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Originally published as JCO Early Release 10.1200/JCO.2005.08.911 on October 17 2005 © 2005 American Society of Clinical Oncology.
Chemoradiotherapy for Cervical Cancer: What Next?Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX In this issue, Lanciano et al1 report the results of the Gynecologic Oncology Group's most recent randomized study of concurrent chemoradiotherapy for cervical cancer (GOG-165). This trial, which compared the results of radiation therapy delivered concurrently with either weekly cisplatin or protracted venous infusion of fluorouracil (FU), was closed well before the planned accrual goal of 416 patients and 150 events because a scheduled interim analysis suggested that patients treated with FU were not likely to have a better outcome than those treated with the control regimen of radiation and weekly cisplatin. Although this negative study does not represent a major advance in the treatment of patients with cervical cancer, it does highlight many of the issues and challenges faced by investigators who seek to improve cervical cancer treatment in the modern era. GOG-165 is best understood in its historical context. The trial was designed and opened in 1997. In that year, the GOG published abstracts describing encouraging preliminary results from GOG trials of cisplatin-based concurrent chemoradiotherapy. However, the inclusion of hydroxyurea in the control arms of these trials and other perceived weaknesses, including problems with the quality of radiation therapy, prevented clinicians from reaching an early consensus about the trials' importance. Therefore, in an effort to consolidate earlier findings, GOG-165 was designed. The study initially was planned with three arms: a control arm of modern radiation therapy alone, a second arm intended to confirm the value of adding weekly cisplatin, and a third, experimental arm that consisted of treatment with radiation and protracted venous infusion FU. This third arm drew on extensive data demonstrating the value of FU-based chemoradiotherapy in patients with gastrointestinal neoplasms and was intended to follow-up on an inconclusive but encouraging Canadian study of concurrent radiation and protracted venous infusion FU in patients with cervical cancer.2 However, in 1999, just 18 months after GOG-165 was opened, the near-simultaneous publication of results from five prospective randomized trials, all of which demonstrated significant improvements in local control and survival with cisplatin-based chemoradiotherapy, led to a National Cancer Institute alert establishing chemoradiotherapy as a standard treatment for patients with locoregionally advanced cervical cancer.3 At that point, the GOG felt compelled to drop the radiation-only control arm of GOG-165 but continued to accrue patients to the two concurrent chemoradiotherapy arms. The results of GOG-165 suggest that radiation plus protracted venous infusion FU was not a better treatment than radiation plus weekly cisplatin, but it does not prove that FU is ineffective as a radiation sensitizer in patients with cervical cancer. More importantly, the study does not answer the potentially more interesting question of whether FU can enhance the beneficial effects of adding cisplatin to radiation therapy. In fact, although randomized trials have demonstrated the benefit of concurrent cisplatin and of concurrent cisplatin with FU, no trial has yet compared the two regimens directly. Although the GOG regimen of radiation plus weekly cisplatin tends to be favored by gynecologic oncologists in the United States, data from the seven randomized trials suggest that radiation plus a combination of cisplatin and FU might be more effective. Of four randomized trials that included radiation therapy plus weekly cisplatin,1,4-6 only one, reported by Keys et al in 1999,6 demonstrated a benefit for radiation therapy plus cisplatin over radiation therapy alone. In that study, patients with bulky stage IB cancers were randomly assigned to prehysterectomy radiation therapy or chemoradiotherapy. Two other trials—the current trial and the GOG three-arm trial published in 1999—did not have a control arm of radiation therapy only; instead, they included chemotherapy of uncertain value in the noncisplatin-containing arm. Although the three-arm GOG trial did demonstrate concurrent cisplatin to be more effective than hydroxyurea, the possibility that hydroxyurea compromised outcome in the control arm cannot be ruled out entirely, which somewhat diminishes the strength of that study. A later trial, reported by Pearcey et al in 2002,4 found no benefit from radiation therapy plus weekly cisplatin versus radiation therapy alone. In contrast, of the three randomized trials to date of radiation therapy plus cisplatin and FU, two had a control arm of radiation therapy only, and all demonstrated a benefit of chemoradiotherapy.7-9 The lack of a survival benefit of cisplatin in the trial by Pearcey et al may reflect the smaller size of that trial. In fact, most clinicians believe that the overall body of evidence is sufficient to prove the effectiveness of weekly cisplatin. Weekly cisplatin also may be somewhat easier to deliver and probably has less acute GI toxicity than the combination of cisplatin and FU. Nevertheless, the data raise sufficient questions that a direct comparison between cisplatin and cisplatin plus FU would be of interest. Although the addition of concurrent chemotherapy to radiation undoubtedly has benefited many patients, there is still considerable room for improvement. Some patients, particularly those with bulky tumors or regionally advanced disease, continue to experience local recurrences, suggesting the need for even more effective chemoradiotherapy regimens. However, investigators face major challenges in trying to design future chemoradiotherapy trials. First, the fact that cisplatin was included in the most successful arms of so many trials has caused investigators to question whether it is ethical to omit cisplatin or even to compromise the cisplatin dose in new chemoradiotherapy regimens. Second, the hematologic toxicity of weekly cisplatin and of the combination of cisplatin and FU limits the dose that can be safely delivered in combination with radiation. For this reason, one attractive approach for future studies will be the incorporation of relatively nonmyelosuppressive biologic response modifiers into current regimens. Recent interest has focused on epidermal growth