CURRENT DEVELOPMENTS IN THE TREATMENT OF NEWLY DIAGNOSED CERVICAL CANCER

CURRENT THERAPEUTIC ISSUES IN GYNECOLOGIC CANCER

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CURRENT DEVELOPMENTS IN THE TREATMENT OF NEWLY DIAGNOSED CERVICAL CANCER Kathryn Greven, MD, Daniel Petereit, MD, Jan B. Vermorken, MD, PhD, and Rachelle Lanciano, MD

NEW ADVANCES IN THE RADIOTHERAPEUTIC MANAGEMENT OF CERVICAL CANCER Kathryn Greven, MD, Daniel Petereit, MD, Rachelle Lanciano, MD

Since the 1920s, radiation has been used effectively to treat and cure cervical cancer. Thousands of patients have been treated with radiation and analyzed so that benchmarks for survival, local control, and complication rates by stage are available. Research continues in order to define the optimal combination of external beam radiation and brachytherapy. The need for dose intensity through the use of brachytherapy and reduction of overall treatment time has been established. The use of high dose-rate (HDR) afterloading techniques is more generally accepted worldwide, and research continues to determine the optimal fractionation schemes for HDR. Research with three-dimensional treatment planning has redefined optimal radiation treatment volumes. Recent results of contemporary phase I11 randomized trials have changed the standard From the Department of Radiation Oncology, Wake Forest University Baptist School of Medicine, Winston-Salem, North Carolina (KG); Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin (DP); Section of Radiation Oncology, Delaware County Memorial Hospital, Drexel Hill, Pennsylvania (RL); and Department of Medical Oncology, Universitair Ziekenhuis, Antwerpen, Belgium (JBV)

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 13. NUMBER 1 FEBRUARY 1999

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of care for advanced cervical cancer with improvement in survival seen with concurrent cisplatin-containing chemoradiation regimens.

Technical Factors of Radiation lntracavitaty Brachytherapy The treatment of cervical cancer with radiation generally requires the use of external beam irradiation combined with intracavitary brachytherapy. External beam irradiation is used to treat the pelvic nodes and parametria; the central disease is treated primarily by the intracavitary implant. The necessity of intracavitary radiation as a component of the curative treatment for cervical cancer is well known. Intracavity radiation results in improved pelvic control and survival over external beam radiation alone. Data from the Patterns of Care Study in the United Stated3 showed that patients with stage I to I11 cervical cancer had 4year survival rates of 36% and pelvic control rates of 46% without the use of brachytherapy compared with 4-year survival rates of 67% and pelvic control rates of 78% with brachytherapy. Technically accurate intracavitary insertions with proper geometric relationship have been demonstrated to result in improved local control compared with patients treated with unsatisfactory placement^.'^ Standard dose-rates at point A are typically 40 to 60 centiGray (cGy) per hour. Total dose per insertion may vary from 20 to 40 Gy depending on the stage of disease and adequacy of the placement. Usually one or two low-dose-rate implants are performed following external pelvic radiation. Although two brachytherapy insertions may allow time for regression of disease between placements, there are no data to support improved pelvic control or survival rates when compared with one insertion.49 High-Dose-Rate Brachytherapy The use of high-dose-rate (HDR) brachytherapy has been increasing over the last decade. The International Commission of Radiation Units and Measurements (ICRU) defines HDR as a dose-rate greater than 12 Gy/h. Two randomized trials and several retrospective studies have suggested that for treatment of cervical cancer patients, HDR is comparable to LDR in cure and complication rates.2,58, 63, 65, A recent review of stage IB and stage I1 cervical cancer patients treated in two eras with LDR (1977-1988, n = 141) and HDR (1989-1996, n = 123) from the University of Wisconsin revealed no statistically significant difference in pelvic control, survival, or complications at 3 years. Complications

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decreased with a reduction in the HDR dose-per-fraction from 9-10 Gy to 54.5 There is a potential for overdosing the normal tissues with HDR brachytherapy because a rapid dose rate and larger fraction sizes are used. However, these potential radiobiologic disadvantages can be overcome through meticulous packing, rigid immobilization, smaller fraction sizes using multiple fractions, and avoidance of excessive parametrial radiation (mid-line block from the beginning). A detailed analysis of efficacious HDR fractionation schedules for treating cervical cancer was recently published by Petereit and P e a r ~ y Unfortunately, .~~ the current literature does not reveal an ideal fractionation schedule. The current HDR fractionation schedule used at the University of Wisconsin, defined below, is based upon the University of Wisconsin experience and the existing literature (Table 1). The Gynecologic Oncology Group (GOG) has accepted HDR as an alternative to LDR brachytherapy in the current GOG No. 165 protocol for advanced cervical cancer. The fractionation schedule is 30 Gy in five HDR fractions in combination with 45 Gy to the whole pelvis. External Fields

Pelvic radiation fields extend superiorly from the top of the fifth lumbar vertebral body, inferiorly to cover the tumor in the cervix or vaginal disease with at least 3-cm margin and laterally to encompass the pelvic brim with a minimum 2-cm margin. When anterior-posterior portals are used, high-energy photons (18 mV) usually provide the best dose distribution. Multiple field arrangements are more standard, typically with a four-field distribution using lateral and anterior-posterior opposed fields. Lateral fields can be shaped to spare the anterior bowel, but without CT scan treatment-planning or lymphangiography, use of this shielding risks inadequate coverage of external iliac lymph nodes and the anterior extent of the uterus.8,43* 59 The major problem with the design of lateral fields is the inadequate posterior margin around the cervical cancer and extension along the Table 1. CURRENT FRACTIONATION SCHEDULES USED AT THE UNIVERSITY OF WISCONSIN FOR TREATING CERVICAL CANCER Stage

Whole Pelvis

5 HDR Fraction [LDR equivalent]

Point A Gy" 10 Parameter

LQEDt

Stage 1/11 Non-bulky Stage 1/11 Bulky Stage IIIB

45 Gy 45 Gy 50.4 Gy

5.5 [35]

96 102 109

80 85 90

6.0 [40] 6.0 1401

Gy = Gray; LQED = linear quadratic effective dose for a 2 Gy fraction. 'Biologically effective dose. tThis dose corresponds to a total dose of external beam radiation, in which 2 Gy fractions are used.

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utero-sacral ligaments. Intraoperative measurement^?^ sagittal MR imaging scans” and CT scan treatment-planning43 have revealed inadequate posterior coverage with standard radiotherapy fields. Kim et a P have documented a significant decrement in local control for stage IB and stage IIB cervical cancer when retrospectively reviewed radiotherapy fields were found to have inadequate margins on tumor. Therefore, the radiotherapy committee of the GOG has redefined the posterior margin on lateral fields to be behind the sacrum to avoid underdosing or missing the tumor (R. Lanciano, personal communication, August 1998). Dose Response and Overall Treatment Time

Radiation factors, including overall treatment time and total dose to Point A, have been investigated as important prognostic factors for local control in cervical cancer. Lanciano et a1 demonstrated a highly significant decrease in survival and pelvic control as the total treatment time was increased from less than 6 weeks to more than 10 weeks. Stage I11 cancers accounted for the majority of the adverse effects from the prolonged treatment time. Multivariate analysis suggested that total treatment time was an independent prognostic factor for cervical cancer.@ Fyles et a130 found a very similar effect of treatment duration on pelvic control in 830 patients with cervical cancer treated by radiation at the Princess Margaret Hospital. The magnitude of the time effect in cervical cancer was approximately 1% loss of local control for each additional day of treatment. At present, five large retrospective studies of radiotherapy for cervical cancer confirm the importance of overall treatment time on outcome and suggest overall treatment time should be limited to 8 weeks, particularly for locally advanced disease.30,32, 48, 61* 61 A radiation dose response has been demonstrated for stage IIIB cervical cancer in the Patterns of Care database for 4-year survival and pelvic control.49 When doses above 85 Gy were delivered to Point A, the infield failure rate was reduced to 36% and survival improved to 49%. Choi et all1 reviewed 594 cervical cancer patients treated with a combination of external and intracavitary brachytherapy and demonstrated a dose response for stage IIB and stage I11 disease with doses greater than 85 Gy associated with significantly improved central control. There was a statistically significant improvement in survival for stage IIB, but not for stage I11 disease. These analyses, as well as institutional experience reported by centers specializing in the treatment of locally advanced cervical cancer, suggest that an optimal dose for point A should be in the range of 85 to 90 Gy.” In the present GOG trial for advanced cervical cancer (GOG No. 165), the point A dose has been increased to 85 Gy, compared with previous GOG studies which delivered 80 Gy (R. Lanciano, personal communication, August 1998).

