Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. It is estimated that the incidence of new ECs diagnosed every year in the United States has increased of more than 9000 cases between 2003 and 2013.1
This feature reflects the increase prevalence of risk factors (eg, obesity) related to EC.2 In addition, the increasing population age and “the feminization of aging” concur to increase this phenomenon.3 In fact, although the EC incidence does not follow the conventional linear pattern between aging and number of new diagnoses as in other solid tumors, aging is related to a higher risk of developing EC.3,4
Regardless of patients’ age, surgery represents the mainstay of treatment for women affected by EC. Hysterectomy (plus the removal of adnexal structures) alone or associated with retroperitoneal staging allows the removal of primary tumor, thus being curative itself and being useful to tailor adjuvant treatments in patients at high risk of recurrence.1,5,6 However, the surgical treatment in elderly women is often controversial. Ideally, the curative approach needs to take in account not only life expectancy but also quality of life and “health expectancy.”7 However, despite the growing incidence of EC in the elderly, only few investigations evaluated how different surgical approaches influence outcomes in older women.7–11 This is because age continues to be considered a relative contraindication to perform minimally invasive surgery.11 Recently, our study group showed that, in experienced hands, laparoscopic surgery is related to better perioperative outcomes than open surgery in women aged 70 and 75 years or older.3,12 However, no data regarding the use of laparoscopic staging surgery in EC patients aged 80 years or older are still available. Hence, we designed the present study to evaluate the feasibility of laparoscopic approach in women aged 80 years or older and to evaluate long-term outcomes of laparoscopic, open abdominal, and vaginal approaches in this vulnerable cohort of patients.
We searched for the data of women who underwent primary surgical treatment of EC at the Gynecologic Oncology Unit of the University of Insubria, Ospedale di Circolo, Fondazione Macchi (Varese, Italy), between January 1992 and May 2013. In our institution, research activities involving the study of existing data are exempt from the requirement for institutional review board approval. Patients gave written consent for the use of personal information for health research.
From 2002, laparoscopic approach was attempted in all women with early-stage EC, unless specific contraindications to laparoscopic surgery or general anesthesia existed. Women who underwent laparoscopic treatment were compared with patients who had open abdominal and vaginal surgery. The open abdominal group consists in a historical cohort of patients aged 80 years or older who had open abdominal surgery before the incorporation of laparoscopy at our institution, during the period 1992 and 2002. The vaginal group consists in a cohort of women aged 80 years or older who had vaginal surgery over the whole study period. Usually, vaginal surgery was offered to patients with preoperative diagnosis of complex/atypical hyperplasia or in case of contraindication to general anesthesia. In laparoscopic and open abdominal group, patients had peritoneal washing and total hysterectomy with the removal of adnexal structure, whereas retroperitoneal staging is generally omitted, unless specific indications and good performance status existed.
Surgical stage and degree of glandular differentiation/atypia to determine architectural grade were in accord to the International Federation of Gynecology and Obstetrics (FIGO) criteria,13 whereas the taxonomy proposed by the World Health Organization was used to identify histologic subtypes.14
The patients’ details were retrospectively abstracted by a dedicated database. The comorbidities level was assessed by the Charlson Comorbidity Index (CCI), which predicts the 10-year mortality due to comorbid conditions.3 The performance status was graded using the Eastern Cooperative Oncology Group (ECOG) score.3
All the procedures were performed by skilled surgeons trained for laparoscopic, open, and vaginal procedures. The detailed description of laparoscopic staging is reported elsewhere.3,15 Open abdominal and vaginal surgeries were performed in accord to standard descriptions.16 Over the study period, there were no significant differences in the facilities available for patient care and in the referral patterns of our service. Other aspects of patient management unrelated to surgical approach remained consistent over time. Laparoscopic and open abdominal interventions were performed under general endotracheal anesthesia, whereas usually vaginal surgery was performed under spinal anesthesia. Women received a single dose of prophylactic antibiotic 1 hour before the surgery; antithrombotic prophylaxis was administered with low–molecular weight heparin (30 days) and compression stockings (until full mobilization). Operative times were recorded from the first skin incision to the last suture (skin to skin). Blood loss was estimated from the contents of suction devices. Hospital stay was counted from the first postoperative day. Intraoperative complications included any events occurred during surgery. Organs damage and need of intraoperative blood transfusions were considered intraoperative complications. Postoperative complications were graded per the Accordion Severity Classification system.17 For the purpose of this study, grade 2 or worse complications, occurred within 6 weeks after surgery, were analyzed.
