The optimal treatment of patients with stage IB2 cervical cancer remains controversial. Most of these patients will be premenopausal and will be cured of their disease. Should survival with different treatment modalities be similar, quality of life issues, including sexual functioning, would become paramount.
The most commonly used treatment modality is primary chemoradiation, with or without extrafascial hysterectomy,1,2 but there are also proponents for primary radical hysterectomy with tailored postoperative radiation3–7 and neoadjuvant chemotherapy followed by radical hysterectomy with tailored adjuvant chemotherapy or radiation therapy.8–10
Randomized clinical trials comparing these treatment modalities for stage IB2 cervical cancer are lacking. In the only randomized study of radical surgery compared with standard pelvic radiation for stages IB–IIA cervical cancer, Landoni et al11 reported that for patients with a cervical diameter larger than 4 cm, there was a significantly higher rate of pelvic relapse among the group who had radiation alone, although patients in this study were not treated with chemoradiation. A recent Surveillance, Epidemiology, and End Results study of 770 patients with stage IB2 cervical cancer treated from 2000 to 2006, when chemoradiation was more commonly used, reported superior survival in the surgery-first group (overall median survival 72 compared with 61.4 months; P<.001), although the radiation-first group had a larger mean tumor diameter (6.0 compared with 5.5 cm; P<.001). In addition, both groups were said to be lymph node--negative, which is impossible to prove in the radiation-first group.12
Our institutional preference has been to use a primary surgical approach with tailored postoperative radiation therapy, regardless of tumor diameter or patient age. In agreement with other reports, we have not found radical hysterectomy in patients with bulky cervical cancers to be associated with increased surgical morbidity,7,13 and we have not found old age to be a contraindication to radical surgery,14 although 10% of older patients will have comorbidities that will make them poor surgical candidates.
This study was undertaken to examine retrospectively the outcome for patients with stage IB2 cervical cancer treated primarily with radical hysterectomy at our institution. Secondary goals were to estimate the need for adjuvant therapy, the sites of recurrence, and the morbidity of the treatment.
MATERIALS AND METHODS
After obtaining approval from the South Eastern Sydney Area Health Service Human Research Ethics Committee, all patients with stage IB2 cervical cancer treated at the Royal Hospital for Women in Sydney from 1988 to 2008 were identified from our database. There were 106 patients identified. Thirteen patients (12.3%) underwent primary radiation therapy because of medical comorbidities, personal preferences, or extensive associated vaginal intraepithelial neoplasia.
This study evaluated 93 patients who underwent primary surgical management. All pathology slides were reviewed by a gynecologic pathologist (J.S.), with particular reference to the histologic type and grade, vascular space invasion, depth of stromal invasion, microscopic parametrial extension, and lymph node status. Medical records of all patients were reviewed, and relevant clinical data were extracted.
Most patients underwent a radical hysterectomy and pelvic lymphadenectomy, removing nodes to the mid-common iliac region. The operation corresponded to a type C1 radical hysterectomy, as described by Querleu and Morrow.15 Briefly, the parametrium was transected at the pelvic sidewall, but the autonomic nerves were preserved by not extending the dissection inferiorly below the deep uterine vein. A preoperative colposcopic examination of the lower genital tract was performed to ensure any associated vaginal intraepithelial neoplasia could be encompassed in the vaginal resection without compromising vaginal length. If the vagina was normal, we removed only about the proximal 1.5 cm. If bulky nodes were found at laparotomy and confirmed to be positive at frozen section, these nodes were excised with no attempt to clear nodes of normal size. In patients with bulky positive nodes (larger than 1.5 cm diameter), a modified radical hysterectomy was performed, with the ureters being dissected out of their tunnels and displaced laterally to ensure clearance of all macroscopic tumor (type B1, Querleu and Morrow15).
