Class II versus Class III Radical Hysterectomy in Stage IB–IIA Cervical Cancer: A Prospective Randomized Study

Gynecologic Oncology 80, 3–12 (2001) doi:10.1006/gyno.2000.6010, available online at http://www.idealibrary.com on

Class II versus Class III Radical Hysterectomy in Stage IB–IIA Cervical Cancer: A Prospective Randomized Study 1,2 Fabio Landoni, M.D.,* Andrea Maneo, M.D.,* ,3 Gennaro Cormio, M.D.,† Patrizia Perego, M.D.,‡ Rodolfo Milani, M.D.,* Orlando Caruso, M.D.,* and Costantino Mangioni, M.D.* *Clinica Ostetrico-Ginecologica, University of Milan, Bicocca, Istituto di Scienze Biomediche San Gerardo, Monza, Italy; †Patologia Ostetrica Universita` di Bari, Bari, Italy; and ‡Department of Pathology, Istituto di Scienze Biomediche San Gerardo, Monza, Italy Received October 20, 1999; published online December 5, 2000

INTRODUCTION

Objective. The objective of this study was to determine the role of the extent of the radicality in the treatment of stage IB–IIA cervical carcinoma with respect to survival, pattern of relapse, and morbidity. Methods. Two-hundred forty-three patients with cervical carcinoma (FIGO stages IB and IIa) were enrolled in a prospective randomized study comparing two types of radical hysterectomy (Piver–Rutledge–Smith class II and class III) between April 1987 and December 1993, and 238 are evaluable. Disease-free survival, overall survival, pattern of recurrences, and morbidity were the endpoints of this study. Results. Mean operative time was significantly (P ⴝ 0.05) shorter in the group of patients undergoing class II hysterectomy (135 min vs 180 min), whereas mean blood loss (530 ml vs 580 ml) and number of patients requiring transfusions (35% vs 43%) were similar in the two arms of treatment. Complications unrelated to the extent of the surgical dissection and mean postoperative stay were similar in the two arms of treatment. Late morbidity was significantly lower in patients in the class II arm (especially urologic morbidity, 13% vs 28%). Postoperative radiotherapy was administered to 64 patients (54%) in class II and to 65 patients (55%) in the class III arm. Recurrence rate (24% class II vs 26% class III) and number of patients dead of disease (18% class II vs 20% class III) were not significantly different in the two groups of treatment. Overall 5-year survival was 81 and 77% and diseasefree survival was 75 and 73%, respectively. Multivariate analysis confirms that survival does not depend on the type of operation. Conclusions. Class II and class III radical hysterectomies are equally effective in surgical treatment of cervical carcinoma, but the former is associated with a lesser degree of late complications. © 2001 Academic Press Key Words: cervical carcinoma; radical hysterectomy; surgical radicality.

Radical hysterectomy with pelvic lymphadenectomy is considered the standard surgical treatment for premenopausal patients with cervical cancer clinically confined to the cervix and upper vagina (FIGO stage IB–IIA), with an overall survival ranging from 50 to 90%, depending on the presence of pathologic risk factors [1–3]. The term “radical hysterectomy,” however, has been widely used to define operations with striking variation in radicality among surgeons from different Institutions. Since Wertheim’s first report, many modifications of the original surgical procedure have been proposed during the years, to improve the feasibility of the procedure, increase cure rate, and reduce side effects [3–7]. These differences in surgical radicality are responsible for the confusion in evaluating the results and morbidity associated with this operation. In 1974 Piver, Rutledge, and Smith reported on five classes of extended hysterectomies used in treating women with cervical cancer. Each class requires a progressively wider dissection than the preceding one, and is associated with increased morbidity [6]. The class II hysterectomy removes the median half of the cardinal and uterosacral ligaments, ligating the uterine artery at the ureter. It has traditionally been limited to cervical cancer with depth of invasion up to 5 mm [1, 6]. The class III radical hysterectomy removes the central lesion with wide radical excision of the parametrial and paravaginal tissue. The uterine artery is ligated at its origin; the lateral and posterior parametria are resected to the pelvic side walls and several centimeters of vagina are removed. It is considered worldwide the standard surgical treatment for frankly invasive and bulky cervical cancer [2, 6]. The proper indications for radical hysterectomy and the role of extreme radicality in effectiveness of cure in patients with cervical cancer still remain debatable [8], and attempts have been made to identify subsets of patients with early invasive cervical cancer suitable for less radical surgery [9]. Complications and outcomes following different types of radical hysterectomy for invasive cervical cancer have been

1 This study was partly supported by the Nerina and Mario Mattioli Foundation at the Mario Negri Institute, Milan, Italy. 2 This study was presented at the sixth biennial meeting of the International Gynecological Cancer Society, Fukuoka, Japan, October 21–24, 1997. 3 To whom correspondence should be addressed at Divisione Ginecologia Ospedale San Gerardo, Via Solferino 16, 20052 Monza (Milano), Italy. Fax: ⫹⫹39-39-2333820. E-mail: [email protected].

