ORIGINAL STUDY
Recurrence of Early Stage Cervical Cancer After Laparoscopic Versus Open Radical Surgery Rosa Maria Laterza, MD,*Þ Stefano Uccella, MD, PhD,Þ Jvan Casarin, MD,Þ Chiara Morosi, MD,Þ Maurizio Serati, MD,Þ Heinz Koelbl, MD,* and Fabio Ghezzi, MDÞ
Objective: The aim of the study was to compare site and time to recurrence in patients affected by early stage cervical cancer (CC) treated with laparoscopy radical hysterectomy (LRH) versus abdominal radical hysterectomy (ARH). Methods: This retrospective study was conducted in a university teaching, tertiary referral center hospital. We included patients undergoing either LRH or open ARH to treat CC. Results: One hundred fifty patients were included, 82 submitted to LRH and 68 submitted to ARH. Baseline characteristics of the 2 groups were comparable, except for body mass index higher in ARH group. Patients undergoing LRH experienced less blood loss (100 vs 400 mL, P G 0.0001), less lymph nodes removed (20 vs 31, P = 0.001), and shorter recovery (4 vs 8 days, P = 0.0005) in comparison with the ARH group. No significant differences were found regarding recurrence rate (9 vs 13, P = 0.17) and time to recurrence (8 vs 17 months, P = 0.066) between LRH and ARH group. Sites of recurrence were also comparable between the 2 groups: 2/9 versus 2/13 (P = 1) local recurrence, 4/9 versus 8/13 (P = 0.66) pelvic recurrence, 4/9 versus 7/13 (P = 1) distant recurrence in LRH and ARH groups, respectively. The most frequent sites of recurrence were pelvic and distant (44.4%) in LRH group and pelvic (61.5%) in ARH group. Conclusions: Our data demonstrate that early stage CC can be treated with LRH with similar recurrence rates and patterns in comparison with ARH, reassuring its continuing clinical use. Key Words: Early stage cervical cancer, Laparoscopy, Radical hysterectomy, Recurrence Received September 16, 2015, and in revised form November 8, 2015. Accepted for publication November 9, 2015. (Int J Gynecol Cancer 2016;26: 547Y552)
surgical management for selected early stage S tandard cervical cancer (CC) is radical hysterectomy (RH).
The use of total laparoscopy RH (LRH) as a possible alternative to traditional abdominal surgery was described in the 90s by Nezhat et al3,4 and Canis et al.5 Progressively, several studies have confirmed safety, feasibility, and effectiveness of the laparoscopic approach, describing also its advantages, such as minimal intraoperative blood loss,
less postoperative pain, faster recovery, and reduction of health care costs.6Y15 Although positive immediate effects of LRH on treatment of CC have been abundantly demonstrated, limited data are so far available on the long-term oncological outcomes in comparison with traditional surgery. This study aims to investigate rates, sites, and time to recurrence of the largest single institutional cohort of consecutive
*Clinical Division of General Gynecology and Gynecological Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria; and †Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy. Copyright * 2016 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000627
Address correspondence and reprint requests to Rosa Maria Laterza, MD, Clinical Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria E-mail: [email protected]. This study was not financed by any source of support. The authors declare no conflicts of interest.
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cases treated with laparoscopic versus open abdominal RH (ARH) for early stage CC.
MATERIALS AND METHODS In our retrospective study, we considered all consecutive patients who underwent surgical treatment for CC (RH class IIIII, either by laparoscopy or by laparotomy + systematic pelvic lymphadenectomy) at our department between 1997 and 2014, after obtaining approval from our institutional review board. All patients included gave written informed consent for the use of personal information for health research. Radical hysterectomy and systematic bilateral pelvic lymphadenectomy were performed as standard surgical treatment for IA1, IA2, IB1, and IIA1, either with laparoscopic or with open approach, according to Piver-Rutledge classification16 and were modulated after the clinical staging and the patient performance status. Laparoscopy RH was introduced at our department for primary treatment of early stage CC (stage IA2-IB1, IIA G4 cm) in 2004.17 Since then, laparoscopic approach had been offered to all patients presenting with CC, unless absolute anesthesiological contraindications to laparoscopy (due to presence of medical comorbidities) existed. The laparoscopic technique has been previously reported6,18; ARH was performed as described by Meigs19 in 1975. All operations were accomplished by skilled laparoscopists with extensive training and experience in gynecologic oncology and in advanced laparoscopic procedures. For the study purpose, the inclusion criteria were the following: age older than 18 years; histologically confirmed invasive CC; clinical International Federation of Obstetrics and Gynaecology (FIGO) stage IA1, IA2, IB1, and IIA1; eligibility for surgical treatment. As exclusion criteria, we considered patients submitted to neoadjuvant chemotherapy, to exclusive radiotherapy, and to exclusive chemoradiotherapy and patients submitted to fertility-sparing treatment (at our institution, we propose coldknife cervical cone excisional procedures to patients younger than 36 years with squamocellular CC stage IA1). Adjuvant treatments (radiotherapy T chemotherapy) were performed in case of positive nodes, parametrial involvement, positive surgical margins after radical surgery, tumor volume of surgical specimen larger than 4 cm, lymphovascular spaces involvement, and deep (91/3) cervical stromal infiltration on surgical specimen together with the presence of others risk factors (adenosquamous histopathology type, G3 histopathology grade). Follow-up evaluations were scheduled every 4 months for the first 3 years after surgery, every 6 months between 2 and 5 years after surgery and annually until 10 years after diagnosis. The follow-up controls consisted in a clinical pelvic evaluation and yearly instrumental examinations (pelvic-abdominal ultrasound, chest radiography, and possibly eventual abdomenpelvic computed tomography if considered necessary after clinical assessment). Cytology by Papanicolau smear was performed 6 and 12 months after surgery and then yearly. Recurrences were classified as follows: local (vaginal), pelvic, lymph nodes (pelvic and para-aortic), and distant
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(hematogenous, peritoneal, and other lymphatic). The recurrence treatment has been personalized on the basis of recurrence site, patient’s performance status, and previous CC treatment. Time to recurrence was calculated from the date of surgery in months. Details of demographic (eg, age, body mass index [BMI], medical history), pathological (eg, histotype, stage, grading), and operative (ie, surgical parameters) characteristics were collected into a dedicated institutional review board approved oncological database. The management and outcome of each postoperative complication were recorded to grade severity on the basis of the Clavien-Dindo scoring system.20 Stage of disease and grading were assessed using the FIGO system.21 Histological subtypes were reported according to the World Health Organization system.22 Statistical analysis was performed using GraphPad Prism, Version 6.00 for Windows (GraphPad Software, San Diego, Calif ) and IBM-Microsoft SPSS Version 20.0 for Mac. Continuous variables were compared with Mann-Whitney or Student t test as appropriate. Proportions of categorical variables were analyzed for statistical significance by using the Fischer exact test. A P value of less than 0.05 was considered statistically significant.