Regarding adjuvant treatment, radiotherapy (whole pelvic radiation [50.4 Gy] with or without vaginal brachytherapy for a maximal dose of 70 Gy) was indicated in women with cancer and tumor (FIGO stages II, IIIA, and IIIB) invading more than 50% of the myometrium. External beam radiation (50.4 Gy for 5–6 weeks) was given to women with proven lymph node metastases (FIGO stage IIIC). Six cycles of platinum-based chemotherapy were administered in cases of systemic spread or type II EC. Chemotherapy dose was modulated based on patient characteristics. A combined chemotherapy-radiotherapy regimen was administered according to the presence of both previously mentioned criteria.1 Follow-up evaluations, with pelvic inspection and ultrasound examination, were planned according to institutional guidelines.3,15 Dates and sites of recurrence were recorded. Patients were considered by the intention-to-treat principle. Hence, for the statistical analysis, laparoscopic and vaginal operations converted to open surgery were included in the laparoscopic and vaginal group, respectively. Statistical analysis was performed with GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, CA). Normality testing (D’Agostino and Pearson test) was performed to determine whether data were sampled from a Gaussian distribution. One-way analysis of variance and Kruskal-Wallis test were performed to compare 3 or more groups of continuous parametric and nonparametric variables, respectively. The χ2 test was used to analyze proportions. The incidence of events between 2 groups was analyzed for statistical significance by using the Fisher exact test. Ninety-five percent confidence intervals were calculated for each comparison. When we evaluated only 2 groups, the t test and Mann-Whitney U test were used to compare continuous parametric and nonparametric variables, respectively. Disease-free and overall survivals, within the first 5 years after surgery, were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. P values less than 0.05 were considered statistically significant. Post hoc power calculation was performed using G*Power version 3.1 (Heinrich Heine University).
During the study period, 726 patients had treatment of their EC. Sixty-three patients (9%) were aged 80 years or older; the proportion of patients aged 80 years or older increased over the study period (P = 0.02, χ2 for trend).
All elderly patients were suitable for surgical treatment. Laparoscopic, open abdominal, and vaginal approaches were performed in 22 (35%), 25 (40%), and 16 (25%) cases, respectively. Patients’ characteristics are listed in Table 1. Overall, no differences in baseline characteristics were recorded between groups. In particular, comorbidities levels (assessed by CCI), ECOG performance status, and the American Society of Anesthesiologists score did not differ statistically between groups (P > 0.05).
All laparoscopic procedures were completed laparoscopically, whereas a conversion (6%) from vaginal to open procedure occurred in a patient with severe pelvic adhesions (P = 0.42; odds ratio, 4.3; 95% confidence interval, 0.16–114.1). Disease’s characteristics are reported in Table 2.
Patients undergoing laparoscopy experienced similar operative time than patients undergoing open abdominal and vaginal surgery (P = 0.75). Estimated blood loss was lower in the laparoscopic group in comparison to open abdominal and vaginal groups (P = 0.008). However, only the vaginal group experienced a higher transfusion rate in comparison to laparoscopy and open surgery (12.5% vs 0% vs 0%; P = 0.04). The median (range) length of hospital stay was 2 (1–15) days, 7 (4–32) days, and 3 (1–8) days in laparoscopic, open abdominal, and vaginal groups, respectively (P < 0.001). Table 3 reports perioperative outcomes.
No intraoperative complications were recorded among the 3 groups (P = not significant). Patients undergoing laparoscopy experienced a lower rate of all postoperative complications (P = 0.09) and Accordion grade greater than or equal to 2 postoperative complications (P = 0.05) in comparison to patients undergoing open abdominal and vaginal surgery. Overall, 7 (11%) postoperative grade greater than or equal to 2 complications occurred, 3 (12%) and 4 (25%) after open abdominal and vaginal surgery, respectively, whereas no grade greater than or equal to 2 complications occurred among the laparoscopic group. In the open abdominal group, complications included prolonged ileus requiring medical treatment (n = 1; Accordion grade 2), pulmonary embolism (n = 1; Accordion grade 2), and bowel obstruction (n = 1; Accordion grade 4). In the vaginal group, complications included febrile morbidity (n = 2; Accordion grade 2) and postoperative anemia requiring blood transfusions (n = 2; Accordion grade 2).
