomy versus either surgery (and selected postoperative radiation) or radiation therapy alone. These emerging treatments should be scrutinized in prospective controlled trials.     

Chemoradiotherapy for cervical cancer

Cervical cancer remains a major health problem worldwide, despite advances in screening. For patients with locally advanced stage disease, failure to obtain local-regional control usually results in death. In an effort to improve local-regional tumour control, neoadjuvant and concurrent chemoradiation has been tested. Recently, five randomised trials performed by the Gynecologic Oncology Group (GOG), Radiation Therapy Oncology Group (RTOG) and the SouthWest Oncology Group (SWOG) studying cisplatin-based chemoradiation have demonstrated a significant survival advantage. Three of the trials compared cisplatin-based concurrent chemotherapy and radiation to radiation alone and two trials compared cisplatin-based concurrent chemotherapy and radiation to radiation with hydroxyurea. In all of the trials, cisplatin-based chemotherapy administered concurrently with radiation therapy was more effective at reducing the risk of death by 30–50%. Acute toxicities, principally neutropenia and gastrointestinal, were more common with chemoradiation, but were transient and the rates of late complications (complications that persisted or occurred for more than 60 days after the treatment) were similar. Based on the results of these five randomised trials, the National Cancer Institute (NCI) released a Clinical Announcement stating that cisplatin-based chemotherapy, as used in these trials (i.e. concurrently with radiation therapy), as the new standard of therapy for cervical cancer.     

Recent developments in chemoradiotherapy for locally advanced cancer of the cervix

Patients with locally advanced cervical cancer comprise a significant proportion of the total population with cervical cancer, particularly in developing countries. The inability to control pelvic tumors is still a significant concern. Although neoadjuvant chemotherapy is associated with a high response rate, data from randomized trials clearly do not support the use of neoadjuvant chemotherapy prior to definitive irradiation. However, the results of concurrent cisplatin (Platinol)-based chemotherapy and radiotherapy are highly promising for locally advanced cancer of the cervix and should be considered as a treatment option. To decrease the risk of distant metastasis and improve survival, more effective drugs or drug combinations need to be developed.     

Primary management of early stage cervical cancer (IA1-IB) and appropriate selection of adjuvant therapy

Cervical cancer is the third most common gynecologic malignancy in the United States but the leading gynecologic cancer worldwide. Most patients will present with clinical early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage IA1-IB). These patients are a clinically heterogeneous group, and primary treatment can be either surgery or radiotherapy. Standard surgery is either radical hysterectomy with lymphadenectomy (stage IA2-IB2) or simple hysterectomy for microinvasive disease (stage IA1). Interest has been increasing in using conservative fertility-sparing surgery through radical trachelectomy as an option for select patients with early-stage disease who want future fertility. Primary radiotherapy is delivered as a combination of external-beam teletherapy and brachytherapy. It is given with concurrent cisplatin-based chemotherapy, based on 5 large randomized controlled trials that showed significant improvement in overall survival with the addition of chemotherapy. Using either radical surgery or radiation therapy in stage IB disease yields 5-year survival rates of 87% to 92%. The addition of postoperative adjuvant radiation with concurrent chemotherapy is recommended in patients with high- or intermediate-risk disease after radical hysterectomy to reduce risk for recurrence and improve progression-free survival. In select patients with stage IB2 disease with bulky tumors undergoing primary chemoradiation, adjuvant hysterectomy may provide benefit after treatment.     

Vaginal cancer

Opinion statement Carcinoma of the vagina is an uncommon gynecologic cancer in the United States and throughout the world. Carcinoma in situ of the vagina and very early stage invasive carcinoma of the vagina may be treated with surgery. However, the standard therapeutic intervention for patients with carcinoma of the vagina is radiation therapy. In early stage vaginal carcinoma, radiation therapy is chosen for definitive treatment to preserve the anatomy and function of the vagina. In more advanced stages of vaginal carcinoma, radiation therapy is chosen as the standard treatment to avoid exenterative surgery, preserve anatomy and function, and to treat known or presumed lymph node metastasis. No randomized studies comparing irradiation alone versus irradiation and chemotherapy have been performed for patients with advanced carcinoma of the vagina. The standard therapy for patients with advanced cervical carcinoma is irradiation and concurrent cisplatin-based chemotherapy. Because the etiology and epidemiology of vaginal carcinoma appears identical to those of patients with invasive cervical carcinoma, patients with advanced vaginal carcinoma should be treated with irradiation and concurrent cisplatin-based chemotherapy.     