RESULTS A total of 331 women were originally considered: 150 patients satisfied our inclusion/exclusion criteria and were considered for the final analysis. Eighty-two were submitted to LRH and 68 to ARH. None of the LRH was converted to open surgery. Pelvic lymphadenectomy has been avoided in 21 patients: in 19 patients because of stage IA1, in 1 patient because of low performance status, and in 1 patient because the diagnosis of microinvasive carcinoma (IA1) was done after LEEP conization with indication for adjuvant therapy (in this case, the lymphadenectomy would have had no oncological purposes). Age, previous abdominal surgery, medical comorbidities (including hypertension, diabetes, thyroid dysfunction, hepathopathies, human immunodeficiency virus, renal dysfunction, lipid dismetabolism, obesity, brain diseases, cardiopulmonary diseases, neuropathies) and FIGO staging resulted comparable between the 2 groups; BMI was significantly higher in the ARH group (Table 1). The number of lymph nodes removed was higher in the ARH group compared with the LRH group (31 vs 20, P = 0.001). In the LRH group, intraoperative blood loss (100 vs 400 mL, P G 0.0001) and hospital stay (4 vs 8 days, P = 0.0006) were significantly lower compared with the ARH group. No differences were found about intraoperative and postoperative complications (Table 2). Intraoperatively, in the LRH group, a patient had a subcutaneous emphysema; in the ARH group, a patient received intraoperatively blood transfusions for anemia. The postoperative complications in the LRH group were 1 readmission (1.2%) at the 13th postoperative day for abdominal pain, 13 patients (15.9%) had urinary retention, 3 patients (3.7%) had fever, 2 patients (2.4%) had urinary tract infection, 1 patient (1.2%) had anemia, and 1 patient (1.2%) had gastroenteritis. The postoperative complications in the ARH group were the following: 1 patient (1.5%) had a lymphocele, 3 patients (4.4%) had severe anemia, 5 patients * 2016 IGCS and ESGO
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Recurrence of Early Stage CC
TABLE 1. Demographic and oncological data LRH (n = 82) Age, (y) BMI Previous abdominal surgery Medical comorbidities FIGO stage, n (%) IA1 IA2 IB1 IIA1
43 23.44 26 22 21 5 53 3
(24Y77) (16.9Y39.76) (31.7) (26.8) (25.6) (6) (64.6) (3.6)
ARH (n = 68)
P
48 (26Y85) 24.52 (19.3Y43.3) 23 (33.8) 23 (33.8)
0.18 0.044 0.86 0.37
9 (13.2) 2 (2.9) 53 (77.9) 4 (5.8)
0.06 0.45 0.1 0.7
Data are expressed as median (range) or n (%).
(7.4%) had urinary tract infection, 2 patients (2.9%) had urinary retention, 1 patient (1.5%) had ascites, and 1 patient (1.5%) had fever (Table 2). No significant differences have been reported in terms of overall recurrence rate between the LRH and ARH groups (10.9% [9/82] vs 19.1% [13/68], P = 0.17), time to recurrence (8 vs 17 months, P = 0.066), and adjuvant therapy (35.3% [29/82] vs 27.9% [19/68], P = 0.38, respectively, Table 3). All recurrences occurred within 5 years after CC diagnosis, except for 1 woman in ARH group who had a disease recurrence after 172 months. One patient in ARH group was lost at first oncological follow-up and it was not possible to know whether she had a recurrence or not. The follow-up was significantly longer in the ARH in comparison with LRH group (121.2 vs 43.5 months, P G 0.0001, Table 3). Nine women (10.9%) treated with LRH had recurrence (6% of all patients after RH); of them, 4 presented distant, 4 pelvic, and 2 local recurrences. The time to recurrence is 8 months.1Y36 Of the 82, the number of women who died of disease in the laparoscopic group were 3 (3.6%).
