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Dicu-Andreescu, I.; Marincaș, A.; Ungureanu, V.; Ionescu, S.; Prunoiu, V.; Brătucu, E.; Simion, L. Multimodal Treatment of Cervical Cancer in Disease Stage. Encyclopedia. Available online: (accessed on 09 December 2023).
Dicu-Andreescu I, Marincaș A, Ungureanu V, Ionescu S, Prunoiu V, Brătucu E, et al. Multimodal Treatment of Cervical Cancer in Disease Stage. Encyclopedia. Available at: Accessed December 09, 2023.
Dicu-Andreescu, Irinel-Gabriel, Augustin-Marian Marincaș, Victor-Gabriel Ungureanu, Sînziana-Octavia Ionescu, Virgiliu-Mihail Prunoiu, Eugen Brătucu, Laurențiu Simion. "Multimodal Treatment of Cervical Cancer in Disease Stage" Encyclopedia, (accessed December 09, 2023).
Dicu-Andreescu, I., Marincaș, A., Ungureanu, V., Ionescu, S., Prunoiu, V., Brătucu, E., & Simion, L.(2023, July 12). Multimodal Treatment of Cervical Cancer in Disease Stage. In Encyclopedia.
Dicu-Andreescu, Irinel-Gabriel, et al. "Multimodal Treatment of Cervical Cancer in Disease Stage." Encyclopedia. Web. 12 July, 2023.
Multimodal Treatment of Cervical Cancer in Disease Stage

Cervical cancer continues to be among the most common malignancies in women, and important measures have been taken to reduce its incidence. The first and most important steps to achieve this goal are oriented toward prevention through screening programs and vaccination, mainly against oncogenic human papillomavirus (HPV) strains 16 and 18. The therapeutic approach is based on the diagnosis and treatment guidelines for cervical cancer, which establish for each stage (FIGO, TNM) specific conduct. These guidelines summarize quite precisely the elements of therapeutic practice, but, in some places, they leave optional variants based on which nuanced approaches could be established. 

cervical cancer FIGO surgery radiotherapy

1. Stage IA1

The depth of stromal invasion is up to 3 mm and can only be diagnosed microscopically. Treatment at this stage depends on the patient’s choice, the maintenance of fertility, and the lymphovascular invasion identified on the biopsy.
If the patient chooses to preserve fertility, cervical conization is recommended [1]. Kim et al. state that this technique has a protective role while also being an independent positive prognostic factor. Therefore, even if later it is decided to perform a hysterectomy, the patients have a higher disease-free survival rate, and the need for adjuvant radiochemotherapy treatment is less common [1]. If the resection margins are negative, conization may represent the definitive treatment [2]. According to the ESGO/ESTRO/ESP guidelines, if the margins are positive, it can be opted for repeating the conization, radical surgical interventions being viewed as overtreatment in this stage [3]. However, the NCCN guidelines maintain radical trachelectomy as a surgical option [4][5][6]. If the lymphovascular invasion is detected, conization with sentinel lymph node biopsy without additional pelvic lymph node dissection is recommended [3]. Additionally, something worth emphasizing is that, at this stage, there are no differences in survival regarding the histological type of neoplasia or the surgical technique chosen, even if one of the main risk factors for recurrence described in the literature is adenocarcinoma [7][8].
If the patient does not want to preserve her fertility, a simple total hysterectomy is chosen, meaning the recurrence rate of the disease is even lower if conization was previously performed [1]. If there is lymphovascular invasion, the recommended intervention is still standard hysterectomy with sentinel lymph node biopsy, again, without additional pelvic lymph node dissection [3].
Pelvic external radiotherapy, followed by brachytherapy, may be an option only if the patient refuses surgery, although the results are controversial. In a study by Yang et al., radiotherapy in stages I and II of cervical cancer resulted in shorter overall and disease-free survival, especially if the neoplasia was diagnosed before menopause [9]. Similarly, when the effect of radiotherapy was analyzed in relation to tumor size, in the case of tumors with dimensions less than 2 cm, the effect was unfavorable [9]. An explanation of this behavior can be the fact that small, “early stage” tumors have an increased ability to defend against the errors in DNA induced by radiotherapy [10].
The prognosis of patients is extremely good, with a 5-year survival of 95.8% [11].

