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Recent Advances in Cervical Cancer

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Recent Advances in Cervical Cancer Recent Advances in Cervical Cancer

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AbstractCancer of the cervix is the most common gyneco-

logical malignancy worldwide [1]. More than 85% of the global burden occurs in developing countries, where it ac-counts for 13% of all female cancers [2]. Furthermore, the mortality due to cervical cancer is higher in the develop-ing countries where screening and treatment modalities are not commonly available or accessible compared with the developed countries [3]. Cervical carcinoma has its origins at the squamous-columnar junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepi-thelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process of tumorigenesis is slow. Longitudinal studies have shown that in 30% to 70% of patients with untreated in situ cervi-cal cancer, will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, pre-cancerous lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane invading the cervical stroma. Extension of the tumor in the cervix may ultimately present as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.

Chapter 1

Recent Research and Review Works in Cervical Cancer Treatment

Arvind Krishnamurthy, Ujjwala Prakash, Lalitha Ramasubramanian and Ramshankar Vijayalakshmi

Department of Preventive Oncology (Research Divi-sion), Cancer Institute (WIA), India

*Corresponding Author: R Vijayalakshmi, Department of Preventive Oncology (Research Division), Cancer Institute (WIA), Adyar, Chennai 600 020, India, Tel: 044-24910754 extn 243; Email: [email protected]

First Published December 16, 2015

Copyright: © 2015 R Vijayalakshmi et al.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source.



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Conventional Management of Cervi-cal Cancers

The management of cervical cancer requires a mul-tidisciplinary approach, role of a gynecologic oncologist, radiation oncologist and medical oncologist may be man-datory. The treatment of cervical cancer varies with the stage of the disease. The management of cervical cancer varies worldwide, largely due to access to surgeons skilled in radical pelvic surgery and the recent emergence of “Fertility-Sparing Surgery” in developed nations.

For early invasive cancers, surgery is generally con-sidered the treatment of choice. In more advanced cases, a combination of radiation with chemotherapy is con-sidered the current standard of care. In patients with ad-vanced and disseminated disease, chemotherapy or radi-ation is used for symptomatic palliative care as deemed appropriate.

Stage Based Management as per Ccur-rent Guidelines

Stage 0 CancerThe management options in Carcinoma in situ (Stage

0) include local ablative or excisional measures such as cryosurgery, laser ablation or loop excision. Surgical re-moval is preferred as it allows tissue for further pathologic evaluation to rule out microinvasive disease. These pa-

tients require continued surveillance post treatment.

Stage IA1 CancerSurgery is the treatment of choice for stage IA1 Car-

cinoma cervix. The surgical options include conisation, total hysterectomy and radical hysterectomy. Lymph node dissection may not be required if the depth of invasion is < 3 mm and in the absence of lymphovascular inva-sion. Fertility Sparing Surgery in the form of therapeutic conization can be offered for selected patients with stage IA1 carcinoma cervix with no lymphovascular space in-vasion. These patients however require close follow-up, with cytology, colposcopy, and endocervical curettage. In patients with comorbidities, medical conditions preclud-ing surgical resection can be successfully managed with radiation therapy. Definitive radiation therapy should consist of pelvic external beam radiation therapy with high-energy photons and intra-cavitary brachytherapy. It should be administered at high doses (>80–90 Grey) and in a short time (<55 days), with the best technological re-sources available.

The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant pelvic radiation for women with stage IA carcinoma cervix and negative lymph nodes in patients who have high-risk factors like a large primary tumor, deep stromal invasion or lympho-vascular space invasion.



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Management of early cervical cancer by lapa-roscopic radical hysterectomy

The adoption of laparoscopic surgery for the surgical management of cervical cancer has been slower due to the technical difficulties associated with laparoscopic surgery in cervix and the diversity of the approaches employed. However, with recent improvements in laparoscopic in-struments and surgical techniques, laparoscopic radical hysterectomy is becoming the preferred surgical approach for the surgical management of early cervical cancer. Lap-aroscopic radical hysterectomy has better surgical out-comes than other methods without affecting survival out-comes or increasing the number of complications. Studies have shown the use of laparoscopic radical hysterectomy limited to small cervical tumors <2 cm [4,5]. However, with the increase in surgical experience, the radicality of laparoscopic radical hysterectomy has become compara-ble to that of open radical hysterectomy [6]. Currently, the indication for radical hysterectomy has been extended to cervical tumors >4 cm [7]. Recent studies suggest that the benefit of laparoscopic surgery extends to elderly and obese patients [8,9].

