In this era of evidence-based medicine, healthcare professionals are overwhelmed with a huge quantity of information from trials and articles of which randomized control trial (RCT) is considered as the top of the pyramid in terms of level of evidence(1).
RTC can offer the highest evidence of reliability when it comes to the effectiveness of interventions. In fact, the whole point of the processes used during the design and conduct of these studies is minimizing the risk of bias and confounding factors, which in turn could have an influence of the results(2). Knowing this, the findings produced by RCTs are more likely to be closer to a realistic effect than the findings generated by other research methods(3).
The LACC trial, not surprisingly, is showing the inferiority of minimally invasive surgery (MIS) in the management of patients with early-stage cervical cancer, especially in terms of disease-free survival rates (DFS) and overall survival (OS), compared to laparotomy. This finding has a major impact on the perspective of the future oncological practice(4). Three significant studies, LACC, ESGO and NCCN, agree on the higher effectiveness of laparotomy in comparison to MIS(5,6).
One has to take note that, besides the known limitations of RCT, as for example the possibility of incorrect statistical inference, the misinterpretation of the outcomes, the low internal or external validity and the publication bias(7), RCTs for surgery are slightly different from other types of RCTs. In this case, there must be taken into consideration the variation in skills and surgical proficiency of participating surgeons, as well as the centers. Besides, there is an important difficulty in blinding a surgical procedure(8). Additional challenges may imply, in the design, conduct, or analysis of RCT for surgery proficiency and surgical technique, and, nonetheless, for pre- or postoperative care(9). We can confirm that there were questions raised by the LACC trial regarding the methodology and possible variations in surgical skills.
RCT might have flaws, but it still remains the highest trusted type of studies in terms of the accuracy of evidence that can be provided. At the same time, there are systematic reviews which can provide level 1 of evidence, if used correctly. If seeing strictly at the interrogation of MIS in the management of patients with cervix cancer, the results are in conflict. Three meta-analyses are showing the equivalent outcome of MIS versus laparotomy, while the other confirms further the result of the LACC trial(10-13).
This article compares all the possible MIS protocols and laparotomy/laparoscopy/robotic surgery for early-stage cervix cancer and makes a synthesis of the OS and DFS, for better understanding the immediate measures that can influence the morbidity and mortality rates among women with cervical cancer. The need of protocol individualization is also taken into consideration and will be evaluated by these means.
2. Surgical approach
Conization of the cervix – also known as cold knife cone (CKC) – is a surgical treatment method used to heal or diagnose cervical dysplasia. It is the excision of a cone-shaped part of the cervix in order to remove a cervical lesion and the entire pathological transformation zone. Surgeons can use this treatment option when there is the availability of a conflicting Pap probe and biopsy specimen. The procedure can be used if the histological results are less severe than of the cytology result or, on the other hand, if there is evidence of very severe dysplasia. Furthermore, it can be used even though there is stage 1A1 squamous cell cervical cancer. The conization of the cervix uses a scalpel, a laser or an electrosurgical instrument – LEEP (Loop Electrosurgical Excision Procedure)(14).
Lesions requiring multiple sweeps for excision or dysplasia surrounding more than a half of the cervical full circumference during the initial conization are associated with recurrent CIN≥2 lesions. The main focus should be during resection in order to prevent positive margins. If surgical margins came up to be positive, then the surgical procedure has to be repeated for women with CIN 2 and CIN 3 lesions or for those with risk factors(15).
2.2. Robotic surgery
Robotic technology is a breakthrough that improved conventional laparoscopy by providing 3D visual stereoscopic, wristed instruments, tremor filtration, and motion scaling. The results are meant to improve dexterity(16,17). These improvements should influence the surgical techniques and, therefore, the oncologic outcomes. However, the platform has some limitations, including, first of all, the high cost, the lack of haptic feedback, and the requirement for more training to achieve competence. Furthermore, and of highly interest to the gynecologists, this platform is not yet intended for simultaneous multiple quadrant surgery(18). Unfortunately, no study has yet compared the radicality of the hysterectomy specimen (size of parametrium or length of vaginal cuff) between robotic and laparoscopic surgery. However, there is only one article, with a low number of individuals, which compared robotic surgery (n=24) and laparoscopy (n=32) in terms of oncologic outcome and found out that there is no statistically significant difference between the procedures, with disease-free survival of 95.8% and 90.6%, respectively(19).
The Wertheim-Meigs surgery method includes the exeresis of the uterus, a quarter of the proximal vagina, the uterosacral ligaments, the uterovesical ligaments and both parametria(20). Moreover, after Meigs, a bilateral pelvic lymphadenectomy is necessary, which includes major lymph node groups: 1) ureteral; 2) obturator; 3) hypogastric and 4) pelvic. This is the classic treatment and gold standard of early stages of cervical cancer(21).