Thirteen patients (19.1%) who undergone ARH had recurrence (8.6% of all patients after RH); of them, 7 presented distant, 8 pelvic, and 2 local recurrences. The time to recurrence is 17 (5Y172) months. Of the 68, the number of patients who died of disease in the open surgery group were 7 (10.2%). The sites of recurrence were comparable between the 2 groups; in the LRH group, the pelvic and distant recurrences were more frequent than the vaginal cuff recurrences (44.4% and 22.2%, respectively); in the ARH group, the most frequent site of recurrence was the pelvis (61.5%, Table 4). Looking at factors correlating with disease recurrence, we observed that patients with recurrence had a more advanced FIGO stage and have been submitted to adjuvant therapy compared with women without recurrence (P G 0.0001 and P G 0.0001, respectively). No significant differences have been found regarding squamocellular histotype, G3 grading, pelvic lymphadenectomy, lymphovascular spaces invasion, and type of surgical approach (Table 5). No differences have been detected about pelvic (6/12 [50%] vs 3/3 [100%], P = 0.22) and extrapelvic (9/12 [75%]
TABLE 2. Surgical details LRH (n = 82) Surgical treatment Piver1 Piver2 Piver3 Lymph nodes removed Positive lymph nodes Intraoperative complications Postoperative complications Complications Clavien-Dindo Q2 Intraoperative blood loss, mL Hospital stay, d
4 (4.8) 7 (8.5) 71 (86.5) 20 (0Y58) 2 (2.4) 1 (1.2) 21 (25.6) 1 (1.2) 100 (20Y1000) 4 (2Y14)
ARH (n = 68) 3 6 59 31 1 1 13 2 400 8
(4.4) (8.8) (71.9) (0Y66) (1.6) (1.6) (19.1) (2.9) (100Y1500) (6Y15)
P 1 1 1 0.001 1 1 0.43 1 G0.0001 0.0005
Data are expressed as median (range) or n (%).
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TABLE 3. Oncological details
Recurrence rate Time to recurrence, m Follow-up, m Adjuvant therapy RT RT + CHT
LRH (n = 82)
ARH (n = 68)
P
9 (10.9) 8 (1Y36) 44.67 (3.4Y158.1) 29 (35.3) 23 (28) 6 (7.3)
13 (19.1) 17 (5Y172) 121.2 (5.9Y266.2) 19 (27.9) 16 (23.5) 3 (4.4)
0.17 0.066 G0.0001 0.38 0.57 0.51
Data are expressed as median (range) or n (%). CHT, chemotherapy; RT, radiotherapy.
vs 1/3 [33.3%], P = 0.24) recurrence in patients submitted to RT adjuvant therapy in comparison with patients not submitted to RT adjuvant therapy, respectively.
DISCUSSION The study shows that not only recurrence rate and time to recurrence, but also the specific anatomical site of recurrence after laparoscopic treatment for early CC, are comparable with those of open surgery. Although it is universally recognized that laparoscopy provides evident and consistent advantages more than traditional abdominal surgery in the short-term outcomes (ie, lower blood loss, less wound complications, less pain, faster recovery23,24), one of the main concerns regarding the use of minimally invasive techniques in the field of gynecologic malignancies is its real safety in terms of oncological radicality and survival. Specifically, detractors of endoscopic surgery argue that laparoscopy RH may be less safe than the open abdominal counterpart, mainly because of the manipulation of the uterus through the vagina during the procedure and the use of CO2 to distend the abdomen, which may hypothetically cause the spread of malignant cells, for example, at the site of the trocar entries. Despite the absence of evidence regarding these TABLE 4. Sites of recurrence
Patients with recurrence Site of recurrence Local (vaginal cuff ) % total Pelvic % total Lymph nodes % total Distant % total
LRH (n = 82)
ARH (n = 68)
9
13
2/9 (22.2) 1.6 4/9 (44.4) 2.6 0 0 4/9 (44.4) 2.6
2/13 (15.3) 1.3 8/13 (61.5) 5.3 0 0 7/13 (53.8) 4.6
Data are expressed as n (%).
550
P
1 1 0.66 0.37 1 1 1 0.54
criticisms, still the scientific community in the field of gynecologic oncology seems reluctant to consider LRH for CC as a safe and advantageous alternative to ARH. Several retrospective and prospective reports have demonstrated that laparoscopic and open RH have similar outcomes in terms of diseasefree and overall survival.11,15,25,26 However, someone may object that different patterns of recurrence between the two procedures may disguise a different ability to obtain local control of the disease, which may be masked by adjuvant treatment or salvage therapy, when looking at the crude general disease-free and overall survival. In other words, if laparoscopic surgery were not equivalent to open surgery in terms of oncological radicality when CC is to be treated, one may expect that the rate of local recurrences (at the level of the vaginal cuff, the pelvis, and the lymph nodes) is higher, irrespectively of the disease-free and overall survival.
TABLE 5. Oncological details in patients with and without recurrence No Recurrence recurrence (n = 22) (n = 127) Squamocellular histotype Grading G3 Pelvic lymphadenectomy Adjuvant therapy Lymphovascular spaces involvement Positive lymph nodes FIGO stage IA1 IA2 IB1 IIA1 LRH
P
14 (63.6)
88 (69.2)
0.62
5 (22.7) 21 (95.4)
33 (25.9) 105 (82.6)
1 0.2
29 (22.8) G0.0001 0 1
19 (86) 0 0
2 (1.5)
0 (0) 0 (0) 15 (68.1) 7 (31.8) 9 (40.9)
1
28 (22) 0.01 7 (5.5) 0.59 92 (72.4) 0.79 0 G0.0001 73 (57.4) 0.16
Data are expressed as n (%).