Stage IA2, IB, or IIA CancerCombined external beam radiation with brachythera-

py or radical hysterectomy with bilateral pelvic lymphad-

enectomy are the conventional management options for patients with stage IB or IIA disease. Both the procedures are equally effective, but differ in terms of morbidity. There is only one randomized trial that has directly com-pared radical hysterectomy and radical radiation therapy done in 343 women with stage IB-IIA disease. The overall and disease-free survivals at 5 years were similar for the two treatment groups, (83% and 74%, respectively). Study showed that 66% of the patients in the surgical arm had adjuvant radiation in view of the associated risk factors. The rate of severe morbidity was 28% in the surgery group and 12% in the radiotherapy group [10]. There is no evi-dence to state that that concurrent chemoradiation would be useful in patients with early cervical cancer (stages IB1 and IIA <4 cm).

Fertility Sparing SurgeryFertility-preserving radical trachelectomy has been

accepted as a reasonable alternative treatment for young women with early cervical cancer to preserve their fertility.Currently, several types of surgical approaches for radical trachelectomy are used in real practice, including vaginal, abdominal, laparoscopic, and robotic radical trachelec-tomy. However, the use of vaginal radical trachelectomy is suited for small cervical cancers with a tumor size <2 cm. Radical vaginal trachelectomy with pelvic lymph node dissection has been shown to be appropriate in women



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with stage IA2 carcinoma cervix and in women with stage IB1 carcinoma cervix whose tumors are 2 cm or less previ-ously [11,12]. However there are studies that have shown that the recurrence rate is significantly higher when the tumor size is >2 cm [13,14]. The recent investigators how-ever suggest that with wider extirpation of parametrial tis-sue made possible by other surgical approaches including abdominal, laparoscopic and robotic trachelectomy [15], radical trachelectomy can be extended to selected patients with a tumour size>2 and <4 cm [16-18].

The principal problems with pregnancy after trache-lectomy are premature labour and the need to undergo caesarean section for delivery [19]. Study by Lakhman et al [20] showed that among patients with stage IB1 cervical carcinoma (n=62) who underwent radical trachelectomy, the pretrachelectomy MRI scans helped identify high-risk patients who were likely to need radical hysterectomy and helped confirm the absence of residual tumor after a cone biopsy with negative margins . A tumor size of >2 cm and deep cervical stromal invasion on MRI scans was associ-ated with an increased chance of radical hysterectomy.

The current management guidelines for stage IA2 to IIA cervical cancers allow for minimally invasive tech-niques, such as traditional laparoscopic and robotically assisted laparoscopic techniques. Many studies have shown that these less minimally invasive procedures are oncologically safe while possessing the added advan-

tage of shorter postoperative recovery times [21-23]. An analysis of patients from the Surveillance, Epidemiology, and End Results (SEER) database who underwent radical hysterectomy with lymphadenectomy revealed that pa-tients with node-negative early-stage cervical cancer who underwent a more extensive lymphadenectomy had im-proved survival. The study showed that when compared with patients who had < 10 nodes removed, patients who had 21-30 nodes removed had 24% less mortality due to disease and those who had > 30 nodes removed had 37% less mortality due to disease [24].

Recent Views on Role of Sentinel Node Biopsy in Cervical Cancer Management

In patients with cervical cancer, metastatic spread to lymph nodes is a well known prognostic parameter, cru-cial for selection of therapy. Radical lymphadenectomy is known to cause lymphedema, voiding disorders, sero-cele formation, paresthesia and possibly reduced immune competence. The risk of lymph node metastases in women with early stage cervical cancer (up to FIGO stage IB1) is approximately 15% only and majority of patients do not benefit from lymphadenectomy [25,26].

The use of sentinel lymph node (SLN) biopsy concept is based on the assumption that if the first draining lymph node is free of disease, all other lymph nodes in the nodal basin should also be free of disease [27]. An initial study



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based on examining the utility of SLN biopsy in patients diagnosed with cervical cancer showed great promise with a detection rate, sensitivity and negative predictive value of 94%, 90.9% and 99.1%, respectively for patients with tumors measuring 2cm or less in diameter [28].

Reports from meta-analysis of 67 studies based on sentinel node biopsy for lymph nodal staging of uterine cervix cancer, shows that detection rate and sensitivity were related to mapping method (blue dye, radiotracer, or both) and history of pre-operative neoadjuvant chem-otherapy. Bilaterally detected pelvic sentinel nodes had higher sensitivity compared unilateral sentinel nodes. Lymphatic mapping could identify sentinel nodes outside the routine lymphadenectomy limits [29].

Other studies have shown that sensitivity was close to 100% in patients where SLNs were detected bilaterally. Ultrastaging with multiple serial sectioning and immu-nohistochemical staining of the SLN has successfully im-proved the detection of nodal metastasis [30-32]. Recent reports suggest sentinel lymph node biopsy in early stage cancer as a more sensitive procedure in detecting pelvic lymph node metastases compared to complete lymphad-enectomy [33]. Though sentinel node mapping can be an accurate method for the assessment of lymph nodal in-volvement in uterine cervical cancer, selection of a popu-lation with small tumor size and lower stage can ensure the lowest false negative rate. Lymphatic mapping can also

used to detect sentinel nodes outside of routine lymphad-enectomy areas provided there are additional histologi-cal information available to improve the staging. There is need a for further studies to explore the impact of sentinel node mapping in fertility sparing surgery and in patients with history of neoadjuvant chemotherapy.