Three different regimens of postoperative radiation were used. First was small-field external beam pelvic radiation for patients with high-risk, node-negative disease. The fields previously have been described from our department16 but, in brief, the upper limit of the field is at S2-3, instead of L4-5 as for a standard pelvic field, and the lower border is at the mid-obturator foramen. The dose used was 50.4 Gy in 180-cGy daily fractions. Second was whole pelvic (chemoradiation) radiation for patients with positive parametrial spread or one microscopically positive node. Third was extended-field (chemoradiation) radiation (to T12-L1) for patients with two or more positive pelvic nodes or bulky positive pelvic nodes with or without resected bulky positive para-aortic nodes. The dose to the para-aortic area was 45–50.4 Gy in 180-cGy daily fractions. Patients having standard or extended-field radiation also received weekly cisplatin, 40 mg/m2, after the publication of the relevant South West Oncology Group--Gynecologic Oncology Group (GOG) study in 2000.17 No patient received brachytherapy. All patients undergoing postoperative radiation therapy were given vaginal dilators and asked to use them at least every second night until they resumed regular sexual intercourse.
Patients with negative lymph nodes were defined as being at high-risk based on the criteria described by the GOG.18 In summary, a relative risk of recurrence was determined for each of three independent prognostic factors, namely, the clinical diameter of the primary tumor, the depth of stromal invasion, and the presence or absence of lymph vascular space invasion. The overall relative risk of recurrence was determined by multiplying each individual relative risk. In a previous publication from our department,16 we referred to the overall relative risk as the “GOG score.” Patients with an overall relative risk (GOG score) of 120 or more were offered small-field external beam pelvic radiation from 1991, because in the GOG paper, Delgado et al18 estimated that this group had a 40% risk of recurrence after radical hysterectomy.
The method of Kaplan-Meier was used to produce time-to-event (local control and overall survival) curves, and the 5-year survival rates were obtained using the same method. The median follow-up time was obtained using the reverse Kaplan-Meier approach19 (censored observations are considered as events and deaths are considered as being censored). Time-to-event outcomes were compared using the log-rank test.
Clinical characteristics of the patients are shown in Table 1. The mean age of the patients was 46 years, with an age range from 26 to 80 years. There were 67.8% of patients 50 years or younger. Seventy-six patients (81.7%) underwent a type III radical hysterectomy and pelvic lymphadenectomy, including two patients in whom the radical hysterectomy was combined with cesarean delivery. In 17 patients (18.3%), bulky nodes were found at laparotomy and excised. In 5 of the 17 patients, there were bulky nodes also present in the para-aortic area, which were resected.
Histopathologic variables are shown in Table 2. As expected, 70% of patients had squamous cancers and 30% had adenocarcinomas. Twenty-one patients (22.6%) had a primary tumor 6 cm or larger in diameter, and the tumor invaded into the outer third of the cervical stroma in 73 patients (78.5%). Occult parametrial extension was present in 15 patients (16.1%), and vascular space invasion was present in 65 patients (69.9%).
The lymph node status of the patients is shown in Table 3. Positive pelvic nodes (range 1–20) were present in 42 patients (45.2%). Bulky positive para-aortic nodes (range 2–24) were documented in 5 (5.4%).
Postoperative adjuvant therapy is shown in Table 4. Nineteen patients (20.4%) received no adjuvant therapy, 29 (31.2%) received small-field pelvic radiation, 17 (18.3%) received standard pelvic radiation, and 28 (30.1%) received extended-field radiation. As shown in Table 2, the median GOG score for the 51 node-negative patients in the group was 210. Thirty-two of the 42 patients (76.2%) with positive nodes received concurrent weekly cisplatin (40 mg/m2), as did 7 of 15 (46.7%) with parametrial extension. Nine of the 15 patients (60%) with parametrial extension also had positive lymph nodes. Some patients having extended-field chemoradiation required a dose reduction of cisplatin to 30 mg/m2 because of bone marrow toxicity. No patient received adjuvant chemotherapy alone.
The median operating time was 150 minutes, the median operative blood loss was 800 mL, and 15% of patients required a blood transfusion. There was no perioperative mortality. Intraoperative (2.2%) and acute postoperative complications (14%) are listed in Table 1. The major long-term surgical morbidity was lower limb lymphedema, which occurred in eight patients (8.6%). Half of these patients also received postoperative radiation.
