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© 2003 American Society for Clinical Oncology Controversies in the Radiotherapeutic Management of Cervical Cancer
From the Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA. Address reprint requests to Wui-Jin Koh, MD, Department of Radiation Oncology, Box 356043 University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195; email: wkoh{at}u.washington.edu.
Radiotherapy is a critical component of treatment for many patients with cervical cancer. The role of concurrent cisplatin-based chemotherapy in the majority of cases where radiotherapy is indicated has been established. However, optimal planning and delivery of radiotherapy require attention to multiple factors beyond combined-modality chemoradiation and the continuing search for novel and effective synergistic systemic agents. Several important issues surrounding radiotherapy for cervical cancer that require clarification include the following: the effect of anemia and tumor hypoxia on outcome and their potential as therapeutic targets, the appropriate incorporation of contemporary imaging and high-technology treatment planning systems in routine clinical practice, the role of prophylactic para-aortic radiation, and the role of radioprotectors. Ongoing and newly proposed studies are expected to provide insights into these questions, which will ultimately lead to enhanced radiotherapeutic and overall care for patients with cervical cancer.
ON THE basis of the recent publication of several landmark randomized clinical trials, there has been widespread acceptance of the concept that, in most cases where radiotherapy is administered for cervical cancer, it should be given with concurrent platinum-based chemotherapy.1,2 The results of these trials demonstrate a consistent improvement in disease-free and overall survival with concomitant chemoradiotherapy across a broad spectrum of clinical presentations and represent the most notable therapeutic gain in cervical cancer management during the past several decades. Although the new paradigm of concurrent radiation and cisplatin-based chemotherapy is a significant step forward, questions remain regarding optimal patient selection and scheduling, dosing, and choice of systemic agents. The integration of new and active combination regimens with radiotherapy is being investigated. In addition to traditional cytotoxic chemotherapy, several new, targeted biologic agents have shown promising preclinical activity when combined with radiotherapy. These aspects of multimodality therapy are addressed in detail in a separate essay in this Journal of Clinical Oncology Supplement issue. With more specific regard to the optimal implementation of radiotherapy in cervical cancer, several areas of important controversy have emerged. This article will focus on issues that are expected to be at the forefront of clinical investigation during the next decade. Ongoing or proposed multicenter trials that address these questions are highlighted.
The adverse association of anemia on outcome after primary radiotherapy for cervical cancer has been well documented in many previous clinical reviews. The mechanisms underlying this correlation are unclear but may be linked to tumor hypoxia and consequent radioresistance, as well as induction of angiogenesis, increased tumor aggressiveness, and enhanced metastatic potential. A recent, large, Canadian multicenter retrospective analysis3 has provided compelling evidence that anemia is an independent negative prognostic factor in cervical cancer. The study found that it was the average hemoglobin (Hgb) level during radiotherapy rather than that before therapy that was more predictive of poor outcome. The significant adverse effect of anemia during radiotherapy was second only to tumor stage in prognostic significance on multivariate analysis. The magnitude of the incremental survival for nonanemic compared with anemic patients exceeded the gain achieved with concurrent chemoradiation strategies. The most provocative suggestion of the Canadian study was that correction of anemia (by transfusion, to an Hgb level ≥ 12 g/dL) abrogated the adverse effect of pre-existing anemia.3 These findings have been echoed by another recent single-institution retrospective report from Austria, although a different threshold Hgb level (≤ 11 g/dL) for anemia was used.4 The influence of anemia in masking the potential synergistic benefit of concurrent cisplatin and radiation has even been advanced to explain the negative results of a randomized trial.5 Despite the potential prognostic and therapeutic implications of anemia in cervical cancer, only one small prospective randomized trial directly addressing this issue has been completed, approximately 3 decades ago. This study indicated improved pelvic control for patients who underwent irradiation whose Hgb level was corrected by transfusion, but the analysis was hampered by limited patient numbers and lack of stratification.6 In an attempt to provide definitive answers, the Gynecologic Oncology Group (GOG) recently initiated a prospective, multicenter, multinational phase III trial (GOG protocol 0191) in which patients with locally advanced cervical cancer undergoing primary chemoradiation (radiotherapy with concurrent weekly cisplatin at a dose of 40 mg/m2) are randomly assigned to Hgb maintenance at a level of 10 g/dL versus aggressive intervention to raise Hgb levels to 12 to 13 g/dL (by transfusion and erythropoietin). To further elucidate the mechanisms by which anemia may exert its negative effect, correlative translation studies are planned. These studies include tumor assays of vascular endothelial growth factor (a proangiogenic agent), thrombospondin-1 (an angiogenic inhibitor), p53, CD31 (an endothelial cell surface protein), and carbonic anhydrase IX (a marker for hypoxia). Tumor hypoxia, as measured by oxygen electrodes, has been identified in many cervical cancers and is a predictor of poor outcome.7,8 As noted above, although there may be a link, the relationship between anemia and tumor hypoxia remains ambiguous. It is expected that GOG-0191 will help clarify the interaction between host status (anemia and Hgb level) and tumor milieu (hypoxia) and their respective prognostic effects. Regardless of the relationship between these two measures, recent studies have identified significant modulation of gene expression in hypoxic tumors that may be associated with tumor aggressiveness and progression, including hypoxia-inducible factor 1, p53, vascular endothelial growth factor, platelet-derived endothelial cell growth factor, nitric oxide synthase, and matrix metalloproteinase.9 These biomolecular markers provide potential new targets for future therapeutic interventions.