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0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

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analyzed only in retrospective studies [10 –12], and we are unaware of randomized studies on the modulation of the radicality in the surgical treatment of invasive cervical cancer. To evaluate the role of surgical radicality in patients with cervical cancer a prospective randomized study comparing class II and class III radical hysterectomy was undertaken, and the results are herein reported. MATERIALS AND METHODS Patients Selection From April 1987 to December 1993 a prospective randomized study was carried out at the Department of Obstetrics and Gynecology of the Istituto di Scienze Biomediche San Gerardo to compare two different types of radical hysterectomy for the treatment of invasive cervical cancer. Pretreatment evaluation consisted of pelvic examination with measurement of the cervical diameter by alginate mold [13] and complete staging workup including chest X ray, lymphangiography, intravenous pyelography, and cystoscopy and rectoscopy when clinically indicated. Stage was assigned according to the 1985 FIGO clinical staging system [14]. Clinical evaluation of the patients was performed jointly by at least two senior gynecologic oncologists; when there was disagreement the case was assigned to the earlier stage. Patients were queried prior to surgery in a systematic fashion regarding symptoms of stress incontinence and any voiding dysfunction. Patients in good general condition (WHO performance status ⬍2) and suitable for radical surgery, with histologically confirmed primary operable cervical cancer clinically confined to the cervix and upper vagina (FIGO stage IB–IIA), of any cervical size and with no previous or concomitant malignancy, were considered eligible for the study. Radiologic evidence of lymph node involvement was not considered an exclusion criterion. Written consent was obtained from all patients before randomization. Study Design Eligible patients were randomized to receive either class II or class III radical hysterectomy, without any further stratification. The treatment was assigned by block randomization (clusters of 10 cases) from a computer-generated table created before starting the trial; the treatments in the table were coded so that no one could discover the next allocation before randomizing the patient, and uncoded after informed consent of the patient. Surgical procedures were performed according to the operative guidelines described by Piver et al. [6], within 3 weeks of randomization. Pelvic lymph node dissection consisted of removal of all fatty lymph node-bearing tissue anterior, lateral, and posterior to the common, external, and internal iliac vessels and anterior, lateral, and inferior to the obturator nerve. Paraaortic nodes

were sampled only if suspected and/or enlarged at lymphangiography or at surgical exploration. In patients aged 40 and younger with squamous histotype one ovary was preserved and suspended to the ipsilateral paracolic gutter outside the pelvis. All operations were performed by the same surgical team. Patients were placed on bowel preparation preoperatively, and received single-dose antibiotic prophylaxis. Antithrombotic prophylaxis with subcutaneous heparin (5000 IU three times daily) was administered. The urethral catheter was removed on the third postoperative day, then intermittent selfcatheterization was performed three times a day until the urinary residual was less than 50 ml. Pathologic examination of the surgical specimens was performed as previously reported elsewhere [15]. Parametrial involvement, positive or close (⬍3 mm) resection margins, lymph-vascular space invasion close to the resection margins, and lymph node metastases were considered risk factors requiring adjuvant radiotherapy. A single microscopic lymph node metastasis was also included in positive lymph node involvement. Radiotherapy included external pelvic irradiation with an 18-MV photon beam, using multiportal technique, with a single dose of 1.8 –2 Gy at the isocenter and two or more portals treated daily. The treatment field included the upper margin of the fifth vertebral body superiorly, the lower edge of the obturator foramen inferiorly, and at least 1.5 cm lateral to the margins of the bony pelvis laterally. The total dose was 50 Gy in 5– 6 weeks. A boost of 5–10 Gy was delivered to the positive pelvic nodes. Paraortic lymph nodes were treated with a dose of 45 Gy in 5 weeks and two shaped opposed fields (AP–PA). Evaluation Methods Complications and morbidity were prospectively recorded and classified according to the nomenclature and grading proposed by Chassagne et al. [16]: grade 1: minor symptoms responding to simple outpatient management; grade 2: major symptoms requiring prolonged therapies or hospitalization for diagnosis and medical management; grade 3: severe morbidity worsening the health of the patients or life-threatening complications; complications requiring invasive or surgical procedures to be cured are classified as grade 3. Follow-up consisted of a pelvic examination every 3 months during the first 2 years, three times yearly from the third to the fifth year, then yearly. Intravenous pyelography were performed in all patients 30 days after the operation and again 1 month after receiving radiotherapy. Urodynamic tests were performed in women reporting any kind of bladder dysfunction. Ultrasound scans of the pelvis and Pap smear were planned every 6 months and chest X ray yearly. The median