The median follow-up was 96 months, with a range of 6–283 months. The overall 5-year survival for the 93 patients was 80.7% (Fig. 1), and the progression-free 5-year survival was 76.5%. There was no significant difference in survival between squamous and adenocarcinomas (P=.37). Patients with negative nodes had a 5-year overall survival of 85%, whereas for those with positive nodes it was 75% (hazard ratio [HR] 2.63, 95% confidence interval [CI] 1--5.6; P=.045) (Fig. 1). Patients with tumors 6 cm or larger in diameter had a 66% incidence of positive nodes (14/21), compared with a 38.9% incidence for tumors smaller than 6 cm (difference 27.1%, 95% CI 5–51%; P=.024). Patients with tumors 6 cm or larger in diameter had a 56% greater risk of death compared with those with tumors smaller than 6 cm, but this was not statistically significant (HR 1.56, 95% CI 0.61--3.98; P=.36). For patients with positive nodes, there was no significant difference in survival between patients who had a complete lymphadenectomy and those who had lymph node debulking (HR 0.44, 95% CI 0.12--1.63; P=.20). Patients with positive pelvic nodes only had an overall 5-year survival of 78%, compared with 60% for patients with positive common iliac nodes and 20% for those with positive para-aortic nodes.
Recurrent disease developed in 23 patients (24.7%). Patterns of first recurrence are shown in Table 5. Approximately one third of the recurrences (8/23) were in the pelvis (central: seven, sidewall: one). Pelvic recurrences occurred mainly in patients with high-risk node-negative disease, with a median disease-free survival of 18.1 months. Systemic metastases occurred mainly in patients with multiple positive lymph nodes, and the median disease-free survival was 12 months.
Long-term radiation complications occurred in nine patients (9.7%). No patient had development of vaginal stenosis. The complications were Radiation Therapy Oncology Group grade 2 in six patients (6.5%) (cystitis in three, enteritis in two, proctitis in one) and Radiation Therapy Oncology Group grade 3 in three patients (3.2%) (small bowel obstruction requiring resection and reanastomosis in two, large bowel obstruction requiring colostomy in one).
For the 93 patients in this study, the progression-free 5-year survival was 76.5%, and the overall 5-year survival was 80.7%. These results are gratifying given the high-risk histopathologic features and the high incidence of positive nodes (45.5%) in the group. Other contemporary reports of primary surgery are summarized in Table 6.
In the GOG study of radiation therapy with or without weekly cisplatin, for patients with bulky stage IB cervical cancer2 followed by hysterectomy, the 6-year progression-free survival was 71% and the overall survival was 78% for the chemoradiation arm. For patients treated with definitive chemoradiation in the Memorial Sloan Kettering study,5 the 3-year overall survival was 55%.
We believe that our results can be further improved. Pelvic recurrences occurred mainly in high-risk, node-negative patients, and six of the pelvic recurrences occurred before we started using adjuvant small-field pelvic radiation for this group of patients in 1991. Five of these six patients would have been eligible for our small-field pelvic radiation protocol.
There was no perioperative mortality, and perioperative morbidity was acceptably low. The major long-term surgical morbidity was mild-to-moderate lower limb lymphedema, which was recorded in eight patients (8.6%). Lymphedema is related to extensive lymph node dissection, particularly if combined with postoperative radiation. We restricted the extent of lymphadenectomy by resecting any bulky nodes early in the operation and obtaining a frozen-section diagnosis. If metastatic disease was confirmed, complete pelvic lymphadenectomy was avoided, because we relied on radiation to sterilize microscopic lymph node metastases. Similarly, we did not perform complete para-aortic lymphadenectomy; instead, we removed only bulky para-aortic nodes and administered extended-field radiation to patients with more than one microscopically positive pelvic node. It may be possible to reduce the incidence of lymphedema further in the future by utilizing sentinel node methodology.22
We have previously reported that resection of bulky positive lymph nodes appears to convert the prognosis to that of a patient with microscopic nodal spread,23 and this was confirmed in the present study. Survival for patients having resection of bulky nodes only was not significantly different from that of patients undergoing complete lymphadenectomy.
