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© 2003 American Society for Clinical Oncology Combined-Modality Therapy of Locally Advanced Cervical CancerFrom the Case Western Reserve University and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, MetroHealth Medical Center, Cleveland, OH. Address reprint requests to Peter G. Rose, MD, Department of Obstetrics and Gynecology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; email: prose{at}metrohealth.org.
Six randomized trials of chemoradiotherapy in cervical cancer have demonstrated improvement with cisplatin-based chemoradiotherapy compared with radiation alone or radiation with hydroxyurea. Only one randomized trial (Gynecologic Oncology Group [GOG] 120) compared different cisplatin-based regimens and demonstrated significantly more hematologic and gastrointestinal toxic effects with the combination of cisplatin, fluorouracil, and hydroxyurea than with weekly cisplatin alone. The use of fluorouracil and mitomycin as radiation sensitizers for cervical cancer is based on their activity in chemoradiotherapy for anal carcinoma. However, a three-fold increase in serious late bowel toxicity was seen in patients treated with fluorouracil and mitomycin compared with fluorouracil alone when combined with radiation therapy for cervical cancer. Another randomized trial demonstrated improvement in survival with fluorouracil infusion compared with radiation alone only in early-stage disease. However, the most recently completed randomized trial by the GOG, which compared continuous fluorouracil infusion with weekly cisplatin, was closed when interim analysis demonstrated no potential superiority to the fluorouracil arm. Uncontrolled studies have evaluated the use of carboplatin on several different schedules, but no controlled trials have yet been performed. In metastatic and recurrent cervical cancer, a number of newer agents, including paclitaxel, gemcitabine, topotecan, and vinorelbine, have demonstrated modest single-agent activity and even greater activity in combination with cisplatin. An expanding series of trials will define the role of these new agents combined with cisplatin and radiation therapy for locally advanced cervical cancer. The potential role of biologic agents in combination with chemoradiotherapy also needs to be examined in locally advanced cervical cancer.
IN THE last 50 years, the introduction of the randomized clinical trial has had a significant effect on clinical patient management.1 Although numerous phase I and II trials and even a few phase III trials have used chemotherapy in conjunction with radiation therapy for locally advanced cervical cancer, no consensus regarding its beneficial effect has been reached.2 The effect of the addition of chemotherapy on progression-free and overall survival could be determined only after carefully designed, randomized, controlled trials were performed that evaluated chemotherapy agents given in either a sequential or concurrent fashion with radiation. From these carefully designed trials, cisplatin-based chemotherapy given in a concurrent schedule with radiation for cervical cancer has emerged as the new standard. This article reviews the randomized clinical trials of combined chemotherapy and radiation therapy that have been conducted in cervical cancer and describes potential future directions of clinical research.
Neoadjuvant and concurrent chemotherapy have been the most common chemotherapy schedules studied in locally advanced cervical cancer. With the neoadjuvant schedule, typically two to four courses of chemotherapy are administered before definitive radiation therapy is initiated. Intuitively, this schedule, which should result in reduction in tumor size before definitive radiation therapy, should be effective. Tumor size, reflected in tumor stage, is the most important predictor of local control and survival after radiation therapy for cervical cancer. In addition, because the chemotherapy and radiation treatments do not overlap, the tolerance for each therapy should be improved. Although chemotherapy for advanced and recurrent cervical cancer has produced disappointing results (response rates of 15% to 25%), chemotherapy delivered in a neoadjuvant fashion seems to be more effective (response rates of 40% to 70%). In addition, after neoadjuvant chemotherapy, up to 25% of patients achieve complete responses. Unfortunately, despite the rationale for this therapy, no randomized trial has demonstrated a benefit to neoadjuvant chemotherapy for cervical cancer (Table 1