Role of Molecular Markers in SLN to Identify Micrometastasis

By definition, macrometastasis are tumor depos-its >2mm, micrometastasis are deposits between >0.2 and 2mm, and isolated tumour cells (ITC) are deposits ≤0.2mm including the presence of single non-cohesive cytokeratin-positive tumor cells [34]. Molecular markers can help in detection of low volume disease as an aid to ultrastaging methods. However the prognostic implica-tions of low volume metastatic disease (micrometastasis and ITC) for patients with cervical cancer are not yet fully understood and serve only partly as prognostic indicators [31].

The first multicenter prospective study in patients with cervical cancer and tumor free lymph nodes by con-ventional histopathology, has addressed the prognostic potential of HPV mRNA in SLN of patients with pN0-status by systematic lymphadenectomy and conventional histopathology. The results have shown HPV-mRNA-positive SLN with a prognostic value independent of tu-



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mor size. This study suggests that particularly in patients with tumors larger than 20mm diameter, HPV mRNA as a molecular marker could help in risk stratification. The re-currence-free survival was significantly longer for patients with HPV-mRNA negative SLN conversely, the presence of HPV-E6-E7-mRNA in SLN of patients with pN0 status was associated with a significantly decreased recurrence free survival [35].

Post Operative Adjuvant Radiation Therapy as per Risk Assessment

Intermediate RiskA Gynecologic Oncology Group (GOG) trial that ran-

domly assigned 277 women to receive pelvic RT (without chemotherapy) or no further treatment demonstrated a benefit for postoperative RT in women with deep cervical stromal invasion (to the middle or one-third depth), lym-phovascular space invasion, and large tumor size (>4 cm). A significant benefit has been shown for progression-free survival, but not for overall survival with a median follow-up of 10 years. Postoperative adjuvant radiation therapy is hence recommended in patients who have at least 2 inter-mediate risk factors (including tumor size > 2 cm, deep stromal invasion or lymphovascular space invasion.

High RiskWomen with one or more worse prognostic factors

such as positive or close surgical margins, positive lymph

nodes, or microscopic parametrial involvement are con-sidered to be at high risk of relapse [36]. A randomized trial showed that patients with parametrial involvement, positive pelvic nodes or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic irradiation. The use of chemo-therapy has been shown associated with a substantially better 4-year overall survival (81% versus 71%) and pro-gression-free survival (80% versus 63%), and the outcome was better for patients who completed three to four cycles of chemotherapy [37]. A combined approach of radiation along with chemotherapy is used in patients with IB2 or IIA cervical cancer and with tumors > 4 cm. Although there are risks associated with combined therapy, many of these patients will meet either the intermediate or the high-risk criteria after radical hysterectomy and are hence strong candidates for this approach.

Treatment of Locally Advanced Cer-vical Cancer (Stage IIB, III, or IVA)

Radiation TherapyFor locally advanced cervical carcinoma (stages IIB,

III and IVA), radiation therapy has been the treatment of choice for many years. Radiation therapy begins with a course of external beam radiation to reduce tumor mass and thereby enabling subsequent intra-cavitary applica-tion. Brachytherapy is delivered by means of after load-



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ing applicators that are placed in the uterine cavity and vagina. The local control rate with radiation therapy alone ranged between 88% and 95% for stage IB, 70%–80% for stage IIB, and 30%–40% for stage III and 5-year survival >80% for stage IB, 65% for stage IIB, and 40% for stage III.

Tailored Radiation Therapy - Intensity Modu-lated Radiation therapy/Proton Therapy

New techniques for delivering radiation to targets, including intensity-modulated radiotherapy (IMRT) and proton therapy, for the management of gynecologic can-cers have been introduced. IMRT was shown to be better at reducing the delivery of radiation to adjacent normal tissue, such as rectum, bladder, and small bowel, result-ing in the delivery of a higher tumor dose compared with conventional or 3-dimensional conformal radiotherapy. It has been shown to provide benefits in terms of increased tumor control and decreased toxicity to normal tissues; however, the study of the clinical significance of IMRT in the management of gynecologic cancers still limited [38-42]. A randomized phase 3 clinical trial is ongoing aimed at comparing the standard radiotherapy to IMRT for the postoperative treatment of endometrial and cervical can-cer (RTOG protocol 1203).