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TYPE II VERSUS TYPE III HYSTERECTOMY IN CERVICAL CANCER

TABLE 1 Patient Characteristics

follow-up time was 63 months (range, 39 –123 months). No patient was lost to follow-up. Endpoints and Statistical Analysis To determine the role of surgical radicality in cervical carcinoma, primary endpoints of the study were overall and disease-free survival, incidence and distribution of local recurrences, and morbidity for the two types of radical hysterectomy. A power analysis before starting the trial determined the need for an accrual target of 200 randomized patients to detect a 20% reduction of risk of death and morbidity (with ␣ ⫽ 0.05 and 1-␤ ⫽ 80%). Survival, recurrences, and complications were computed for intention to treat to minimize the bias due to randomization crossovers. No interim analysis was planned. A ␹ 2 test with Yates’ continuity correction was used to test the association between a couple of variables. Quantitative data have been compared by two-way analysis of variance (ANOVA). Survival and disease free-survival curves were calculated by the life-table method and compared with the log-rank test. Multivariate Cox regression analysis was performed to adjust treatment comparisons for all factors resulting in significant overall survival in univariate analysis [17]. A forward regression technique was employed, with variables being added according to maximum likelihood estimate statistics. Continuous data such as age, cervical diameter, and thickness of uninvolved cervical stroma were categorized in discrete groups to achieve results that could be useful and informative from the clinical point of view. Adjuvant radiotherapy, being offered only to patients with pathologic risk factors, cannot be regarded as a risk factor itself and was not evaluated in the uniand multivariate analyses. RESULTS Accrual Among 335 consecutive patients scheduled for radical surgery during the study period, 243 were considered eligible and enrolled in the study. Ninety-two patients did not enter the trial because of age (⬍20 or ⬎75), medical illness, previous or concurrent malignancy, referring physician’s preference, or anesthesiologic contraindication. Five randomized cases were excluded from further analysis because pathologic examination of the surgical specimen revealed a primitive endometrial cancer with cervical extension; the remaining 238 cases (119 in each arm) are evaluable for intention to treat. Twelve patients in the class III arm crossed the allocation arm. Five cases presented massive pelvic lymph node metastases at laparotomy; the metastatic nodes could not be completely removed and those patients were not deemed eligible for a major surgical extirpation of the primary tumor. Seven further patients underwent a class II operation for intraoperative anesthesiologic conditions (severe blood loss, arrhythmia).

Mean age (years) Range SD FIGO stage IB II A Cervical diameter ⱕ4 cm ⬎4 cm Average size Range SD

Class II (n ⫽ 119)

Class III (n ⫽ 119)

47 22–75 13

47 24–75 12

0.8

109 (91%) 10 (9%)

111 (93%) 8 (7%)

0.8

90 (76%) 29 (24%) 3.74 1.5–6.0 0.81

89 (75%) 30 (25%) 3.85 2.0–6.0 0.91

0.9

P

These cases have been analyzed considering the original allocation arm. Clinical characteristics of the patients (age, FIGO stage, cervical diameter) were well balanced in the two treatment groups (Table 1). In particular, the two groups of treatment show the same distribution of cervical diameter although it was not a stratification factor in the trial design. Pathology and Adjuvant Treatment Pathologic findings are summarized in Table 2. The two groups were well balanced with respect to histologic type, parametrial involvement, and lymph node metastases. The mean number of pelvic lymph nodes removed was 31 in the class II arm (range, 22– 46) and 33 in the class III arm (range, 19 – 44). Positive surgical resection margins did not appear to be significantly related to the surgical procedure adopted. In all cases of “massive” parametrial involvement, neoplastic invasion was confined to the proximal portion of the lateral parametria. Preoperative parameters predictive of histologically confirmed parametrial involvement were cervical diameter (ⱕ4 cm vs ⬎4, P ⫽ 0.008) and FIGO stage (IB vs IIA, P ⬍ 0.0001), while histotype and grade showed no significant value. Patients submitted to class II hysterectomy had a higher rate of paraortic lymph node metastases compared with patients in the class III arm. Overall 129 patients (54%) received external radiotherapy following surgery. The need for adjuvant treatment was not related to the extent of surgical dissection, as radiotherapy was administered to 64 patients (54%) in the class II arm and to 65 patients (55%) in the class III arm. Cervical diameter was a significant predictor (P ⫽ 0.000003) of the need for adjuvant radiotherapy, which was delivered to 80% (47/59) of the patients with cervical diameter greater than 4 cm compared with 46% (82/179) of those patients with small (聿4 cm) cervical diameter. The same applies to clinical stage: 112 of 220 pa-

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TABLE 2 Pathologic Findings a Class II (n ⫽ 119) Adenocarcinoma Poorly differentiated Lymph-vascular space invasion Parametrial involvement Massive parametrial Microscopic parametrial Microscopic cut through a Anterior Posterior Lateral Positive lymph nodes