No between-group differences in adjuvant therapy administration rate were observed (P > 0.05). The mean (SD) follow-up for laparoscopic, open abdominal, and vaginal surgery was 30.7 (21.7) months, 54.1 (45) months, and 29.5 (17) months, respectively (P = 0.02). Overall, at 3 years, 71%, 12%, and 17% of patients were alive without evidence of disease, death of disease, and death for other causes, respectively, whereas at 5 years, 52%, 22%, and 26% of patients were alive without evidence of disease, death of disease, and death for other causes, respectively. The route of surgical approach did not influence the risk of developing recurrence; recurrences after laparoscopic, open abdominal, and vaginal approaches were 3 (14%), 5 (20%), and 3 (19%), respectively (P > 0.05). Table 4 displays the survival outcomes. In addition, the 5-year disease-free survival (P = 0.97, log-rank test) and 5-year overall survival (P = 0.94, log-rank test) were similar between groups (Fig. 1).
The present study showed that laparoscopy is a safe and feasible approach for EC staging in patients older than 80 years. In comparison to open abdominal and vaginal approaches, laparoscopic surgery is related to better perioperative outcomes because of reducing estimated blood loss, hospital stay, and complication rate without neglecting the long-term oncologic outcomes.
Aging reduces physiological reserve and increases vulnerability to stressor events, including surgery. Hence, the reduction of length of hospital stay and complications is paramount, especially in those older patients who poorly tolerate hospital-related morbidity. In fact, in elderly, prolonged hospitalization is related to an increased risk of cognitive dysfunction, poor outcomes, and risk of death.18
Although growing evidence suggested that minimally invasive surgery overcomes open surgery in perioperative outcomes in the management of early-stage EC,3,19,20 the data in the elderly population are limited. Only few studies investigated the safety of laparoscopic approach in women older than 65 years.8–11 In 2001, Scribner et al8 reported encouraging results about the applicability of laparoscopy for EC patients aged 65 years or older. However, more than 10 years later, only few studies reporting outcomes of elderly patients are still available. In addition, to the best of our knowledge, studies focused on patients older than 80 years are not yet performed.
In a recent investigation of our study group comparing laparoscopic and open abdominal approaches for EC patients aged 75 years or older, we observed that laparoscopy is related to improved perioperative outcomes.3 The present study corroborates these findings, breaking the barrier of 80 years old.
The results of the present study show that laparoscopy overcomes both open abdominal and vaginal approaches in women older than 80 years. Although our results agree with a large body of the literature suggesting better surgical outcomes of laparoscopy in comparison to open surgery, no other studies comparing laparoscopy with vaginal approach for the management of elderly EC are identified. Looking at perioperative results, vaginal route is still considered the less invasive gynecological procedure for the removal of the uterus. However, our data showed that laparoscopy ensures better perioperative outcomes than vaginal surgery. We can speculate that atrophic tissues, a narrow vagina, and the location of adnexal structure, which is not often favorable, may influence surgical results in women aged older than 80 years.
Interestingly, in our series, the proportion of patients aged 80 years or older increased over the study period, thus underlining the progressive growth of the geriatric population in developed countries. This figure suggested the practical need to identify the best surgical approach for these patients. Moreover, our data underlined that despite the mere chorological age, patients experienced reasonable long-term survival outcomes, thus suggesting the need to eradicate the disease and not only deliver symptomatic treatments. In fact, in the last decades, life and health expectancy increased dramatically.3
The main merits of the present investigation are represented by the innovative topic and the potential applicability of our results in selected clinical settings, whereas the main limitation includes the retrospective single-center design. In addition, 3 points of our investigation deserve to be addressed as follows: (1) All surgical procedures were performed by the same team of skilled surgeons, then our results are not projectable for a setting that lacks experience in laparoscopic surgery; (2) In our series, only a few patients had retroperitoneal staging. The current evidence does not provide evidence supporting the execution of lymphadenectomy in elderly patients with low-risk and intermediate-risk EC.1,5,6 Hence, because elderly women have a higher risk of morbidity, we usually omit the execution of retroperitoneal staging in this group; (3) Owing the relative small sample size of the study, we were not able to adjust our population in accord to different variables. In fact, because women were not randomly assigned to a surgical procedure, the possibility of confounding due to inherent differences between women eligible for different surgical procedures cannot be ruled out as an explanation of our results. However, although we can suppose that women undergoing vaginal surgery were more medically ill than patients who had other surgical approaches, the use of a standardized methods to “weight” comorbidities (CCI 7) and performance status (ECOG) allow us to clearly objectify patients’ overall status and then their capability to upfront surgery. In addition, a post hoc power calculation suggested that more than 3000 patients are needed to achieve a statistical difference (with a 5% level of significance and 80% power) in complications and survival between groups, thus suggesting that such a trial is not feasible.