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Our single-center study on a notable number of patients shows that these objections are not valid. The rate of local recurrences, as well as the total number of recurrences, is comparable between open and laparoscopic approach. It should be noted that the high percentage of patients submitted to adjuvant treatment as well as the inclusion of low stage tumors in our population may have had some impact on the results and may explain the low rate of recurrence that we observed. However, tumor characteristics as well as postoperative therapies were well balanced between groups, thus providing strength to our findings. In our study population, disease recurrence rate for early stage CC was 10% to 19% after RH and systematic pelvic lymphadenectomy; this finding is in keeping with the available reports, thus strengthening our results.27Y29 Lower blood loss and shorter recovery stay have been found in patients submitted to LRH in comparison with ARH, according to previous studies14,15,30Y32 and confirming the lower morbidity of the laparoscopic approach. However, it should be taken into account that the higher BMI score and the higher number of lymph nodes removed in the ARH group could have influenced these results. Of note, the intraoperative and postoperative complications were comparable and did not influence neither adjuvant therapy nor its choice. A specific comment should be provided regarding the difference in the number of lymph nodes removed, which is higher in the ARH group. This is likely related to the fact that after laparoscopic surgery was introduced at our institution, we inevitably experienced a period of learning curve of the laparoscopic technique. As already demonstrated,33,34 the surgical skills of performing pelvic lymphadenectomy by laparoscopy improve with experience. Despite the mere difference in terms of nodal count removed between the two groups, both the number of positive nodes and, most importantly, the rate of nodal recurrences were similar between the two groups; this implies that probably extensive nodal dissections performed on all patients without selection of cases may be of little value for the oncological prognosis of patients with CC. The findings of similar rate of positive lymph nodes between recurrence and no recurrence groups confirm our assumption. The higher rate of patients submitted to adjuvant therapy in the recurrence group could be explained by advanced FIGO stage of this population. In contrast with some cases reports of port-site recurrences after laparoscopic surgery for CC,35Y37 we had no cases of relapse at the sites of entry in the LRH. Of course, our study was underpowered to evaluate in depth this specific aspect. However, it must be emphasized that no preventive measure was adopted to reduce the risk of port-site metastases in our series; although limited by the low incidence of such event, our data suggest that the risk of trocar recurrences (if real) may not be regarded as a major concern when discussing of the use of LRH. Considering the more recent introduction of the laparoscopic approach, patients who underwent ARH had a longer follow-up than patients who received LRH. However, except for one case, all the recurrences occurred within 60 months (median, 9Y17 months) in the two groups. These data are in
Recurrence of Early Stage CC
accordance with the literature and further strengthen our study.38,39 One of the limits of the present study is represented by its retrospective nature. Moreover, the long study period considered, if on the one hand, offers advantages to evaluate parameters such as disease-free and overall survival; on the other hand, it does not allow to guarantee homogeneity about surgical techniques, therapies, and imaging techniques. However, it should be kept in mind that because of the decreasing incidence of cervical carcinoma, it is unlikely that large well designed randomized trials with long-lasting follow-up will be performed on the recurrence patterns of CC in the near future. In this view, retrospective data have still an importance to shed light on this specific issue. Among the strengths of our study, we mention that it represents a single center experience of surgical management of early stage CC (with the intrinsic advantage of a higher homogeneity of treatment and technique, despite the long study period), the use of standardized institutional protocols and definitions, and the fact that it is one of the very few studies specifically focusing on the patterns of recurrence of early stage CC treated with laparoscopic versus open RH. From this study, we can conclude that there is a substantial comparability of laparoscopy and laparotomy in terms of long-term oncological outcomes in patients affected by early stage CC; in particular, our results show that the laparoscopic approach does not influence the recurrence rate, the localization of recurrence, and the time to recurrence. Our study supports the use of LRH for appropriately selected patients with early stage CC. Although larger prospective multicenter randomized trials are needed to confirm our results, our investigation provides further evidence for the implementation of LRH in the treatment of patients with early stage CC.