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Radiotherapeutic Management

Stage IA For women with microinvasive cervical cancer who are not candidates for surgery, irradiation with intracavitary treatment provides excellent survival and pelvic control rates. Grigsby et a P reported a progression-free survival rate of 100% at 10 years for 34 patients with stage IA cervical cancer. Estimates of nodal involvement in these patients vary from 4% to lo%, with the size of the lesion and the presence of lymphovascular involvement. Treatment of lymph nodes with the addition of pelvic radiation in these patients should be considered on an individual basis. Patients with lesions less than 3 mm of invasion deep to the basement membrane and without lymphovascular invasion do not require treatment of lymph nodes. Stages IS to IIA Various prognostic factors that were not included in the prior stag-

ing system have been reported to influence the outcome of patients with cervical cancer. These factors probably account for the variation in reported outcomes among different investigators. The most important factor for determining outcome for patients with carcinoma of the cervix is tumor volume, which was adopted into the current staging system in 1994.80Larger tumor volumes are associated with a higher incidence of pelvic nodes, pelvic failure, and decreased survival. Other poor prognostic factors include lymph node involvement, young patient age, adenocarcinoma histology, and a reduction in pretreatment hemato~rit.25~31. 39,49, 84 Radiotherapy Versus Surgery. Patients with early-stage disease may be definitively treated with either radical hysterectomy or irradiation. Landoni et a150reported on the only randomized trial comparing radical radiotherapy and radical hysterectomy for stage IB and stage IIA cervical cancer. Between 1986 and 1991, 343 eligible patients were randomly selected for radical hysterectomy or radical radiotherapy and were stratified by cervical diameter. Sixty-three percent of the patients who were treated by radical hysterectomy had one or more pathologic risk factors-surgical stage IIB or above, less than 3 mm of uninvolved cervical stroma, or cut through and lymph node metastases-and received postoperative pelvic radiotherapy. After a median follow-up of 87 months, 5-year overall and disease-free survival rates were identical in the surgery and radiotherapy groups (83% and 749'0, respectively, for both groups). Severe morbidity was increased in the radical hysterectomy arm, with 28% grade 2 or grade 3 complications compared with

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12% in the radiotherapy arm.5oA consensus conference held by the National Institutes of Health in 1996 concluded that patients with stage IB and stage IIA cervical cancer are appropriately treated by either radical hysterectomy with pelvic lymphadenectomy or radiation therapy, with equivalent results.54Since the combination of radical surgery and irradiation has greater morbidity compared with either modality alone, complete preoperative assessment is crucial to minimize the need for both treatments. Radiotherapy Followed by Surgery. Because pelvic recurrences may be higher in bulky stage I tumors, some groups have advocated the addition of an extrafascial hysterectomy to improve the outcome of such lesions, even though several retrospective reports fail to support the value of adjuvant hysterect~rny.~~, 24, 51, 60, 62 Two prospective randomized trials studying patients with stage IB bulky cervical cancer (defined as 2 4 cm) have been completed by the GOG, and early results have been published. The first study reported by Keys et alMrandomized 282 patients between 1984 and 1991 with stage IB2 cervical cancer to radiation alone (80 Gy to point A) or to radiation (75 Gy to point A) followed by extrafascial hysterectomy. Ninety-one percent of patients were evaluable for progression and survival. Forty-five percent of tumors were 4 to 5 cm in size; 55% were greater than 5 cm in the largest dimension. There was no statistical difference in survival for patients receiving radiation alone compared with those receiving the combined radiation and surgery, with 5-year survival rates of 61.4% and 64.49'0, respectively. A nonsignificant decrease in the recurrence rate was seen for the combined group (43.3% versus 34.5%). There was a substantial reduction in the frequency of local recurrence (cervix, vagina, and pelvis) in the combined group (14.4% versus 25.8%), but there was a higher chance of distant failure among combined modality patients (15.9% versus 8.9%). Hysterectomy did not increase the frequency of reported grade 3 and grade 4 adverse effects, although the frequency of any reported adverse effect was higher for the hysterectomy group (54.8% versus 62.1%). Therefore, the authors concluded that the addition of hysterectomy to standard radiation provided no improvement in survival but possibly caused some reduction in pelvic recurrence. The authors also suggested that more effective radiation may obviate the need for adjuvant hysterectomy in this patient population.MBecause the second trial was designed and started before the results of the first trial were available, radiation and adjuvant extrafascial hysterectomy were considered the standard arm for the second trial. The second trial, also reported by Keys et al, randomized 374 patients with stage IB2 cervical cancer between 1992 and 1997 to radiation (75 Gy to point A) plus adjuvant hysterectomy with or without weekly cisplatin (40 mg/m2 through external radiation for 6 weeks, maximum dose 70 mg). Both survival and recurrence-

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free interval (RFI) showed statistically significant improvement in the radiation and cisplatin group, with a 50% reduction in relapse and death in patients receiving weekly cisplatin compared with those treated by radiation alone. Survival at 24 months was 89% versus 79%, and RFI 81% versus 69%. Grade 3 and grade 4 hematologic and gastrointestinal toxicities were more frequent in the cisplatin group; other toxicities were similar for the two groups.41 Chemotherapy Followed by Surgery. The GOG is currently studying the role of neoadjuvant chemotherapy (three cycles of vincristine 1 mg/m2 and cisplatin 50 mg/m2 every 10 days each) in a phase I11 randomized trial prior to radical hysterectomy compared with radical hysterectomy alone for bulky stage IB2 cervical cancer. Patients with high-risk features for local recurrence receive postoperative pelvic radiation in a nonrandomized fashion. The study was activated December 1996 with 72 patients accrued out of a target of 415 patients as of July 1998. Surgery Followed by Radiotherapy. Several pathologic factors have been demonstrated to influence disease control following radical hysterectomy. Involvement of the pelvic lymphatics strongly influences the outcome of these patients. In addition, large tumor size, deep invasion in the cervix, capillary lymphatic space involvement, and positive or close surgical margins have all been associated with recurrence after radical hysterectomy. Thomas and Dembos8concluded that 72% of recurrences after radical hysterectomy are associated with pelvic relapse. For this reason, numerous investigators have suggested that the addition of postoperative radiation may be beneficial. However, most reports suggest that postoperative pelvic radiotherapy produces a reduction in pelvic relapses with no effect on survival.52A recent multi-center randomized phase I11 trial reported no difference in recurrence patterns or survival in high-risk patients treated with either chemotherapy alone or chemotherapy with pelvic radiati~n.'~ High-risk patients had either positive nodes, bulky tumors, parametrial involvement, or nonsquamous histology. Criticisms of this trial include a low radiation dose (40 Gy), delayed onset to time of radiation (as much as 12 weeks), and insufficient numbers of patients necessary to demonstrate a difference between the two arms. A recently completed intergroup trial (GOG No. 109) randomized node-positive patients or patients with positive surgical margins or parametrial involvement to pelvic external beam radiation (4930 cGy/30 fractions) versus pelvic external beam radiation plus concurrent 5-fluorouracil (5-FU) and four cycles of cisplatin (1 g/m2 5-FU on days 14, cisplatin 70 mg/m2 on day 1 every 3 weeks) following radical hysterectomy and pelvic lymphadenectomy. This study may help to determine whether concurrent chemoradiation can reduce the rate of distant metastases and also improve local control. Patients most likely to benefit from improved pelvic control by the

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addition of pelvic radiation may be those with high-risk features but negative nodes. The GOG has completed a phase I11 trial randomizing patients to pelvic external beam radiation or no further therapy following radical hysterectomy and pelvic lymphadenectomy (GOG No. 92). Between 1988 and 1995, 277 patients with at least two risk factors (greater than one-third cervical stromal penetration, capillary space involvement, and large tumor size) were randomized to pelvic radiotherapy (5040 cGy) versus no further treatment. Of the 137 patients randomized to pelvic radiation, 85% received within 90% of the protocol dose whereas 9 patients refused radiation. A significant reduction of recurrence (44%, 0.58 relative risk) was seen at 2 years with postoperative pelvic radiation, with recurrence-free survival rates of 88% versus 79% for patients receiving no further treatment. Survival analysis awaits further follow up. Gynecologic Oncology Group grade 3 and 4 urologic or gastrointestinal adverse events occurred in 2.9% and 2.9% of patients treated with pelvic radiation and in 1.4% and 0% of patients receiving surgery At the present time, retrospective and prospective data document an improvement in pelvic control with pelvic radiation following radical hysterectomy for stage IB cervical cancer patients with positive nodes as well as for patients with negative nodes who have high-risk features of the primary. Pelvic radiation consists of 45 to 50 Gy external beam radiation with specific sites boosted with further external beam or intracavitary radiation as needed. Determination of the benefit of concurrent chemotherapy for patients with positive nodes awaits publication of GOG No. 109. The documentation of a survival benefit for postoperative pelvic radiation awaits maturation of the GOG No. 109 and GOG No. 92 trials. Stage llB to IVA Involvement of the para-aortic lymph nodes is the most important adverse prognostic factor for advanced cervical cancer and reduces survival by half. Twiggs et a1 reported a 90% 3-year survival rate if pelvic and para-aortic lymph nodes were uninvolved, compared with a 45% rate if pelvic and para-aortic lymph nodes were involved.92The GOG reported para-aortic lymph nodes metastases, followed by pelvic lymph nodes metastases and tumor bulk, to be the most important negative prognostic factors for stage IIB ‘to IVA cervical cancer.MTumor bulk has been defined in various ways for advanced cervical cancer. Reports from four large retrospective studies found tumor bulk within each stage to have prognostic significance.23* 38* 49, For stage IIB,bulky disease was defined as lateral or bilateral parametrium, or barrel-shaped endocervical lesion greater than 6-cm in size and resulted in a 5-year

