Radical Hysterectomy: Excessive Treatment for Low-Volume Stage IB1 Cervical Cancer

Abstract

Objective: The purpose of this study was to identify a subset of patients with low volume stage IB1 cervical cancer who may benefit from simple hysterectomy as opposed to conventional radical hysterectomy. Design: This study was designed as a retrospective review. Setting: The study took place at the West of Scotland Gynaecological Cancer Centre. Population: The study population was a total of 90 patients with stage IB1 cervical cancer. Methods: A case note review of patients who underwent radical hysterectomy over 7 consecutive years from April 2001 to April 2008 was performed. Following diagnostic large loop excision of the transformation zone (LLETZ), tumor volume was assessed by multiplying length×width×depth measurements. Volumes above the cutoff value of 500 mm³ were considered to be significant tumor volume (STV) and those below this value were considered to be nonsignificant tumor volume (NSTV). Tumors that were macroscopically evident were regarded as STV, and only punch biopsies were taken. Results: The median tumor dimensions in patients who underwent LLETZ biopsy were: 11.79 mm length, 6.67 mm width and 6.52 mm depth. There were 51 (56%) patients in the STV group. Within this group, 14 (27%) had parametrial involvement and 7 (14%) had vaginal involvement. There were 39 (44%) cases in the NSTV group and none had parametrial or vaginal involvement (p<0.001 and p=0.01, respectively). Among the patients with STV, 42 (82%) had residual disease as opposed to only 10 (25%) patients in the NSTV group (p<0.0005). The median follow-up period was 35 months (range 1–85). There were only 3 (3%) recurrences in total, all of which were within the STV group. Conclusions: The data from this study support the current growing opinion that radical hysterectomy can be regarded as overtreatment for selected cervical cancer patients with low volume disease. (J GYNECOL SURG 29:65)

Introduction

Cervical cancer is the most common gynecologic malignancy in women worldwide. Radical hysterectomy and bilateral pelvic lymphadenectomy (RHND) has remained the mainstay of treatment for early stage IB1 cervical carcinoma for the past 100 years.¹ This procedure involves removal of the cervix en bloc with the uterus, parametrium, and upper vagina, in combination with bilateral pelvic lymphadenectomy (PLN).

RHND is associated with significant morbidity compared with simple hysterectomy, including high-volume blood loss, bladder hypotonia, anorectal dysfunction, and urinary tract fistulae formation. The majority of complications are attributed to parametrial and vaginal resections. The parametrium is rich in vasculature and autonomic nerve fibers; therefore, transection of these structures is the underlying cause of higher morbidity compared with simple hysterectomy, in which these structures are preserved. Furthermore, long-term psychosexual complications often further diminish the patient's quality of life.^2–5

The aim of this study was to identify a subset of patients with low volume stage IB1 cervical carcinoma who may benefit from simple hysterectomy as opposed to conventional radical hysterectomy. The recurrence rate and survival within that subset was also examined.

Methods

This study is a retrospective case note review of all patients consecutively diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 cervical cancer in the West of Scotland Gynaecological Cancer Centre between April 2001 and April 2008. All subjects underwent RHND in the center. A total of 193 patients from five health boards within the region during the abovementioned period were identified using the center's cancer network database. Patients with poor prognostic tumor types, such as glassy-cell, clear-cell, small-cell, and neuroendocrine carcinomas were excluded. Furthermore, patients with incomplete data and those who had undergone fertility-preserving treatment were removed from the study.

One hundred and three cases were excluded from the study group: 28 had undergone fertility-preserving procedures (repeat large loop excision of the transformation zone [LLETZ] biopsy and/or laparoscopic lymphadenectomy) and 17 had poor prognostic histology, and, in 49 cases, critical pathologic data were not obtainable from peripheral hospitals. RHND was not performed in 4 patients because the patients were assessed as unfit for surgery. In a further 5 cases, RHND was not performed because of the unexpected intraoperative macroscopic findings of nodal or parametrial disease. Such suspicions were confirmed on frozen section examination and operations were abandoned. Hence, the study group was limited to 90 patients with squamous-cell carcinoma, adenocarcinoma, and adenosquamous carcinoma histology.