In the concurrent chemotherapy schedule, chemotherapy and radiation are given simultaneously. Because of the potential for overlapping hematologic toxic effects, considerably more attention must be given to the toxicity of the chemotherapy agent used. The agents most commonly used with concurrent radiation in cervical cancer have included hydroxyurea, cisplatin, fluorouracil, and mitomycin. Among these agents, cisplatin-based chemotherapy has most consistently demonstrated a beneficial result in randomized trials that used radiation or radiation with hydroxyurea as the control arm. Six large randomized trials that evaluated the role of concurrent cisplatin-based chemoradiotherapy have now been reported.14–19 Remarkably, the results of the first five trials, all of which showed benefit, matured in early 1998.14–18 These trials evaluated cisplatin-based chemotherapy in a variety of disease settings, including patients with high-risk factors after radical hysterectomy, patients with bulky stage IB2 tumors, and patients with locally advanced stage IIB, III, and IVA disease.14–18 In three of these trials, chemoradiotherapy was compared with radiation therapy alone,14,15,17 and in two trials chemoradiotherapy was compared with radiation with hydroxyurea16,18 (Table 2  ). In each of these trials, an increase in relative progression-free survival and relative survival of 30% to 50% was seen (Fig 1). These studies, representing more than 1,800 patients, formed the basis for the National Cancer Institute’s consensus statement that advocated cisplatin-based chemoradiotherapy as the new standard of care for patients who require radiation therapy for cervical cancer.20 More recently, the results of a sixth randomized trial have matured.19 This trial did not demonstrate a statistical benefit to cisplatin-based chemoradiotherapy. However, the collective results of six randomized trials support cisplatin-based chemoradiotherapy in cervical cancer (Fig 2).
The randomized trials of cisplatin-based chemotherapy were conducted in a variety of clinical scenarios, from apparent early-stage disease with high-risk factors to locally advanced disease. Although radical hysterectomy is often used for the treatment of early-stage cervical cancer, some patients remain at high or intermediate risk for recurrence. Patients with pelvic nodal metastasis, parametrial extension, or involved surgical margins are the highest-risk group.21 The Southwest Oncology Group enrolled 243 assessable patients with clinical stage IA2, IB, and IIA cervical cancer who, after radical hysterectomy, had high-risk factors (nodal metastasis, parametrial extension, or involved margins of resection). Patients were randomly assigned to receive either radiation therapy with cisplatin and fluorouracilor radiation alone (Southwest Oncology Group trial 8797).14 The projected progression-free survival favored the chemoradiotherapy arm (80%) versus radiation alone (63%). The projected survival also favored the chemoradiotherapy arm. Interestingly, after radiation alone, patients who had adenocarcinoma of the cervix had significantly worse outcomes than patients who had squamous cell carcinoma. Patients with both conditions responded equally and had significantly better outcomes with combined chemotherapy and radiation. Tumor size has long been recognized as a prognostic risk factor for stage IB cervical cancer.22 However, the designation by the International Federation of Gynecology and Obstetrics of stage IB1 and IB2 in 1994 established criteria for differentiating the clinical management of smaller from larger gross cervical tumors limited to the cervix. In a retrospective review, Finan et al23 reported that patients treated with primary radical hysterectomy for stage IB2 tumors had a significantly poorer survival than patients with IB1 tumors despite the more frequent use of postoperation radiation therapy. The role of adjuvant hysterectomy for bulky stage IB cervical cancer has been evaluated by the Gynecologic Oncology Group (GOG) in a randomized trial of radiation versus radiation and adjuvant hysterectomy. Preliminary results indicated a lower relapse rate in the pelvis for patients who underwent hysterectomy with immature survival results. Therefore, in the subsequent trial, radiation and adjuvant hysterectomy became the standard against which concurrent weekly cisplatin, radiation, and adjuvant hysterectomy were compared (GOG-123).15 Among 369 assessable patients, significant differences in progression-free survival and overall survival also favored the chemoradiotherapy arm. Estimated survivals at 36 months were 83% and 74%, respectively, for chemoradiotherapy versus radiation therapy alone followed by hysterectomy. Pathologic examination of the hysterectomy specimens demonstrated a significant decrease in persistent disease with chemoradiotherapy. More leukopenia and gastrointestinal toxic effects were seen with frequent and severe chemoradiotherapy, but these were transient and without serious sequelae. In patients with locally advanced cervical cancer (stage IIB to IVA), the GOG