2. Stage IA2

The depth of stromal invasion is 3–5 mm and does not exceed 7 mm in surface extension [12]. The tumor is diagnosed by microscopy.
The standard surgical treatment is radical hysterectomy with pelvic lymphadenectomy (Wertheim intervention) or radiotherapy [13]. However, to avoid the complications of more invasive methods, simple hysterectomy, trachelectomy, or conization, with or without pelvic lymphadenectomy, can also be considered without significant differences in survival [14].
Radical hysterectomy involves the resection of the cervix, the uterus, the upper part of the vagina, and the parameters [13]. It can be performed classically by laparotomy, or by laparoscopy [15].
Regarding the laparoscopic approach, a significant debate and controversy in the medical community was produced by the LACC trial, published in 2018, that aimed to compare the efficacy of laparoscopic radical hysterectomy versus abdominal radical hysterectomy in the treatment of early-stage cervical cancer. The initial results suggested a higher rate of disease recurrence and worse survival outcomes in patients who underwent laparoscopic surgery. However, subsequent analysis and discussions raised concerns about potential biases and limitations in the trial design. Therefore, the choice between laparoscopic or open surgery should be made, taking into consideration the stage of the disease, the patient’s option, and the skills of the surgeon [16].
It should be noted that conization is recommended before laparoscopic hysterectomy to minimize the recurrence of the disease [1]. It is considered that a reason for recurrence in patients in whom conization was not performed is the use of the uterus manipulator and repeated traumatization of the tumor during the laparoscopic intervention [1].
Trachelectomy is especially recommended for patients who want to preserve their fertility, and it is also the most used method in this situation. The main risks of this procedure are premature birth and pregnancy loss, which are more frequent than in the general population, especially in the 2nd trimester [6][17]. The approach can be transvaginal or abdominal—the last technique is easier due to its similarity with radical hysterectomy. Additionally, it can be performed minimally invasive—laparoscopic or robotically assisted, in which postoperative recovery is much faster. The intervention is completed by lymph node assessment performed either by imaging explorations or by the sentinel node technique and pelvic lymphadenectomy [6]. The sentinel node technique, often used for breast cancer or malignant melanoma, has the potential to limit the complications of lymphadenectomy [18].

3. Stages IB1, IB2, IIA1

Tumors invade the stroma to a depth of at least 5 mm, with lesions confined to the cervix and surface extension up to 4 cm [12].
If the patient wishes to preserve her fertility, radical trachelectomy with extended pelvic or even para-aortic lymphadenectomy can be performed [5]. If the tumor is larger than 2 cm but less than 4 cm (stage IB2), neoadjuvant therapy can be an option. It is represented either by preoperative brachytherapy, which can minimize the indication of adjuvant radiotherapy, or by chemotherapy, generally based on a combination of platinum salts and paclitaxel. Chemotherapy is not established as a standard treatment at this stage because there are still not enough studies to demonstrate its efficiency. However, combined with brachytherapy may subsequently allow a limited surgical intervention with minimal impact on fertility [17][19]. This is possible up to stage IB2 and is associated with a disease recurrence rate of 10% and a mortality rate of 2.9% [17].
If the patient chooses a more extensive treatment, the standard treatment is a radical hysterectomy with pelvic lymphadenectomy [5].
A study by Ungar et al. emphasized the overwhelming importance of lymphadenectomy, as it is well known that, most frequently, recurrences originate from the regional lymph nodes [20]. Thus, in a group of 492 patients, they concluded that the complete excision of the pelvic lymph node tissue leads to a higher survival rate for operable cervical cancers, even in the absence of any adjuvant treatment, with results comparable to that of the less invasive techniques with adjuvant treatment [20]. However, in stage IB1, the sentinel node technique can also be used to minimize the postoperative risks of lymphadenectomy, but the tumor must be below 2 cm in size, the stromal invasion must be minimal (below 1 cm), and there must be no lymphovascular invasion [21].
A novelty in the approach of these stages is represented by image-guided interstitial irradiation for “bulky” tumors, with superior results to intracavitary brachytherapy and also associated with low toxicity, according to the EMBRACE (Image guided External radiochemotherapy and MRI-based BRAchytherapy in locally advanced CErvical cancer) and retroEMBRACE studies [12]. This technique can be used up to stage IIIB [22]. Additionally, a randomized clinical trial led by Gupta indicated that radiotherapy, even in the standard form, in combination with cisplatin, leads to a higher disease-free survival than the combination of neoadjuvant chemotherapy followed by radical hysterectomy and then adjuvant radiotherapy [23]. However, Landoni et al. state that, at this stage, no survival evidence overwhelmingly tilts the balance towards one treatment or another, concluding that the approach must be based on the particularities of the patient [24].
If the patient refuses surgery or her general condition contraindicates surgery, then treatment is limited to radiotherapy with or without chemotherapy [5].
The prognosis remains good, with a 5-year survival of 83.6%, the best in stage IB1—91.6%. If the patient is infected with HPV strain 18, she needs a more careful follow-up and rigorous periodic controls, more than in the case of other strains [25]. It should be noted that the use of image-guided brachytherapy, according to the EMBRACE and retroEMBRACE studies, led to a significant increase in survival, up to 96% at 3 years [26].