不同病理类型局部晚期(ⅠB2及ⅡA2期)宫颈癌的预后情况分析

目的探讨不同病理类型局部晚期(ⅠB2、ⅡA2期)宫颈癌的预后情况。方法选取169例ⅠB2、ⅡA2期宫颈癌(鳞状细胞癌149例,腺癌或腺鳞癌20例)患者,根据治疗模式的不同将其分为同期放化疗组、根治性手术组、新辅助化疗+根治性手术组。比较不同病理类型及不同治疗模式局部晚期宫颈癌患者的2年无复发生存率,分析120例接受过根治性手术的局部晚期宫颈癌患者的病理类型与其他临床特征的关系,并比较新辅助化疗+根治性手术组中不同病理类型局部晚期患者对新辅助化疗的反应。结果截至随访结束,随访超过2年者137例,2年无复发生存率为83.9%(115/137),其中,鳞状细胞癌患者的2年无复发生存率高于腺癌或腺鳞癌患者(P﹤0.05)。同期放化疗组、根治性手术组、新辅助化疗+根治性手术组患者的2年无复发生存率分别为77.3%、87.0%、87.2%。接受根治性手术或新辅助化疗后行根治性手术+术后辅助放疗和(或)化疗的120例宫颈癌患者中,肌层浸润情况与局部晚期宫颈癌患者的病理类型可能有关(P﹤0.05)。接受新辅助化疗+根治性手术+术后辅助放疗和(或)化疗的62例患者中,鳞状细胞癌患者58例,包括CR患者14例,PR患者40例,SD患者4例;腺癌/腺鳞癌患者4例,包括CR患者1例,PR患者3例。鳞状细胞癌患者与腺癌/腺鳞癌患者对新辅助化疗的反应比较,差异无统计学意义(P﹥0.05)。结论局部晚期宫颈癌患者的近期预后较好,腺癌或腺鳞癌患者的预后较鳞状细胞癌患者差。对于病理类型为腺癌/腺鳞癌的局部晚期宫颈癌,建议在治疗方式上较鳞状细胞癌更激进,不建议保留卵巢功能,更倾向于以根治性手术为主的综合治疗,可望改善患者预后。     

Counterpoint: test the value of hyperthermia in patients with carcinoma of the cervix being treated with concurrent chemotherapy and radiation.

Major advances in the treatment of locally advanced cervical carcinoma were reported in 1999-2000 in five studies from the Gynecologic Oncology Group, Radiation Therapy Oncology Group and Southwestern Oncology Group. Collectively these trials reported a decrease in the risk of recurrence or death from cervical cancer ranging from 30-50% with the use of concurrent chemoradiation, as compared with radiation alone. On the basis of these trials the National Cancer Institute in 1999 issued a clinical alert concluding 'Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.' Concurrently with these publications there appeared the publication in the Lancet in 2000 of the Dutch Deep Hyperthermia Group trial of radiotherapy alone versus combined radiation and hyperthermia for locally advanced pelvic tumors including carcinoma of the cervix. This multi-center phase III trial demonstrated an approximate doubling of the three year survival from 27 to 51% for the addition of hyperthermia to radiotherapy in patients with locally advanced cervical carcinoma. Additional trials to test the value of hyperthermia in patients with cervical carcinoma treated with concurrent chemotherapy and radiation are imperative and take precedence over a trial to investigate the value of chemotherapy in patients treated with hyperthermia and radiation.     

A systematic overview of radiation therapy effects in cervical cancer (cervix uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn. There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer. There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer. The NCI has recently published an announcement stating that cisplatin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages ( >IIB). There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea. There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer. There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.     

COUNTERPOINT: Test the value of hyperthermia in patients with carcinoma of the cervix being treated with concurrent chemotherapy and radiation

Major advances in the treatment of locally advanced cervical carcinoma were reported in 1999-2000 in five studies from the Gynecologic Oncology Group, Radiation Therapy Oncology Group and Southwestern Oncology Group. Collectively these trials reported a decrease in the risk of recurrence or death from cervical cancer ranging from 30-50% with the use of concurrent chemoradiation, as compared with radiation alone. On the basis of these trials the National Cancer Institute in 1999 issued a clinical alert concluding 'Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.' Concurrently with these publications there appeared the publication in the Lancet in 2000 of the Dutch Deep Hyperthermia Group trial of radiotherapy alone versus combined radiation and hyperthermia for locally advanced pelvic tumors including carcinoma of the cervix. This multi-center phase III trial demonstrated an approximate doubling of the three year survival from 27 to 51% for the addition of hyperthermia to radiotherapy in patients with locally advanced cervical carcinoma. Additional trials to test the value of hyperthermia in patients with cervical carcinoma treated with concurrent chemotherapy and radiation are imperative and take precedence over a trial to investigate the value of chemotherapy in patients treated with hyperthermia and radiation.     