randomly assigned 368 assessable patients to receive radiation therapy with concurrent cisplatin and fluorouracil infusion for 4 days versus hydroxyurea (GOG-85).16 Patients in the cisplatin-containing treatment arm had significantly better progression-free and overall survival. With a median follow-up of 8.7 years, this difference in survival is 55% v 43% for cisplatin and fluorouracil versus hydroxyurea, respectively. In a subsequent trial, the Radiation Therapy Oncology Group (RTOG) randomly assigned 388 assessable patients with stage IB to IVA disease to chemoradiotherapy with cisplatin and fluorouracil versus extended-field radiation (RTOG-9001).17 This trial was based on a previous RTOG trial that demonstrated superiority of extended-field radiation in advanced cervical cancer.24 Chemoradiotherapy with cisplatin and fluorouracil was again superior, resulting in an overall survival of 73% compared with 58% for radiation alone. Chemoradiotherapy decreased both the rate of local failure and the rate of distant failure. Acute toxic effects were more common with chemoradiotherapy, but rates of late complications (complications that persisted or occurred more than 60 days after treatment) were similar. To further study single-agent cisplatin delivered weekly and the combination of cisplatin, fluorouracil, and hydroxyurea, the GOG performed a three-arm trial in 526 assessable patients with stage IIB to IVA cervical cancer comparing weekly cisplatin versus cisplatin, fluorouracil, and hydroxyurea versus hydroxyurea alone; all three treatment arms were administered concurrently with radiation therapy (GOG-120).18 These results demonstrated superior survival rates for both concurrent cisplatin regimens (67% and 66%, respectively) compared with concurrent hydroxyurea alone (50%). Again, local failure rates were significantly decreased in the cisplatin arms, indicating that chemotherapy was acting as a radiation sensitizer. The toxic effects of treatment were least severe with the single-agent cisplatin regimen. All five trials that compared cisplatin-based chemoradiotherapy with radiation alone show a significant reduction in the risk of recurrence and death with chemoradiotherapy.14–18 The five randomized cervical cancer trials involved a total of 1,894 women with a wide variety of disease stages of cervical cancer in which radiation therapy would be used. There is remarkable symmetry in the reduction of relative risk of relapse or death by 30% to 50%. This consistency of results presents compelling evidence for the inclusion of cisplatin-based chemotherapy with radiation in the treatment of patients with cervical cancer who require radiation. On the basis of the results of these five trials, the National Cancer Institute released a clinical announcement stating that "strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation for women who require radiation therapy for the management of cervical cancer."20
After this clinical alert, the sixth large randomized trial was reported by the National Cancer Institute of Canada.19 This trial evaluated patients with stage IB (> 5 cm) to IVA disease and treated patients with radiation therapy at an optimal dose and schedule, with or without concurrent weekly cisplatin. Survival was not significantly different at 3 years (69% v 66%) or 5 years (62% v 58%) for cisplatin and radiation or radiation alone, respectively. The strengths of the Canadian study were that it was a multicenter, prospective, randomized trial; it used appropriate doses of chemotherapy (cisplatin 40 mg/m2 delivered weekly); and the distribution of radiation therapy dose and schedule were similar between the two regimens. However, this trial was relatively small (253 patients), with large confidence intervals that potentially failed to recognize a significant (up to 39%) improvement in survival. In addition, in contrast to the previous studies in advanced disease, in which patients underwent surgical staging to exclude para-aortic nodal metastases, the patients in the Canadian trial were staged only by computed tomographic (CT) scan. Previous studies have demonstrated that CT scan only detects one third of patients with para-aortic nodal metastases. On the basis of stage at accrual, an estimated 20% of patients would have had para-aortic nodal metastasis, 13% of whom would have been undetected by CT scanning. Inclusion of this patient population would further lessen the potential benefit seen with localized radiation therapy. In addition, patients treated with cisplatin-based chemoradiotherapy had significantly greater anemia. Retrospective data demonstrate that anemia has a negative effect on local control with radiation therapy.25 The degree of anemia seen in the Canadian trial would have further disadvantaged the cisplatin-based treatment arm by an estimated 8% to 10%. Other possible explanations for this discrepancy that have been refuted include increased anemia in the control arms that used hydroxyurea or extended-field radiation and a possible synergistic action of fluorouracil.26 Individually and collectively, all six of the cisplatin-based randomized trials of chemoradiotherapy demonstrate decreased pelvic failure, indicating an additive or synergistic effect of the combined-modality therapy (Table 3