4. Stages IB3 and IIA2

The tumor invades the upper 2/3 of the vagina, but without invasion of the parameters, and exceeds 4 cm in size [12].
The NCCN guidelines establish the following treatment alternatives: firstly, external radiotherapy associated with concurrent chemotherapy with platinum salts followed by brachytherapy, this approach being accepted in a uniform consensus. Another alternative treatment is radical hysterectomy with pelvic lymphadenectomy accompanied or not by para-aortic lymphadenectomy. In stages IB3 and IIA2, surgical treatment is recommended only as an isolated option on highly selected cases and only after the general consensus of a multidisciplinary committee [5]. The last alternative is external pelvic radiotherapy associated with concurrent chemotherapy with platinum salts and brachytherapy followed by complementary hysterectomy for certain selected cases. Survival in stage IB3 is 76.1% [11].
In stage IIA2, which is a locally advanced stage and the tumor exceeds 4 cm—the so-called “bulky” tumor, the standard of treatment is a combination of radio- and chemotherapy, and the survival seems comparable to other more radical methods of treatment [27][28]. However, according to NCCN guidelines, some experts express the opinion that at this stage, a pelvic lymph node dissection can be performed, and if there is no lymph node invasion, then a radical hysterectomy can be executed. If there is lymph node invasion, then the hysterectomy should be abandoned, and patients should undergo chemoradiation [5].
The 5-year survival prognosis in stage IIA2 is 65.3% [11].
In the guide of the Oncological Institute “Prof. Dr. Al. Trestioreanu” Bucharest, these stages are treated similarly to the other locally advanced stages (stage IB3-IV) [29].

5. Stage IIB

At this stage, most of the therapeutic guidelines—European Society of Gynecological Oncology (ESGO), European Society for Radiotherapy & Oncology (ESTRO), and NCCN recommend concurrent chemoradiotherapy (external irradiation 45–50 Gy + intracavitary brachytherapy up to 85–90 Gy simultaneously with Cisplatin-based chemotherapy), with the possibility of additional external irradiation with 5–10 Gy, in the case of parametrial invasion, as well as irradiation of the paraaortic lymph nodes [3].
Guide of the Oncological Institute “Prof. Dr. Al. Trestioreanu” Bucharest follows the European treatment guidelines but keeps an alternative variant for cases in which it is considered that the optimal radiation dose for lymph node involvement cannot be reached, this dose varying between 54 and 63 Gy. In these cases, the first step recommended is concurrent radiochemotherapy, similar to that proposed by the guidelines—external irradiation 45–50 Gy + intracavitary brachytherapy 15 Gy + Cisplatin-based chemotherapy [29]. However, this step is followed after an interval of 6–8 weeks by surgical intervention, which consists of different approaches depending on the extent of the lesions—e.g., radical hysterectomy + pelvic lymphadenectomy with or without para-aortic lymph node sampling or para-aortic lymphadenectomy for curative purposes, if there is an invasion of the paraaortic nodes [29].
This approach is based on the results of a study that showed that out of a total of 461 patients with locally advanced cervical cancer from the Oncological Institute “Prof. Dr. Al. Trestioreanu” Bucharest who was initially treated with chemoradiotherapy and then adjuvant surgical intervention was performed, in 254 patients, residual tumors were found at the histopathological examination. The response to treatment varied according to the histological subtype of cervical cancer and was 50.6% in cases of squamous cell carcinoma and 77.6% in cases of adenocarcinoma or adenosquamous carcinoma [30].
A series of other studies have shown that in stage IIB when the tumor invades the parameters but without touching the walls of the pelvis, the standard of treatment is combined chemoradiotherapy [12]. However, they specify that in some countries in Europe, the combination of neoadjuvant chemoradiotherapy is also recommended to be followed by radical hysterectomy and pelvic lymphadenectomy [31][32]. Probably the differences in approach are due to the perception related to radical hysterectomy, as well as from the attempt to minimize the toxicity of radiochemotherapy treatment [31]. This approach is also mentioned in the NCCN guidelines, where it is stated that in locally advanced stage disease, including FIGO stage IIB, in the United States, patients are treated with definitive chemoradiotherapy, but there are some countries, in which selected cases, stage IIB patients, can be treated with initial radical hysterectomy or neoadjuvant chemotherapy followed by radical hysterectomy [5].
On the other hand, it is worth mentioning that another study has shown higher morbidity, especially urinary, after postradiotherapy surgery, compared to definitive concurrent radiochemotherapy, with comparable overall survival [33]. Probably, the best approach is individual-based, after a complete evaluation of the risks and benefits and also an independent evaluation of the experience of the surgical team.
The 5-year survival prognosis in stage IIB is 63.9% [11]. However, using image-guided brachytherapy, the EMBRACE and retroEMBRACE trials showed survivals of up to 89%, although these were reported at 3 years, not at 5 [26].