The incorporation of contemporary imaging technology in cervical cancer, especially for locally advanced disease, has contributed significantly to radiation treatment planning and field design. However, computed tomography (CT) and even magnetic resonance imaging (MRI) remain relatively insensitive to low-volume nodal disease.10,11 Positron emission tomography (PET) is a metabolism-based imaging process that is increasingly used in the effective staging of multiple cancer sites. Early experience in cervical cancer has shown improved sensitivity and specificity for the detection of nodal metastases by PET compared with other imaging modalities.12,13 In a study of 32 patients with locally advanced cervical cancer who underwent imaging before surgical staging lymphadenectomy, PET had a sensitivity of 75%, a specificity of 92%, a positive predictive value of 75%, and a negative predictive value of 92% for para-aortic nodal disease, and a 100% accuracy rate for pelvic nodal metastases.12 In another recent analysis of 101 consecutive cervical cancer patients evaluated with both CT and PET, it was shown that PET findings were the better predictor of outcome.13 To further evaluate its clinical utility, the GOG is developing a prospective multi-institutional trial of preoperative PET imaging followed by complete pelvic and para-aortic lymphadenectomy in patients with locally advanced disease. It is anticipated that the routine incorporation of PET imaging will complement clinical staging of cervical cancer and enhance treatment implementation. However, unresolved issues remain regarding tumor volume threshold for detection, general availability, cost, and reimbursement policies. Contemporary imaging technologies may also be ultimately used to help select appropriate therapy. Although concurrent chemotherapy is typically prescribed for patients undergoing primary radiotherapy, questions have been raised as to whether all patients, especially those with less bulky tumors, benefit from the addition of chemotherapy. Several recent studies have indicated that imaging characteristics based on MRI, including tumor volume and early rate of response, may predict outcomes for patients who fare well with radiation alone and, hence, could avoid the added potential toxic effects of chemotherapy.14,15 The emerging technology of image fusion, which coregisters, merges, and overlays imaging data from various modalities such as CT, MRI, and PET, allows for further improvement in tumor detection and delineation. This will lead to better treatment planning and has specific implications for image-guided radiotherapy, including intensity-modulated radiation therapy (IMRT), which is discussed in greater detail below.