Other radiation-sensitizing agents that have been studied in the past have not convincingly produced benefit and have not been generally accepted by the medical community. Both fluorouracil and mitomycin, which are commonly used in anal cancer, have been studied in cervical cancer. In a series of phase II and III trials at the Princess Margaret Hospital (Toronto, Canada), fluorouracil with or without mitomycin was studied in combination with pelvic radiation for cervical cancer. However, retrospective analysis demonstrated that the addition of mitomycin was associated with a three-fold greater risk of gastrointestinal toxic effects, and its further use was abandoned.27 Fluorouracil alone was then studied in cervical cancer at the Princess Margaret Hospital, where patients were randomly assigned in a four-arm study design to either standard radiation fractionation or partially hyperfractionated radiation therapy, in which patients received twice-daily therapy for the first and last weeks of treatment.28 Within these two radiation schemas, patients were randomly assigned to receive fluorouracil infusion or nothing. Although overall no statistical benefit was seen, improvement was noted among a subset of patients who had stage IB or IIB lesions with only unilateral parametrial involvement. To evaluate the efficacy of fluorouracil infusion therapy, the GOG recently conducted a randomized trial in which patients who had their tumors clinically and radiologically staged were randomly assigned to receive infusion fluorouracil or weekly cisplatin. This trial was closed when it was evident that there was no potential benefit of infusion fluorouracil compared with cisplatin. Therefore, in randomized trials, single-agent, weekly cisplatin has demonstrated superiority to fluorouracil and hydroxyurea and is equally effective and less toxic than the combination of cisplatin, fluorouracil, and hydroxyurea. If we accept the importance of platinum-based therapy in combined chemoradiotherapy, is it possible to make further progress in the chemotherapy regimen? Carboplatin, which has fewer gastrointestinal toxic effects, renal toxic effects, and neurotoxicity than cisplatin, has not been extensively studied as a radiation sensitizer. A number of uncontrolled studies have evaluated the use of carboplatin on a variety of different schedules.29–31 To simulate the weekly cisplatin chemoradiation, carboplatin has been administered as weekly low-dose therapy (area under the concentration-time curve 2).32 However, to date, no controlled trials have been performed with carboplatin as a radiation sensitizer for cervical cancer. Because cisplatin is relatively nonmyelosuppressive, another alternative is to consider combination therapy with cisplatin. Recently, in metastatic and recurrent cervical cancer, a number of new drugs, including paclitaxel, gemcitabine, topotecan, and vinorelbine, have demonstrated modest single-agent activity, with response rates of 17%, 8%, 12.5%, and 18%, respectively.33–36 Greater activity was seen with these agents in combination with cisplatin, with response rates of 46%, 41%, 33%, and 64% for paclitaxel, gemcitabine, topotecan, and vinorelbine, respectively.37–40 One of these agents, paclitaxel, has been evaluated in a randomized trial in advanced and recurrent squamous cell carcinoma, which compared paclitaxel and cisplatin with cisplatin alone.41 This combination demonstrated a significantly greater response rate (19.4% v 36.2%; P = .002) than single-agent cisplatin. More recently, phase I studies of weekly cisplatin and paclitaxel, gemcitabine, or tirapazamine with concurrent pelvic radiation have been performed.42–44 In the GOG trials, these regimens are being evaluated both with pelvic and extended (pelvic and para-aortic) radiation. Phase III randomized trials will help to define the role of these new agents combined with radiation therapy for the treatment of locally advanced cervical cancer. Biologic therapy for cancer is expanding and can be potentially applied to cervical cancer in the near future. Cervical cancer highly expresses the epidermal growth factor and vascular endothelial growth factor. These growth factor inhibitors both alone and in combination with cisplatin chemotherapy need to be studied for recurrent and metastatic disease and as radiation sensitizers in locally advanced disease.