Chemotherapy for cervical carcinoma

Although cisplatin-based chemotherapy is standard regime for cervical cancer, the major question remains as to what kind of drug is the best candidate for combination with cisplatin. According to recent reports, platinum+taxane is supposed to be a promising combination for not only squamous cell carcinoma but also adenocarcinoma of cervix. Studies of neoadjuvant chemotherapy followed by radiotherapy demonstrate no advantage for overall survival of locally advanced cervical carcinoma. Otherwise, neoadjuvant chemotherapy followed by radical surgery was confirmed to offer a survival advantage in a few prospective randomized trials but its statistical power was low due to small number of patient cases. The platinum+taxane combination is good and its effects should be evaluated on overall survival in the same modality. Concurrent radiotherapy with weekly cisplatin is standard therapy for primary and adjuvant setting for squamous cell carcinoma and adenocarcinoma of cervix.     

A Systematic Overview of Radiation Therapy Effects in Cervical Cancer (Cervix Uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn.There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer.There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer.The NCI has recently published an announcement stating that cisplantin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages (>IIB).There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea.There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer.There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.     

Concurrent chemotherapy and radiation for locally advanced cervical cancer: the new standard of care

Radical pelvic irradiation has constituted the definitive therapy for patients with large cervical cancers. No substantial improvements have been made in treatment outcomes. In the past year, however, a series of large, well-conducted randomized trials has evaluated the role of concurrent chemotherapy with pelvic irradiation in cervical cancer. These trials include definitive treatment of patients with stage IB2 to IVA disease and adjuvant treatment after radical surgery in stage IB2-IIA disease. Five trials have shown a consistent 30% to 50% reduction in the risk of death from disease when concurrent chemotherapy is used. Questions still remain as to what constitutes the best chemotherapy dose and schedule. In all of the positive trials, cisplatin was used, but three also used 5-fluorouracil. The level of survival improvement that occurs when chemotherapy is added to optimal irradiation and whether patients with stage IIIB and IVA benefit are also unclear. Improvements in survival rates for patients with solid tumors occur slowly. Based on the evidence, it is likely that concurrent chemotherapy with radiation will become the new standard of care for bulky and advanced cervix cancer.     

Concurrent chemoradiation in lung cancer

Concurrent chemoradiation has become for the 15 last years the standard treatment for locally advanced non-small cell lung cancer, either as a definite therapy in non resectable tumors, or in a neoadjuvant setting in potentially resectable tumors. Associating sequential and concurrent schedules, by administering chemotherapy before or after concurrent chemoradiation, has been recently investigated, but the best sequence remains a matter of controversy. Increasing local control and survival after definite chemoradiation seems possible not only by using optimized radiation fractionation schedules and escalated total doses, but also by associating more convenient and less toxic chemotherapy agents at the right cytotoxic or radio-sensitizing dose. Moreover, recent data have suggested that surgery following induction chemoradiation is feasible and effective in selected patients without mediastinal nodes involvement, if a complete resection can be performed. In patients with localized small cell lung cancer, early concurrent chemoradiation with platinium and etoposide has been recognized as the state-of-the-art treatment. The increasing number of ongoing trials including modern radiation schedules combined with newer chemotherapy agents shows that chemoradiation is one of the most promising therapeutic strategies in thoracic oncology.     

Effects of different chemotherapy regimens on survival for advanced cervical cancer: systematic review and meta-analysis