The Radiation Therapy Oncology Group (RTOG) has previously reported a randomized trial (RTOG 79–20) that demonstrated improved survival for patients with stage IIB and bulky IB/IIA cervical cancer who received pelvic and prophylactic para-aortic radiation compared with pelvic radiation alone. Patients undergoing extended-field radiotherapy (which included the pelvis and para-aortic nodes) had a 10-year overall survival rate of 55% compared with 44% for patients who were treated with pelvic radiation only (P = .02).16 However, a more recent study by the RTOG (RTOG 90–01) showed the superiority of concurrent cisplatin and fluorouracil chemotherapy plus pelvic radiation over the control arm of extended-field radiotherapy without chemotherapy, with 5-year overall survival rates of 73% and 58%, respectively (P = .004).17 The question of whether further therapeutic gain can be achieved by using concurrent chemotherapy and prophylactic para-aortic radiation in selected patients with locally advanced cervical cancer (eg, those with clinically pelvic-confined disease but with multiple pelvic lymph node metastases) remains to be answered. The tolerability of concomitant extended-field irradiation and cisplatin-based chemotherapy has been reported.18,19 A randomized trial comparing pelvic radiation alone versus extended-field radiation in patients with cervical cancer clinically confined to the pelvis (concurrent with weekly cisplatin in both arms) has been proposed through the GOG but has not been activated at this time. Underlying the question of prophylactic para-aortic radiation is the assumption that the para-aortic nodes represent the only site of occult extrapelvic disease in some patients for whom sterilization by radiotherapy would translate to cure (assuming achievable pelvic control). In the absence of routine surgical staging, the incidence of para-aortic nodal metastases is clearly underestimated by routine imaging such as CT or MRI. As a clinically silent site, the rate of para-aortic failure as the first site of treatment relapse after pelvic radiation is also undetermined. A GOG surgicopathologic staging study noted positive para-aortic nodes in 21% of stage IIB and 31% of stage III tumors.10 In a recent report of PET imaging in 101 consecutive cervical cancer patients (stage I to IVA), para-aortic lymphadenopathy was demonstrated in 21% of the patients. If PET or a combination of imaging modalities achieves extremely high sensitivity for the detection of small-volume para-aortic metastases and such imaging becomes widely used, the issue of radiation prophylaxis to the para-aortic nodes may become inconsequential.
IMRT represents an exciting new technology in radiotherapy delivery that combines high-resolution imaging, advances in computer treatment software and linear accelerator collimation capabilities, inverse planning, and radiation beam flux modulation to produce highly conformal dose distributions unachievable using conventional approaches. It has been most widely used in head and neck and prostate cancers, simultaneously allowing the sparing of surrounding normal structures and dose intensification to the tumor target volume. Dosimetric evaluation of its use in gynecologic cancers has shown that IMRT can significantly reduce unwanted radiation exposure to adjacent bowel and bladder while preserving tumor coverage.20 Early clinical experience at the University of Chicago (Chicago, IL) has demonstrated a significant reduction in acute gastrointestinal toxicity for gynecologic cancer patients undergoing pelvic IMRT compared with contemporaneous historical controls treated with traditional standard techniques.21 Recent analysis has also indicated a decrease in acute hematologic suppression, favoring patients treated with IMRT, especially in patients who also received chemotherapy.22 Although there is little doubt that IMRT will gain increasingly widespread clinical application based on its dosimetric superiority over current conventional approaches, questions remain about target definition standardization, intrapatient and interpatient reproducibility, and time-intensive requirements for treatment planning. To implement IMRT for cervical cancer, a paradigm shift in delineation of target volume is required, from historical dependence on bony landmarks to the definition of specific targets based primarily on soft-tissue anatomy. The traditional uniformity of pelvic radiation for cervical cancer will be modified to direct dose asymmetrically based on tumor volume distribution. The use of high-resolution imaging, including image fusion technologies, is essential to the accurate definition of target and normal tissue volumes for IMRT. The need for standardization and target definition in IMRT, especially for clinical trials, has been recognized. The GOG Radiation Oncology Committee is seeking to evaluate and establish parameters that are readily and reproducibly applied. An opportunity for real-time assessment of individual patient treatment plans lies in central review, facilitated by electronic submission over the Internet using currently available digital imaging and communication in medicine–radiation therapy data transfer programs. The role of brachytherapy in cervical cancer is well established. However, historical application of brachytherapy has generally depended on achieving symmetry of insertion relative to the central position of the uterus within the pelvis, thereby creating the classic pear-shaped isodose distribution. Although in its infancy, the role of image-guided brachytherapy, where radiation isodoses are biased toward residual tumor volume rather than simple central symmetry, should be further assessed.