DR. CANNISTRA: What efforts are currently under way to ask whether 5FU plus cisplatin versus cisplatin alone constitutes an advantage? Is that an important enough question to be asking, given the fact that 5FU is a potentially active agent and that the two drugs have been used together in some of the recent randomized trials? DR. ROSE: One could look at this in advanced and recurrent disease, and if it’s applicable in that setting, it might be applicable as a radiation sensitizer. There’s been a lack of enthusiasm since the mid-80’s for the combination of cisplatin and 5FU in advanced and recurrent cervical cancer. In fact, we’ve never been able to show until recently that there was a significant benefit to any other agent. DR. CANNISTRA: But as a radiation sensitizer, you’re asking 5FU to serve a different role. DR. ROSE: That’s true. DR. RUSTIN: There were two meta-analyses presented by Jayne Tierney [London, England: ASCO, 824 and 825], one where she looked at chemotherapy followed by radiotherapy and the other where she looked at chemotherapy followed by surgery. The chemotherapy followed by surgery shows a significant improvement in survival compared to just surgery alone. Obviously, this would not be for the most advanced cases. The EORTC is now doing a randomized trial (EORTC 55994) of chemoradiation similar to your protocol versus neoadjuvant chemotherapy followed by surgery. I’d like to hear people’s views on the long-term side effects of the radiotherapy. DR. ROSE: If you look at the randomized trial by Sarti, he treated all patients with greater than 2-cm lesions with neoadjuvant chemotherapy versus no therapy followed by radical hysterectomy, and all patients got radiation therapy. He found increased resectability with neoadjuvant chemotherapy followed by surgery, but all patients got this trimodality treatment. What we found also in GOG-141 was that most of the patients ended up getting radiation therapy after their radical hysterectomy because they had adverse risk factors that would then lead them to radiation. In fact, since chemoradiation has now been shown to be superior, they got neoadjuvant chemotherapy, radical hysterectomy, and chemoradiation. I agree with the EORTC trial, and we proposed something similar to GOG. GOG took a little different approach. They decided to use primary surgery followed by radiation versus concurrent chemoradiation. DR. KOH: The EORTC trial is somewhat influenced by the Benedetti-Pannici trial [J Clin Oncol 20:179–188, 2001], where neoadjuvant chemotherapy followed by surgery was better than radiation alone. In contrast to surgery, neoadjuvant chemotherapy followed by radiation has some biological disadvantages because of potential accelerated repopulation. Even if a tumor is smaller due to response with neoadjuvant chemotherapy, an accelerated rate to tumor cell division is detrimental during a course of fractionated radiation. There is not evidence of benefit to neoadjuvant chemotherapy followed by radiotherapy in multiple trials and on meta-analysis. With surgery, that’s a different situation, because if you can shrink the tumor and get it out, the kinetics of the tumor at the time you do the surgery might not be important. With regard to GOG-141, patients who received neoadjuvant chemotherapy did not have any reduction in surrogate risk factors, such as extracervical extension, positive nodes, or the need to adjuvant radiotherapy, compared with those who underwent surgery alone. This raises some issues about the benefit of neoadjuvant chemotherapy preceding surgery. I guess where neoadjuvant chemotherapy preceding surgery may be beneficial would be for some of the bulky tumors that are borderline resectable but where nodal metastases can be ruled out, for example, with PET imaging. DR. RUSTIN: The other issue that came out of the Tierney meta-analysis was the actual type of chemotherapy, because the original studies contained lots of different types. She showed that if the frequency of chemotherapy is fewer than 14 days between courses, they seem to do better. The new regimens, for example, paclitaxel and cisplatin, which seem to have a far higher response rate, might need to be relooked at in that situation. DR. ROSE: There’s no question that there’s morbidity associated with radiation therapy. The question is whether it’s worse after radical hysterectomy if you end up having to do neoadjuvant chemotherapy, radical hysterectomy, and then radiation therapy. When you look at these meta-analyses and randomized trials, you have to look at the radiation therapy doses that are being delivered. Like in the Benedetti-Pannicci study, it’s 70 Gy, which is much lower than is acceptable by US standards. DR. CANNISTRA: I believe that a significant fraction of the patients in that study received postoperative radiation because of high-risk features discovered at the time