31 (26%) 50 (42%) 74 (62%) 30 (25%) 9 (30%) 21 (70%) 13 (11%) 7 (54%) 3 (23%) 3 (23%) 32 (27%)

Micrometastasis Macrometastasis Extranodal metastasis

5 (16%) 19 (59%) 8 (25%)

1 node involved 2 nodes involved ⬎2 nodes involved Positive lumboaortic nodes Adjuvant therapy

9 (28%) 5 (16%) 18 (56%) 7 (22%) 64 (54%)

a

P 0.5 0.2 0.8 0.8

Class III (n ⫽ 119)

0.9 0.5

26 (22%) 61 (51%) 71 (60%) 32 (27%) 12 (37%) 20 (63%) 14 (12%) 7 (50%) 4 (28%) 3 (22%) 27 (23%)

0.5

7 (26%) 12 (44%) 8 (30%)

0.4 0.2 0.9

12 (44%) 4 (15%) 11 (41%) 2 (7%) 65 (55%)

0.7 0.9

Cut through-positive resection margin.

tients (51%) with stage IB lesions received adjuvant radiation therapy, compared with 17 of 18 cases (94%) with stage IIA tumors (P ⫽ 0.0004). The pathologic risk factors requiring adjuvant treatment in 129 patients were the following: lymph node metastases (59 cases, 46%), neoplastic involvement of the surgical margins (11 cases, 8%), parametrial involvement (20 cases, 15%), ⬍3 mm of uninvolved cervical stroma (33 cases, 26%), lymphvascular space involvement close to the resection margin (5 cases, 4%) and bulky vaginal spread (1 case, 1%). Forty-six patients (19%) had lymph-vascular space involvement as the only pathologic risk factor and did not receive adjuvant irradiation.

a uterine artery (class III arm), hematoma disconnecting the rectal wall (class II arm), and a ureterovaginal fistula (class III arm). Pulmonary embolism occurred in three patients, one of whom died. Pelvic hematoma required drainage in one patient. Other early complications occurred in two cases (wound abscess and deep vein thrombosis of the lower limbs, respectively). As a whole, intraoperative and early complications (Table 4) were observed in six patients (5%) after class II and in five patients (4%) after class III. Late Morbidity The incidence of late morbidity differed between the two arms (Table 4), affecting 33 (28%) patients in the class II arm compared with 45 (38%) in the class III arm (P ⫽ 0.1, odds ratio ⫽ 1.6). The sum of the early and late complications at the bottom of Table 4 exceeds the total number of complications because some patients experienced multiple morbidity. Complications unrelated to the extent of surgical dissection (abdominal hernia, wound infection, ileum, leg edema, lymphocyst) were similar in the two arms of treatment. Long-term urologic complications (hydroureteronephrosis, stress incontinence, miscellaneous vesical complications) affected 3 patients (5%) after class II and 13 patients (20%) after class II and radiotherapy (P ⫽ 0.03, odds ratio ⫽ 4.4), versus 16 patients (30%) after class III and 18 patients (37%) after class III and radiotherapy (P ⫽ 0.9, odds ratio ⫽ 1.4). Vesical complications were significantly more frequent in the class III group, as demonstrated by a longer self-catheterization time (P ⫽ 0.02) and a higher rate of bladder dysfunctions (atonic bladder, stress incontinence, low-compliance bladder, P ⫽ 0.02). Moreover, increased urologic morbidity was recorded in those patients who received radiotherapy (RT) following a more extensive dissection of the pelvic tissue. In fact, hydroureteronephrosis occurred in 6 patients (9%) after class II plus RT, in 3 (5%) after class III and in 8 (12%) after class III plus RT (P ⫽ 0.45); the relative risk of incidence of

Operating Data and Early Morbidity Mean operative time was significantly (P ⫽ 0.01) shorter in the group of patients undergoing class II hysterectomy (135 min vs 180 min), whereas mean blood loss and number of patients requiring blood transfusions were similar in the two arms of treatment (Table 3). Mean postoperative length of stay was similar in the two groups of patients. Intraoperative complications occurred in two cases (1%): resection of the obturator nerve (class III arm) and ureteral injury (class II arm, patient with double ureter). In all cases the lesion was immediately recognized and repaired; primary healing was achieved without functional sequelae. Three patients (1.3%) required a second laparotomy after 1, 2, and 33 days after surgery, respectively for hemorrhage from

TABLE 3 Operative Data

Mean operative time (min) Range SD Mean blood loss (ml) Range SD No. transfusions (%) Days to discharge Mean ⫾ SD Range

Class II (n ⫽ 119)

Class III (n ⫽ 119)

135 120–170 32 530 150–2500 120 42 (35%)

180 150–200 43 580 150–1850 134 51 (43%)