In conclusion, the present study suggests the feasibility, safety, and long-term effectiveness of laparoscopic surgery in the management of EC aged older than 80 years. In accord to our results, age per se should not be considered longer a contraindication to minimally invasive surgery. In fact, in experienced hands, laparoscopy is related to improved perioperative outcomes without neglecting long-term outcomes. Further attempts are needed to reduce the rate of open abdominal approach, thus improving perioperative outcomes.
1. Bogani G, Dowdy SC, Cliby WA, et al. Role of pelvic and para-aortic lymphadenectomy in endometrial cancer
: current evidence. J Obstet Gynaecol Res. 2014; 40: 301–311.
2. Ward KK, Roncancio AM, Shah NR, et al. The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women. Am J Obstet Gynecol. 2013; 209: 579.e1–579.e5.
3. Bogani G, Cromi A, Uccella S, et al. Laparoscopic staging
in women older than 75 years with early stage endometrial cancer
: comparison with open surgery. Menopause. 2014; Jan 27. Doi: 10.1097/GME.0000000000000202 [Epub ahead of print].
5. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer
: a paradigm shift in surgical staging
. Gynecol Oncol. 2008; 109: 11–18.
6. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer
of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010; 375: 816–823.
7. Robbins JR, Gayar OH, Zaki M, et al. Impact of age-adjusted Charlson comorbidity score on outcomes for patients with early-stage endometrial cancer
. Gynecol Oncol. 2013; 131: 593–597.
8. Scribner DR Jr, Walker JL, Johnson GA, et al. Surgical management of early-stage endometrial cancer
in the elderly
: is laparoscopy
feasible? Gynecol Oncol. 2001; 83: 563–568.
9. Frey MK, Ihnow SB, Worley MJ Jr, et al. Minimally invasive staging
of endometrial cancer
is feasible and safe in elderly
women. J Minim Invasive Gynecol. 2011; 18: 200–204.
10. Vaknin Z, Perri T, Lau S, et al. Outcome and quality of life in a prospective cohort of the first 100 robotic surgeries for endometrial cancer
, with focus on elderly
patients. Int J Gynecol Cancer. 2010; 20: 1367–1373.
11. Ball A, Bentley JR, O’Connell C, et al. Choosing the right patient: planning for laparotomy or laparoscopy
in the patient with endometrial cancer
. J Obstet Gynaecol Can. 2011; 33: 468–474.
12. Ghezzi F, Cromi A, Siesto G, et al. Use of laparoscopy
in older women undergoing gynecologic procedures: is it time to overcome initial concerns? Menopause. 2010; 17: 96–10.
13. Pecorelli S. Revised FIGO staging
for carcinoma of the vulva, cervix and endometrium. Int J Gynaecol Obstet. 2009; 105: 103–104.
14. Scully RE, Bonfiglio TA, Kurman RJ, et al. World Health Organization International Histologic Classification of Tumors: Histological Typing of Female Genital Tract Tumors. 2nd ed. Berlin, Germany: Springer-Verlag; 1994: 13–18.
15. Bogani G, Cromi A, Uccella S, et al. Safety of peri-operative aspirin therapy in minimally invasive endometrial cancer staging
. J Minim Invasive Gynecol. 2014; Jan 21. Doi: 10.1016/j.jmig.2014.01.008. [Epub ahead of print].
16. Thompson JD. Hysterectomy
. In: Thompson JD, Rock JA, eds. TeLinde’s Operative Gynecology. 7th ed. Philadelphia, PA: JB Lippincott; 1992: 633–738.
17. Strasberg SM, Linehan DC, Hawkins WG. The accordion severity grading system of surgical complications. Ann Surg. 2009; 250: 177–186.
18. Hassan A, Anderson C, Kypson A, et al. Clinical outcomes in patients with prolonged intensive care unit length of stay after cardiac surgical procedures. Ann Thorac Surg. 2012; 93: 565–569.
19. Palomba S, Ghezzi F, Falbo A, et al. Laparoscopic versus abdominal approach to endometrial cancer
: a 10-year retrospective multicenter analysis. Int J Gynecol Cancer. 2012; 22: 425–433.
20. Mok ZW, Yong EL, Low JJ, et al. Clinical outcomes in endometrial cancer
care when the standard of care shifts from open surgery to robotics. Int J Gynecol Cancer. 2012; 22: 819–825.
Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Endometrial cancer; Laparoscopy; Staging; Hysterectomy; Elderly