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survival rate of 78% compared with a rate of 86% for medial or unilateral parametri~m.~~, 49, 6o For stage 111, bulky disease was defined as bilateral side wall fixation or lower-third vaginal involvement and resulted in a 5-year survival rate of 45% compared with a rate of 68% for unilateral side wall fixation.36, 49, 6o The standard treatment approach for stages IIB to IVA cervical cancer has been radiation alone with combined external pelvic radiation and brachytherapy. Neoadjuvant chemotherapy prior to radiation has not improved survival in locally advanced cervical cancer and therefore is considered investigational.46,83, 87 The recent GOG reports of concurrent cisplatin and 5-FU chemotherapy with definitive radiotherapy, described subsequently, have changed the standard of care for advanced cervical cancer. Recent studies performed by the GOG have investigated the role of concurrent 5-FU and cisplatin chemotherapy and radiation in comparison with radiation and hydroxyurea. Gynecologic Oncology Group Trial No. 85 randomized 367 eligible and evaluable patients from 1986 through 1990 to hydroxyurea (3 g/m2) twice weekly during radiation compared with 5-FU (1 g/m2 for 96 hours, on days 1 and 29) and cisplatin (50 mg/m2, on days 1 and 29) during pelvic radiation. Grade 3 and grade 4 neutropenia were significantly increased with concurrent hydroxyurea compared with 5-FU/cisplatin (24.5% versus 3.6%). Although there was no improvement in progression-free interval reported for the 5-FU/cisplatin group, a statistically significant survival benefit was reported.97 The most recently completed phase I11 trial (GOG No. 120) compared the three-drug regimen (5-FU 1 g/mz for 96 hours on days 1 and 29, cisplatin 50 mg/m2 on days 1and 29 and hydroxyurea 2 g/m2 orally twice weekly) to weekly cisplatin (40 mg/mz/week) and to hydroxyurea (3 g/m2 orally twice weekly). Each chemotherapy arm was combined with concurrent radiation. From 1992 to 1997, 487 eligible and evaluable patients were enrolled and analyzed. Both cisplatin-containing regimens (weekly cisplatin and the three-drug regimen) have improved progression-free intervals when compared with hydroxyurea, and have reduced the risk of progression by 43% and 46%, respectively. The percentage of patients progression free at 24 months was 68.4% for the weekly cisplatin, 64.8% for the three-drug regimen, and 48.1% for hydroxyurea. Overall survival was also significantly improved for the cisplatin-containing regimens. Since grade 3 and grade 4 toxicity (leukopenia and gastrointestinal toxicity) were greater for the three-drug regimen than for weekly cisplatin, weekly cisplatin is the preferred regimen.70 The current GOG phase I11 trial (GOG No. 165) for advanced cervical cancer is comparing standard radiation therapy plus concurrent weekly cisplatin (40 mg/m2/week for 6 weeks) versus concurrent protracted venous infusion of 5-FU (225 mg/m2/d for 5 weeks) as radiation

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sensitizers. With emerging information on the importance of overall treatment time/dose intensity and the documentation of pelvic recurrence with inadequate treatment field margins, the GOG sought to optimize the radiotherapy fields/dose in GOG No. 165. The dose of radiation to Point A has been increased to 85 cGy, the pelvic fields were redefined for better posterior coverage, and overall treatment time was reduced to improve the dose intensity and accuracy of radiotherapy (R. Lanciano, personal communication, August 1998). The Radiation Therapy Oncology Group (RTOG) has recently completed a phase I11 trial comparing pelvic radiation and 5-FU/cisplatin-based chemotherapy versus pelvic and para-aortic radiation, both followed by intracavitary radiation; published results are pending. In contrast to the above positive results with concurrent cisplatinbased chemotherapy regimens and radiotherapy, the Toronto group found no significant benefit to infusional5-FU (1 g/mz) daily during the first and last four days of pelvic radiotherapy. Staging Pathways for Cervical Cancer

Cervical cancer is clinically staged according to guidelines established by the International Federation of Gynecology and Obstetrics (FIGO). The goals of staging are to identify potential sites of regional and metastatic spread, to guide therapy, and to allow comparison of results among institutions. Currently, FIGO does not allow diagnostic imaging studies such as CT, MR imaging, or lymphangiography, or surgical evaluation to determine disease extension-although many centers routinely employ these modalities. For patients undergoing primary radiotherapy (usually stage IB2 to IVA), the above diagnostic modalities can be very helpful in delineating the most appropriate radiation fields-pelvic versus pelvic/paraaortic-because a portion of these patients are still curable when the para-aortic lymph nodes are involved. In addition, those patients at high risk for occult microscopic para-aortic metastases have been shown to benefit from extended field radiotherapy7* Surgical and radiographic staging are often used to detect paraaortic lymph node involvement. Some centers routinely employ surgical staging to detect para-aortic lymph node metastases because it is the most accurate method. The absolute benefit of surgical staging can be determined by the success of subsequent extended field radiotherapy in relation to the incidence of para-aortic lymph node metastases by stage. Surgical staging studies from the GOG identified para-aortic metastatic rates of 5%, 21%, and 31% at presentation for stages IB, W,and IIIB, re~pectively.~~ The Mallinckrodt Institute of Radiology reported cure

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rates of &YO, 30%, and 22% for stage IB, IIB, and IIIB patients, respectively, with documented and treated para-aortic lymph nodes.35Table 2 indicates the maximum therapeutic gains of surgical detection and subsequent extended field radiation for each stage of cervical cancer. This table suggests that about 2%, 6%, and 7% of patients with stage IB, IIB, and IIIB disease, respectively, would ultimately benefit from histologic identification of involved para-aortic lymph nodes and treatment. High pelvic and metastatic rates observed in stage IIIB patients explain why only 7% of patients derive benefit. Conversely, patients with high pelvic control rates and low metastatic events also experience a very modest benefit because the prevalence of para-aortic disease is quite small (i.e., 2% of stage IB patients). While these numbers may have some degree of inaccuracy because of the limitations of existing data, the total incremental number of patients who are cured as a result of surgical identification of para-aortic lymph nodes and subsequent treatment is not influenced dramatically. For example, if the incidence of para-aortic involvement in stage IIB patients was 30% instead of the reported 20%,37 a 30% cure rate would result in an additional three patients being saved (nine patients rather than six). Therefore, the conundrum in surgically evaluating all cervical cancer patients is that those patients with the highest incidence of para-aortic disease benefit the least from aggressive staging and para-aortic radiation because of high rates of pelvic and distant failure; yet those patients with the greatest chance of pelvic control have the lowest incidence of para-aortic involvement. Therefore, para-aortic radiation for patients with involved lymph nodes provides an incremental survival benefit only if distant metastases are absent and locoregional control is safely achieved both in the pelvis and in the paraaortic region. The objective is to identify patients at high enough risk for para-aortic spread who also have a reasonable chance of obtaining pelvic control and who are medically fit to undergo extraperitoneal lymphadenectomy of the para-aortic region and extended field radiotherapy, thus justifying the added costs and potential morbidity of additional staging beyond that recommended by FIG0.47 Table 2. TOTAL PATIENTS SAVED BY SURGICAL STAGING* WHO RECEIVED SUBSEQUENT EXTENDED FIELD RADIATION (EFI) (OUT OF 100 PATIENTS) Stage IB

YO Para-aortic lymph nodes % para-aortic lymph nodes detected YO Cured EFIt % of patients benefiting

5 5 45 2.5

Stage IIB

Stage IllB

21 21 30 6.3

31 31 22 6.8

"No presurgical selection of patients with CT, MR imaging, or lymphangiography. tCure rate based on data from Mallinckrodt Institute of Radiology in Grigsby P W Principles and Practices of Gynecology/Oncology In Hoskins WJ, Perez CA, Young RC (eds), Philadelphia, LippincottRaven, 1997, p 841.

