2059 Adjuvant Small Field Pelvic Radiation for Patients with High Risk, Stage IB Lymph Node Negative Cervix Carcinoma after Radical Hysterectomy and Pelvic Lymph Node Dissection A Pilot Study Frédéric J. Kridelka, M.B., Derek O. Berg2 Menahem Neuman, M.D.2 Lyndal S. Edwards2 Greg Robertson2 Peter T. Grant2 Neville F. Hacker, M.D.2 1 Ch.B. 1 Department of Gynecology, CHU Liège, Liège, Belgium. 2 Gynaecological Cancer Centre, Royal Hospital for Women, Randwick New South Wales, Australia. Presented at the Australian Society of Gynecological Oncology, Bowral, Australia, May 19 –23, 1996 (awarded Keith Free Price for Best Presentation by a Fellow in Gynecological Oncology) and at TOW Research Price, Prince of Wales Hospital, Sydney, Australia, October 31, 1996 (winner of the Tow Research Price, Clinical Division). Supported by a fellowship for overseas clinical research from the Léon Frédérick Foundation, University of Liège, Belgium and by the Gynecologic Oncology Fund of the Royal Hospital for Women Foundation, Randwick, Australia. The authors thank Mrs. T. Moryosef for data management, Mr. R. Fisher for the statistical analysis, and Mrs. S. Rainer and M. Schneider for assisting in radiotherapy imaging production. Address for reprints: Prof. Neville F. Hacker, Gynaecological Cancer Centre, Royal Hospital for Women, Barker Street, Randwick, NSW 2031, Australia. Received August 7, 1998; revisions received January 11, 1999 and March 18, 1999; accepted March 18, 1999. © 1999 American Cancer Society BACKGROUND. After radical hysterectomy and pelvic lymph node dissection, an identifiable subgroup of patients with International Federation of Gynecology and Obstetrics Stage IB lymph node negative cervix carcinoma remains at high risk of pelvic recurrence. This study attempted to determine whether postoperative small field of pelvic radiation can improve the disease free survival (DFS) of this high risk group of patients without producing significant morbidity. METHODS. Between 1991 and 1995, after radical surgery, 25 patients with Stage IB lymph node negative cervix carcinoma were considered to be at high risk of pelvic recurrence on the basis of tumor dimension, depth of stromal invasion, and the presence of lymph-vascular space invasion. All had a score $ 120 as determined by the Gynecologic Oncology Group (GOG) study. These patients received 50.4 gray of adjuvant radiation to a small central pelvic field and were followed prospectively. A Kaplan–Meier 5-year DFS curve was generated. A log rank analysis produced an estimated log rank P value (est P value) by comparing the 5-year DFS of the patients in the current study with the 5-year DFS of the corresponding high risk group of the GOG study (observation only). The morbidity of small field pelvic radiation was recorded. RESULTS. Among the 25 patients who received small field pelvic radiation, the mean GOG score was 166 (range, 120 –263) and the mean follow-up was 32 months (range, 12– 64 months). There was 1 recurrence (4%) recorded at 16 months. The log rank analysis demonstrated a significant improvement in the 5-year DFS for the group who received adjuvant small field pelvic radiation (est P value 5 0.005) when compared with the DFS of the high risk GOG patients who were observed postoperatively. Four cases of minor morbidity were recorded: lymphedema (three cases) and mild rectal incontinence (one case). No major morbidity was reported. CONCLUSIONS. With low morbidity, adjuvant small field pelvic radiation appears to improve significantly the 5-year DFS of patients with high risk, lymph node negative Stage IB cervical carcinoma. However, this pilot study requires verification. Cancer 1999;86:2059 – 65. © 1999 American Cancer Society. KEYWORDS: early cervical carcinoma, adjuvant radiation, Gynecologic Oncology Group score, 5-year disease free survival, radiation morbidity. T here is no standard management of International Federation of Gynecology and Obstetrics Stage IB cervical carcinoma.1 As a group, most patients are treated by radical surgery, but some institutions prefer a radiotherapeutic approach. Combinations of surgery 2060 CANCER November 15, 1999 / Volume 86 / Number 10 FIGURE 1. Protocol for management of patients with carcinoma of the cervix. GOG: Gynecolgic Oncology Group; RT: radiotherapy. Reproduced with permission from Hacker WF, Wain GV, Nicklin JL. Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynecol Cancer 1995;5:250 –7. and radiotherapy also are used frequently, although specific protocols vary considerably. Our current protocol for the treatment of patients with Stage IB cervix carcinoma has been reported previously (Fig. 1).2 In general, all medically fit patients undergo primary radical hysterectomy with bilateral pelvic lymph node dissection regardless of the diameter of the cervix or the patient’s age. According to the Annual Report on Treatment for Gynecological Cancer,3 patients with positive pelvic lymph nodes have a 5-year survival of 59% and are at risk of both pelvic and distant recurrences. Retrospective studies4,5 suggest that adjuvant pelvic radiation in this setting can reduce the risk of pelvic recurrence after radical surgery by 30 – 40%. These same studies fail to demonstrate an impact on overall survival due to the inability of adjuvant pelvic radiation to influence distant metastases. Improvement in survival for this group of patients awaits the development of effective chemotherapeutic regimens. The situation with respect to lymph node negative patients is different. Overall 5-year survival is 89% after radical hysterectomy and pelvic lymph node dissection.3 However, this group contributes about 50% of the treatment failures, the majority of these which (70%) occur in the pelvis.6 – 8 This makes it attractive theoretically to offer adjuvant pelvic radiation to the lymph node negative patients who are at high risk of local recurrence, because there should be a realistic expectation of improving overall survival by decreasing the pelvic recurrence rate.6,9,10 Two problems have to be addressed before implementing such a strategy. The first is to identify the group of lymph node negative patients who are at high risk of recurrence so that the others can be spared adjuvant therapy. This was achieved in the prospective surgicalpathologic study performed by the Gynecologic Oncology Group (GOG)11 in which 645 patients with Stage IB cervical carcinoma underwent surgery and were observed prospectively for 5 years without receiving adjuvant treatment. Of these patients, 545 had a negative lymph node status, whereas microscopic metastatic disease in the pelvic lymph nodes was identified in the remaining 100 patients. Patients with macroscopic involvement of the pelvic or paraaortic lymph nodes were excluded. Three independent prognostic variables (clinical tumor size, depth of tumor penetration, and presence of lymph-vascular space invasion [LVSI]) were identified, and the GOG developed a scoring system to allow relative risk of recurrence to be quantified. A GOG score $ 120 correlated with a 40% risk of recurrence, which clearly would justify consideration of adjuvant therapy11 (Fig. 2). The second problem relates to the high rate (5 to 10%) of major complications associated with adjuvant pelvic radiation after radical hysterectomy and pelvic lymph node dissection. Radiation morbidity is correlated highly with the radiation target volume.9,12,13 A clinical review of our own experience with Stage IB lymph node negative cervical carcinoma showed that 87% of recurrences occurred in the central pelvis (vaginal vault or paravaginal soft tissues). Therefore, there seemed to be little benefit in extending the upper border of the treatment field to lumbar segments 4 –5 (L4 –L5) as in the standard field approach. By using a smaller target volume focused on the central pelvis (small pelvic field; Table 1, Fig. 3), we hoped to decrease the incidence of pelvic recurrence while reducing the subsequent morbidity. After the 1990 GOG study,11 we developed a protocol to select high risk patients with Stage IB, lymph node negative cervix carcinoma on the basis of a GOG score $ 120. All identified patients were offered adjuvant external beam small field pelvic radiation. This article reports the preliminary results of our protocol. MATERIALS AND METHODS Between May, 1991 and September, 1995, 123 patients with Stage IB carcinoma of the cervix were treated in our institution with primary radical hysterectomy and bilateral pelvic lymph node dissection. The procedures were performed by one of the gynecologic oncologists, either assisted by or supervising a gynecologic oncology fellow. A negative lymph node status was confirmed in 92 cases. By using the GOG protocol (Fig. 2),11 a GOG score was calculated for each of these patients by multiplying the three relative risk scores Treatment of Stage IB Cervix Carcinoma/Kridelka et al. 2061 FIGURE 2. Disease free interval by relative risk group for patients with Stage IB carcinoma of the cervix. Reproduced with permission from Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgicalpathological study of disease-free interval in patients with Stage 1IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352–7. TABLE 1 Anteroposterior and Lateral Portals of Pelvic Radiation: Standard Field versus Small Field Portal Anteroposterior Superior Inferior Lateral Lateral Anterior Posterior Standard field Small field L4–L5 junction Inferior obturator foramen 1.5 cm lateral to pelvic brim S1–S2 junction Midobturator foramen Follows bony pelvic brim Outer edge of pubic symphysis Ischial tuberosities 1 cm posterior to pubic tubercule Anterior sacral plane L4–L5: lumbar spinal segments 4–5; S1–S2: sacral spinal segments 1–2. associated with clinical tumor size, depth of tumor penetration, and presence or absence of LVSI. Clinical tumor size was noted preoperatively. The depth of invasion was measured from the basement membrane of the surface epithelium to the deepest point of invasion. The presence of tumor cells within endothelial-lined spaces was reported as LVSI positive. Additional information (number of lymph nodes resected, histologic grade of differentiation) was recorded. Although this study was prospective, all 92 cases were reviewed by one pathologist (L.S.E.) to verify the histopathologic risk factors. The pathologist was blinded to the outcome of the patients. Twenty-five lymph node negative patients were considered at high risk of pelvic recurrence on the basis of their GOG scores (.120). All received adjuvant small field of pelvic radiation. Their mean age was 47 FIGURE 3. Anteroposterior portals for pelvic radiation: standard field versus small field. years (range, 33– 82 years). The histology was reported as squamous cell carcinoma in 20 cases and adenosquamous in 5 cases. The number of lymph nodes removed at the time of radical hysterectomy ranged from 11 to 55, with an average count of 30.52 lymph nodes. The tumor was moderately differentiated (Grade 2) in 15 cases and poorly differentiated (Grade 3) in 10 cases. The mean tumor size was 32 mm (range, 20 – 60 mm), and all tumors invaded to the outer onethird of the cervical wall. LVSI was positive in all but 1 patient in whom the GOG score reached 145 on the basis of a 4-cm tumor invading 20 mm through a cervical stroma that measured 27-mm thick. The 2062 CANCER November 15, 1999 / Volume 86 / Number 10 FIGURE 4. Disease free interval for high risk patients (relative risk . 120) with Stage IB carcinoma of the cervix: adjuvant small field pelvic radiation versus observation. mean GOG score for the group was 166 (range, 120 – 263). The median time from surgery to commencement of radiation treatment was 6 weeks (range, 4 –12 weeks). The objectives and potential risks of our protocol were discussed with each patient, and all consented to receive adjuvant small field pelvic radiation. Table 1 and Figure 3 compare the anteroposterior and lateral portals of the small pelvic field with those of the standard pelvic field. The total dose delivered was 50.4 grays (Gy) in 28 fractions (1.8 Gy per fraction) using a four-field technique. In patients who experienced a recurrence, the site of recurrence was noted. A 5-year disease free survival (DFS) curve was generated by using the Kaplan–Meier formula. In comparing the 5-year DFS curve of the small field group with the 5-year DFS curve of the corresponding high risk patients from the GOG study who were observed postoperatively, we calculated an “estimated” log-rank P value (est P value). This was based on measuring disease free rates from an enlargement of the GOG disease free interval curve at each of the 13 relevant distinct times for which a censored time occurred prior to 43 months and, in our study group, at 14 months, the time at which 1 patient experienced a recurrence. In the GOG group, we assumed that there were no censored times prior to the last observed recurrence. This latter assumption appears to be correct, because the actuarial disease free rate after the last observed recurrence corresponds closely to the crude disease free rate (83 of 141 patients; 59%). Treatment-related, long term complications of the Small Field technique were recorded. Another group of 17 patients with Stage IB, lymph node negative cervical carcinoma was treated in our department between 1987 and 1990 with primary radical surgery followed by adjuvant standard field pelvic radiation. During that period, the indication for adjuvant radiation was a combination of high risk variables (clinical tumor size . 