9.1 ⫾ 1.8 5–18

9.5 ⫾ 1.4 8–16

P 0.04

0.2

0.3

0.4

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TYPE II VERSUS TYPE III HYSTERECTOMY IN CERVICAL CANCER

TABLE 4 Morbidity a Class II

Class III Surgery ⫹ RT (n ⫽ 64)

Surgery (n ⫽ 55)

Surgery (n ⫽ 54)

Surgery ⫹ RT (n ⫽ 65)

Early morbidity Lymph-vascular complications Thrombosis Pulmonary embolism Hemorrhage Pelvic hematoma Urologic complications Ureteral fistula Ureteral injury Intestinal complications Rectal hematoma Other complications Nerve injury Abdominal abscess

— 1 — 1

— 1 — —

1 1 1a —

— — — —

— 1

— —

1a —

— —

1a

—

—

—

— —

— 1

1 —

— —

— 9

4 7

— 4

5 3

— — 3 — — 16 ⫾ 10.8

6 2 5 — — 24 ⫾ 24

3 1 12 — — 31 ⫾ 42

8 2 8 3 3 37 ⫾ 40

—

2

—

5

4 — 17 (31%)

— 1 20 (31%)

1 — 20 (37%)

3 — 29 (45%)

Late morbidity Lymph-vascular complications Leg edema Lymphocyst Urologic complications Hydroureteronephrosis Stress incontinence Atonic bladder High-pressure bladder Actinic cystitis Mean time to voiding b (days ⫾ SD) Intestinal complications Obstruction Other complications Abdominal hernia Actinic osteitis Total c a

Patients requiring a second laparotomy. P ⫽ 0.02. c The sum of early and late complications exceeds the total number of complications because some patients experienced multiple morbidity. b

this complication for the class III arm versus the class II arm is 1.9; for class II ⫹ RT versus class III it is 1.7; and for class III ⫹ RT versus class III it is 2.3. Patients receiving adjuvant radiotherapy had a higher incidence of leg edema than those who underwent exclusive radical surgery. Other types of complications do not differ substantially between the two arms of randomization (Table 4). Pattern of Recurrence and Survival Overall and disease-free survival curves are shown in Fig. 1. As a whole 29 recurrences (24%) were observed in the class II arm and 31 (26%) in the class III arm; this difference was not statistically significant. Forty-five patients died (72 and 77% of the relapses in the two groups, respectively). Details about

pattern of pelvic recurrences (urethra/vagina, midpelvis, pelvic sidewall, distant) according to treatment modality are summarized in Table 5. In situ vaginal lesions (VAIN3) have been included, although these can be considered an expression of multifocal disease rather than relapse of the primary cervical tumor. The extension of the surgical dissection does not appear to influence pelvic recurrences significantly, as 10 of 29 relapses (34%) were observed inside the pelvis after a class II operation, compared with 13 of 31 pelvic relapses (42%) after a class III operation (P ⫽ 0.7). Similarly, sites of pelvic recurrence (central versus lateral) are equally shared between the two groups: 7 of 10 (70%) pelvic relapses in the class II arm are on the pelvic wall compared with 9 of 13 (69%) in the class III arm.

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LANDONI ET AL.

FIG. 1. Overall (OV) and disease-free (DF) survival by class of surgery. P overall survival ⫽ 0.7. P disease-free survival ⫽ 0.9.

The recurrence rate in patients with small (ⱕ4 cm) cervical diameter was 21% (19/90) in the class II arm and 24% (21/89) in the class III arm (P ⫽ 0.8). Patients with a large cervical diameter (⬎4 cm) had a higher recurrence rate: 34% (10/29) in the class II arm and 33% (10/30) in the class III arm (P ⫽ 0.8). In both cases, however, no significant difference between the two classes could be found and survival within each group of cervical diameter did not depend on the type of surgery performed (Fig. 2). Four of the twelve patients (33%) who crossed the allocation TABLE 5 Location of Recurrences according to Treatment Modality Class II

Urethra Vagina (VAIN3) Vagina (invasive) Pelvis Central Lateral Distant Total Deceased a

Class III

Surgery (n ⫽ 55)

Surgery ⫹ RT (n ⫽ 64)

Surgery (n ⫽ 54)

Surgery ⫹ RT (n ⫽ 65)

— 1 1

— — 3

— — 2

2 1 4

2a 5 11

1 4 1

3 5 8

1a 2 3

8 (15%) 21 (33%) 29 (24%) 21 (72%)

8 (15%) 23 (35%) 31 (26%) 24 (77%)

One patient in each group with central relapse associated with distant metastasis.