Data were collected from original medical records, and histologic reports on the diagnostic biopsies (punch or LLETZ) and radical hysterectomy specimens. Information on age, histopathology type, grade, resection margins, lymphovascular space invasion (LVSI), unifocality or multifocality, and tumor dimensions was collected. In addition, histologic evidence of nodal, parametrial, and vaginal involvement was recorded.

Preoperative tumor volume was estimated as defined by Burghardt et al.^6. In patients who underwent LLETZ biopsy, tumor volumes were calculated by multiplying length, width, and depth measurements. In the absence of a width measurement, the length was halved and that value used as a substitute for a width measurement. This formula has been derived from original work on tumor volumetry by Burghardt et al.⁶ On review of data, a cutoff value of 500 mm³ appeared significant for parametrial and nodal metastasis. This value also approximately corresponded to twice the volume of stage IA2 (7×7×5=245 mm³).

In this study, patients with tumor volumes >500 mm³ were regarded as having significant tumor volume (STV) and those with volumes <500 mm³ were regarded as having nonsignificant tumor volume (NSTV). According to regional guidelines, all patients with suspected macroscopic features of malignancy underwent punch biopsy only. On confirmation of malignancy, all such cases were regarded as STV in this study.

The association between tumor volumes as defined, and presence or absence of parametrial, vaginal, and nodal disease was calculated using statistical χ² and Fisher's exact tests. Recurrence and survival data were also collated. Statistical survival analysis was not attempted, because of the very low number of relapses in this cohort of patients.

Results

The median age in this study group was 44 (range 23–70). In 58 (64%) cases, staging was based on tumor measurements of the LLETZ biopsy. In the remaining 32 (36%), only a punch biopsy was taken for histologic confirmation, as the tumor was macroscopically visible.

Histologically, 58 (64%) cases were squamous cell carcinoma, 25 (28%) were adenocarcinoma, and 7 (8%) were adenosquamous carcinoma. Tumor grade was recorded in 73 cases (81%) only. Of these, 13 (18%) were poorly differentiated, 33 (45%) were moderately differentiated, and 27 (37%) were well differentiated. LVSI was noted in 26 (29%) cases.

Median tumor dimensions on LLETZ biopsies were: 11.8 mm in length (range 4–15 mm), 6.5mm in depth (range 2–7 mm), and 6.7 mm in width (range 2–13 mm). In 39 (67%) cases, tumor cells either reached or were reported to be in close proximity to at least one diathermy margin, and multifocality was noted in 10 (17%) cases. In this group of patients, the measurements were based on the largest confluent area.

There were 51 (57%) patients with STV and 39 (43%) with NSTV at time of presentation. Residual disease following radical hysterectomy was detected in 42 patients (82%) in the STV group as opposed to only 10 (25%) in the NSTV group (p<0.0005). In the NSTV group with residual disease (10 patients), only 2 (20%) had residual disease that was clinically regarded as significant, involving >25% of the cervical stroma, regardless of findings on preoperative imaging. Furthermore, there was no parametrial or vaginal involvement in this group. Within the STV group, 14 (27%) patients had parametrial involvement and 7 (14%) had vaginal involvement. These findings were noted to be of significance compared with the NSTV group (p<0.001 and p=0.01 respectively) (Table 1).

Table 1.

Association Between Patients with STV and NSTV and Four Main Pathologic Factors: Parametrial, Vaginal, and Nodal Involvement, as Well as Absence or Presence of Residual Disease

	Residual disease		Lymph node involvement		Parametrial tissue involvement		Vaginal tissue involvement
Tumor volume	Yes	No	Yes	No	Yes	No	Yes	No
NSTV (39)	10 (25%)	29 (75%)	1 (3%)	38 (97%)	0	39 (100%)	0	39 (100%)
STV (51)	42 (82%)	9 (18%)	14 (28%)	37 (72%)	14 (28%)	37 (72%)	7 (14%)	44 (86%)
p-Values	0.0001		0.0014		0.0002		0.0176

STV, significant tumor volume; NSTV, nonsignificant tumor volume.

The median number of lymph nodes removed was 20 (range 7–38). In the STV group, there were 14 cases with histologic evidence of nodal involvement (27%) as opposed to only 1 case (3%) in the NSTV group (p=0.001).

The median follow-up was 35 months (range 1–85). During this period, only 3 (3%) women developed recurrent disease. All 3 were in the STV group and there was significant residual disease with evidence of nodal or parametrial involvement in 2 of the 3. The small number of recurrent cases precluded any meaningful statistical survival analysis.