BACKGROUND: A large number of trials have assessed various chemotherapy regimens for the treatment of advanced cervical cancer, but there is uncertainty about the magnitude of survival benefits. METHODS: We searched (last update January 2006) for trials in women with locally advanced or disseminated cervical cancer that compared neo-adjuvant or concurrent chemotherapy plus radiotherapy versus radiotherapy alone; or different chemotherapy regimens among themselves (with or without background radiotherapy in both arms). Sixty-five trials were identified with survival data on 11,180 women. Results for survival were combined with fixed and random effects models and between-study heterogeneity was estimated. Separate results were obtained for different regimens, cycle length, and type of chemotherapy (neo-adjuvant, concurrent, without radiotherapy). RESULTS: Twenty two comparisons had survival data on 3837 women randomized to receive chemotherapy plus radiotherapy versus radiotherapy alone; the summary relative hazard for mortality was 0.95, 95% CI, 0.83-1.08. Modest between-study heterogeneity (I2=38%) seemed to be due to contradictory results in early trials; trials published in the last decade had a summary relative hazard 0.89 (95% CI, 0.78-1.02) and no between-study heterogeneity (I2=0%). Results were similar for neo-adjuvant chemotherapy and for concurrent chemo-radiotherapy. Cisplatin or cisplatin-based combinations had no significant benefit overall, but a potential benefit was seen with short-length cycles (14 days) and a marginally significant harm with longer-length cycles (summary relative hazards 0.80, 95% CI, 0.66-0.99 and 1.18, 95% CI, 1.02-1.38, respectively). The summary relative hazard was 1.02, (95% CI, 0.84-1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI, 0.73-1.00) for trials using concurrent chemotherapy. CONCLUSIONS: Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy.     

Lack of Proven Efficacy of Chemotherapy for Patients With Carcinoma of the Uterine Cervix

This article reviews prospective randomized phase III studies that use chemotherapy and irradiation for the treatment of patients with carcinoma of the uterine cervix. Neoadjuvant chemotherapy has been administered in four separate trials. None of these has shown a benefit to neoadjuvant therapy compared with irradiation alone. One study has been performed in which postoperative pelvic irradiation was adminsitered to all patients with positive pelvic nodes following radical hysterectomy. Those randomized to also receive chemotherapy failed to show an improvement in survival. Radiosensitization with hydroxyurea or misonidazole has shown little, if any, benefit. Only one concurrent chemotherapy and irradiation trial has been published and showed no benefit in the chemotherapy arm. Data are maturing or accruing in the Gynecological Oncology Group and the Radiation Therapy Oncology Group for concurrent chemotherapy studies. In conclusion, no prospective phase III studies have shown a survival advantage for the use of chemotherapy for patients with carcinoma of the uterine cervix.     

Evidence-based medicine for urological cancer chemotherapy

We reviewed the treatment results of urological cancer chemotherapy from the standpoint of evidence based medicine. In the treatment of advanced transitional cell carcinoma of the urothelium, M-VAC (MTX + VBL + ADM + CDDP) is regarded as the standard regimen; however, durable event-free survival is rare. There is no level 1 evidence to date showing that the use of neoadjuvant or adjuvant cisplatin-based regimens will improve survival in cases of locally advanced bladder cancer. Immunotherapy with interferon or interleukin-2 produces a small survival advantage in patients with metastatic renal cell carcinoma. There is no evidence that adjuvant interferon-alpha administration will improve the survival in those with non-metastatic renal cell carcinoma. Systematized cisplatin-based treatment protocols have been established in patients with advanced testicular germ cell tumor by means of many randomized controlled trials. Several clinical trials are under way to prove the efficacy of high dose chemotherapy (with autologous stem-cell support) in patients with poor risk germ cell tumors. We do not yet have sufficient data to conclude whether maximal androgen blockade will prolong the survival in patients with metastatic prostate cancer, nor to conclude whether neoadjuvant androgen depletion treatment improve disease free survival of the patients after radical prostatectomy.     

Neoadjuvant chemotherapy followed by radical surgery compared to concurrent chemotherapy in stage I b2- III b cervical cancer

For the treatment of bulky cervical cancer, the most promising modality is surgery followed neoadjuvant chemotherapy( NAC-S)or concurrent chemoradiation therapy (CCRT). The purpose of this study is to compare the efficacy and complications associated with each treatment. The CCRT group included significantly more elderly and advanced patients than the NAC-S group. From 2001 to 2005, 76 consecutive previously untreated patients with bulky cervical cancer staged as I b2- III b were treated with NAC-S or CCRT. The response rate of NAC was 63% and 84% of patients received radical surgery. There was no significant difference in the intra-pelvic or extra-pelvic recurrence rate between NAC-S and CCRT group. In addition, there was no significant difference in 3-year relapse-free survival or overall survival. When we consider the bias, these results suggest that CCRT is superior to NAC-S.     

Neoadjuvant Chemotherapy in Bladder Cancer

Despite radical cystectomy for muscle-invasive bladder cancer, approximately 50% of patients with this disease will develop metastatic progression. Neoadjuvant systemic chemotherapy can be administered to decrease the risk of recurrence. Multiple randomized trials have addressed the effect of neoadjuvant chemotherapy on survival in patients with muscle-invasive bladder cancer. A recently published meta-analysis demonstrated a survival benefit with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer.