Advances in the Treatment of Gynecologic Malignancies

November 1, 2002

In their review, Drs. Kim, Alvarez, and Omura have outlined a diverse group of clinical trials in a very limited space. Their summary highlights some of the most important insights gained from these trials, placing particular emphasis on the role and perspective of the Gynecologic Oncology Group (GOG). Although their review appropriately divides these studies into three major groups (early cervical cancer, locally advanced cervical cancer, and vulvar cancer), the results also reveal common themes that can be used to guide the overall management of women with carcinomas of the female lower genital tract.

In their review, Drs. Kim, Alvarez, and Omura have outlined adiverse group of clinical trials in a very limited space. Their summaryhighlights some of the most important insights gained from these trials, placingparticular emphasis on the role and perspective of the Gynecologic OncologyGroup (GOG). Although their review appropriately divides these studies intothree major groups (early cervical cancer, locally advanced cervical cancer, andvulvar cancer), the results also reveal common themes that can be used to guidethe overall management of women with carcinomas of the female lower genitaltract.

Postoperative Adjuvant Treatment

Several studies demonstrate the potential value of postoperative radiationfor patients with regional metastases or other high-risk features, but alsosuggest that selecting patients to avoid the need for both radical surgery andradiation might reduce the overall morbidity of treatment. Although the authorssuggest that postoperative radiation therapy does not affect survival inpatients who have regional metastases from early cervical cancers, I wouldcontend that the question has never been adequately studied—retrospectivecomparisons are rife with selection bias, and a randomized trial initiated inthe early 1990s closed when it failed to accrue more than a handful of patients.

Homesley et al[1] demonstrated that the improved regional control rateachieved with postoperative therapy for vulvar cancer does lead to a bettersurvival rate. Sedlis et al[2] reported a significant improvement in pelvicdisease control and an encouraging (although preliminary) comparison of survivalrates with postoperative radiation for node-negative intermediate-risk cervicalcancer. It would be surprising if survival rates did not improve with betterlocal control of node-positive patients. However, the Southwest Oncology Group (SWOG)trial published by Peters et al[3] clearly demonstrates an unacceptably highpelvic recurrence rate of more than 20% with pelvic irradiation alone andconvincingly demonstrates the improvement achievable with the addition ofconcurrent chemotherapy.

Although the postoperative cervical cancer trials demonstrated importantimprovements with adjuvant treatment, patients who received the most aggressivetreatment in each trial continued to fail locally at a rate of about 10%. TheHomesley trial showed few regional recurrences, but the preliminary report wasmade with short follow-up and was never updated.

One wonders whether selected patients would benefit from even more aggressivetherapy—eg, concurrent chemotherapy for certain intermediate-risk patients orhigher-dose, conformal radiation therapy (or brachytherapy) for selectednode-positive patients. However, as Kim et al point out, these treatments arenot without harm—each modality increases the risk of major treatment-relatedmorbidity, and indiscriminate use of trimodality therapy cannot be condoned.

The tools at our disposal should be carefully used to avoid radical surgeryin patients who require postoperative radiation therapy and to accurately selectpatients who will benefit from adjuvant radiation or chemoradiation. Advancedimaging with magnetic resonance imaging and positron-emission tomography mayhelp make some of these selections. Ultimately, we need much more sensitiveindicators of the risk of recurrence than the currently used histologic andmorphologic prognostic factors. Early studies of biochemical,immunohistochemical, and molecular tests suggest that the future might provideus with better ways of selecting these treatments.

The Role of Chemotherapy

Clinical trials have repeatedly failed to define a role for neoadjuvantchemotherapy in patients with locally advanced cervical cancer, particularlywhen chemotherapy precedes radiation. In contrast, randomized trials haveyielded compelling evidence that the addition of concurrent chemotherapy toradiation can significantly improve the outcome of patients whose disease isconfined to the pelvis, particularly when the risk of local recurrence withradiation alone exceeds about 20%. Although the results of these trials have ledto an important change in the standard of care, the different eligibilitycriteria, control arms, and weaknesses of these trials still leave areas ofcontroversy.