Discussion

Carcinoma confined to the cervix is regarded as stage I regardless of size, which can vary from microscopic foci to a large macroscopic lesion measuring >4 cm. National cervical cancer screening has resulted in earlier detection, and hence a rise in the number of patients with low volume microscopic disease.^7,8 Despite these diagnostic advances, the surgical management of early stage cervical cancer has remained unchanged for many decades. This may be because of historic data suggestive of high risk of parametrial involvement (6%–31%) in stage IB cervical carcinomas.^9–13

Tumor volumetry has been shown to be of significance in most solid tumors, and this includes cervical cancer.^14–17 In 1991, in a large multicenter study involving 1004 patients, Burghardt et al. demonstrated a significant association between the tumor volume and local tumor spread beyond the cervix and poor survival.⁶ They found that patients with no evidence of parametrial or nodal disease had mean estimated tumor volumes between 4.9 and 9.4 cm³. The estimated mean tumor volumetry for patients with evidence of parametrial and nodal involvement was much higher and varied between 9.2 and 19.1 cm³. They therefore proposed that maximum parametrial resection is not necessary for tumors <10 cm³. Similarly, in a series of 83 patients, Kinney et al. identified that patients with tumor volumes <4.19 cm³ were at zero risk of parametrial involvement.¹⁸ Their findings closely correspond with this study in a similar size cohort. However, unlike other studies, this study did not evaluate LVSI because in nearly 25% of patients, it had not been reported. A literature review on the reported rate of LVSI in cervical cancer could be as high as nearly 50%, hence its usefulness as a discriminator is questionable.^6,18 LVSI often is not known preoperatively, and would, therefore, not be of use in preoperative surgical planning, with regard to the extent of the operation.

Current literature supports less-radical operative procedures in patients who are presenting with low volume early stage cervical carcinoma. Several retrospective studies have shown that patients with early cervical cancer and favorable pathologic characteristics (low tumor size, low grade histology, absence of LVSI, and negative PLN) have a <1% risk of parametrial involvement.^17,19–24 The largest study thus far is by Covens et al., and this involved 842 patients with early stage cervical cancer who underwent radical hysterectomy.²⁰ Parametrial invasion was associated with an older age group, nodal metastasis, LVSI, deep stromal invasion, and higher tumor grade. However, the incidence of parametrial involvement was only 0.6% in patients with tumor size <2 cm, negative lymph nodes, and depth of invasion <10 mm. The 5 year recurrence-free survival rate was 96% following a median follow-up of 51 months. Similarly, in the second largest study by Wright et al. in 2007 that included 594 patients, the rate of parametrial involvement in tumors <2 cm with negative nodes and absence of LVSI was only 0.4%.²² There are an additional five major studies from different centers in the world, highlighting the low risk of parametrial tumor involvement in well-selected, low volume stage IB1 cervical cancer patients (Table 2).

Table 2.

Main Published Studies on Risk of Parametrial Involvement In Patients with Early Stage, Low Volume Cervical Cancer

1^st Author & reference	Year published	# of Patients	Selection factors	Parametrial invasion
Kinney¹⁸	1995	83	Tumor ≤2 cm squamous histology only No LVSI	0
Covens²⁰	2002	842	Tumor ≤2 cm Stromal inv. 10 mm Negative PLN	0.4-0.6%
Stegeman²¹	2007	103	Tumor ≤2cm Stromal inv. <10 mm No LVSI Negative PLN
Steed²³	2006	110	Negative PLN	1%
Wright²²	2007	594	Tumor ≤2 cmNo LVSINegative PLN	0.4%
Strnad²⁴	2008	158	Stromal inv. <2/3Sentinel nodes negative	0
Frumovitz²⁵	2009	125	Tumor ≤2 cmNo LVSI	0

LVSI, lymphovascular space invasion; inv., invasion; PLN, pelvic lymphadenectomy.