4 cm, presence of LVSI, deep tumor penetration, disease free margin , 2 mm). The mean total dose was 51 Gy (range, 45–55 Gy) delivered in 1.8-Gy fractions using a four-field technique. The long term morbidity experienced by the patients who received adjuvant standard field pelvic radiation was compared with that of the patients who received adjuvant small field pelvic radiation. RESULTS For the 25 patients who received adjuvant small field pelvic radiation, the mean follow-up was 32 months (range,12– 60 months). No patient was lost to followup. There was one recurrence (5%) at 16 months. This patient initially suffered a poorly differentiated (Grade 3) squamous cell carcinoma of the cervix. Recurrent disease was present within the previously irradiated field but also outside the radiation field along the small bowel mesentery, causing both small bowel and bilateral ureteric obstruction. The patient died at 24 months after initial diagnosis. Comparison of the 5-year DFS curve of the high risk, lymph node negative patients who were treated with adjuvant small field pelvic radiation with the 5-year DFS curve of the corresponding high risk GOG patients who were treated with observation only after radical surgery is shown in Figure 4. A log-rank anal- Treatment of Stage IB Cervix Carcinoma/Kridelka et al. TABLE 2 Long Term Radiation Morbidity: Comparison of Standard and Small Pelvic Fields Long term radiation morbidity/site Major Bowel obstruction Total Minor Leg lymphedema Rectal incontinence Intermittent diarrhea Total Standard field (17 patients) Small field (25 patients) 2 (11%) 2 (11%) 0 0 2 0 1 3 (17%) 3 1 0 3 (16%) ysis confirms a statistically significant improvement in the DFS for the patients who were treated with small field pelvic radiation (est P value 5 0.005). The acute morbidity of the small field treatment was mild, and, in all cases, radiotherapy was completed without interruption. Table 2 compares the long term major morbidity of adjuvant small field radiation with that of adjuvant standard field radiation for patients at our institution. In the small field group, four minor, long term complications occurred. Three patients developed mild leg lymphedema, although none of these patients experienced recurrent local cellulitis. The fourth patient, who reported mild rectal incontinence prior to surgery, believed that the symptoms had worsened somewhat. No case of major morbidity was recorded. Of the 17 Stage IB, lymph node negative patients who received adjuvant standard field pelvic radiation between 1987 and 1990, 2 patients (11.7%) experienced major morbidity according to the European Organization for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) criteria of radiation morbidity. Both patients developed a bowel obstruction. This required ileal resection in one patient and ileal resection and end colostomy in the other. An additional patient had significant vaginal stenosis and did not resume intercourse after treatment. Minor morbidity was experienced by three other patients. This included two patients with mild lymphedema and one patient with intermittent diarrhea. DISCUSSION Patients with Stage IB, lymph node negative cervical carcinoma traditionally are observed without adjuvant treatment after radical hysterectomy and pelvic lymph node dissection. However, there is increasing evidence that a subgroup of these patients is at high risk of recurrence9 –11 and that the recurrences occur pre- 2063 dominantly in the pelvis.6 – 8 Nevertheless, experience with adjuvant pelvic radiation for such patients remains limited. Fioricca et al.9 reported 33 patients who received adjuvant standard field pelvic radiation because of the presence of one or more of the following high risk factors: large tumor volume, deep stromal invasion, presence of LVSI, or extension to the lower uterine segment. A mean total dose of 47 Gy (range, 44.8 –55 Gy) in 1.8-Gy fractions was delivered. Local control of disease was achieved in 32 of 33 patients (96.9%), but 3 patients (9%) experienced major gastrointestinal morbidity. Similar results were reported recently by Takamura et al.10 in a study in which 70 patients with lymph node negative, Stage I and II cervical carcinoma with histologically confirmed parametrial extension received adjuvant standard field pelvic radiation to a total dose of 50 Gy in 2-Gy fractions. Local control was achieved in 66 of 70 patients (94%). Twenty-eight (40%) complications requiring medical treatment occurred (leg edema in 20 patients, bowel