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24. Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol. 2009;27:5331Y5336. 25. Ditto A, Martinelli F, Bogani G, et al. Implementation of laparoscopic approach for type B radical hysterectomy: a comparison with open surgical operations. Eur J Surg Oncol. 2015;41:34Y39. 26. Taylor SE, McBee WC Jr, Richard SD, et al. Radical hysterectomy for early stage cervical cancer: laparoscopy versus laparotomy. JSLS. 2011;15:213Y217. 27. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet. 1997;350:535Y40. 28. Lim KC, Howells RE, Evans AS. The role of clinical follow up in early stage cervical cancer in South Wales. BJOG. 2004;111:1444Y1448. 29. Bodurka-Bevers D, Morris M, Eifel PJ, et al. Posttherapy surveillance of women with cervical cancer: an outcomes analysis. Gynecol Oncol. 2000;78:187Y193. 30. Spirtos NM, Eisenkop SM, Schlaerth JB, et al. Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy in patients with stage I cervical cancer: surgical morbidity and intermediate follow-up. Am J Obstet Gynecol. 2002;187:340Y348. 31. Nam JH, Park JY, Kim DY, et al. Laparoscopic versus open radical hysterectomy in early-stage cervical cancer: long-term survival outcomes in a matched cohort study. Ann Oncol. 2012;23:903Y911. 32. Park JY, Kim DY, Kim JH, et al. Laparoscopic versus open radical hysterectomy in patients with stage IB2 and IIA2 cervical cancer. J Surg Oncol. 2013;108:63Y69. 33. Tahmasbi Rad M, Wallwiener M, Rom J, et al. Learning curve for laparoscopic staging of early and locally advanced cervical and endometrial cancer. Arch Gynecol Obstet. 2013;288:635Y642. 34. Ghezzi F, Cromi A, Uccella S, et al. Nerve-sparing minilaparoscopic versus conventional laparoscopic radical hysterectomy plus systematic pelvic lymphadenectomy in cervical cancer patients. Surg Innov. 2013;20:493Y501. 35. Tjalma WA, Winter-Roach BA, Rowlands P, et al. Port-site recurrence following laparoscopic surgery in cervical cancer. Int J Gynecol Cancer. 2001;11:409Y412. 36. Kohlberger PD, Edwards L, Collins C, et al. Laparoscopic port-site recurrence following surgery for a stage IB squamous cell carcinoma of the cervix with negative lymph nodes. Gynecol Oncol. 2000;79:324Y326. 37. Lavie O, Cross PA, Beller U, et al. Laparoscopic port-site metastasis of an early stage adenocarcinoma of the cervix with negative lymph nodes. Gynecol Oncol. 1999;75:155Y157. 38. Wang J, Wang T, Yang YY, et al. Patient age, tumor appearance and tumor size are risk factors for early recurrence of cervical cancer. Mol Clin Oncol. 2015;3:363Y366. 39. Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol. 2012;30:695Y700.
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Recurrence of Early Stage Cervical Cancer After Laparoscopic Versus Open Radical Surgery Rosa Maria Laterza, MD,*Þ Stefano Uccella, MD, PhD,Þ Jvan Casarin, MD,Þ Chiara Morosi, MD,Þ Maurizio Serati, MD,Þ Heinz Koelbl, MD,* and Fabio Ghezzi, MDÞ
Objective: The aim of the study was to compare site and time to recurrence in patients affected by early stage cervical cancer (CC) treated with laparoscopy radical hysterectomy (LRH) versus abdominal radical hysterectomy (ARH). Methods: This retrospective study was conducted in a university teaching, tertiary referral center hospital. We included patients undergoing either LRH or open ARH to treat CC. Results: One hundred fifty patients were included, 82 submitted to LRH and 68 submitted to ARH. Baseline characteristics of the 2 groups were comparable, except for body mass index higher in ARH group. Patients undergoing LRH experienced less blood loss (100 vs 400 mL, P G 0.0001), less lymph nodes removed (20 vs 31, P = 0.001), and shorter recovery (4 vs 8 days, P = 0.0005) in comparison with the ARH group. No significant differences were found regarding recurrence rate (9 vs 13, P = 0.17) and time to recurrence (8 vs 17 months, P = 0.066) between LRH and ARH group. Sites of recurrence were also comparable between the 2 groups: 2/9 versus 2/13 (P = 1) local recurrence, 4/9 versus 8/13 (P = 0.66) pelvic recurrence, 4/9 versus 7/13 (P = 1) distant recurrence in LRH and ARH groups, respectively. The most frequent sites of recurrence were pelvic and distant (44.4%) in LRH group and pelvic (61.5%) in ARH group. Conclusions: Our data demonstrate that early stage CC can be treated with LRH with similar recurrence rates and patterns in comparison with ARH, reassuring its continuing clinical use. Key Words: Early stage cervical cancer, Laparoscopy, Radical hysterectomy, Recurrence Received September 16, 2015, and in revised form November 8, 2015. Accepted for publication November 9, 2015. (Int J Gynecol Cancer 2016;26: 547Y552)
surgical management for selected early stage S tandard cervical cancer (CC) is radical hysterectomy (RH).
The use of total laparoscopy RH (LRH) as a possible alternative to traditional abdominal surgery was described in the 90s by Nezhat et al3,4 and Canis et al.5 Progressively, several studies have confirmed safety, feasibility, and effectiveness of the laparoscopic approach, describing also its advantages, such as minimal intraoperative blood loss,
less postoperative pain, faster recovery, and reduction of health care costs.6Y15 Although positive immediate effects of LRH on treatment of CC have been abundantly demonstrated, limited data are so far available on the long-term oncological outcomes in comparison with traditional surgery. This study aims to investigate rates, sites, and time to recurrence of the largest single institutional cohort of consecutive
*Clinical Division of General Gynecology and Gynecological Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria; and †Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy. Copyright * 2016 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000627
Address correspondence and reprint requests to Rosa Maria Laterza, MD, Clinical Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria E-mail: [email protected]. This study was not financed by any source of support. The authors declare no conflicts of interest.
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cases treated with laparoscopic versus open abdominal RH (ARH) for early stage CC.