The incorporation of more aggressive treatment regimens, as well as the increased cure rates realized, can lead to more long-term complications. Various agents that confer protection against radiation have been developed, of which the most promising is amifostine (WR 2721). Amifostine is an organic thiophosphate that is dephosphorylated to a sulfhydryl moiety, which then acts as a scavenger for the free radicals created by ionizing radiation. In a phase III trial of primary radiotherapy for head and neck cancer, patients randomly assigned to receive amifostine had significantly less acute and chronic xerostomia compared with patients who underwent irradiation alone.23 Limited clinical experience has shown that systemic administration of amifostine, when used in conjunction with pelvic radiation, reduces gastrointestinal, genitourinary, and perineal skin toxicity.24,25 Furthermore, amifostine provides cytoprotection against the hematologic, renal, and neurologic effects of cisplatin.26 In all reported experiences, no sparing of tumor response by amifostine has been noted. A previous impediment to the acceptance of amifostine with radiotherapy has been the need for daily intravenous dosing and the premedication and hydration required to address nausea, vomiting, and hypotension. Recent studies have indicated that subcutaneous delivery is an effective alternative, allowing for ease of administration and avoidance of the problematic autonomic adverse effects discussed above.25 The role of amifostine or other radioprotectors in reducing or ameliorating treatment-related normal-tissue injury deserves further evaluation. Some insights regarding the possible benefits of amifostine may be eventually gleaned from a recently initiated phase I/II RTOG study (protocol C-0116) in which cervical cancer patients with positive common iliac and para-aortic nodes are treated with concurrent cisplatin and extended-field irradiation. In this two-part trial, the initial patients accrued undergo chemoradiation alone and serve as a cohort comparison for a subsequent group who receive amifostine together with their chemoradiotherapy.
Although the issues discussed here may be controversial at present, they represent opportunities for further clinical investigation. Indeed, some of these questions are being currently addressed in ongoing or proposed multicenter clinical trials. Combined with parallel efforts that seek to identify more effective agents that provide greater systemic activity and better locoregional radiosensitization, it is anticipated that these avenues of study will lead to better radiotherapeutic management and overall care of patients with cervical cancer.
DR. CANNISTRA: Dr. Koh, you suggested that IMRT may not require a randomized trial to prove its value, and yet you also raised some important points regarding whether you could be excluding part of the tumor volume with the technique. Can you clarify this issue? DR. KOH: The dosimetric sparing of normal tissues is so clear cut that it is unlikely that you’re going to say to a patient, "We’d like to put you in this trial where we could be treating all of these normal tissues with standard radiotherapy versus another approach that’s going to reduce the normal tissue dose by 60%." Dosimetrically wise, it’s hard to argue against IMRT. DR. CANNISTRA: But you’re depending on the dosimetric evaluation to ensure that the tumor is receiving all the radiation that you prescribe. As I understand it, your dosimetric calculations are based upon computer-generated modelling. Is it possible that there might be discordance between what you think the patient is receiving with the new fields that you’ve calculated, versus what the patient actually received? How much of a gold standard is the dosimetric calculation when you’re studying new techniques with new software algorithms that help you define the dosimetry? DR. RUSTIN: Also, the actual mapping out of the region of interest is operator dependent. So if you do a randomized trial, every tumor will have a separate actual region of interest. DR. KOH: I don’t think the dosimetric issue in IMRT is a major problem, because in a real sense, we depend on dosimetry to define dose delivery in standard radiation therapy today. Dosimetry allows us to say that if we prescribed 180 cGy to a patient daily, that the patient is actually getting 180 cGy. As part of normal quality assurance, dosimetric calculations of radiation dose would have to be calibrated against in vitro and in vivo dose measurements. I do think, however, that the individual interpretation of those imaging studies, definition of target of interest, and also patient reproducibility are important issues that are critical to IMRT implementation. DR. DePRIEST: Do you believe that you have increased the number of variables that go into treatment planning with IMRT? And if so, are they human error liable? DR. KOH: Yes and no. With IMRT you are able to define a much more constrained target volume and exploit modern imaging technology, but there is clearly the potential for human error in your definition. There is also human error in set-up, as well as daily motion of the internal organs that are not accounted for by a single pretreatment imaging study. Better patient immobilization mitigates some of these potential errors. In summary, IMRT gives you more precise radiation dose delivery, but that precision is only as useful as the accuracy and reproducibility of the target volume definition. DR. CANNISTRA: I would like to return to the issue of how to evaluate periaortic nodes in patients with advanced cervix cancer in whom we contemplate chemoradiation. Let’s exclude stage IB2 tumors for a moment and consider a typical patient with stage III cervix cancer in whom you’re considering chemoradiation. We generally don’t do lymphangiograms anymore. Typically, a CAT scan will be obtained to exclude hydronephrosis and obvious periaortic nodal enlargement. But if nodes are not radiographically involved in such a patient, do you recommend further evaluation with surgical staging? DR. ROSE: It depends on whom the patient sees. If they have a IIIB tumor and see a gynecologic oncologist, they likely may undergo