Proton therapy has energy delivery at a defined depth and has no exit energy after the Bragg peak. It can de-crease the irradiated volume and reduce the dose to ad-jacent normal tissues beyond the possible achievement by

IMRT; however, there is no clinical data to confirm that proton therapy can reduce normal tissue toxicity. Photon therapy still remains mostly an investigational tool for the management of gynecologic cancers. Prospective clini-cal trials are therefore required to evaluate the efficacy of IMRT and proton therapy in the management of gyneco-logic cancers.

Advent of Chemo-RadiationThere are 5 randomized, phase III trials (GOG-85,

RTOG-9001, GOG-120, GOG-123, SWOG-8797) that have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy [43-47]. This was subsequently also confirmed in further reviews and meta-analysis, the most recent of which was based on individual patient data from 18 randomized tri-als which demonstrated an absolute 5-year survival ben-efit of 8% for overall disease-free survival, 9% for loco-regional disease-free survival, and 7% for metastases-free survival across all stages [48]. The advantage is also shown for non-platinum-based chemotherapy. Consequently, the use of cisplatin-based chemotherapy in combination with radiation has become the standard of care for prima-ry management of patients with locally advanced cervical cancer.



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Optimal Schedule of Concurrent Chemoradiation

The optimal radiation therapy, consisting of high dos-es (80–90 Grey) administered over a short time (<50–55 days), significantly impacts on outcome. The optimal regi-men for chemotherapy has yet to be defined, but weekly single-agent cisplatin at 40 mg/m2/week during external beam therapy is widely used; concurrent carboplatin or non-platinum chemo-radiation regimens are other op-tions for patients who may not tolerate cisplatin-contain-ing schedules.A recent study indicates a significant benefit for the use of adjuvant chemotherapy following chemo-radiation. Patients with locally advanced cervical cancer (stages IIB to IV) treated with cisplatin–gemcitabine, both during and after radiation therapy, demonstrated a great improvement in progression-free survival and overall survival. Despite these encouraging results, systemic con-solidation has not been used in regular practice [49]. A systematic review from 18 trials and 2074 patients dem-onstrated that the timing and dose intensity of cisplatin-based neoadjuvant chemotherapy before radiation could affect outcome. However, the data was heterogeneous and merits further confirmation.

Role of Neoadjuvant ChemotherapyA meta-analysis of neoadjuvant chemotherapy fol-

lowed by radical hysterectomy showed an absolute im-

provement of 14% in 5-year survival compared with radiotherapy [50]. despite several objections to this meta-analysis because patients in the control arm received only radiation therapy not in combination with chemotherapy and radiation therapy. Neoadjuvant chemotherapy fol-lowed by radical surgery could have an important role in the treatment of locally advanced cervical cancer, but the appropriate indications still need to be established. The on-going trial EORTC 55994 will help clarify whether neoadjuvant chemotherapy followed by surgery will result into a better outcome compared with chemoradiotherapy in patients with stages IB2 to IIB cervical cancer.

Response Evaluation and Follow UpNo definitive agreement exists on the best post-treat-

ment surveillance. A gynecological examination includ-ing Pap smear is usually performed every 3 months for the first 2 years, every 6 months for the next 3 years, and yearly thereafter CT or PET/CT scan can be performed as clinically indicated.

Management of Recurrent Cervical Cancers

For recurrent disease, the choice of therapy is largely influenced by the prior treatment employed.The manage-ment of pelvic recurrences after primary surgical manage-ment should include single-agent chemotherapy and radi-ation, whereas the management for recurrences elsewhere



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should include combination chemotherapy [51]. For cen-tral pelvic recurrence after radiation therapy, a modified radical hysterectomy (only if the recurrence is < 2 cm) or pelvic exenteration should be undertaken [52]. For tumors recurring after chemotherapy and radiation therapy, a dis-ease-free interval of > 16 months is considered to desig-nate the tumor as platinum-sensitive [53]. The standard of care in these cases is chemotherapy with a platinum-based doublet of paclitaxel and cisplatin. Recurrences arising in a previously irradiated field or after a disease-free interval of < 16 months are less likely to respond to subsequent therapies. Patients with such early recurrences should be strongly encouraged to participate in clinical trials.

Stage IVB and Advanced Recurrent Cancer

Although early-stage disease can be cured with radi-cal and even fertility-sparing surgery, patients with meta-static and recurrent cervical cancer have poor prognosis with historically limited treatment options and incurable disease. Significant advances in cervical cancer treat-ment have emerged as the result of clinical trials that have sought to determine the best therapy to prolong overall and progression-free survival. Most recently, trials that have involved angiogenesis blockade in addition to stand-ard chemotherapy have demonstrated improved overall and progression-free survival.