of surgery. DR. CANNISTRA: Dr Rustin, what is the current EORTC study design addressing this question? DR. RUSTIN: The EORTC design is basically chemoradiation standard, delivered by itself, versus neoadjuvant chemo followed by surgery. DR. KOH: Does that trial tightly control the use of adjuvant radiotherapy or does it use it for all the indications that, for example, Benedetti-Pannici did? Because if one really wants to test the benefit of neoadjuvant chemotherapy, one should arguably restrict the amount of postoperative adjuvant therapy that is given. That’s one of the reasons that GOG-141 was closed—so many patients received radiation afterwards that it was felt that the question of neoadjuvant chemotherapy benefit would never be answered. DR. RUSTIN: It does state specifically who should be given it and who shouldn’t. Obviously, you can’t deny it to somebody whose resection margins are involved. DR. CANNISTRA: Which drugs would be reasonable to consider in future clinical trials in combination with cisplatin, in an attempt to enhance the radiosensitization effect? DR. ROSE: Certainly, the taxanes, gemcitabine, and vinorelbine are the most exciting. DR. DePRIEST: Would you say that for bulky IB cervix cancer that the standard of care is chemoradiation therapy? DR. ROSE: I don’t think there is a standard of care. The most controversial subject is how a bulky IB2 should be treated. If you accept the results of GOG-92 [Gynecol Oncol 73:175–176, 1999], which looked at the intermediate-risk patient who had deep myocervical invasion, large tumor size, or vascular lymphatic invasion, then I think you would radiate those patients. It’s very unlikely that you’re going to take a IB2 patient to the OR and not give them radiation for the high-risk factors, positive nodes, parametrial extension, or positive margins, or the intermediate-risk factors, large tumor size, deep myocervical invasion, or vascular lymphatic invasion. DR. BEREK: I would add that maybe all that study shows is that we’re more effective at combining surgery and radiation therapy than we used to be. Whether it’s the right thing to do or not is a different issue, but probably the morbidity is not quite what it was back when Gilbert Fletcher and others were reporting their combined data. Be that as it may, I was also in the audience for the presentation of the meta-analysis [Proc Int Gynecol Cancer Soc abst CV002, 2002]. I came away with the conclusion that the meta-analysis with neoadjuvant chemotherapy and surgery was only with five trials. Two of them were the Sarti papers [Gynecol Oncol 49:156–165, 1993] and one was the Benedetti-Pannicci study [J Clin Oncol 20:179–188, 2002]. The meta-analysis clearly showed, with all the potential flaws of the various studies, that there was a survival advantage in that group of parents. So the conclusion was that this is still potentially viable. Maybe we need to tweak the drugs a little better, tweak the timing, or watch how we combine things, but the sequence and the approach with advanced stage disease using neoadjuvant chemotherapy followed by surgery should not be abandoned at this point. DR. RUSTIN: In the real world, the majority of patients are now waiting 6 to 18 weeks to start their radical radiotherapy. I don’t know what the case is in this country. If you’re going to have to wait more than X weeks, would you be better off getting neoadjuvant chemo followed by surgery? DR. BEREK: That’s one of the reasons in Latin America and Argentina that they started that. They had this practical circumstance where these patients lie around with huge tumors, many of whom never got to radiotherapy, or by the time they got there, the disease had progressed. So they said let’s give them these drugs while we’re waiting, and a lot of the tumors shrunk. So then they asked now what do we do? They said let’s either radiate them more and, if we can’t get them there, let’s operate and take them out. And lo and behold, some of those patients who they thought were incurable were cured. DR. KOH: I want to clarify a point. What Fletcher showed was that a dose of 4,500 to 5,000 sterilizes microscopic disease 90% of the time in surgically undisturbed tissue. If you look at the radiation post radical hysterectomy, pelvic control is only improved by approximately 50% with those doses. Therefore, with microscopic residual disease following radical surgery, you may need to increase the dose to 60 to 65 Gy for maximal local control, as has been suggested in postoperative head and neck cancer cases. DR. VASEY: Is there a way in which you could monitor response to treatment during the neoadjuvant phase to such an extent that you would withdraw treatment? DR. RUSTIN: We routinely do MRIs before each course of neoadjuvant chemo as part of a blood flow study. However, the biggest danger is you’ve got somebody progressing through the chemo.