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The University of Minnesota Group is a strong proponent for surgically staging all cervical cancer patients.16They rationalize this approach based on the high sensitivity and specificity of surgical staging, in addition to the therapeutic benefit of debulking the pelvic and paraaortic lymph nodes. An update of their experience was recently analyzed from 266 patients who underwent an extraperitoneal lymphadenectomy prior to radiotherapy. The 5- and 10-year survival was reported among four groups that had a lymph node dissection: Group A had negative lymph nodes; Group B had resected microscopic lymph nodes; Group C had macroscopically positive lymph nodes that were resected; and Group D had unresectable lymph nodes. All patients with positive lymph nodes underwent extended field radiotherapy. The similar 5- and 10-year results for Groups B and C suggested a therapeutic advantage of debulking the lymph nodes. Interestingly, the metastatic rate was also similar for Groups B and C. However, substantial toxicity rates were encountered, with 20% lymphocysts (7%required drainage), 18% lymphedema, and 11%grade 4 small bowel and genitourinary complications. Grade 3 complications were not reported. Although the University of Minnesota experience suggests a therapeutic advantage to surgical staging and subsequent debulking for some groups of cervical cancer patients, it should be emphasized that 50% of their patients underwent an unnecessary procedure with substantial cost and morbidity. No survival gains were detected in a similar study reported by Potter et a1 that A randomized trial may be assessed the impact of surgical ~taging.6~ warranted to determine the benefit of surgical staging in selecting cervical cancer patients. Many institutions use modalities that are slightly less accurate and less invasive to determine the status of the para-aortic lymph nodes. The sensitivity and specificity of CT, MR imaging, and lymphangiography are shown in Table 3. Lymphangiography is the most accurate test in determining the para-aortic lymph node status in the absence of surgical staging. The GOG conducted a prospective trial to assess the relative effectiveness of CT, lymphangiography, and ultrasound in deTable 3. SENSITIVITY AND SPECIFICITY OF CT, LYMPHANGIOGRAPHY (LAG), AND

MR IMAGING IN PARA-AORTIC LYMPH NODE DETECTION

Sensitivity Suecificitv ~

CT

LAG

MR Imaging

34% 96%

79% 73%

55%

71%

~

CT and LAG data from Heller P, Malfetano J, Bundy 8, et al: Clinical-pathologic study of stage IIB, III,and N A carcinoma of the cervix. Extended diagnostic evaluation for para-aortic node metastasis-A Gynecologic Oncology Group Study. Gynecol Oncol 3425,1990. MR imaging data from Ebner F, Tamussino K, Kressel HY,et al: Magnetic resonance imaging in cervical carcinoma: Diagnosis, staging and follow up. Magnetic Resonance Quarterly 1022,1994.

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tecting para-aortic spread in patients with stage IIB to IVA cervical ~ancer.3~ Lymphangiography and CT were 79% and 34% sensitive and 73% and 96% specific, respectively. The false-negative rates were 25% for CT and 14% for lymphangiography. The excellent negative predictive value for lymphangiography (89% to 99%) is critical, because a negative lymphangiography indicates a relatively low yield of positive para-aortic lymph nodes if surgical confirmation is performed (1% for stage IB cancers, 6% for stage IIB cancers, and 11%for stage IIIB cancers). This overall yield of nonselective surgical staging is even lower if the cure rates for positive and treated para-aortic lymph nodes are taken into consideration. For example, it is useful to calculate the number of stage IIB patients lost per 100 patients with a false-negative lymphangiogram (Table 4). With a negative predictive value of 94%, 6 patients out of 100 would have undetected para-aortic disease. The Mallinckrodt Institute of Radiology reported a 30% 5-year survival for stage IIB patients who had positive and treated para-aortic meta~tases.~~ Therefore, 30% of the six stage IIB patients, or 2 patients out of 100 with a false-negative lymphangiogram would be lost. Performing these same calculations for stage IIIB patients (negative predictive value of 89% for lymphangiogram, with a 22% 5-year survival for this patient cohort), again about 2 Table 4. NUMBER OF PATIENTS LOST BY ASSESSING THE PARA-AORTIC STATUS NONSURGICALLY (OUT OF 100 PATIENTS)

% False Negative Rate

Stage IB (5% Para-aortic Disease) LAG CT MR imaging Stage IIB (21%para-aortic disease) LAG CT MR imaging Stage IIIB (31%para-aortic disease) LAG CT MR imaging

5-Year Survival in Patients with Positive Para-aortic Disease Based on MIR Data

1 4 3

45%

6 15 14

30%

11 24 22

22%

% Patients Lost by Not Detecting and Treating Para-aortic Disease

0.5 2 1.5 2

4.5 4 2.5 5 5

LAG = lymphangiography; MIR = Mallinckrodt Institute of Radiology. Frequency of para-aortic disease based on GOG studies from Heller P, Malfetano J, Bundy B, et a1 Clinical-pathologic study of stage IIB, 111, and IVA carcinoma of the cervix: Extended diagnostic evaluation for para-aortic node metastasis-A Gynecologic Oncology Group Study. Gynecol Oncol 38425,1990. Five-year survival data from Coia L, Won L, Lanciano R, et al: The patterns of care outcome study for cancer of the uterine cervix: Results of the Second National Practice Survey. Cancer 662451,1990.

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patients out of 100 would be lost. Similarly, for stage I patients, less than 1 patient out of 100 would die of undetected and untreated paraaortic disease. The effect of using CT or MR imaging alone to assess para-aortic lymph node metastases, and the number of patients that would have undetected and untreated disease, is also demonstrated in Table 4. Among all stage IIB and stage IIIB cervical cancer patients, about 5% of patients would be lost. It is in this patient cohort, especially among stage IIB patients who have a 70% chance of cure, that surgical assessment of the para-aortic lymph nodes may be appropriate in the setting of a negative CT scan. In sensitivity, specificity, and negative and positive predictive values, MR imaging appears similar to CT but the data are limited.21The number of lives lost by using either CT or MR imaging instead of surgical staging is similar-5% of patients with either stage I1 or stage I11 cervical cancer. As with CT scans, new generation MR imaging scanners may be better in detecting nodal disease. Additional advantages of MR imaging over CT include potential cost savings, better definition of local extension, and possibly improved assessment of lymphatic spread with the use of magnetic resonance angiography which may differentiate vascular structures from lymphatics. Although it is recognized that polarized views exist on the role of surgical staging for cervical cancer, the last line of Table 2 demonstrates the reality of the very modest gains achieved through nonselective surgical staging. In the absence of surgical staging, lymphangiography is the best diagnostic test, with few lives lost from a low false-negative rate (Table 4).Unfortunately, few institutions have access to lymphangiography. Computed tomography and MR imaging are reasonable tests to evaluate the lymph nodes initially. Table 4 suggests that about 4 to 5% stage I1 and stage I11 patients would be lost as the result of the falsenegative rate of CT and MR imaging. Surgical staging is probably reasonable when patients have positive pelvic and/or para-aortic lymph nodes and there is a low chance of nodal control with radiation alone and a good chance of tumor control with radiation. Surgical staging is probably also useful in stage I1 and possibly in some stage IB2 and stage IIIB patients who have a reasonably high chance of pelvic control, but who have CT- or MR imaging-negative nodes, for whom the added morbidity of extended field radiotherapy would be avoided if the para-aortic lymph nodes were negative. An appraisal of the ultimate benefit to the patient is essential before using the tools available to assess lymph node involvement for each stage of disease. The absolute yield for surgically evaluating all stages of cervical cancer is low, because those patients most likely to have involved para-aortic lymph nodes have the lowest probability of cure as the result of high pelvic and metastatic failures, and those patients with

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the highest probability of cure are least likely actually to harbor occult para-aortic disease. To maximize the survival benefit associated with the identification and detection of extrapelvic nodal disease and its subsequent therapy requires defining the patients who have a modest risk for para-aortic metastases and who still have a reasonably high chance of pelvic control. Therefore, the current GOG trial for advanced cervical cancer (GOG No. 165) will stratify patients by diagnostic method used to evaluate the para-aortic region, but surgical staging is no longer mandated (R. Lanciano, personal communication, August 1998). Treatment of the Para-aortic Region

Patients with documented para-aortic lymph node metastases are usually treated with extended fields to encompass the retroperitoneum. In order to keep bowel complications to a minimum, the dose of radiation to the para-aortic region should not exceed 45 to 50 Gy and surgical staging, if performed, should be limited to an extraperitoneal approach. Five-year survival rates range from 20% to 40% in recent series for extended field radiation; most surviving patients have low-volume pelvic disease which is more likely to be c o n t r ~ l l e d .Likewise, ~~ survival rates are higher for patients with microscopic or small para-aortic node disease than for patients with massive para-aortic i n ~ o l v e m e n t Be.~~ cause distant failure is a predominant pattern of failure for these patients, effective systemic therapy needs to be incorporated into the design before an increase in survival can be appreciated. The GOG completed a phase I1 study in November 1993 of combined infusional 5-FU (1 g/m2 on days 2-5 and 30-33), cisplatin (50 mg/m2 on days 1 and 29) and concurrent pelvic and para-aortic radiation followed by brachytherapy (GOG No. 125). Three-year progression-free survival appears promising for the protocol, with 52% of stage I, 36% of stage 11, and 22% of stage III/IV patients with biopsy-confirmed para-aortic lymph node metastases free of disease.94 Prophylactic para-aortic radiation is an alternative to surgical staging for advanced cervical cancer. Patients felt to be at high risk for para-aortic lymph node metastases may be treated with extended field radiation for potential microscopic disease. Two randomized trials have studied the relative benefits of prophylactic radiation to this region. A study by the European Organization for Research and Treatment of Cancer (EORTC) found no survival advantage to prophylactic paraaortic r a d i a t i ~ nThe . ~ ~ majority of patients in this study had bulky stage I1 or stage I11 disease with a high locoregional failure rate which may have overwhelmed any beneficial effect of prophylactic para-aortic radiation. The RTOG published results of a phase I11 trial demonstrating a statistically increased survival rate at 10 years of 55% for patients receiv-