FIG. 2. Overall survival by class of surgery and cervical diameter. P ⫽ 0.4 (class II vs class III ⱕ4 cm) and 0.6 (class II vs class III ⬎4 cm).

arm and underwent a class II operation relapsed in the following anatomical sites: vagina, central pelvis, lateral pelvis, and lung. These relapses were evaluated for intention to treat, as specified above. Six patients with relapse in the class II arm (4 pelvic relapses and 2 distant) were salvaged with concurrent chemoradiotherapy (3 cases) or surgery (3 cases); in the class III arm 3 patients with pelvic recurrence underwent concurrent chemoradiotherapy (2 cases) or surgery (1 case) and are currently alive without evidence of disease. This accounts for a salvage rate of 21% in the former group and 10% in the latter (P ⫽ 0.3). The overall actuarial 5-year survival is 79%. Eight patients died from intercurrent disease and one from fatal pulmonary embolism, as stated above. The number of patients dead of disease (21 class II vs 24 class III) was similar in the two groups of treatment. Overall 5-year survival was 81 and 77%, and disease-free survival was 75 and 73%, respectively, in the group of patients submitted to class II and class III radical hysterectomy. These differences were not statistically significant (Fig. 1). Independent of the class of radical surgery, patients who received adjuvant postoperative radiotherapy had a poorer prognosis compared with those who had surgery alone (Fig. 3). Univariate analysis carried out for all known prognostic factors showed that large cervical diameter, parametrial involvement, lymph-vascular space involvement, intact cervical stroma thinner than 3 mm, cut through, and presence and pattern of lymph node metastasis are significantly related to a poorer prognosis (Table 6). The extension of surgery has no impact on survival. Multivariate analysis shows that cervical diameter (P ⫽

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TYPE II VERSUS TYPE III HYSTERECTOMY IN CERVICAL CANCER

FIG. 3. Overall survival by class of surgery and adjuvant therapy. P ⫽ 0.8 (surgery only class II vs class III) and 0.7 (surgery plus radiotherapy class II vs class III).

0.02), thickness of the intact cervical stroma (P ⫽ 0.004), retroperitoneal involvement (P ⫽ 0.009), and type of nodal metastasis (P ⫽ 0.009) remain associated with a poorer prognosis, while the lack of benefit of more radical surgery (class III hysterectomy) is confirmed across all subgroups of patients. Capillary-like space involvement, although not significant in multivariate analysis, proves to be a risk factor not to underestimate, as 8 of 46 patients (17%) with lymph-vascular space invasion, no other risk factors, and no adjuvant therapy died of disease, compared with 3 of 63 (5%) without risk factors or lymph-vascular space invasion (P ⫽ 0.05).

Consequently, radical surgery should not just transect the parametria, but resect them at their lateral insertion [20]. Conversely, DiSaia did not find any evidence of disease in the lateral parametria in operated patients with a stage IB or IIA lesion, and suggested that spreading from the primary tumor to the pelvic lymph nodes occurs as an embolic phenomenon [7]. Other investigators found lymph node involvement in the distal parametrium in only 1–3% of patients, usually in association with pelvic node metastases. They concluded that parametrial lymph node metastases had no impact on survival, and suggested a less radical procedure at least for early and nonbulky lesions [11, 21]. Moreover, retrospective data from the literature on invasive cervical cancer inadvertently treated by standard hysterectomy showed that patients with small-volume invasive disease treated by simple hysterectomy and postoperative radiation therapy carry a prognosis similar that of patients treated primarily by either radical surgery or radiation therapy [22, 23]. In a study on 210 patients with stage IB cervical cancer treated in an alternating pattern with classic radical hysterectomy or TABLE 6 Univariate Analysis for Overall Survival

Variable Type of surgery Age Stage Cervical size Histotype Grade

DISCUSSION The classification of Piver, Rutledge, and Smith [6] of radical operations for cervical carcinoma has considerable practical value, pointing out the need to adapt surgery to the extent and characteristics of the disease. In fact, given the spectrum of risk factors in cervical carcinoma (disease volume, occult parametrial involvement, lymph node status) and subsequent outcomes following radical hysterectomy, a standardized surgical procedure may represent insufficient modality in some patients, being at the same time unnecessarily radical in others. Literature data regarding the role of surgical radicality in cervical cancer are scanty and controversial. The need for extensive dissection of the cardinal ligament, as in class III hysterectomy, is supported by the high frequency of pelvic relapses observed in patients previously operated for cervical cancer [18]. The presence of lymph nodes scattered all over the parametrial tissue could explain these results [19].