surgical staging. I surgically stage those patients who are young and otherwise healthy, because I know I’m talking about a 30% incidence of nodal involvement. DR. BEREK: Another issue is whether debulking nodes surgically enhances the ultimate effect. There are some interesting data from my colleague Neville Hacker from the Royal Hospital for Women [Int J Gynecol Cancer 5:250–256, 1995], where they took debulked patients with bulky nodes. The survival of those patients was considerably better than their historical controls. DR. BEREK: There also are some data from his experience that show that high common and low periaortic node patients who have some microscopic disease that’s resected and then irradiated also do better. It raises the issue of whether or not you should take patients who have those positive PET scans and not just do surgical staging but go in with the idea of resecting disease so that the application of extended field radiation might have a better biologic effect. DR. CANNISTRA: What selection criteria do you use to help you decide who needs an operation for the purpose of staging? If you find periaortic nodes, do you debulk? How does that change your postoperative management in terms of radiation fields and combined modality? DR. ROSE: If I find pelvic nodes, I would debulk them. If there is gross disease in sites where you’re only going to be able to give 5,000 rads, you’re not going to effectively treat them. DR. DePRIEST: If we have a young woman with advanced pelvic disease, with probable pelvic lymph nodes involved, but the periaortics appear normal, then we would surgically stage that patient to find out if extended field radiation would be warranted. DR. CANNISTRA: But would you debulk the pelvic nodes in that situation? DR. DePRIEST: No, I think debulking an ovarian cancer can still be considered controversial in some countries. So I’m not certain that debulking a pelvic lymph node and definitely not a periaortic lymph node is mandatory or may help the greater population of patients. The second point I would raise is whether or not that debulking should be done laparoscopically or by open technique. One of our patients from the western part of the country underwent debulking of periaortic lymph nodes after laparoscopy for stage III disease but had massive spread throughout the abdomen and cancer at each port site. DR. RUSTIN: If you’re doing periaortic lymphadenectomy and then giving high-dose radiotherapy, aren’t you increasing the chance of bowel toxicity? DR. ROSE: Bowel toxicity is not increased since the surgery is not transperitoneal; it’s all retroperitoneal. DR. BEREK: We individualize the management of those patients because I don’t think anybody knows the answer. We resect lymph nodes when they are bulky when we’re there. The question is how often should one go in after them if you’re not going to be there otherwise. If we have an otherwise young and healthy patient in whom we see a positive PET scan or something at least near the common iliac that looks enlarged, we will take those nodes out through an extraperitoneal approach and give them the extended field radiation. DR. CANNISTRA: With chemotherapy? DR. BEREK: With chemo sensitization. DR. KOH: In the pelvis, I could argue, based on general radiobiologic considerations, that even using standard (non-IMRT) radiation techniques, we ought to be able to cover nodal disease up to about 2 cm, because you could get reasonably high dose (60–65 Gy) to the nodes. That is not true for the periaortics, where you could get less dose (45–50 Gy), so that the likelihood of control for anything over 1 cm would be limited. So one could argue that you could have two cutoffs for nodal size control with radiation. DR. CANNISTRA: What is the proper off-study role of PET scanning now and should we even be using it? Should it be considered a standard modality or should we only restrict it to investigational trials? DR. BOOKMAN: At our institution, the radiation therapists are the ones who are using it. DR. CANNISTRA: Is that proper? Do we know enough about the information gained from PET scanning to be able to make therapeutic decisions that have proven benefit for the patient? DR. DePRIEST: We don’t get it routinely, and I’m fearful of the patients who pay for it out of pocket, particularly with the ovary. They come in begging for it with ovarian cancer and then there are false positives in the mediastinum. DR. KOH: Is there not sufficient effectiveness and approval of PET with many other epithelial malignancies that if somehow it was a reimbursable procedure, they would be getting it? DR. ROSE: Definitely. DR. BOOKMAN: I think the question is very different in ovary versus cervix. In ovary, more detailed imaging modalities have not allowed us to take better care of the patients with advanced or recurrent disease. DR. CANNISTRA: What is the pattern of care of gynecologic oncologists around the country with respect to surgical staging in advanced disease? How many would recommend surgical staging in order to better define the presence of periaortic lymph node involvement? DR. KOH: It’s about 20% according to a show of hands at a GOG meeting. DR. CANNISTRA: Another topic discussed by Dr. Koh was that of red cell transfusion support. How aggressively should we be pursuing correction of anemia in the treatment of advanced cervix cancer with radiation, keeping in mind that perhaps anemia is simply serving as a surrogate for poor performance status as opposed to being responsible for inferior outcomes with radiation? DR. ROSE: Transfused patients? DR. CANNISTRA: How aggressively would you transfuse with the idea that you’re perhaps improving the effectiveness of radiation by improving local tissue oxygenation? DR. ROSE: I think what you state is pretty much what everyone’s practice pattern has been; transfuse if someone has got a hemoglobin less than 10. There are some data to suggest that transfusion is going to be negative in terms of immune response and outcome [Int J Radiat Oncol Biol Phys 54:1345, 2002]. There’s a suggestion that erythropoietin may be therapeutic against the cancer and the anemia. There’s certainly a lot of costs related to erythropoietin.