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ing prophylactic para-aortic radiation compared with 44% patients receiving pelvic radiation alone. This improvement primarily resulted from a reduced rate of distant metastases in patients achieving pelvic control in the para-aortic radiation arm.” This study did not include stage I11 cervical cancer, which may be the reason for the positive results. The RTOG has recently completed a randomized trial comparing pelvic and para-aortic radiation with pelvic radiation and 5-FU/cisplatin, which should be published soon. Conclusions

Radiation is the most active curative agent for cervical cancer. Brachytherapy is the most important component of the radiation treatment plan. With aggressive radiotherapeutic management, tumors with significant bulk are effectively treated and cured. Exciting recent results from the GOG have changed the standard of care for advanced-stage cervical cancer with concurrent weekly cisplatin and radiation improving survival for bulky stage IB to IVA disease. The benefit of continuous infusion 5-FU as a radiation sensitizer is the subject of the current GOG trial for advanced disease. The challenge of the twenty-first century is a better understanding of the three-dimensional dose distribution of both brachytherapy and external beam to reduce late complications while improving dose delivery and ultimately increasing the cure rate. COMBINED MODALITY TREATMENT IN CERVICAL CANCER: NEOADJUVANT CHEMOTHERAPY AND SURGERY Jan B. Vermorken, MD, PhD

Invasive cervical cancer is the second most common malignancy among women worldwide, with respect to both incidence and mortality.57In the last decade, significant advances have been made in understanding the etiology and patterns of spread of cervical cancer. Accessibility of the cervix for cytologic evaluation via the Pap smear, visual inspection by colposcopy, and histologic evaluation by biopsy have made cervical cancer a preventable and potentially curable disease. Identification and successful treatment of precursor lesions (cervical intraepithelial neoplasia) have accounted for a decreasing incidence of invasive cervical cancer. Indeed, the death rate has decreased by 70% in many developed countries when adequate screening programs are in place. Nevertheless, the 5-year survival rate stage for stage has not significantly improved either in developed countries or worldwide.&

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This finding indicates that with presently available treatment modalities, used in their traditional manner, no further improvement is to be expected. New therapeutic approaches or a better integration of the existing modalities (i.e., radical surgery, radiotherapy, and chemotherapy) in the primary treatment of poor-risk patients may improve an otherwise poor outlook and are being studied in numerous trials. Patients considered poor-risk include cervical cancer patients with advanced stages of the disease (FIG0 stage I11 and IV) and those with early-stage disease in whom lymph nodes proved to be involved or in whom other poor prognostic features are present, such as bulky tumors (>4 cm), deep invasion (relative or absolute), capillary/lymphatic space involvement, occult parametrial involvement, positive or close surgical margins, and vaginal extension.1s,20, 93 The presence or absence of disease in the lymph nodes is the single most important prognostic factor in early-stage cervical cancer.82This finding and most of the other unfavorable features are mainly based on pathology data obtained after surgery. Such factors can be used to select patients for adjuvant therapies following primary treatment with radical surgery. Although there are some clear indications for the use of postoperative pelvic irradiation,&,89 the role of adjuvant chemotherapy after surgery in such patients is uncertain and is presently under evaluation in a large intergroup study (EORTC protocol No. 55954). On the other hand, patients receiving radiotherapy as primary treatment for their early-stage disease do not seem to benefit from the additional use of extrafascial hystere~tomy,~~ and the routine use of adjuvant chemotherapy would lead to a tremendous overtreatment for the majority of such patients: if lymph nodes are uninvolved, the 5-year survival is about 90% without any further systemic thera~y.9~ For clinicians it would clearly be ideal if models could be developed utilizing only preoperative data to predict the presence of involved lymph nodes, thereby indicating whether a more aggressive approach in the primary treatment would be appropriate. The use of chemotherapy in these circumstances (i.e., induction chemotherapy or neoadjuvant chemotherapy) might be attractive on theoretical grounds.

Neoadjuvant Chemotherapy Rationale

The rationale for the use of neoadjuvant chemotherapy has been published previously.’ The presence of an intact tumor vasculature may improve drug delivery, and dose-intensive regimens before definitive local therapy may be better tolerated. The tumor may also be more

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chemosensitive before radiotherapy or surgery, and chemodebulking could improve the effectiveness of local radiotherapy or could facilitate tumor resection. Moreover, subclinical metastases may be eradicated earlier, while the secretion of antiangiogenic factors by the primary tumor might be circulating.26Another potential advantage is that the response to neoadjuvant chemotherapy (NACT) can be used to determine definitive local therapy and provides the ability to monitor drug sensitivity in vivo, reducing patients' exposure to further ineffective therapy. The use of NACT may also decrease the risk of intraoperative dissemination of tumor cells. Neoadjuvant Chemotherapy Followed by Radiotherapy

Five randomized trials of NACT followed by radiotherapy versus radiotherapy alone in patients with locally advanced cervical cancer (mainly stage I11 and stage N disease) have been disappointing, both in terms of complete response rates and of increase in survival that could be achieved with NACT.'O, 46, 87 In fact, none of the five reported studies showed any survival benefit. Pelvic failure was more common on the NACT arm in some of these trials, and a negative influence on survival was reported in two. In addition, treatment morbidity was sometimes severe.86,87 Explanation for these negative results cannot be given with certainty, but it has been suggested that chemotherapy could lead to an accelerated regrowth of surviving clones of cells, thus lessening the effect of subsequent radi~therapy.~~ Another possibility is the development of (cross)resistance between certain chemotherapeutic agents and radi~therapy.~~ Short-interval chemotherapy followed by rad i ~ t h e r a p yand ~ ~ simultaneous radiotherapy and ~hemotherapy~~ may be more successful strategies and should be further explored. Neoadjuvant Chemotherapy Followed by Surgery

Data on NACT before surgery seemed to have more promise from the start. In the late 1980s, several groups from different parts of the world (Argentina, Australia, Korea, and Italy) reported on their initial results with platinum-based combination chemotherapy given preoperatively in patients with bulky tumors.7,42, 45, 76 The disease stages varied from FIG0 stage IB (mostly with lesions >4 cm) to stage IIIB. A marked tumor response was observed, with clinical response rates ranging from 66.6% to 89%. At histologic examination, the most favorable regressions were observed in vaginal disease, followed by cervical disease and parametrial disease. Although the overall pathologic complete response rates were disappointingly low (ranging from 0% to 13%), the incidence of lymph node metastases found at surgery in these patients was 8% to

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33%, in comparison with the incidence of 40% to 80% previously reported in similar groups of patients without the use of NACT.12,29,55*68 With the caveat that the aggressiveness of the lymph node dissection may not have been the same in all studies, this finding suggests that chemotherapy may also have had an impact on tumor deposits in lymph nodes, as it did on the primary tumor. If indeed this is the case, then contrary to what seems to occur with radiotherapy, surgery may potentially remove resistant foci and may lead to an improved disease-free survival. However, randomized trials are necessary to prove this hypothesis. Unfortunately, most efforts continue to be directed to nonrandomized studies and pilot trials, the results of which are very difficult to interpret because of limited sample size, short follow-up, or vague patient-selection criteria. Some of these prospective studies, however, provide data on tolerance, operability, and postoperative complication rate, and give some information on the effect of chemotherapy in early versus more advanced stages. Table 5 summarizes the studies from 1990 onwards that include at least 25 patients and give full data on both clinical and histologic response. In most series, tolerance to chemotherapy was reported as being quite acceptable. However, some series have documented serious, even fatal, pulmonary toxicity as well as cases of hemolytic uremic syndrome.28,76 Dense fibrosis around the pelvic lymph nodes is often mentioned? 6, l9 but serious intraoperative complications or major postoperative complications, beyond those that might be expected from surgery alone without prior exposure to chemotherapy, are rare. Patients with stage IB or stage IIA disease have been selected from those studies in Table 5, and presented in Table 6 for comparison. It should be emphasized that in all these cases, the lesion had a diameter of 4 cm or more. Indeed, the data suggest that even in these bulky cases, operability is nearly 100% and that the overall incidence of positive lymph nodes is extremely low. Another interesting finding is that reaching a clinical complete response is an important prediction of lymph node status, because positive nodes were found almost exclusively in patients with a less than complete response to chemotherapy. Indeed, in a multivariate analysis carried out by Benedetti-Panici et a1,3 response to NACT came forward as a new independent prognostic factor for survival, following clinical substage, tumor size, and parametrial involvement. The question of whether the reduction in incidence of nodal metastases might translate into a better survival can only be answered by randomized trials. Some comparative but nonrandomized studies have been suggestive in that respect. Namkoong et a153reported on 92 patients with locally advanced (largest diameter >3 cm) stage IB, stage IIA, and

N rD L

26

Benedetti-Pancini4 Benedetti-Pancini6 dot tin^'^ FontanelliZ7 Chang9 EddyZ Total

Ib-IVa

Ib

Ib-I11 Ib-I11 Ib-IVa Ib-IIb Ib-IIa

Stages (FIGO)

PB X 1 PBM X 3 BOMP X 1 PB X 1 VBP X 2-3 VP x 3

Drugs and No. Courses 88 (19) 83 (15) 100 (35) 78 (11) 85 (24) 82 ( 6 ) 80 (17)

Response Rate (CRR) 81 83 100 96 100 94 91

Operability

22 (10)

0 (0)

5 (19) 10 (13) 4 (14) 1 (7) 2 (6)

PCR n (%)

2 (9.5) 15 (24) 9 (32) 4 (15) 6 (18) 8 (25) 44 (22)

Positive LN n (%)

CRR = complete response rate; PCR = pathologic complete response; LN = lymph nodes; PB = cisplatin and bleomycin; PBM = cisplatin, bleomycin and methotrexate; BOMP = bleomycin, vincristine, mitomycin C and cisplatin; VBP = vincristine, bleomycin, and cisplatin; VP = vincristine and cisplatin.