Patients with metastatic or advanced recurrent cervi-

cal cancer are commonly symptomatic. The role of chem-otherapy/radiotherapy in such patients is palliative, with the primary objective to relieve symptoms and improve quality of life. Cisplatin is considered the single most ac-tive cytotoxic agent. Overall, the duration of the objective response to cisplatin in patients with metastatic or recur-rent disease has remained disappointing with a survival of approximately 7 months. There is not a clear dose-re-sponse effect. Cisplatin-based combination therapy, such as cisplatin–paclitaxel and cisplatin–topotecan, has been extensively investigated in clinical trials. Only the cispl-atin–topotecan combination reported an overall survival advantage compared with monotherapy. A recent phase III trial assessed four cisplatin-doublet regimens. (cispl-atin–paclitaxel, cisplatin–topotecan, cisplatin–gemcit-abine, and cisplatin–vinorelbine) No significant differenc-es in overall survival were seen; however, the trends for response rate, PFS, and OS suggest that cisplatin–paclitax-el is the preferred regimen [54]. The NCCN also recom-mends docetaxel, gemcitabine, ifosfamide, 5-fluorouracil, mitomycin, irinotecan, and topotecan as possible candi-dates for second-line therapy (category 2B recommenda-tion), as well as pemetrexed and vinorelbine (category 3 recommendation). In addition, bevacizumab as single-agent therapy is also acceptable.



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Role of Anti-Angiogenic Agents for Targetted Therapy

BevacizumabAntiangiogenesis agents are efficacious in other sol-

id malignant tumors with similar tumor biology, such as non–small cell lung cancer. Bevacizumab is the most studied agent in gynecologic neoplasms and other solid tumors. Bevacizumab is an anti-VEGF monoclonal anti-body that blocks tumor angiogenesis by binding and in-activating VEGF and thereby inhibiting endothelial cell activation and proliferation, thus denying tumors the ability to recruit new vessel development. Bevacizumab also counteracts the survival (antiapoptotic) signaling that supports the immature vasculature usually associated with neoplastic growth and prevents constant endothelial remodeling required for local tumor spread, thus restor-ing normal structure and function to disorganized, highly permeable vessels typically seen in malignant tumors [51].

The first prospective Phase II trial of bevacizumab in cervical cancer was conducted through the coopera-tive research network led by the Gynecologic Oncology Group (GOG). GOG 227C was a multicenter Phase II study of bevacizumab monotherapy that revealed the tolerability and efficacy of the drug in heavily pretreated patients with recurrent cervical cancer. Bevacizumab was found to be effective even better than expected particu-larly compared with other historical control groups in this

setting. Subsequently, other agents with antiangiogenic activity have also been studied in advanced and recurrent cervical cancer, including oral tyrosine kinase inhibitors.Treatment with bevacizumab plus cisplatin and paclitaxel or topotecan and paclitaxel was approved by the FDA in August 2014 for persistent, recurrent, or metastatic cervi-cal cancer as per NCCN reports. Statistically significant improvement in overall survival and an increase in the rate of tumor shrinkage was shown in women treated with bevacizumab plus chemotherapy compared with chemo-therapy alone. However, hypertension, thromboembolic events, and GI fistulas were higher in the bevacizumab group. Bevacizumab/paclitaxel/cisplatin or topotecan is considered a first-line regimen for recurrent or metastatic cervical cancer [55].

PazopanibPazopanib (targets VEGF receptor, platelet-derived

growth factor receptor, and c-kit) and lapatinib (dual anti–epidermal growth factor receptor and anti-HER2/neu) were studied in a Phase II trial comparing pazopanib (800 mg/d) or lapatinib (1,500 mg/d) monotherapy ver-sus combination therapy with both drugs. The combi-nation therapy treatment arm was closed for futility and imbalanced toxic effects after the first interim analysis. This head-to-head comparison revealed the superiority of antiangiogenesis over anti-EGF therapy [51]. Pazopanib treated patients showed improved PFS compared to lapa-tinib treated patients, however there was no OS benefit.



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The study supports further investigations of antiVEGF treatments in cervical cancer, but unfortunately epider-mal growth factor receptor–based therapies, such as ce-tuximab and erlotinib, have resulted in several negative clinical trials.

Role of HPV VaccinesThe primary prevention using prophylactic vaccines

has been shown in several reports. The prophylactic vac-cine stimulates the development of the humoral immune response, which occurs after contact with the “virus-like particles” (VLPs), which are non-infectious structures and simulate a natural HPV infection [56-63]. The two oncogenic types included in both vaccines are HPV 16 and 18, responsible for at least 70% of the cases of cervical cancer worldwide. In the case of the quadrivalent vaccine, it also included two non-oncogenic types of HPV, 6 and 11, responsible for approximately 90% of cases of anogeni-tal condylomata acuminata. Safety and tolerability of both vaccines have been evaluated extensively with similar pro-files in the vaccinated and control groups, irrespective of age or ethnicity. Studies about safety assessment indicated that local and systemic injection-related symptoms were generally mild. Serious adverse effects (AE) that are con-sidered to be vaccine related are rare and similar to other vaccine types [64,65].