In this study, 79.6% of patients (74/93) received adjuvant radiation. Indications for postoperative radiation were positive nodes, microscopic parametrial extension, or node-negative with a GOG score of 120 or more. To decrease complications from postoperative radiation in this latter group while still decreasing the risk of central recurrence, we devised the “small-field” pelvic radiation protocol and reported the results of a pilot study of 25 patients in 1999.16 Japanese workers subsequently have confirmed the validity of this approach for decreasing both pelvic recurrence rates and radiation-related complications.24,25
The major argument in favor of primary chemoradiation for stage IB2 cervical cancer is that the morbidity is too high when radiation therapy follows primary radical surgery. In the GOG trial of primary radiation with or without weekly cisplatin for stage IB2 cervical cancer, major late adverse events occurred in 7 of 183 patients (3.8%) in the chemoradiation arm.2 In our study, grade 3 or 4 Radiation Therapy Oncology Group late adverse events occurred in 3 of 93 patients (3.2%). Two of the three patients in our study had development of radiation enteritis. Both patients had a laparotomy with resection of the affected bowel segment and stapled reanastomosis. Neither had any further sequelae. By contrast, the late toxicity in the chemoradiation arm of the GOG study consisted of three patients with a vesicovaginal fistula, two patients with a rectovaginal fistula, and one each with an intestinal and colonic perforation. We believe that much of this morbidity was related to the brachytherapy, which was not used in our study. We acknowledge that major morbidity may be under-reported in single-institution retrospective studies, but only three patients were lost to follow-up before 5 years, and our median follow-up was 96 months.
The GOG reported a late morbidity rate of 6.6% in their phase III randomized trial of postoperative pelvic radiation for high-risk stage IB cervical cancer.26 In a study of 478 patients having postoperative radiotherapy after hysterectomy for cervical cancer at the Christie Hospital in Manchester, patients having no adjuvant brachytherapy had a late morbidity rate of less than 0.7% (2/278).27
In 2010, the Royal College of Radiologists published the results of an audit of radiotherapy for cervical cancer involving 1,243 patients from 42 centers in the United Kingdom. Overall, grade 3–4 late complications occurred in 10% of 471 patients undergoing chemoradiation and in 5% of 249 patients undergoing surgery and postoperative radiotherapy.28
We believe that the major advantage of a primary surgical approach to stage IB2 cervical is that brachytherapy can be eliminated, so vaginal stenosis and vaginal fistulae will be decreased. The true incidence of vaginal stenosis after chemoradiation for cervical cancer appears to be significantly under-reported in the literature. A systematic review of data from 18 randomized trials by the Medical Research Council's Clinical Trials Unit in London, United Kingdom, reported that data on late vaginal toxicity was available in only four studies (22%).29 Guth et al30 reported total vaginal necrosis in 3.1% of 98 patients treated with chemoradiation, and thought that this severe late complication was significantly under-reported in the literature. In a recent audit of radiotherapy for cervical cancer in the United Kingdom, the vagina was the commonest site of late morbidity. The authors commented that patients receiving chemoradiation had development of complications up to 7 years later.31
We believe that too much vagina has been removed at radical hysterectomy in the past, and our aim is to take no more than a 1.5-cm cuff unless a preoperative colposcopic examination reveals vaginal intraepithelial neoplasia in the upper vagina. We previously have reported favorable sexual outcome after radical hysterectomy from this center32 and agree with others that cervical cancer survivors treated with radiotherapy have worse sexual functioning than those treated with radical hysterectomy.33
We believe that the good survival and acceptably low morbidity reported in this and other recent studies justify a randomized prospective trial to compare the results of primary chemoradiation with primary surgery and tailored postoperative radiation for patients with stage IB2 carcinoma of the cervix. This was attempted in GOG 201, but the trial was closed prematurely because of failure to accrue, so the study may need to be conducted internationally. Critical to any such study would be a prospective evaluation of long-term morbidity, including sexual morbidity, and quality of life. Even if survival outcomes were found to be equivalent, patients would be better-able to make an informed decision about their treatment.
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