33 34 223

27

75 28

No. Patients

Authors (Reference)

Table 5. RESULTS OF NEOADJUVANT CHEMOTHERAPY FOLLOWED BY RADICAL SURGERY IN CERVICAL CANCER

6 9

Benedetti-Pancini' Benedetti-Pancini6 DottinoIg Fontanelliz7 chang9 Eddyz2 Total PB X 1 PBM X 3 BOMP X 1 PB X 1 VBP X 2-3 VP x 3

Drugs and No. Courses 100 (100) 88 (33) 100 (50) 68 (15) 85 (24) 82 (6) 84 (22.5)

Response Rate (CRR)

0 (0) 2 (6)

0 (0) 8 (8)'

100 94 97

2 (20)

NR

4 (67)

PCR n (%)

100 100

100 88

(%I

Operability

0 (0) 0 (0) 0 (0) 3 (16) 6 (18) 8 (25) 17 (15)

Positive LN n (%)

*Mean figure only of 5 studies. CRR = complete response rate; PCR = pathologic complete response; LN = lymph nodes; PB = cisplatin and bleomycin; PBM = cisplatin, bleomycin and methotrexate; BOW = bleomycin, vincristine, mitomycin C and cisplatin; VBP = vincristine, bleomycin, and cisplatin; VP = vincristine and cisplatin; NR = not reported.

10 19 33 34 111

No. Patients

Authors (Reference)

Table 6. RESULTS OF NEOADJUVANT CHEMOTHERAPY IN STAGES Ib-lla CERVICAL CANCER (> 4 CM IN DIAMETER)

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stage IIB cervical cancers, who had completed 4 years of follow-up after treatment with preoperative adjuvant chemotherapy (vinblastin/ bleomycin/cisplatin every 3 weeks for two to five cycles, depending on the response) prior to radical surgery. These patients were compared with 138 patients treated with radical surgery alone in the same time period (1986-1989) and in the same hospital. The incidence of positive lymph nodes was reduced in the group treated with NACT in comparison with the group treated with surgery alone (16/92 [17%] versus 47/ 138 [34%], P = 0.005). Also, the recurrence rate was reduced in the NACT group (18.5% versus 35.5%, P = 0.004), and the progression-free interval was longer ( P = 0.0067). A second study of note was recently reported by Serur et al.79Using a historicul prospective design, data on patients with bulky stage IB (tumor diameter >4 cm), who had been treated during a certain period of time with either three cycles of NACT (vincristine/bleomycin/cisplatin combination) followed by radical hysterectomy (n = 20) or with primary radical hysterectomy (n = 32), were reviewed. Mean pretreatment tumor diameter was found to be significantly larger in the NACT group. The percentage of patients in both groups receiving postoperative adjuvant radiotherapy or chemotherapy was similar (65% versus 63%). Pathologic findings showed that the incidence of positive lymph nodes was reduced in the NACT group (10.0% versus 37.5%). Moreover, positive vascular space involvement, undiagnosed parametrial disease, and greater than 75% depth of invasion were less commonly observed. Although larger tumors were treated in the NACT group, the 5-year survival was observed to be slightly better, though this finding was not statistically significant (80.0% versus 68.79'0, P = 0.162). The most important information is derived from the randomized studies (Table 7). These studies are clearly preliminary; two of the three studies summarized in the table are interim analyses, and one of them includes insufficient patient numbers. There is only one prospective randomized trial that yields definite data in patients with bulky disease (defined as tumors >2 cm colposcopically and cervical volumes >27 cm3).77In this trial, NACT followed by radical hysterectomy and pelvic radiotherapy was compared with radical hysterectomy followed by pelvic radiotherapy. Chemotherapy consisted of vincristine 1 mg/m2, and cisplatin 50 mg/m2 on day 1 and bleomycin 25 mg/m2 by continuous infusion over 6 hours, days 1 through 3, given every 10 days for three cycles. Overall survival for all stage IB patients was significantly better in the NACT group than in the control group (8lY0 versus 66% after 8 years of follow-up, P < 0.05). Furthermore, there were significantly more pelvic recurrences in the control group (17% versus 7%, P < 0.001), but the occurrence of distant metastases was not significantly different (8% versus 5%). A subdivision by tumor size showed no significant survival

All IB IB1 182 IIIB IB2-111

Stage FIG0

102 41 61 53 211

NACT + S

54

NACT + RT

No. Patients per Study Arm

103t 47t 56t 54$ 202$

Control

=

cisplatin, vincristine, and

81% vs 66%, 8 yr FUP (P < 0.05) 82% vs 77%, 8-yr FUP (NS) 80% vs 61%, 9-yr FUP (P < 0.01) 63% vs 53% vs 37% ( P < 0.05)* (FUP 4 years) OS 68.5% vs 60% (P = 0.005) PFS 52% vs 44% (P = 0.02) (median FUP 27 months)

Survival Data

“ACT + S versus NACT -+ RT, non-significant; NACT --f S versus Control, P = 0.005; NACT + RT versus Control, P = 0.025. tSurgery 2 radiotherapy $Radiotherapy RT = radiotherapy; S = surgery; NS = not significant; FUP = follow-up; 0 s = overall survival; PFS = progression-free survival; NACT blemycin in references 75 and 77; platinum-based in reference 5.

SardP Benedetti-Panici5

Sardi”

Authors (Reference)

Table 7. RESULTS OF TRIALS USING NEOADJUVANT CHEMOTHERAPY (NACT) FOLLOWED BY SURGERY

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difference for patients with tumors between 2 cm and 4 cm in diameter, but patients with larger tumors (>4 cm in diameter) significantly benefited from NACT. Resectability in the patients with larger tumors was higher in the NACT group compared with the control group (100% versus 85%; P < 0.01). Moreover, pathologic risk factors such as vascular space involvement, parametrial infiltration, and lymph node involvement were all improved in patients responding to NACT ( P < 0.001). An interim analysis of the study in 1993 reported a recurrence rate in the pelvis of 24.3% in the control group and of 7.6% in the NACT Thomas argued that the recurrence rate in the control group was unusually high and indicated that the pelvic recurrence rate observed in the NACT group was more comparable to that usually achieved with standard radiation alone, implying that standard radiation might still be the standard against which this new approach should be tested.90Although this argument may be valid, the interim report of the Italian study, in which the control arm is radiotherapy5 (Table 7), suggests otherwise. Interestingly, all these preliminary results from randomized trials support the suggestion of benefit mentioned in nonrandomized studies (see Tables 5 and 6) and in comparative studies. These results and the interesting data on concomitant chemotherapy and radiotherapy in patients with stages IIB, stage 111, and stage IVA cervical cancer, presented at the most recent meeting of the American Society of Clinical Oncology, points to a role for chemotherapy in the primary treatment of patients with cervical cancer.7oHowever, the current chemotherapy regimens are toxic and have limited antitumor efficacy. The introduction of new agents into the clinic and their combination with existing conventional agents is one way to improve the efficacy of regimens to be used in the neoadjuvant setting.14,57 From this review, it can be concluded that NACT is still investigational and that its role prior to surgery needs to be further explored. Randomized trials of NACT and other investigational approaches in high-risk cervical cancer are still needed, and participation in such studies is highly recommended. References 1. Alberts DS, Aristizabal S, Sunvit EA, et a1 Preliminary chemotherapy for high risk recurrence cervix cancer. In Surwit EA, Alberts D (eds): Cervix. Boston, Martinus Nijhoff, 1987, p 161 2. Arai T, Nakano T, Morita R, et a1 High dose remote afterloadingintracavitary radiation therapy for cancer of the uterine cervix. Cancer 69175, 1992 3. Benedetti-Panici P, Greggi S, Scambia G, et al: UCSC experience on neoadjuvant chemotherapy (NACT) & radical surgery (FS) in locally advanced cervical cancer (LACC):Multivariate analysis (MA) of prognostic factors. Proceedings of International Gynecological Cancer Society 3:210, 1991