The implementation of HPV vaccination in low- or middle-income countries has encountered many hurdles,

including that of cost. Malaysia was the first middle-in-come country in the world to implement a national HPV vaccination program in 2010. This is a school-based vac-cination program targeting girls attending grade seven in schools (13-year-old girls). Immunization in the clinic is proposed to 13-year-old out-of-school girls. This pro-gram has been very successful as 95.9% and 97.9% of par-ents gave consent to their daughters to be vaccinated and 97.9% and 95.9% of girls who obtained parental consent completed all three courses of the vaccination in 2010 and 2011, respectively. In 2012, a catch-up vaccination pro-gram was introduced targeting girls aged 18 years. The reasons for the success of this program includes endorse-ment and recommendation by the medical profession, po-litical will and leadership, the involvement of stakeholders early on in the program, predicting and managing poten-tial risks, monitoring implementation closely, a good ex-isting school health program, the involvement of the Min-istry of Education, and giving sufficient information about the vaccine and its safety to parents.

PrognosisThe prognosis of cervical cancer is largely influenced

by it stage, with survivals touching 100% for women with microscopic forms of cervical cancer. The five-yearoverall rate of cervical cancer (all stages combined) is about 72%. With standard treatment, 80 to 90% of women with stage I cancer and 60 to 75% of those with stage II cancer are alive 5 years after diagnosis. Survival rates decrease to 30



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to 40% for women with stage III cancer and 15% or fewer of those with stage IV cancer 5 years after diagnosis.

Other Promising TherapiesThe development of targeted therapies that selectively

target specific molecular pathways involved in tumorigen-esis may lead to other major advances in the management of cervical cancer. The role of immunotherapy is a promis-ing and exciting new area of research that can potentially lead to further advancements in the treatment of locally advanced, recurrent, or metastatic cervical cancer. Devel-opment of the immune checkpoint blockade PD-1 and CTLA-4 inhibitors has shown promise and will need to be further studied as a means to achieve a durable response in cervical cancer.

References1. Arbyn M, Castellsague X, de Sanjose S, Bruni L,

Saraiya M, et al. Worldwide burden of cervical cancer in 2008. Ann. Oncol. 2011; 22: 2675–2686.

2. Ferlay J, Shin HR, Bray F.GLOBOCAN 2008, Can-cer Incidence and Mortality Worldwide: IARC Cancer Base No. 10. Lyon, France: International Agency for Research on Cancer; 2010.

3. Akhtar-Danesh N, Lytwyn A. Elit L. Five-year trends in mortality indices among gynecological cancer patients in Canada. Gynecol. Oncol. 2012;

127: 620–624.

4. Nam JH, Kim JH, Kim DY, Kim MK, Yoo HJ, et al. Comparative study of laparoscopico-vaginal radical hysterectomy and abdominal radical hys-terectomy in patients with early cervical cancer. Gynecol Oncol. 2004; 92: 277-283.

5. Nam JH, Park JY, Kim DY, Kim JH, Kim YM, 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: 903-911.

6. Park JY, Nam JH. Laparotomy conversion rate of laparoscopic radical hysterectomy for early-stage cervical cancer in a consecutive series without case selection. Ann Surg Oncol. 2014; 21: 3030-3035.

7. Park JY, Kim DY, Kim JH, Kim YM, Kim YT, et al. Laparoscopic versus open radical hysterectomy in patients with stage IB2 and IIA2 cervical cancer. J Surg Oncol. 2013; 108: 63-9.

8. Park JY, Kim DY, Kim JH, Kim YM, Kim YT, et al. Laparoscopic versus open radical hysterectomy for elderly patients with early-stage cervical can-cer. Am J Obstet Gynecol. 2012; 207: 195.e1-8.

9. Park JY, Kim DY, Kim JH, Kim YM, Kim YT, et al. Laparoscopic compared with open radical hyster-



www.avidscience.com

ectomy in obese women with early-stage cervical cancer. Obstet Gynecol. 2012; 119: 1201-9.

10. Landoni F, Maneo A, Colombo A, Placa F, Milani R, et al. Randomised study of radical surgery ver-sus radiotherapy for stage Ib-IIa cervical cancer. Lancet. 1997; 350: 535–540.

11. Schneider A, Erdemoglu E, Chiantera V. Clinical recommendation radical trachelectomy for fertil-ity preservation in patients with early stage cervi-cal cancer. Int J Gynecol Cancer. 2012; 22: 659-666.

12. Maneo A, Sideri M, Scambia G. Simple coniza-tion and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience. Gynecol Oncol. 2011; 123: 557-560.

13. Plante M, Renaud MC, Francois H, Roy M. Vagi-nal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol On-col. 2004; 94: 614-23.

14. Dargent D, Franzosi F, Ansquer Y, Martin X, Mathevet P, et al. Extended trachelectomy relapse: plea for patient involvement in the medical deci-sion. Bull Cancer. 2002; 89: 1027-1030.