1. Streptomycin in Tuberculosis Trials Committee: Streptomycin treatment of pulmonary tuberculosis. Br Med J 2:769–782, 1948[Medline] 2. National Institutes of Health Consensus Development Conference statement on cervical cancer: April 1–3, 1996. Gynecol Oncol 66:351–361, 1997[CrossRef][Medline] 3. Chauvergne J, Rohart J, Héron JF, et al: Essai randomisé de chimiothérapie initiale dans 151 carcinomes du col utérin localement étendus (T2b-N1, T3b, MO). Bull Cancer (Paris) 77:1007–1024, 1990[Medline] 4. Tobias EJ, Buxton G, Blackledge JJ, et al: Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer. Cancer Chemother Pharmacol 26:S59–S62, 1990 (suppl) 5. Souhami L, Gil R, Allan S, et al: A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol 9:970–977, 1991[Abstract] 6. Cardenas J, Olguin A, Figueroa F, et al: Neoadjuvant chemotherapy (CT) + radiotherapy vs radiotherapy alone in stage IIIB cervical carcinoma: Preliminary results. Proc Am Soc Clin Oncol 11:232, 1992 (abstr 743) 7. Kumar L, Kaushal R, Nandy M, et al: Chemotherapy followed by radiotherapy versus radiotherapy alone in locally advanced cervical cancer: A randomized study. Gynecol Oncol 54:307–315, 1994[CrossRef][Medline] 8. Leborgne F, Leborgne JH, Doldan R, et al: Induction chemotherapy and radiotherapy of advanced cancer of the cervix: A pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 37:343–350, 1997[CrossRef][Medline]
9. Tattersall MHN, Larvidhaya V, Vootiprux V, et al: Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. J Clin Oncol 13:444–451, 1995 10. Sundfor K, Trope CG, Hogberg T, et al: Radiotherapy and neoadjuvant chemotherapy for cervical carcinoma: A randomized multicenter study of sequential cisplatin and 5-fluorouracil and radiotherapy in advanced cervical carcinoma stage 3B and 4A. Cancer 77:2371–2378, 1996[CrossRef][Medline] 11. Chiara S, Bruzzone M, Merlini L, et al: Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma: GONO (North-West Oncologic Cooperative Group). Am J Clin Oncol 17:294–297, 1994[Medline]
12. Tannock IF, Browman G: Lack of evidence for a role of chemotherapy in the routine management of locally advanced head and neck cancer. J Clin Oncol 4:1121–1126, 1986 13. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131–146, 1988[Medline]
14. Peters WA III, Liu PY, Barrett RJ, et al: Cisplatin and 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive in high-risk early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a phase III intergroup study. J Clin Oncol 18:1606–1613, 2000
15. Keys HM, Bundy BM, Stehman FB, et al: A comparison of weekly cisplatin during radiation therapy versus irradiation alone each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma: A randomized trial of the Gynecologic Oncology Group. N Engl J Med 340:1154–1161, 1999
16. Whitney CW, Sause W, Bundy BN, et al: A randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study. J Clin Oncol 17:1339–1348, 1999
17. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high risk cervical cancer: A randomized Radiation Therapy Oncology Group clinical trial. N Engl J Med 340:1137–1143, 1999
18. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based chemoradiation improves progression free and overall survival in advanced cervical cancer: Results of a randomized Gynecologic Oncology Group study. N Engl J Med 340:1144–1153, 1999
19. Pearcy R, Brundage M, Drouin P, et al: Phase III trial comparing radical radiation therapy with and without cisplatin chemotherapy in patients with advanced squamous cell carcinoma of the cervix. J Clin Oncol 20:966–972, 2002 20. NCI Clinical Announcement: Concurrent Chemoradiation for Cervical Cancer. Washington, DC, United States Department of Public Health, February 1999 21. Delgado G, Bundy B, Zaino R, et al: Prospective surgical-pathological study of disease-fee interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group Study. Gynecol Oncol 38:352–357, 1990[CrossRef][Medline]