MATERIALS AND METHODS In our retrospective study, we considered all consecutive patients who underwent surgical treatment for CC (RH class IIIII, either by laparoscopy or by laparotomy + systematic pelvic lymphadenectomy) at our department between 1997 and 2014, after obtaining approval from our institutional review board. All patients included gave written informed consent for the use of personal information for health research. Radical hysterectomy and systematic bilateral pelvic lymphadenectomy were performed as standard surgical treatment for IA1, IA2, IB1, and IIA1, either with laparoscopic or with open approach, according to Piver-Rutledge classification16 and were modulated after the clinical staging and the patient performance status. Laparoscopy RH was introduced at our department for primary treatment of early stage CC (stage IA2-IB1, IIA G4 cm) in 2004.17 Since then, laparoscopic approach had been offered to all patients presenting with CC, unless absolute anesthesiological contraindications to laparoscopy (due to presence of medical comorbidities) existed. The laparoscopic technique has been previously reported6,18; ARH was performed as described by Meigs19 in 1975. All operations were accomplished by skilled laparoscopists with extensive training and experience in gynecologic oncology and in advanced laparoscopic procedures. For the study purpose, the inclusion criteria were the following: age older than 18 years; histologically confirmed invasive CC; clinical International Federation of Obstetrics and Gynaecology (FIGO) stage IA1, IA2, IB1, and IIA1; eligibility for surgical treatment. As exclusion criteria, we considered patients submitted to neoadjuvant chemotherapy, to exclusive radiotherapy, and to exclusive chemoradiotherapy and patients submitted to fertility-sparing treatment (at our institution, we propose coldknife cervical cone excisional procedures to patients younger than 36 years with squamocellular CC stage IA1). Adjuvant treatments (radiotherapy T chemotherapy) were performed in case of positive nodes, parametrial involvement, positive surgical margins after radical surgery, tumor volume of surgical specimen larger than 4 cm, lymphovascular spaces involvement, and deep (91/3) cervical stromal infiltration on surgical specimen together with the presence of others risk factors (adenosquamous histopathology type, G3 histopathology grade). Follow-up evaluations were scheduled every 4 months for the first 3 years after surgery, every 6 months between 2 and 5 years after surgery and annually until 10 years after diagnosis. The follow-up controls consisted in a clinical pelvic evaluation and yearly instrumental examinations (pelvic-abdominal ultrasound, chest radiography, and possibly eventual abdomenpelvic computed tomography if considered necessary after clinical assessment). Cytology by Papanicolau smear was performed 6 and 12 months after surgery and then yearly. Recurrences were classified as follows: local (vaginal), pelvic, lymph nodes (pelvic and para-aortic), and distant
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(hematogenous, peritoneal, and other lymphatic). The recurrence treatment has been personalized on the basis of recurrence site, patient’s performance status, and previous CC treatment. Time to recurrence was calculated from the date of surgery in months. Details of demographic (eg, age, body mass index [BMI], medical history), pathological (eg, histotype, stage, grading), and operative (ie, surgical parameters) characteristics were collected into a dedicated institutional review board approved oncological database. The management and outcome of each postoperative complication were recorded to grade severity on the basis of the Clavien-Dindo scoring system.20 Stage of disease and grading were assessed using the FIGO system.21 Histological subtypes were reported according to the World Health Organization system.22 Statistical analysis was performed using GraphPad Prism, Version 6.00 for Windows (GraphPad Software, San Diego, Calif ) and IBM-Microsoft SPSS Version 20.0 for Mac. Continuous variables were compared with Mann-Whitney or Student t test as appropriate. Proportions of categorical variables were analyzed for statistical significance by using the Fischer exact test. A P value of less than 0.05 was considered statistically significant.
RESULTS A total of 331 women were originally considered: 150 patients satisfied our inclusion/exclusion criteria and were considered for the final analysis. Eighty-two were submitted to LRH and 68 to ARH. None of the LRH was converted to open surgery. Pelvic lymphadenectomy has been avoided in 21 patients: in 19 patients because of stage IA1, in 1 patient because of low performance status, and in 1 patient because the diagnosis of microinvasive carcinoma (IA1) was done after LEEP conization with indication for adjuvant therapy (in this case, the lymphadenectomy would have had no oncological purposes). Age, previous abdominal surgery, medical comorbidities (including hypertension, diabetes, thyroid dysfunction, hepathopathies, human immunodeficiency virus, renal dysfunction, lipid dismetabolism, obesity, brain diseases, cardiopulmonary diseases, neuropathies) and FIGO staging resulted comparable between the 2 groups; BMI was significantly higher in the ARH group (Table 1). The number of lymph nodes removed was higher in the ARH group compared with the LRH group (31 vs 20, P = 0.001). In the LRH group, intraoperative blood loss (100 vs 400 mL, P G 0.0001) and hospital stay (4 vs 8 days, P = 0.0006) were significantly lower compared with the ARH group. No differences were found about intraoperative and postoperative complications (Table 2). Intraoperatively, in the LRH group, a patient had a subcutaneous emphysema; in the ARH group, a patient received intraoperatively blood transfusions for anemia. The postoperative complications in the LRH group were 1 readmission (1.2%) at the 13th postoperative day for abdominal pain, 13 patients (15.9%) had urinary retention, 3 patients (3.7%) had fever, 2 patients (2.4%) had urinary tract infection, 1 patient (1.2%) had anemia, and 1 patient (1.2%) had gastroenteritis. The postoperative complications in the ARH group were the following: 1 patient (1.5%) had a lymphocele, 3 patients (4.4%) had severe anemia, 5 patients * 2016 IGCS and ESGO
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Recurrence of Early Stage CC
TABLE 1. Demographic and oncological data LRH (n = 82) Age, (y) BMI Previous abdominal surgery Medical comorbidities FIGO stage, n (%) IA1 IA2 IB1 IIA1
43 23.44 26 22 21 5 53 3
(24Y77) (16.9Y39.76) (31.7) (26.8) (25.6) (6) (64.6) (3.6)
ARH (n = 68)
P
48 (26Y85) 24.52 (19.3Y43.3) 23 (33.8) 23 (33.8)
0.18 0.044 0.86 0.37
9 (13.2) 2 (2.9) 53 (77.9) 4 (5.8)
0.06 0.45 0.1 0.7
Data are expressed as median (range) or n (%).