Parametria Corpus uteri LVSI Cut through Uninvolved cervical stroma Lymph nodes No. nodal metastases

Pattern of nodal metastases

Level

No. of patients

No. with NED

Class II Class III ⱕ50 years ⬎50 years IB IIA ⱕ4 cm ⬎4 cm Squamous Adenocarcinoma G1–G2 G3 Negative Positive Negative Positive Absent Present Absent Present

119 119 155 83 220 18 179 59 181 57 127 111 176 62 179 59 93 145 211 27

91 (75%) 88 (73%) 123 (79%) 56 (67%) 168 (76%) 11 (61%) 141 (79%) 38 (64%) 137 (76%) 42 (74%) 95 (75%) 84 (76%) 141 (80%) 38 (61%) 142 (79%) 37 (62%) 82 (88%) 97 (67%) 164 (78%) 15 (55%)

ⱖ3 mm ⬍3 mm Negative Positive 1 2 ⬎2

134 104 179 59 21 9 29

114 (85%) 65 (62%) 148 (83%) 31 (52%) 13 (62%) 5 (55%) 13 (45%)

12 31 16

10 (83%) 10 (32%) 11 (69%)

Micro Macro Extranodal

P

0.7 0.3 0.1 0.004 0.9 0.6 0.02 0.4 0.006 0.07

0.003 0.004

0.5

0.005

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Te-Linde extrafascial hysterectomy, Stark [24] found no differences in postoperative irradiation rate, frequency of metastasis and recurrence, and overall survival. He concluded that the parametria may not be removed completely in early invasive cervical cancer, since late results are similar and fewer complications are expected with the less radical approach. In our study overall survival and disease-free survival were similar in the two groups even when stratified by cervical diameter and adjuvant radiotherapy, suggesting that the two classes of radical hysterectomy are equally effective in both low- and high-risk cases. Multivariate analysis confirms that overall survival does not depend on the degree of surgical radicality and identifies cervical diameter as the only preoperative prognostically significant characteristic. Pelvic recurrences were similar in the two groups of patients, in contrast to those who believe that the less radical surgical procedure is unable to prevent pelvic failures, especially on the sidewalls. It is interesting to note that in our series the extent of radicality had no significant influence on the detection of parametrial involvement (25% in class II vs 27% in class III) and on the site of positive resection margins (lateral, anterior, or posterior). Analysis of the patterns of spread of cervical carcinoma may explain these results. In a previous paper on 230 surgical specimens of invasive cervical cancer [15] we found that both intracervical and extracervical spread occurs equally in all directions: anteriorly (through the vesicovaginal septum and pubocervical ligaments), laterally (through the cardinal ligaments and parametria), and posteriorly (through the uterosacral ligaments and rectovaginal septum). Such a growth pattern would confirm that radical hysterectomy, to whatever extent, can be radical only with respect to the lateral and possibly posterior parametria, while the intent of radicality cannot be fully accomplished in case of anterior extracervical extension, as demonstrated by the higher frequency of neoplastic involvement of the anterior resection margins in the present series (Table 2), regardless of the degree of radicality. This concept may help to confirm the adequacy of the surgical procedures performed in our patients, notwithstanding the remarkable rate of involved margins. The frequency of parametrial involvement in presumably a localized disease is rather high in our series (26%). The rate of parametrial spreading in FIGO stage IB cervical cancer commonly reported is 15–18% [25–27]. On the other hand it is well known that clinical staging does not define the true extent of disease in approximately one-third of the patients with early cervical cancer [28], and unless clear nodular tumor extension into the parametria was palpable, we did not classify any patient as stage IIB. Adjuvant radiotherapy was delivered to 54% of patients; the selection criteria for irradiation were similar to those of the vast majority of other authors. Recent reports suggest that patients with single occult lymph node involvement could be safely treated with surgery alone [29]: being these data were based on

a small number of cases from retrospective series, we have not shifted our policy so far and continue to include the single node metastasis among the postsurgical irradiation criteria. The delivery of adjuvant postoperative treatment was not related to the extent of the surgical procedure, suggesting that other prognostic factors rather than degree of radicality should be identified to predict the need for adjuvant radiation therapy. The high rate of postoperative treatment in our series, compared with the 23– 45% reported for cases with IB cervical cancer [30, 31], can be explained by the different staging and selection criteria adopted by other authors, the incidence of parametrial involvement in our cases, and the fact that in our study even patients with cervical diameter ⬎4 cm were selected for primary surgery, while since 1994 our institutional policy has changed and these cases would undergo exclusive radiotherapy or preoperative chemotherapy, not to combine the morbidity of both radical surgery and irradiation. Patients with cervical size ⱕ4 cm show a much lower requirement for postsurgical treatment, suggesting that they are the best candidates for a primary surgical approach. In fact, following this strategy the rate of postoperative treatment in our experience after 1994 was lowered to 29%. Large cervical diameter (⬎4 cm) appeared to be a major preoperative predictor of the need for adjunctive treatment, as previously reported by Piver and Chung [32] and confirmed by our experience [33]. Moreover, in the present series cervical size was significantly related to survival and recurrence rate in both uni- and multivariate analysis. Nowadays, magnetic resonance imaging is considered the most accurate diagnostic tool to detect preoperatively the tumor volume, the extent of the disease [34], and the thickness of the uninvolved cervical stromal ring [35] in patients with cervical cancer. All these factors might be essential to plan the optimal treatment. Another reason to explain the interest in searching for the optimal extent of surgical treatment derives from the recognition of the morbidity associated with each procedure. Although improvements in surgical technique and postoperative care have dramatically reduced complications, the amount and degree of morbidity following radical hysterectomy are strictly related to the extent of resection [3, 6, 10, 11]. In our study no operative death was recorded, and intraperioperative complications were extremely low, reflecting a marked improvement in surgical technique in recent years. Mean operative time was significantly longer in patients undergoing class III hysterectomy, while intraoperative blood loss, number of patients requiring transfusions, and mean time to discharge were similar in the two arms of treatment. Previous reports have underlined that class II hysterectomy is associated with a lower rate of ureteral injuries because blood supply of the ureter is preserved [6, 10, 12]. Bladder dysfunction still represents the main cause of morbidity following surgical treatment for early invasive cervical cancer. A number of voiding disorders (sensory loss, urgency, stress incontinence, hypotonic and hypertonic vesical dysfunction,