15. Saso S, Ghaem-Maghami S, Chatterjee J, Naji O, Farthing A, et al. Abdominal radical trachelec-

tomy in West London. BJOG. 2012; 119: 187-93.

16. Li J, Wu X, Li X, Ju X. Abdominal radical trache-lectomy: is it safe for IB1 cervical cancer with tu-mors ≥ 2 cm? Gynecol Oncol. 2013; 131: 87-92.

17. Lintner B, Saso S, Tarnai L, Novak Z, Palfalvi L, et al. Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diam-eter. Int J Gynecol Cancer. 2013; 23: 1065-1070.

18. Wethington SL, Sonoda Y, Park KJ, Alektiar KM, Tew WP, et al. Expanding the indications for radi-cal trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer. 2013; 23: 1092-1098.

19. Speiser D, Mangler M, Köhler C, Hasenbein K, Hertel H, et al. Fertility outcome after radical vag-inal trachelectomy: a prospective study of 212 pa-tients. Int J Gynecol Cancer. 2011; 21: 1635-1639.

20. Lakhman Y, Akin O, Park KJ, Sarasohn DM, Zheng J, et al. Stage IB1 Cervical Cancer: Role of Preoperative MR Imaging in Selection of Patients for Fertility-Sparing Radical Trachelectomy. Radi-ology. 2013; 269: 149-158.

21. Lowe MP, Chamberlain DH, Kamelle SA, Johnson PR, Tillmanns TD. A multi-institutional experi-ence with robotic-assisted radical hysterectomy for early stage cervical cancer. Gynecol Oncol.



www.avidscience.com

2009; 113: 191-194.

22. Nezhat FR, Datta MS, Liu C, Chuang L, Zakashan-sky K. Robotic radical hysterectomy versus total laparoscopic radical hysterectomy with pelvic lymphadenectomy for treatment of early cervical cancer. JSLS. 2008; 12: 227-237.

23. Cantrell LA, Mendivil A, Gehrig PA, Boggess JF. Survival outcomes for women undergoing type III robotic radical hysterectomy for cervical cancer: a 3-year experience. Gynecol Oncol. 2010; 117: 260-265.

24. Shah M, Lewin SN, Deutsch I, Burke WM, Sun X, et al. Therapeutic role of lymphadenectomy for cervical cancer. Cancer. 2011; 117: 310-317.

25. Delgado G, Bundy BN, Fowler WC, Jr., Stehman FB, Sevin B, et al. A prospective surgical patho-logical study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group Study. Gynecol Oncol. 1989; 35: 314-320.

26. Look KY, Brunetto VL, Clarke-Pearson DL, Av-erette HE, Major FJ, et al. An analysis of cell type in patients with surgically staged stage IB carcino-ma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1996; 63: 304-311.

27. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, et al. Technical details of intraopera-

tive lymphatic mapping for early stage melanoma. Arch Surg. 1992; 127: 392-399.

28. Altgassen C, Hertel H, Brandstadt A, Kohler C, Durst M, et al. Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol. 2008; 26: 2943-2951.

29. Kadkhodayan S, Hasanzadeh M, Treglia G, Azad A, Yousefi Z et al. Sentinel node biopsy for lymph nodal staging of uterine cervix cancer: a systemic review and meta-analysis of the pertinent litera-ture. Eur J Surg Oncol 2015; 41: 1–20.

30. Darlin L, Persson J, Bossmar T, Lindahl B, Kan-nisto P, et al. The sentinel node concept in early cervical cancer performs well in tumors smaller than 2 cm. Gynecol Oncol. 2010; 117: 266-269.

31. Cibula D, Abu-Rustum NR, Dusek L, Slama J, Zikan M, et al. Bilateral ultrastaging of senti-nel lymph node in cervical cancer: Lowering the false-negative rate and improving thedetection of micrometastasis. Gynecol Oncol. 2012; 127: 462-466.

32. Lecuru F, Mathevet P, Querleu D, Leblanc E, Morice P, et al. Bilateral negative sentinel nodes accurately predict absence of lymph node metas-tasis in early cervical cancer: results of the SEN-TICOL study. J Clin Oncol. 2011; 29: 1686-1691.



www.avidscience.com

33. Gortzak-Uzan L, Jimenez W, Nofech-Mozes S, Ismiil N, Khalifa MA, et al. Sentinel lymph node biopsy vs. pelvic lymphadenectomy in early stage cervical cancer: is it time to change the gold stand-ard? Gynecol Oncol. 2010; 116: 28-32.

34. Schwartz GF, Giuliano AE, Veronesi U and Con-sensus Conference C. Proceedings of the consen-sus conference on the role of sentinel lymph node biopsy in carcinoma of the breast, April 19-22, 2001, Philadelphia, Pennsylvania. Cancer. 2002; 94: 2542-2551.