Presented at the conference on Progress in the Management of Gynecologic Cancer, Cambridge, MA, October 25–26, 2002.
1. Thomas GM: Improved treatment for cervical cancer: Concurrent chemotherapy and radiotherapy. N Engl J Med 340:1198–1200, 1999 2. National Cancer Institute: Concurrent chemoradiation for cervical cancer. Clinical Announcement. National Institutes of Health, Bethesda, MD, February, 1999 3. 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] 4. Kapp KS, Poschauko J, Geyer E, et al: Evaluation of the effect of routine packed red blood cell transfusion in anemic cervix cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 54:58–66, 2002[Medline]
5. Pearcey R, Brundage M, Drouin P, et al: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20:966–972, 2002 6. Bush RS, Jenkin RDT, Allt WEC, et al: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37:302–306, 1978 (suppl 3)
7. Hockel M, Schlenger K, Aral B, et al: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509–4515, 1996 8. Fyles AW, Milosevic M, Wong R, et al: Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48:149–156, 1998[CrossRef][Medline] 9. Dachs GU, Tozer GM: Hypoxia modulated gene expression: Angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer 36:1649–1660, 2000 10. Heller PB, Malfetano JH, Bundy BN, et al: Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix: Extended diagnostic evaluation for paraaortic node metastasis—A Gynecologic Oncology Group study. Gynecol Oncol 38:425–430, 1990[CrossRef][Medline] 11. Scheidler J, Hricak H, Yu KK, et al: Radiological evaluation of lymph nodes metastasis in patients with cervical cancer: A meta-analysis. J Am Med Assoc 278:1096–1101, 1997[Abstract]
12. Rose PG, Adler LP, Rodriguez M, et al: Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: A surgicopathologic study. J Clin Oncol 17:41–45, 1999
13. Grigsby PW, Siegel BA, Dehdashti F: Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19:3745–3749, 2001 14. Mayr NA, Taoka T, Yuh WTC, et al: Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys 52:14–22, 2002[CrossRef][Medline] 15. Kodaira T, Fuwa N, Kamata M, et al: Clinical assessment by MRI for patients with stage II cervical carcinoma treated by radiation alone in multicenter analysis: Are all patients with stage II disease suitable candidates for chemoradiotherapy. Int J Radiat Oncol Biol Phys 52:627–636, 2002[CrossRef][Medline] 16. 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: Ten-year treatment results of RTOG 79-20. J Am Med Assoc 274:387–393, 1995[Abstract]
17. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137–1143, 1999 18. Varia MA, Bundy BN, Deppe G, et al: Cervical carcinoma metastatic to para-aortic nodes: Extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy—A Gynecologic Oncology Group Study. Int J Radiat Oncol Biol Phys 42:1015–1023, 1998[CrossRef][Medline] 19. Malfetano JH, Keys H, Cunningham MJ, et al: Extended field radiation and cisplatin for stage IIB and IIIB cervical carcinoma. Gynecol Oncol 67:203–207, 1997[CrossRef][Medline] 20. Portelance L, Chao KSC, Grigsby PW, et al: Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys 51:261–266, 2001[Medline] 21. Mundt AJ, Lujan AE, Rotmensch J, et al: Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 52:1330–1337, 2002[CrossRef][Medline] 22. Brixey CJ, Roeske JC, Lujan AE, et al: Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 54:1388–1396, 2002[CrossRef][Medline]
23. Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339–3345, 2000 24. Liu T, Liu Y, He S, et al: Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer 69:2820–2825, 1992[CrossRef][Medline]
25. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 18:2226–2233, 2000
26. Kemp G, Rose P, Lurain J, et al: Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: Results of a randomized controlled trial in patients with advanced ovarian cancer. J Clin Oncol 14:2101–2112, 1996 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