6. Stage III

It is subdivided into three stages: IIIA—the tumor invades the lower third of the vagina, without invasion of the pelvic wall; IIIB—the tumor invades the pelvic wall, with or without hydronephrosis and concomitant renal damage; and stage IIIC—the tumor invades the pelvic and/or para-aortic lymph nodes, regardless of its extension or dimensions, according to FIGO 2018 staging [12].
Concomitant cisplatin-based chemoradiotherapy is the standard of therapy, with surgery being associated with higher morbidity, especially when combined with adjuvant radiotherapy [5][34][35]. Additionally, comparing survival in patients who received concurrent chemoradiotherapy with those who received radiotherapy alone at the same dose, it was found that there was an improvement in prognosis at 5 years in the combined chemoradiotherapy category [35]. It should be noted that the frequency of hematological and gastroenterological adverse reactions was higher in platinum salt-based therapies than in those in which another chemotherapy was used [36].
As a surgical treatment, there is a case published by J.P. Micha and J.V. Brown in 1998 in which a stage IIIB cervical cancer patient with ovarian, round ligament, and fallopian tube metastases who had an indication for total pelvic exenteration had an 8-year disease-free survival in the absence of any chemo- or radiotherapy treatment [37].
Palliative care also plays a key role in the management of stage III cervical cancer, especially in cases where the cancer is advanced or not responsive to curative treatment.
Palliative care can be provided alongside curative treatments or as the primary focus of care, depending on the individual’s needs and treatment goals. It is an essential component of comprehensive cancer care and helps ensure that patients with stage III cervical cancer receive holistic support, symptom management, and improved quality of life [38].

7. Stage IV

The tumor extends to adjacent organs, such as the urinary bladder and rectum, or distant metastases are identified [12]. The prognosis is reserved, with 5-year survival in stage IVA, in which the tumor invades only neighboring organs up to 24%, and in stage IVB, with distant metastases, only 14.7% [11].
The independent prognostic factors reported in the literature are the performance status, the location of the metastases, and the local invasion of the disease. Because there is a large individual variation in the evolution of the disease at this stage, it has long been considered difficult to establish a standard approach.
The most commonly used treatment is, as in the case of stage III, chemotherapy based on platinum salts and radiotherapy [39]. Subsequently, if a satisfactory post-chemotherapy response is obtained, tumor excision surgery and metastasectomy can be considered depending on the biological status of the patient and the number and resectability of metastases [39].
During treatment, immunotherapeutic agents such as bevacizumab and pembrolizumab can be administered [40].
For recurrent or persistent centrally located pelvic disease after radiotherapy, pelvic exenteration (pelvectomy) can be considered [41]. Preoperative evaluation for this procedure must exclude distant metastases. Additionally, the intraoperative exploration must assess the possibility of complete resection, which means that the resection margins do not contain any neoplastic tissue at the histopathological examination [41].
Depending on the tumor location, resection may include anterior exenteration, posterior exenteration, or total exenteration [41]. In cases where the location of the tumor allows the achievement of satisfactory oncological safety margins without resection of the pelvic floor and the anal sphincter muscle, they can be preserved (supralevator exenteration) [41].
It must be highlighted that pelvectomies are extremely complex procedures and must be performed in centers with a high level of experience and where multidisciplinary surgical teams can be assembled [42].
Primary pelvectomy (without prior pelvic irradiation) can also be performed, but it is limited to the rare cases where irradiation is contraindicated or to patients who have previously undergone pelvic irradiation for another cancer and then developed a metachronous, locally advanced cervical tumor [42].


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