In this study, there was no parametrial or vaginal involvement in patients with NSTV, nor were there any recurrences in this group. Absence of data on adjuvant treatment limits interpretation of such an excellent survival outcome. However, we can safely assume that most these patients did not receive any adjuvant treatment, as there were only 2 patients (of 39 patients with NSTV) with clinically significant residual disease. In addition, 29 patients (75%) with NSTV disease had no residual disease in the final radical hysterectomy specimen. This finding corroborates literature evidence of no residual disease following radical trachelectomy in patients who opted for fertility-preserving proecedures.²⁵ Current selection criteria for radical trachelectomy in most centers includes tumors with a maximum dimension of <2 cm (regardless of LVSI or tumor grade). The absence of residual disease in this group of patients has been reported to be ∼65%.^26–30 Such realization over the past decade has resulted in even more conservative surgical approaches in patients with suspected low volume disease.³¹

Within this center, >27 patients with stage IB1 cervical carcinoma have been successfully treated with repeat LLETZ biopsy in conjunction with laparoscopic PLN. This conservative approach has resulted in a significant reduction in surgical morbidity compared with conventional radical hysterectomy.³²

This work adds to the pool of data in support of less radical surgical strategy in low volume, early stage cervical cancer. More importantly, it highlights the value of tumor volume estimation, even in the absence of measurements for third dimensions. This may well assist clinicians in further preoperative risk stratification of the patients and selection of suitable candidates for a more conservative surgical approach. Like most retrospective studies, this study suffers from certain drawbacks. The experience is limited to a single cancer center and is based on a relatively small sample size with potential bias because of incomplete data availability, preventing meaningful multivariate analysis. Lack of information on adjuvant treatment and a short 39 month median follow-up data set also hampers any survival analysis.

There is an urgent need for a large randomized, multicenter international clinical trial to confirm the safety and efficiency of these retrospective findings. The Simple Hysterectomy and Pelvic Node Dissection in Early Cervix Cancer (SHAPE) Trial organized by the National Cancer Institute of Canada (NCIC) has been designed to address the abovementioned issues. This randomized control study aims to determine the safety and superiority of a conservative approach such as simple hysterectomy compared with conventional radical hysterectomy, in low volume stage IA2 or IB1 disease.

Conclusions

These data support the current growing opinion that radical hysterectomy can be regarded as overbtreatment for selected cervical cancer patients with low volume stage IB1 disease.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Piver

, Rutledge

, Smith

. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol, 1974; 44:265.

Low

, Mauger

, Carmichael

. The effect of Wertheim hysterectomy upon bladder and urethral function. Am J Obstet Gynecol, 1981; 139:826.

Kadar

, Saliba

, Nelson

. The frequency, causes and prevention of severe urinary dysfunction after radical hysterectomy. Br J Obstet Gynaecol, 1983; 90:858.

Sood

, Nygaard

, Shahin

, Sorosky

, Lutgendorf

, Rao

. Anorectaldysfunction after surgical treatment for cervical cancer. J Am Coll Surg, 2002; 195:513.

Frumovitz

, Sun

, Schover

, Munsell

, Jhingran

, Wharton

et al. Quality of life and sexual functioning in cervical cancer survivors. J Clin Oncol, 2005; 23:7428.

Burghardt

, Baltzer

, Tulusan

, Haas

. Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer, 1992; 70:648.

Naik

, Cross

, Nayar

, Mayadevi

, Lopes

, Godfrey

et al. Conservative surgical management of small-volume stage IB1 cervical cancer. BJOG, 2007; 114:958.

Selman

, Luesley

, Murphy

, Mann

. Is radical hysterectomy for early stage cervical cancer an outdated operation? BJOG, 2005; 112:363.

Landoni

, Bocciolone

, Perego

, Maneo

, Bratina

, Mangioni

. Cancer of the cervix, FIGO stages IB and IIA: Patterns of local growth and paracervical extension. Int J Gyncecol Oncol, 1995; 5:329.

10.

Benedetti-Panici

, Maneschi

, D'Andrea

et al. Early cervical carcinoma: The natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer, 2000; 88:2267.

11.

Bleker

, Ketting

, van Wayjen-Eecen

, Kloosterman

. The significance of microscopic involvement of the parametrium and/or pelvic lymph nodes in cervical cancer stages IB and IIA. Gynecol Oncol, 1983; 16:56.

12.

Burghardt

, Pickel

, Haas

, Lahousen

. Prognostic factors and operative treatment of stages IB-IIB cervical cancer. Am J Obstet Gynecol, 1987; 156:988.

13.

Girardi

, Lichtenegger

, Tamussino

, Haas

. The importance of parametrial lymph nodes in the treatment of cervical cancer. Gynecol Oncol, 1989; 34:206.

14.