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4. Benedetti-Panici P, Greggi S, Scambia G, et al: High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: A preliminary report. Gynecol Oncol 41:212, 1991 5. Benedetti-Panici P, Landoni F, Greggi S, et al: Randomized trial of neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) vs exclusive radiotherapy (RT) in locally advanced squamous cell cervical cancer (LASCCC). An Italian multicenter study [abstract No. 0511. International Journal of Gynecologic Cancer 7(suppl 2):18, 1997 6. Benedetti-Panici P, Scambia G, Baiocchi G, et al: Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Prognostic factors for response and survival. Cancer 67372, 1991 7. Benedetti-Panici P, Scambia G, Greggi S, et al: Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study. Obstet Gynecol 17344, 1988 8. Bonin S, Lanciano R, Corn B, et al: Bony landmarks are not an adequate substitute for lymphangiogram in defining pelvic lymph node location for the treatment of cervical carcinoma with radiotherapy. Int J Radiat Oncol Biol Phys N167, 1996 9. Chang HC, Lai CH, Chou PC, et al: Neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin and radical surgery in early-stage bulky cervical carcinoma. Cancer Chemother Pharmacol30:281, 1992 10. Chauvergne J, Lhomme C, Rohart J, et a1 Chimiotherapie nboadjuvante des cancers du col utkrin aux stades IIb et 111. Rksultats 6loign6s d'un essai randomise pluricentriaue Dortant sur 151 Datients. Bull Cancer (Paris) 801069. 1993 11. Choi D, Wong L, Sham'J, et al: Dose-tumor response for carcinoma of cervix: Analysis of 594 patients treated by radiotherapy. Gynecol Oncol49311, 1993 12. Chung CK, Nahhas WA, Stryker JA, et a1 Analysis of factors contributing to treatment failures in stage IB and IIA carcinoma of the cervix. Am J Obstet Gynecol138:550,1980 13. Coia L, Won L, Lanciano R, et al: The patterns of care outcome study for the cancer of the uterine cervix: Results of the 2ndNational Practice survey. Cancer 66:2451, 1990 14. Colombo N, Landoni F, Pellegrino A, et al: Phase I1 study of cisplatin, ifosfamide and paclitaxel (CIP) as neoadjuvant chemotherapy in patients with locally advanced cervical carcinoma (LACC) [abstract No. 13091. Proceedings from the American Society of Clinical Oncology 16367a, 1997 15. Corn B, Hanlon A, Pajak T, et al: Technically accurate intracavitary insertions improve pelvic control and survival among patients with locally advanced carcinoma of the uterine cervix. Gynecol Oncol53:294, 1994 16. Cosin JA, Fowler JM, Chen MD, et a1 Pretreatment surgical staging of patients with cervical cancer. The case for lymph node sampling. Cancer 82:2241, 1998 17. Curtin J, Hoskins W, Venkatraman E, et al: Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): A randomized phase I1 trial. Gynecol Oncol 61:3, 1996 18. Delgado G, Bundy BN, Fowler WC: A prospective surgical pathological study of stage I squamous carcinoma of the cervix. A Gynecologic Oncology Group Study. Gynecol Oncol 35:314, 1990 19. Dottino PR, Plaxe SC, Beddoe AM, et al: Induction chemotherapy followed by radical surgery in cervical cancer. Gynecol Oncol40:7, 1991 Groenier KH, de Bruijn HWA, et al: Pretreatment serum squamous cell 20. Duk JM, carcinoma antigen: A newly identified prognostic factor in early-stage cervical carcinoma. J Clin Oncol 14:111, 1996 21. Ebner F, Tamissino K, Kressel HY, et al: Magnetic resonance imaging in cervical carcinoma: Diagnosis, staging and follow-up. Magnetic Resonance Quarterly 10:22, 1994 22. Eddy GL, Manetta A, Alvarez RD, et al: Neoadjuvant chemotherapy with vincristine and cisplatin followed by radical hysterectomy and pelvic lymphadenectomy for FIGO stage IB bulky cervical cancer: A Gynecologic Oncology Group pilot study. Gynecol Oncol57412, 1995 23. Eifel P, Morris M, Wharton J, et al: The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 29:9, 1994 1

1

\

,

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24. Eifel P, Thomas W, Smith T, et al: The relationship between brachytherapy dose and outcome in patients with bulky endocervical tumors treated with radiation alone. Int J Radiat Oncol Biol Phy 28:113, 1994 25. Eifel PJ, Morris M, Oswald MJ, et al: Adenocarcinoma of the uterine cervix. Prognosis and patterns of failure in 367 cases. Cancer 65:2507, 1990 26. Folkman J, Shing Y: Angiogenesis. J Biol Chem 26710391, 1992 27. Fontanelli R, Spatti G, Raspagliesi F, et a1 A preoperative single course of high-dose cisplatin and bleomycin with glutathion in bulky stage IB/II carcinoma of the cervix. Ann Oncol 3:117, 1992 28. Friedlander ML, Atkinson K, Coppleson et a1 The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study. Gynecol Oncol 19:1, 1984 29. Fuller AF Jr, Elliot N, Kosloff C, et al: Lymph node metastases from carcinoma of the cervix, stage IB and IIA:Implications for prognosis and treatment. Gynecol Oncol 13:165, 1982 30. Fyles A, Keane T, Barton M, et al: The effect of treatment duration in the local control of cervix cancer. Radiother Oncol25:273, 1982 31. Girinsky T, Pejovic-Lenfant M, Bourhis J, et al: Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of cervix treated by radiation therapy: Results of a retrospective study of 386 patients. Int J Radiat Biol Phys 16:37, 1989 32. Girinsky T, Rey A, Roche 8, et al: Overall treatment time in advanced cervical carcinomas: A critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys 271051, 1993 33. Greer B, Koh W, Figge D, et al: Gynecologic radiotherapy fields defined by intraoperative measurements. Gynecol Oncol38:421, 1990 34. Grigsby PW, Perez C: Radiotherapy alone for medically inoperable carcinoma of the cervix: Stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21:375, 1991 35. Grigsby P W In Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, Lippincott-Raven, 1997, p 841 36. Haie L, Pesovic M, Gerbaulet A, et al: Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Result of controlled clinical trial of the EORTC radiotherapy group. Radiother Oncol 11:101, 1988 37. Heller P, Malfetano J, Bundy B, et al: Clinical-pathologic study of stage IIB, 111, and IVA carcinoma of the cervix: Extended diagnostic evaluation for para-aortic node metastasis-A Gynecologic Oncology Group study. Gynecol Oncol38425, 1990 38. Horiot J, Pigneux J, Pourquier H, et al: Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: A French cooperative study of 1383 cases. Int J Radiat Oncol Biol Phys 14605, 1988 39. Kapp D, Fischer D, Gutierrez E, et al: Pretreatment prognostic factors in carcinoma of the uterine cervix: A multivariate analysis of the effects of age, stage, histology and blood counts on survival. Int J Radiat Oncol Biol Phys 9445, 1983 40. Keys H, Bundy B, Stehman F, et a1 Adjuvant hysterectomy after radiation therapy reduces detection of local recurrence in “Bulky” stage IB cervical cancer without improving survival: Results of a prospective randomized GOG trial. Presented at the American Radium Society Annual Meeting, New York City, May 3, 1997 41. Keys H, Bundy B, Stehman F, et al: Weekly cisplatin chemotherapy during irradiation improves survival and reduces relapses for patients with bulky Stage IB cervical cancer treated with irradiation and adjuvant hysterectomy: Results of a randomized GOG Trial [abstract No. 1111. Gynecol Oncol 68:100, 1998 42. Kim DS, Moon H, Hwang YY, et a1 Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib, IIa, with bulky tumor. Gynecol Oncol29:321,1988 43. Kim R, McGinnis S, Spencer S, et al: Conventional four-field pelvic radiotherapy technique without computed tomography-treatment planning in cancer of the cervix: Potential geographic miss and its impact on pelvic control. Int J Radiat Oncol Biol Phys 31309, 1995 44. Kinney WK, Alvarez RD, Reid GC, et al: Value of adjuvant whole-pelvis irradiation