35. Dürst M, Hoyer H, Altgassen C, Greinke C, Häfner N, et al. Prognostic value of HPV-mRNA in sen-tinel lymph nodes of cervical cancer patients with pN0-status. Oncotarget. 2015; 6: 23015-23025.

36. Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Mud-erspach LI, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lym-phadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol. 1999; 73: 177-183.

37. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of

the cervix. J Clin Oncol. 2000; 18: 1606-1613.

38. Lim K, Small W, Jr, Portelance L, Creutzberg C, Jurgenliemk-Schulz IM, et al. Consensus guide-lines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys. 2011; 79: 348–355.

39. Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, et al. Intensity-modulated whole pel-vic radiotherapy in women with gynecologic ma-lignancies. Int J Radiat Oncol Biol Phys. 2002; 52: 1330–1337.

40. Chen MF, Tseng CJ, Tseng CC, Kuo YC, Yu CY, et al. Clinical outcome in posthysterectomy cervi-cal cancer patients treated with concurrent Cispl-atin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2007; 67: 1438–1444.

41. Kidd EA, Siegel BA, Dehdashti F, Rader JS, Mutic S, et al. Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxy-glucose-positron emission tomography simula-tion in patients with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2010; 77: 1085–1091.

42. Gandhi AK, Sharma DN, Rath GK, Julka PK, Sub-ramani V, et al. Early clinical outcomes and tox-



www.avidscience.com

icity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cer-vix carcinoma: a prospective randomized study. Int J Radiat Oncol Biol Phys. 2013; 87: 542–548.

43. Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999; 17: 1339-1348.

44. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, et al. Pelvic radiation with concurrent chemo-therapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999; 340: 1137-1143.

45. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, et al. Concurrent cisplatin-based radio-therapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999; 340: 1144-1153.

46. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, et al. Cisplatin, radiation, and ad-juvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999; 340: 1154-1161.

47. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000; 18: 1606-1613.

48. Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervi-cal cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials.J Clin Oncol. 2008; 26: 5802-5812.

49. Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S et al. A phase III, open-label, rand-omized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cis-platin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011; 29: 1678-1685.

50. Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration (NACCCMA). Neo-adjuvant chemotherapy for locally advanced cer-vix cancer. Cochrane Database Syst Rev. 2004; 2: CD001774.

51. Monk BJ, Willmott LJ, Sumner DA. Anti-angio-genesis agents in metastatic or recurrent cervical



www.avidscience.com

cancer. Gynecol Oncol. 2010; 116: 181–186.

52. Berek JS, Howe C, Lagasse LD, Hacker NF. Pelvic exenteration for recurrent gynecologic malignan-cy: survival and morbidity analysis of the 45-year experience at UCLA. Gynecol Oncol. 2005; 99: 153-159.

53. Moore DH. Chemotherapy for advanced, recur-rent, and metastatic cervical cancer. J Natl Compr Canc Netw. 2008; 6: 53-57.

54. Moore KN, Herzog TJ, Lewin S, Giuntoli RL, Armstrong DK, et al. A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer. Gynecol Oncol. 2007; 105: 299-303.

55. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, et al. Improved survival with bevaci-zumab in advanced cervical cancer. N Engl J Med. 2014; 370: 734-743.

56. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, et al. HPV screening for cervical cancer in rural IndiaN Engl J Med. 2009; 360: 1385–1394.

57. Harper DM. Impact of vaccination with Cervarix (trade mark) on subsequent HPV-16/18 infection and cervical disease in women 15–25 years of age. Gynecol Oncol. 2008; 110: S11–S17.

58. Paavonen J, Jenkins D, Bosch FX, Naud P, Salm-erón J, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against in-fection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial.Lancet. 2007; 369: 2161–2170.

59. Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogen-ital diseases.N Engl J Med. 2007; 356: 1928–1943.

60. F.I.S. Group Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical le-sions. N Engl J Med. 2007; 356: 1915–1927.

61. Ault KA, Future II Study Group. Effect of prophy-lactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neopla-sia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials.Lancet. 2007; 369: 1861–1868E.

62. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, et al. Efficacy of a quad-rivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vac-cine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007; 369: 1693–1702.

36 www.avidscience.com

Recent Advances in Cervical Cancer

63. Parellada C, Campaner AB. Human papillomavi-rus vacines: current status. Ver Bras Patol Trato Genit Infer. 2012; 2: 47-53.

64. Lu B, Kumar A, Castellsagué X, Giuliano AR. Ef-ficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among wom-en: a systematic review & meta-analysis.BMC In-fect Dis. 2011; 11: 13 C3034689.

65. Ballalai I, Bravo F, Silva RAB, Araujo EMM. Hu-man papillomavirus vaccines: immunogenicity and duration of protection against cervical cancer and precursor lesions. Rev Bras Patol Trato Genit Infer. 2012; 2: 54-60.

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