Only two studies (Radiation Therapy Oncology Group [RTOG] 90-01[4] and theNational Cancer Institute of Canada (NCIC) trial[5]) compared cisplatin-basedchemoradiation with radiation-only control arms. Both used radiation schedulesthat delivered high doses in relatively compact schedules. The RTOG trialdemonstrated a large and highly significant improvement with cisplatin andfluorouracil (5-FU), whereas the NCIC trial failed to demonstrate a significantimprovement with weekly cisplatin. These results are difficult to resolve,although the smaller size of the NCIC trial may have reduced the power of thatcomparison to detect modest differences.

Two other trials (the SWOG postoperative trial[3] and GOG-141[6]) addedsurgery to a comparison of radiation with or without chemotherapy; bothdemonstrated highly significant advantages for chemoradiation. The other two GOGtrials[7,8] included hydroxyurea in the control arm and somewhat low-dose,protracted radiation therapy but also demonstrated a marked benefit of cisplatin-basedchemotherapy over the control. Despite the one negative trial, these six studiesstrongly indicate a benefit with chemotherapy.

This result is even more convincing when viewed in the context of trials inpatients with carcinomas of the head and neck, esophagus, anus, bladder, andlung; many of these trials have shown a benefit with concurrent, usuallycisplatin-based chemotherapy. However, important questions about the role ofextended-field irradiation, the most effective and tolerable schedule ofcisplatin, the role of 5-FU, and the value of other drugs (particularly forpatients with renal dysfunction) remain to be answered.

Conclusions

Cervical and vulvar cancers are rare in the United States, and the treatmenttechniques for these diseases are highly specialized. A Patterns of Care studydemonstrated that, from 1992 to 1994, most nonacademic radiation oncologyfacilities treated fewer than three cases of intact cervical cancer per year.[9]Locoregionally advanced vulvar cancers are even less common; some gynecologiconcologists may find these cases to be only a small part of their practice.

The findings of prospective studies have increased the indications foradjuvant radiation and concurrent chemotherapy, adding to the complexity oftreatment. Many of the women diagnosed with these cancers have socioeconomicproblems and concurrent illnesses that further complicate treatment. Theimportance of close multidisciplinary cooperation and referral to centers withspecial experience in treating these neoplasms cannot be overemphasized.

References:

1. Homesley HD, Bundy BN, Sedlis A, et al: Radiation therapy versus pelvicnode resection for carcinoma of the vulva with positive groin nodes. ObstetGynecol 68:733, 1986.

2. Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvicradiation therapy versus no further therapy in selected patients with stage IBcarcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: AGynecologic Oncology Group study. Gynecol Oncol 73:177-183, 1999.

3. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al: Concurrent chemotherapy andpelvic radiation therapy compared with pelvic radiation therapy alone asadjuvant therapy after radical surgery in high-risk early-stage cancer of thecervix. J Clin Oncol 18:1606-1613, 2000.

4. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrentchemotherapy compared with pelvic and paraaortic radiation for high-riskcervical cancer. N Engl J Med 340:1137-1143, 1999.

5. Pearcey R, Brundage M, Drouin P, et al: Phase III trial comparing radicalradiotherapy with and without cisplatin chemotherapy in patients with advancedsquamous cell cancer of the cervix. J Clin Oncol 20:966-972, 2002.

6. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvanthysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161,1999.

7. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-basedchemotherapy and radiotherapy for locally advanced cervical cancer. N Engl J Med340:1144-1153, 1999.

8. Whitney CW, Sause W, Bundy BN, et al: A randomized comparison offluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiationtherapy in stages IIB-IVA carcinoma of the cervix with negative para-aorticlymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. JClin Oncol 17:1339-1348, 1999.

9. Eifel PJ, Moughan J, Owen JB, et al: Patterns of radiotherapy practice forpatients with squamous carcinoma of the uterine cervix. A Patterns of Carestudy. Int J Radiat Oncol Biol Phys 43:351-358, 1999.