Trakul

, Chang

, Harris

, Chapman

, Rao

, Shen

et al. tumor volume-adapted dosing in stereotactic ablative radiotherapy of lung tumors. Int J Radiat Oncol Biol Phys, 2012; 84:231.

15.

Thaw

, Sahmoun

, Schwartz

. Serum calcium, tumor size, and hormone receptor status in women with untreated breast cancer. Cancer Biol Ther, 2012; 13:467.

16.

Pierorazio

, Hyams

, Lin

, Mullins

, Allaf

. Laparoscopic radical nephrectomy for large renal masses: Critical assessment of perioperative and oncologic outcomes of stage t2a and t2b tumors. Urology, 2012; 79:570.

17.

Chen

, Sung

, Wang

, Sheu

, Doong

, Yuan

. Correlation of three-dimensional tumor volumetry with cervical cancer prognostic parameters. Eur J Gynaecol Oncol, 2002; 23:401.

18.

Kinney

, Hodge

, Egorshin

, Ballard

, Podratz

. Identification of a low risk subset of patients with stage IB invasive squamous cancer of the cervix possibly suited to less radical surgical treatment. Gynecol Oncol, 1995; 57:3.

19.

Morice

, Piovesan

, Rey

, Atallah

, Haie-Meder

, Pautier

et al. Prognostic value of lymphovascular space invasion determined with hematoxylin-eosin staining in early stage cervical carcinoma: Results of a multivariate analysis. Ann Oncol, 2003; 14:1511.

20.

Covens

, Rosen

, Murphy

, Laframboise

, DePetrillo

, Lickrish

et al.

How important is removal of the parametrium at surgery for carcinoma of the cervix?

Gynecol Oncol, 2002; 84:145.

21.

Stegeman

, Louwen

, van der Velden

, ten Kate

, den Bakker

, Burger

et al. The incidence of parametrial tumour involvement in select patients with early cervix cancer is too low to justify parametrectomy. Gynecol Oncol, 2007; 105:475.

22.

Wright

, Grigsby

, Brooks

, Powell

, Gibb

, Gao

et al. Utility of parametrectomy for early stage cervical cancer treated with radical hysterectomy. Cancer, 2007; 110:1281.

23.

Steed

, Capstick

, Schepansky

, Honore

, Hiltz

, Faught

. Early cervical cancer and parametrial involvement: Is it significant? Gynecol Oncol, 2006; 103:53.

24.

Strnad

, Robova

, Skapa

, Pluta

, Hrehorcak

, Halaska

et al. A prospective study of sentinel lymph node status and parametrial involvement in patients with small tumour volume cervical cancer. Gynecol Oncol, 2008; 109:280.

25.

Frumovitz

, Sun

, Schmeler

, Deavers

, Dos Reis

, Levenback

et al. Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer. Obstet Gynecol, 2009; 114:93.

26.

Beiner

, Covens

. Surgery insight: Radical vaginal trachelectomy as a method of fertility preservation for cervical cancer. Nat Clin Pract Oncol, 2007; 4:353.

27.

Gien

, Covens

. Fertility-sparing options for early stage cervical cancer. Gynecol Oncol, 2010; 117:350.

28.

Rob

, Pluta

, Strnad

, Hrehorcak

, Chmel

, Skapa

et al. A less radical treatment option to the fertility-sparing radical trachelectomy in patients with stage I cervical cancer. Gynecol Oncol, 2008; 111:116.

29.

Abu-Rustum

Nadeem R.

, Sonoda

Yukio

, Black

Destin

, Levine

Douglas A.

, Chi

Dennis S.

, Barakat

Richard R.

Fertility-sparing radical abdominal trachelectomy for cervical carcinoma: Technique and review of the literature. Gynecol Oncol, 2006; 103:807.

30.

Schmeler

, Frumovitz

, Ramirez

. Conservative management of early stage cervical cancer: Is there a role for less radical surgery? Gynecol Oncol, 2011; 120:321.

31.

Maneo

, Sideri

, Scambia

, Boveri

, Dell'anna

, Villa

et al. Simple conization and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience. Gynecol Oncol, 2011; 123:557.

32.

Alexander-Sefre

, Chee

, Spencer

, Menon

, Shepherd

. Surgical morbidity associated with radical trachelectomy and radical hysterectomy. Gynaecol Oncol, 2006; 101:450.