DEVELOPMENTS IN TREATMENT OF NEWLY DIAGNOSED CERVICAL CANCER

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

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after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: A matched-control study. Gynecol Oncol 34:258, 1989 Kirsten F, Atkinson KH, Coppleson JVM, et a1 Combination chemotherapy followed by surgery or radiotherapy in patients with locally advanced cervical cancer. Br J Obstet Gynaecol 94:583, 1987 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, 1994 Lanciano R, Corn B: The role of surgical staging for cervical cancer. Seminars in Radiation Oncology 446, 1994 Lanciano R, Pajak T, Martz K, et al: The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A patterns-of-care study. Int J Radiat Oncol Biol Phys 25:391, 1993 Lanciano R, Won M, Coia L, et al: Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: A final report of the 1973 and 1978 patterns of care studies. Int J Radiat Oncol Biol Phys 20:667, 1991 Landoni F, Maneo A, Colombo A, et a1 Randomized study of radical surgery versus radiotherapy for stage IB-IIA cervical cancer. Lancet 350:535, 1997 Mendenhall W, Sombeck M, Freeman D, et al: Stage IB and IIA-B carcinoma of the intact uterine cervix: Impact of tumor volume and the role of adjuvant hysterectomy. Seminars in Radiation Oncology 4:6, 1994 Morrow C: Is pelvic radiation beneficial in the postoperative management of stage IB squamous cell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? Gynecol Oncol 10:105, 1980 Namkoong SE, Park JS, Kim JW, et al: Comparative study of the patients with locally advanced stages I and I1 cervical cancer treated by radical surgery with and without preoperative adjuvant chemotherapy. Gynecol Oncol59:136, 1995 National Insititute of Health Consensus Conference Cervical Cancer 14:(1), April 1-3, 1996 Noguchi H, Shizoma I, Sakai Y, et al: Pelvic lymph node metastasis of uterine cervical cancer. Gynecol Oncol27150, 1987 Ozols RF, Masuda H, Hamilton TC: Keynote address: Mechanisms of cross-resistance between radiation and antineoplastic drugs. National Cancer Institute Monographs 6:159, 1988 Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54594, 1993 Pate1 FD, Sharma SC, Pritam SN, et al: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: A clinical trial. Int J Radiat Oncol Biol Phys 28:335, 1993 Pendlebury S, Cahill S, Crandon A, et al: Role of bipedal lymphangiogram in radiation treatment planning for cervix cancer. Int J Radiat Oncol Biol Phys 27959, 1993 Perez C, Grigsby P, Nene S, et al: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69:2796, 1992 Perez C, Grigsby P, Nene S, et al: Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy outcome of radiation therapy. Int J Radiat Oncol Biol Phys 29:1275, 1995 Perez C, Kao M Radiation therapy alone or combined with surgery in the treatment of barrel-shaped carcinoma of the uterine cervix (stage IB, IIA, IIB). Int J Radiat Oncol Biol Phys 11:1903, 1985 Petereit D, Pearcey R Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: Is there an optimal fractionation schedule? Int Radiat Oncol Biol Phys, in press Petereit D, Sarkaria J, Chappel R, et al: The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 32:1301, 1995 Petereit D, Schink J, Potter D, et al: High dose rate brachytherapy is equivalent to low dose rate brachytherapy in the treatment of stage IB and I1 cervical cancer [abstract No. 1241. Gynecol Oncol68103, 1998

302

GREVEN et a1

66. Petterson F (ed): 22"d Annual Report on the Results of Treatment in Gynaecological Cancer. FIGO, New York, Elsevier, 1994 67. Pignata S, De Vivo R, Ricchi P, et al: Chemotherapy in squamous cell carcinoma of the cervix uteri: Present role and perspectives. Cancer Treatm Rev 24:27, 1998 68. Piver MS, Chung WS Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 46:507, 1975 69. Potter ME, Spencer S, Soong SJ, et al: The influence of staging laparotomy for cervical cancer on patterns of recurrence and survival. International Journal of Gynecologic Cancer 3169, 1993 70. Rose P, Bundy 8, Thigpen J, et al: Significant preliminary results of a phase 111 randomized study of concomitant chemotherapy with weekly cisplatin vs hydroxyurea, 5-fluorouracil infusion and bolus cisplatin vs. hydroxyurea in advanced cervical cancer: A Gynecologic Oncology Group (GOG) study [abstract No. 1391].17360a, 1998 71. Rotman M, Aziz H, Eifel P: Irradiation of pelvic and para-aortic nodes in carcinoma of the cervix. Seminars in Radiation Oncology 423, 1994 72. Rotman M, Pajak T, Choi T, et al: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IIA cervical carcinomas. Ten-year treatment results of RTOG 7920. JAMA 274387, 1995 73. Russell A, Walter J, Anderson M, et al: Sagittal magnetic resonance imaging in the design of lateral radiation treatment portals for patients with locally advanced squamous cancer of the cervix. Int J Radiat Oncol Biol Phys 23:449, 1992 74. Sardi J, Sananas C, Giaroli A, et al: Results of a prospective randomized trial with neoadjuvant chemotherapy in stage IB, bulky, squamous carcinoma of the cervix. Gynecol Oncol49:156, 1993 75. Sardi J, Sananas C, Rueda NG, et al: Randomized trial with neoadjuvant chemotherapy in stage IIIB squamous carcinoma cervix uteri: An unexpected therapeutic management. International Journal of Gynecologic Cancer 6:85, 1996 76. Sardi JE, DiPaola GR, Cachau A, et al: A possible new trend in the management of the carcinomas of the cervix uteri. Gynecol Oncol25:139, 1986 77. Sardi JE, Giaroli A, Sananas C, et al: Long-term follow-up of the first randomization trial using neoadjuvant chemotherapy in stable Ib squamous carcinoma of the cervix: The final results. Gynecol Oncol 6761, 1997 78. Sedlis A, Bundy B, Rotman M, et al: Treatment of selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Pelvic radiation therapy versus no further therapy. A GOG study [abstract No. 921. Gynecol Oncol 68:104, 1998 79. Serur E, Mathews RP, Gates J, et al: Neoadjuvant chemotherapy in stage IB2 squamous cell carcinoma of the cervix. Gynecol Oncol65:348, 1997 80. Shephard J: Staging announcement, FIGO staging of gynecologic cancers: Cervix and vulva. International Journal of Gynecologic Cancer 5:319, 1995 81. Shigemastsu Y, Nishiyama K, Masaki N, et al: Treatment of carcinoma of the uterine cervix by remotely controlled afterloading intracavitary radiotherapy with high dose rate: A comparative study with a low dose rate system. Int J Radiat Oncol Biol Phys 9:351, 1983 82. Shingleton HM Orr JW (eds): Cancer of the Cervix-Diagnosis and Treatment. New York, Churchill Livingstone, 1987 83. Souhami L, Gil RA, Allan SE, et a1 A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol9970, 1991 84. Stehman F, Bundy B, DiSaia P, et al: Carcinoma of the cervix treated with radiation therapy. A multivariate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 672776, 1991 85. Symonds RP, Cowie V, Davidson SE, et a 1 The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer [abstract NO. 501. International Journal of Gynecologic Cancer 7(suppl2):18, 1997 86. Tattersall MHN, Ramirez C, Coppleson MA: A randomized trial comparing platinumbased chemotherapy followed by radiotherapy vs radiotherapy alone in patients with locally advanced cervical cancer. International Journal of Gynecologic Cancer 2244, 1992

DEVELOPMENTS IN TREATMENT OF NEWLY DIAGNOSED CERVICAL CANCER

303

87. Tattersall MHN, Lorvidhaya V, Vootiprux V, et al: A randomized trial of epirubicin and cisplatin followed by pelvic radiation in locally advanced cervical cancer. J C h Oncol 13:444, 1995 88. Thomas G, Dembo A: Is there a role for adjuvant pelvic radiotherapy after radical hysterectomy in early stage cervical cancer? International Journal of Gynecologic Cancer 13, 1991 89. Thomas GM, Dembo AJ, Myhr T, et al: Long-term results of concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after surgery. Int J Gynecol Oncol 3:193, 1993 90. Thomas GM: Is neoadjuvant chemotherapy a useful strategy for the treatment of stage IB cervix cancer? [editorial]. Gynecol Oncol 49:153, 1993 91. 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, 1998 92. Twiggs L, Potish R, George R, et al: Pretreatment extraperitoneal surgical staging in primary carcinoma of the cervix uteri. Surg Gynecol Obst 158243, 1984 93. Van Bommel PFJ, Van Lindert ACM, Kock HCLV, et al: A review of prognostic factors in early stage carcinoma of the cervix (FIG0 IB and IIA) and implications for treatment strategy. Eur J Obstet Gynecol Reprod Biol 26:69, 1987 94. Varia M, Bundy B, Deppe G, et al: Cervical carcinoma metastatic to para-aortic nodes: A GOG study of extended field chemoradiation therapy [SGO abstract No. 781. Gynecol Oncol 64:309,1997 95. Vigliotti A, Wen B, Hussey D, et al: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23:501, 1992 96. Whithers HR, Taylor JMF, Maciejewski B The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol27:131, 1988 97. Whitney C, Bundy B, Malfetano J, et al: A randomized comparison of 5-fluorouracil, cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB, III, and IVA carcinoma of the cervix [abtract]. Presented at the Third International Conference on Infusion Chemotherapy-Radiation Interaction, Organ Salvage and Prevention of Second Primary Neoplasms, 1996 Address reprint requests to Kathryn Greven, MD Department of Radiation Oncology Wake Forest University Baptist School of Medicine Medical Center Boulevard Winston-Salem, NC 27157