TYPE II VERSUS TYPE III HYSTERECTOMY IN CERVICAL CANCER

and prolonged use of self-catheterization) have been reported after radical hysterectomy as a consequence of iatrogenic denervation at the time of parametrial dissection [36, 37]. The degree of lower urinary tract dysfunction following radical hysterectomy has been related to postoperative bladder rehabilitation as well as to the degree of surgical radicality as a consequence of direct damage to the autonomous innervation of the pelvic organs. In a previous paper on a limited number of patients enrolled in this trial we reported the immediate postoperative period loss of both bladder sensitivity and detrusor voiding activity with reduced compliance in the majority of patients, regardless of the surgical procedure performed. At 3-month follow-up exam, however, the improvement in urethrovesical function (in both the filling and voiding phases) was significantly (P ⫽ 0.05) related to less extensive dissection of pelvic connective tissue, resulting manifest in 50% of patients after a class II operation and in 13% after class III [38]. As expected, in the present trial bladder dysfunction was more common in the group of patients submitted to wider dissection of the paracervical tissue (class III). In patients requiring adjuvant radiotherapy after radical surgery, long-term urologic morbidity is frequent and this is particularly manifest in the class III arm. Past studies demonstrated that a number of temporary postoperative hydronephroses and vesical dysfunctions can resolve spontaneously, but become persistent when irradiation is added. Serious complications occur in only 3–5% of patients with surgery alone, but rates are increased to 10 –13% when adjuvant radiation therapy is employed following surgery [39], confirming that the association of the two modalities should be avoided. The prospective collection of the complications in our study, compared with the retrospective analyses reported in the vast majority of the literature, contributes to justifying the considerable rate of urologic morbidity, even with type II hysterectomy. However, clinically detected complications have all been confirmed by radiologic and urodynamics tests, as stated above. The proper modulation of radicality in women submitted to surgical treatment for invasive cervical cancer still remains a matter of debate. The results of our study suggest that in patients with stage IB–IIA cervical cancer, suitable for radical surgery, a limited radical hysterectomy (class II) should always be preferred. Recurrence pattern, disease-free survival, and overall survival were similar in the two arms of treatment even when compared by adjuvant treatment, whereas class III radical hysterectomy was associated with a higher rate of urologic morbidity, particularly when postoperative radiotherapy was delivered. However, to assess the effectiveness of adjuvant radiotherapy is not among the goals of the present study. Recurrence rate and overall survival in patients with pathologic risk factors were significantly poorer compared with those who received surgery alone, regardless of the type of radical hysterectomy. With an overall 33–35% recurrence rate in those patients treated with surgery and irradiation, the results would suggest the need for reassessment of the overall man-

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agement of the patient population. In addition, a significant number of the associated late morbidity issues appear to be a reflection of the radiation therapy following surgical manipulation. Therefore a judicious pretreatment selection of the patients is essential to avoid the increased incidence of complications associated with adjuvant radiotherapy after radical surgery. Patients with preoperatively evaluable risk factors which probably would require adjuvant treatment (large cervical diameter, bulky tumor volume, lymph node involvement, limited uninvolved pericervical stroma, suspect of extracervical spread) should not be scheduled for primary radical surgery, as the chance of requiring adjunctive treatment after surgery would be high: 80% of patients in our series with cervical diameter ⬎4 cm received postoperative radiotherapy. If platin based chemotherapy, either neoadjuvant or adjuvant, will result in less morbidity and similar effectiveness as radiotherapy, this modality might be successfully included in the management of cervical cancer. ACKNOWLEDGMENTS We thank Professor Giuseppe Mattioli for his important collaboration in designing the study and for his precious and expert teaching assistance during most of the operations, and Mrs. Graziella Giacobbe for her secretarial skills.

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