obstruction in 2 patients, rectal bleeding in 3 patients, and hemorragic cystitis in 3 patients). Six of the 66 patients (9%) who were treated developed major complications requiring further surgery (bowel obstruction in 5 patients, femoral neck fracture in 1 patient). Our experience with adjuvant standard field pelvic radiation for patients with Stage IB, lymph node negative cervical carcinoma (1987–1990) was similar. Pelvic disease recurred in 2 of 17patients (11.7%), and major bowel complications occurred in 2 patients (11.7%; EORTC/RTOG criteria for radiation morbidity). In addition, 1 patient developed severe vaginal stenosis. It must be emphasized that the latter observations are based on limited numbers of patients (n 5 17). Therefore, suggestions regarding the relative efficacy of adjuvant standard field and small field radiation must be confirmed. The combined results of these three studies show that pelvic disease was controlled in 92% of patients (111 of 120) but that 9.2% of patients (11 of 120) suffered major complications. More recently, Sedlis et al.14 presented the early data from a GOG study that included 277 patients with Stage IB carcinoma of the cervix and with at least two of the following risk factors: large tumor size, deep (greater than one-third) stromal invasion, or the presence of LVSI. After radical hysterectomy, these patients were assigned randomly to receive no further treatment (140 patients) or to receive adjuvant standard field pelvic radiation to a dose of 50.4 Gy (137 patients). Although conclusions regarding overall patient survival await further follow-up, this preliminary analysis showed that adjuvant standard field pelvic radiation reduced the risk of recurrence by 44%, but it 2064 CANCER November 15, 1999 / Volume 86 / Number 10 was associated with a 5.8% incidence of severe (Grade 3 and 4) urologic and gastrointestinal morbidity. This suggests that adjuvant pelvic radiation may have a significant role to play in the treatment of patients with early stage, high risk, lymph node negative cervical carcinoma if a reproducible method for identifying such patients could be developed and if radiation morbidity (in particular, gastrointestinal morbidity) could be reduced. By using the score defined by Delgado et al. in the GOG study,11 we have standardized our selection criteria. Patients with a GOG score $ 120, which carries a 5-year recurrence risk of 40%, were offered adjuvant pelvic radiation. To overcome the problem of morbidity, the small field technique was designed with the aim of reducing the volume irradiated without jeopardizing local disease control. A comparison of the standard field and small field anteroposterior portals (Fig. 3) confirms that the small field technique, although it targets a significantly smaller volume, focuses on the area at high risk of recurrence (vault and paravaginal soft tissues). The small field of pelvic radiation prevented pelvic recurrence in 24 of the 25 high risk patients (96%) who were treated in our institution since 1991. This translates into a significant improvement in DFS (est log-rank P value 5 0.005) compared with the outcome of patients who were treated by observation only in the GOG study (GOG score . 120; Fig. 4). At the same time, the long term complication rate after adjuvant small field pelvic radiation remained very low. Four cases of minor morbidity were recorded, and there was no case of major morbidity. Most important, no case of major bowel morbidity was observed. This marks a significant improvement compared with the morbidity experienced by our patients when they were treated with adjuvant standard field pelvic radiation. The reduction in the volume of small bowel irradiated when using the small field technique is shown in comparative planning abdominopelvic X-rays after a barium meal and may explain the low gastrointestinal morbidity of the small field technique (Fig. 5). With a median follow-up of 32 months, it also is possible that major morbidity still may occur in the future, and these patients will remain under careful surveillance. Despite the relatively limited numbers of patients analyzed, this prospective pilot study suggests that an adjuvant small field of pelvic radiation has the potential to decrease pelvic recurrence and significantly improve DFS for high risk patients with Stage IB, lymph node negative cervix carcinoma who are treated primarily by radical hysterectomy and pelvic lymph node FIGURE 5. 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