Laparoscopy has been used for some of the steps or even the complete oncological procedure. The literature describes a combination of standards and procedures for early cervical cancer, such as pelvic lymphadenectomy, laparoscopic radical hysterectomy, laparoscopic-assisted radical vaginal hysterectomy, laparoscopic-assisted radical vaginal trachelectomy and vaginal-assisted radical laparoscopic trachelectomy(22).
2.4. Radical trachelectomy
There is an increased incidence of cervical cancer in younger age groups with undefined progeny. Now, more than ever, there is a higher need for fertility preserving techniques.
Infertility generated by cervical cancer, in this particular situation, can cause depression, anxiety, stress and sexual dysfunction in women and the preserving alternative needs to be addressed to the patient.
Radical trachelectomy was first described as totally vaginal procedure. The steps include the removal of the cervix, the vaginal cuff and parametria, keeping thus the uterine body, fundus and attachments. Pelvic lymphadenectomy was conducted laparoscopic(23).
The vaginal radical trachelectomy is the most performed fertility-sparing procedure in the medical world for low stages of cervical cancer. Over 700 cases have been reported in the literature, with later 250 pregnancies that generated approximately 100 live births. Some study groups have described success in almost 80% of pregnancy attempts with the use of assisted reproduction procedure(24).
There are strict indications for the procedure, and it seems important not to overlook them, knowing that the recurrence rate can be high: age under 45 years old, desire to preserve fertility, especially if one has no children, stages IA1 with invasion of lymphovascular spaces, IA2 and IB1<2 cm, with MRI describing no parametrial invasion and no evidence of lymph node or distant metastases(25). Factors such as invasion of lymphovascular space, high grade tumors and the diameter above 2 cm can be considered contraindications for fertility-preserving surgery(24). A recent study teaches us that radical trachelectomy could be indicated in patients with tumor size between 2 and 4 cm in 30% of patients who would be candidates for fertility-losing radical surgery(25), but the current consensus is to indicate this procedure in patients with tumors up to 2 cm.
Laparotomy started to be used in radical trachelectomy over the past decade. In 500 patients undergoing abdominal radical trachelectomy, there was a 10% conversion to radical hysterectomy, 0.4% deaths and three intraoperative complications. During 32 months of follow-up, the recurrence rate was 3.8%. Of those who tried to conceive, 60% were able to get pregnant, with 40% term pregnancies(26).
The techniques and steps of radical trachelectomy through laparoscopy and by robotic surgery have been feasible in initial studies, with low rates of intraoperative complications and no conversion to laparotomy with seasoned teams(27).
The laparoscopic approach has been less used, possibly because of the technical difficulty to perform the suturing of the isthmus/residual cervix to the vaginal cuff. However, for surgical professionals with experience in laparoscopic radical surgery for cervical cancer, it remains an alternative access with reduced morbidity, similar oncological outcomes and good fertility rates(28).
2.5. Open surgery (classic surgery)
Hysterectomy is the surgical removal of the uterus with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are both removed. In a total hysterectomy with salpingo-oophorectomy, the uterus plus one (unilateral) ovary and fallopian tube are removed, or the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures imply a low transverse incision or a vertical incision.
The mean age was 48.3 years old and the range selected was 23-83 years old, while the mean BMI was 25.7 kg/m2. The end risk of recurrence for women who went through minimally invasive surgery was twice as high as that in the open surgery group (HR 2.07; 95% CI; 1.35 to 3.15; p=0.001). Following this discovery, the risk of death was almost two and a half times higher than in the open surgery group (HR 2.45; 95% CI; 1.30 to 4.60; p=0.005). Furthermore, women who underwent MIS using a uterine manipulator had a 2.76-times higher chance of relapse (HR 2.76; 95% CI; 1.75 to 4.33; p<0.001) and, surprisingly, women without the use of a uterine manipulator had similar disease-free-survival to the open surgery group (HR 1.58; 95% CI; 0.79 to 3.15; p=0.20). Patients who underwent MIS with protective vaginal closure had similar rates of relapse to those who underwent open surgery (HR 0.63; 95% CI; 0.15 to 2.59; p<0.52)(29).
The classic laparotomy radical hysterectomy has shown a lower recurrence rate when directly compared with laparoscopic operation and robotic surgery in those cervical cancer patients with a foci diameter less than 2 cm. But minimally invasive surgery can have benefits on the morbidity rates, having lower post-surgery complications than the open surgery. Bearing in mind, less bleeding, less hospitalization days, less infections, and a quicker recovery rate.
Comparing all these oncological treatment options, the open surgery remains the gold standard, especially due to its higher surviving rate, until new protocols and studies emerge. This is why gynecological oncologists should recommend open radical hysterectomy for patients with early-stage cervical cancer.
Furthermore, multicenter prospective trials are needed to confirm the results on a larger scale.
Conflict of interests: The authors declare no conflict of interests.