22. Piver MS, Chung WS: Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 46:507–510, 1975 23. Finan MA, DeCesare S, Fiorica JV, et al: Radical hysterectomy for stage 1B1 vs 1B2 carcinoma of the cervix: Does the new staging system predict morbidity and survival? Gynecol Oncol 62:139–147, 1996[CrossRef][Medline] 24. Rotman M, Pajak TF, Choi K, et al: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. J Am Med Assoc 274:387–393, 1995[Abstract] 25. Grogan M, Thomas GM, Melamed I, et al: The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86:1528–1536, 1999[CrossRef][Medline]
26. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: Does it help? J Clin Oncol 20:891–893, 2002 (editorial) 27. Rakovitch E, Fyles AW, Pintilie M, et al: Role of mitomycin C in the development of late bowel toxicity following chemoradiation for locally advanced carcinoma of the cervix. Int J Radiat Biol Oncol Phys 38:979–987, 1997[CrossRef][Medline] 28. Thomas G, Dembo A, Ackerman I, et al: A randomized trial of standard versus partially hyperfractionated radiation with or without concurrent 5-fluorouracil in locally advanced cervical cancer. Gynecol Oncol 69:137–145, 1998[CrossRef][Medline] 29. Corn BW, Hernandez E, Anderson L, et al: Phase I/II study of concomitant irradiation and carboplatin for locally advanced carcinoma of the uterine cervix: an interim report. Am J Clin Oncol 19:317–321, 1996[CrossRef][Medline] 30. Muderspach LI, Curtin JP, Roman LD, et al: Carboplatin as a radiation sensitizer in locally advanced cervical cancer: A pilot study. Gynecol Oncol 65:336–342, 1997[CrossRef][Medline] 31. Micheletti E, LaFace B, Bianchi E, et al: Continuous infusion of carboplatin during conventional radiotherapy treatment in advanced squamous carcinoma of the cervix uteri IIB-IIIB (UICC): A phase I/II and pharmacokinetic study. Am J Clin Oncol 20:613–620, 1997[CrossRef][Medline] 32. Higgins RV, Naumann WR, Hall JB, et al: Concurrent weekly carboplatin with radiation therapy in the primary treatment of cervix cancer. Gynecol Oncol (in press)
33. McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group Study. J Clin Oncol 14:792–795, 1996 34. Schilder RJ, Blessing JA, Morgan M, et al: Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Gynecol Oncol 76:204–207, 2000[CrossRef][Medline] 35. Bookman MA, Blessing JA, Hanjani P, et al: Topotecan in squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Gynecol Oncol 77:446–449, 2000[CrossRef][Medline] 36. Morris M, Brader KR, Levenback C, et al: Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol 16:1094–1098, 1998[Abstract]
37. Rose PG, Blessing JA, Gershenson DM, et al: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group Study. J Clin Oncol 17:2676–2680, 1999 38. Burnett AF, Roman LD, Garcia AA, et al: A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76:63–66, 2000[CrossRef][Medline] 39. Fiorica J, Grendys E, Holloway R, et al: Phase II trial of topotecan combined with cisplatin in squamous and non-squamous cervical cancer: Preliminary results. Proc Am Soc Clin Oncol 18:373a, 1999 (abstr 1441)
40. Pignata S, Silvestro G, Ferrari E, et al: Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix. J Clin Oncol 17:756–760, 1999 41. Moore DH, McQuellon RP, Blessing JA, et al: A randomized phase III study of cisplatin versus cisplatin and paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 2001;20:201a (abstr 801) 42. Chen MD, Paley PJ, Potish RA, et al: Phase I trial of Taxol as a radiation sensitizer with cisplatin in advanced cervical cancer. Gynecol Oncol 67:131–136, 1997[CrossRef][Medline] 43. Zarba J, Jaremtchuk A, Cedaro L, et al: GETICS: A phase I -II study of weekly cisplatin and gemcitabine with concurrent radiotherapy in locally advanced cervical cancer. Proc Am Soc Clin Oncol 20:206a, 2001 (abstr 822) 44. Craighead PS, Pearcey R, Stuart G: A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 48:791–795, 2000[CrossRef][Medline] Submitted January 29, 2003; accepted February 28, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