(7.4%) had urinary tract infection, 2 patients (2.9%) had urinary retention, 1 patient (1.5%) had ascites, and 1 patient (1.5%) had fever (Table 2). No significant differences have been reported in terms of overall recurrence rate between the LRH and ARH groups (10.9% [9/82] vs 19.1% [13/68], P = 0.17), time to recurrence (8 vs 17 months, P = 0.066), and adjuvant therapy (35.3% [29/82] vs 27.9% [19/68], P = 0.38, respectively, Table 3). All recurrences occurred within 5 years after CC diagnosis, except for 1 woman in ARH group who had a disease recurrence after 172 months. One patient in ARH group was lost at first oncological follow-up and it was not possible to know whether she had a recurrence or not. The follow-up was significantly longer in the ARH in comparison with LRH group (121.2 vs 43.5 months, P G 0.0001, Table 3). Nine women (10.9%) treated with LRH had recurrence (6% of all patients after RH); of them, 4 presented distant, 4 pelvic, and 2 local recurrences. The time to recurrence is 8 months.1Y36 Of the 82, the number of women who died of disease in the laparoscopic group were 3 (3.6%).
Thirteen patients (19.1%) who undergone ARH had recurrence (8.6% of all patients after RH); of them, 7 presented distant, 8 pelvic, and 2 local recurrences. The time to recurrence is 17 (5Y172) months. Of the 68, the number of patients who died of disease in the open surgery group were 7 (10.2%). The sites of recurrence were comparable between the 2 groups; in the LRH group, the pelvic and distant recurrences were more frequent than the vaginal cuff recurrences (44.4% and 22.2%, respectively); in the ARH group, the most frequent site of recurrence was the pelvis (61.5%, Table 4). Looking at factors correlating with disease recurrence, we observed that patients with recurrence had a more advanced FIGO stage and have been submitted to adjuvant therapy compared with women without recurrence (P G 0.0001 and P G 0.0001, respectively). No significant differences have been found regarding squamocellular histotype, G3 grading, pelvic lymphadenectomy, lymphovascular spaces invasion, and type of surgical approach (Table 5). No differences have been detected about pelvic (6/12 [50%] vs 3/3 [100%], P = 0.22) and extrapelvic (9/12 [75%]
TABLE 2. Surgical details LRH (n = 82) Surgical treatment Piver1 Piver2 Piver3 Lymph nodes removed Positive lymph nodes Intraoperative complications Postoperative complications Complications Clavien-Dindo Q2 Intraoperative blood loss, mL Hospital stay, d
4 (4.8) 7 (8.5) 71 (86.5) 20 (0Y58) 2 (2.4) 1 (1.2) 21 (25.6) 1 (1.2) 100 (20Y1000) 4 (2Y14)
ARH (n = 68) 3 6 59 31 1 1 13 2 400 8
(4.4) (8.8) (71.9) (0Y66) (1.6) (1.6) (19.1) (2.9) (100Y1500) (6Y15)
P 1 1 1 0.001 1 1 0.43 1 G0.0001 0.0005
Data are expressed as median (range) or n (%).
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TABLE 3. Oncological details
Recurrence rate Time to recurrence, m Follow-up, m Adjuvant therapy RT RT + CHT
LRH (n = 82)
ARH (n = 68)
P
9 (10.9) 8 (1Y36) 44.67 (3.4Y158.1) 29 (35.3) 23 (28) 6 (7.3)
13 (19.1) 17 (5Y172) 121.2 (5.9Y266.2) 19 (27.9) 16 (23.5) 3 (4.4)
0.17 0.066 G0.0001 0.38 0.57 0.51
Data are expressed as median (range) or n (%). CHT, chemotherapy; RT, radiotherapy.
vs 1/3 [33.3%], P = 0.24) recurrence in patients submitted to RT adjuvant therapy in comparison with patients not submitted to RT adjuvant therapy, respectively.
DISCUSSION The study shows that not only recurrence rate and time to recurrence, but also the specific anatomical site of recurrence after laparoscopic treatment for early CC, are comparable with those of open surgery. Although it is universally recognized that laparoscopy provides evident and consistent advantages more than traditional abdominal surgery in the short-term outcomes (ie, lower blood loss, less wound complications, less pain, faster recovery23,24), one of the main concerns regarding the use of minimally invasive techniques in the field of gynecologic malignancies is its real safety in terms of oncological radicality and survival. Specifically, detractors of endoscopic surgery argue that laparoscopy RH may be less safe than the open abdominal counterpart, mainly because of the manipulation of the uterus through the vagina during the procedure and the use of CO2 to distend the abdomen, which may hypothetically cause the spread of malignant cells, for example, at the site of the trocar entries. Despite the absence of evidence regarding these TABLE 4. Sites of recurrence
Patients with recurrence Site of recurrence Local (vaginal cuff ) % total Pelvic % total Lymph nodes % total Distant % total
LRH (n = 82)
ARH (n = 68)
9
13
2/9 (22.2) 1.6 4/9 (44.4) 2.6 0 0 4/9 (44.4) 2.6
2/13 (15.3) 1.3 8/13 (61.5) 5.3 0 0 7/13 (53.8) 4.6
Data are expressed as n (%).