factor modulators and vascular endothelial growth factor modulators, cyclooxygenase-2 inhibitors, and agents that specifically target hypoxic cells. Despite the challenges, we must also continue to evaluate potentially radiosensitizing drugs that could prove to be more effective than cisplatin or equally effective but less toxic or less costly. In doing so, we should consider concurrent chemoradiotherapy regimens that have proved to be successful against tumors at other sites—particularly carcinomas of the head and neck, which have response characteristics that are in many ways similar to those of cervical cancers. Conversely, although preradiation chemotherapy has been used with some success in other sites, randomized trials have repeatedly failed to show a benefit from neoadjuvant chemotherapy in patients with cervical cancer. Although some investigators have suggested sequencing neoadjuvant chemotherapy and chemoradiotherapy, the possibility that preradiation induction chemotherapy could compromise the intensity of subsequent chemoradiotherapy diminishes the attractiveness of this approach. In GOG-165, investigators sought to improve the quality of radiation therapy by setting stricter standards for the dose and duration of treatment than those followed in earlier GOG trials. Recent advances in radiation therapy technology suggest ways to improve further the quality of radiation therapy, in terms of both increased efficacy and reduced toxicity. Improved diagnostic imaging methods, particularly functional imaging technologies, should improve our understanding of the extent of regional disease, leading to more accurate design of treatment fields. Optimized conformal radiation techniques make it possible to increase the dose of radiation to involved regional sites without increasing the dose to critical structures. In the future, the development of image-based, optimized methods of brachytherapy treatment planning should improve radiation oncologists' ability to determine the appropriate dose and limit adverse effects on normal tissues. Patterns of care survey studies suggest that more than two thirds of US patients currently treated with radiation for intact cervical cancer receive concurrent chemotherapy.10 In contrast, at the time when the GOG, Radiation Therapy Oncology Group, and Southwest Oncology Group trials that showed the benefit of concurrent cisplatin-based chemotherapy were being conducted, fewer than 5% of US patients treated with radiation for intact cervical cancer were entered onto prospective trials.10 Thus, the generalizability of the trial results to the larger population is unknown. One focus of future research should be to assess compliance to standard protocols in general practice and to determine whether the good results seen in randomized trials are also seen in general practice. Creative approaches will be needed to repeat past successes. The higher survival rates obtained with chemoradiotherapy mean that the window for additional improvement has been narrowed. To achieve a reasonable chance of obtaining significant results, future studies will need to include many more patients than earlier studies. The relative rarity of cervical cancer in the United States and other western countries will undoubtedly make it more difficult to complete studies in those countries in a reasonable period of time, although it may be possible to increase accrual rates through more intense intergroup cooperation. In other parts of the world, particularly in medically underserved nations, cervical cancer continues to be a leading cause of cancer death. In these regions, the expense of radical chemoradiotherapy may be a serious obstacle; to have the greatest impact on the disease worldwide, one goal of future trials should be to seek the least costly of effective regimens. In the future, advancement of the field will undoubtedly depend on international collaboration combining the resources and patients of several nations to support well-designed trials. In the last 20 years, investigators have determined that concurrent administration of chemotherapy can enhance or complement the effects of radiation therapy in a number of clinical settings. However, we are only beginning to understand why different schedules and combinations appear to be most successful in the treatment of different neoplasms. Why has cisplatin arisen as the cornerstone of chemoradiotherapy in gynecologic neoplasms, whereas FU has dominated in the management of GI tumors? Do these choices really reflect differences in the radiation response or biology of these tumors, and if so, what are the mechanisms that define differential responses? We still have a great deal to learn from future clinical trials of these agents. In particular, we should not allow GOG-165 to close the door to future investigation of the role of FU in treatment of cervical cancer. Although protracted venous infusions of FU alone will not replace current standard regimens, the benefit of FU or of more convenient oral regimens such as capecitabine in combination with cisplatin still needs to be explored in future trials. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Lanciano R, Calkins A, Bundy BN, et al: A randomized comparison of weekly cisplatin or protracted venous infusion fluorouracil in combination with pelvic radiation in advanced cervix cancer: A Gynecologic Oncology Group Study. J Clin Oncol 23:8289-8295, 2005 2. 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
3. McNeil C: New standard of care for cervical cancer sets stage for next questions. J Natl Cancer Inst 91:500a-501a, 1999
4. 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
5. Rose PG, Bundy BN, Watkins J, et al: Concurrent cisplatin-based chemotherapy and radiotherapy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999
6. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999
7. Eifel PJ, Winter K, Morris M, et al: Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: An update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 22:872-880, 2004
8. Peters WA III, Liu PY, Barrett RJ II, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18:1606-1613, 2000
9. 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 10. Eifel PJ, Moughan J, Erickson B, et al: Patterns of radiotherapy practice for patients with carcinoma of the uterine cervix: A patterns of care study. Int J Radiat Oncol Biol Phys 60:1144-1153, 2004[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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