550
P
1 1 0.66 0.37 1 1 1 0.54
criticisms, still the scientific community in the field of gynecologic oncology seems reluctant to consider LRH for CC as a safe and advantageous alternative to ARH. Several retrospective and prospective reports have demonstrated that laparoscopic and open RH have similar outcomes in terms of diseasefree and overall survival.11,15,25,26 However, someone may object that different patterns of recurrence between the two procedures may disguise a different ability to obtain local control of the disease, which may be masked by adjuvant treatment or salvage therapy, when looking at the crude general disease-free and overall survival. In other words, if laparoscopic surgery were not equivalent to open surgery in terms of oncological radicality when CC is to be treated, one may expect that the rate of local recurrences (at the level of the vaginal cuff, the pelvis, and the lymph nodes) is higher, irrespectively of the disease-free and overall survival.
TABLE 5. Oncological details in patients with and without recurrence No Recurrence recurrence (n = 22) (n = 127) Squamocellular histotype Grading G3 Pelvic lymphadenectomy Adjuvant therapy Lymphovascular spaces involvement Positive lymph nodes FIGO stage IA1 IA2 IB1 IIA1 LRH
P
14 (63.6)
88 (69.2)
0.62
5 (22.7) 21 (95.4)
33 (25.9) 105 (82.6)
1 0.2
29 (22.8) G0.0001 0 1
19 (86) 0 0
2 (1.5)
0 (0) 0 (0) 15 (68.1) 7 (31.8) 9 (40.9)
1
28 (22) 0.01 7 (5.5) 0.59 92 (72.4) 0.79 0 G0.0001 73 (57.4) 0.16
Data are expressed as n (%).
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Our single-center study on a notable number of patients shows that these objections are not valid. The rate of local recurrences, as well as the total number of recurrences, is comparable between open and laparoscopic approach. It should be noted that the high percentage of patients submitted to adjuvant treatment as well as the inclusion of low stage tumors in our population may have had some impact on the results and may explain the low rate of recurrence that we observed. However, tumor characteristics as well as postoperative therapies were well balanced between groups, thus providing strength to our findings. In our study population, disease recurrence rate for early stage CC was 10% to 19% after RH and systematic pelvic lymphadenectomy; this finding is in keeping with the available reports, thus strengthening our results.27Y29 Lower blood loss and shorter recovery stay have been found in patients submitted to LRH in comparison with ARH, according to previous studies14,15,30Y32 and confirming the lower morbidity of the laparoscopic approach. However, it should be taken into account that the higher BMI score and the higher number of lymph nodes removed in the ARH group could have influenced these results. Of note, the intraoperative and postoperative complications were comparable and did not influence neither adjuvant therapy nor its choice. A specific comment should be provided regarding the difference in the number of lymph nodes removed, which is higher in the ARH group. This is likely related to the fact that after laparoscopic surgery was introduced at our institution, we inevitably experienced a period of learning curve of the laparoscopic technique. As already demonstrated,33,34 the surgical skills of performing pelvic lymphadenectomy by laparoscopy improve with experience. Despite the mere difference in terms of nodal count removed between the two groups, both the number of positive nodes and, most importantly, the rate of nodal recurrences were similar between the two groups; this implies that probably extensive nodal dissections performed on all patients without selection of cases may be of little value for the oncological prognosis of patients with CC. The findings of similar rate of positive lymph nodes between recurrence and no recurrence groups confirm our assumption. The higher rate of patients submitted to adjuvant therapy in the recurrence group could be explained by advanced FIGO stage of this population. In contrast with some cases reports of port-site recurrences after laparoscopic surgery for CC,35Y37 we had no cases of relapse at the sites of entry in the LRH. Of course, our study was underpowered to evaluate in depth this specific aspect. However, it must be emphasized that no preventive measure was adopted to reduce the risk of port-site metastases in our series; although limited by the low incidence of such event, our data suggest that the risk of trocar recurrences (if real) may not be regarded as a major concern when discussing of the use of LRH. Considering the more recent introduction of the laparoscopic approach, patients who underwent ARH had a longer follow-up than patients who received LRH. However, except for one case, all the recurrences occurred within 60 months (median, 9Y17 months) in the two groups. These data are in
Recurrence of Early Stage CC
accordance with the literature and further strengthen our study.38,39 One of the limits of the present study is represented by its retrospective nature. Moreover, the long study period considered, if on the one hand, offers advantages to evaluate parameters such as disease-free and overall survival; on the other hand, it does not allow to guarantee homogeneity about surgical techniques, therapies, and imaging techniques. However, it should be kept in mind that because of the decreasing incidence of cervical carcinoma, it is unlikely that large well designed randomized trials with long-lasting follow-up will be performed on the recurrence patterns of CC in the near future. In this view, retrospective data have still an importance to shed light on this specific issue. Among the strengths of our study, we mention that it represents a single center experience of surgical management of early stage CC (with the intrinsic advantage of a higher homogeneity of treatment and technique, despite the long study period), the use of standardized institutional protocols and definitions, and the fact that it is one of the very few studies specifically focusing on the patterns of recurrence of early stage CC treated with laparoscopic versus open RH. From this study, we can conclude that there is a substantial comparability of laparoscopy and laparotomy in terms of long-term oncological outcomes in patients affected by early stage CC; in particular, our results show that the laparoscopic approach does not influence the recurrence rate, the localization of recurrence, and the time to recurrence. Our study supports the use of LRH for appropriately selected patients with early stage CC. Although larger prospective multicenter randomized trials are needed to confirm our results, our investigation provides further evidence for the implementation of LRH in the treatment of patients with early stage CC.
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