**3. Current clinical treatmemts**

*Staging and Treatment Options:* Despite prevention initiatives to stay the tide of carcinogenesis caused by HR-HPV, thousands worldwide still require treatment. Currently, the most effective course of managing cervical carcinoma involves surgery and/or radiation. However, surgery provides the management team better insight into the extent of the disease because it allows the assessment of lymph node involvement [64, 65]. The surgical options available range from total removal of the cervix (radical hysterectomy) to less extreme options that preserve the fertility of the patient (radical trachelectomy), and are somewhat contingent upon disease progression. Other procedures such as chemotherapy, radiotherapy, or a combination thereof are routinely used, and their utilization depends on cancer stage as well. Factors further impacting the course of management include pregnancy; disease recurrence; fertility preser‐ vation; cervical location of the lesion; cancer type; age and general physical health. But the most important treatment determinant for cervical cancer is stage of disease, and years of clinical trials and case studies have formed the standard by which each stage is managed.

The staging of cervical cancer is based on the physical examination and is established by the International Federation of Gynecology and Obstetrics (FIGO). The World Health Organiza‐ tion reaffirms the FIGO organization of cervical carcinoma progression into four stages (I-IV):

*Stage I*: cancer found only in the cervix.

*Stage II*: cancer found beyond the cervix in the vagina, but has not spread to the pelvic wall and excludes the lower third of the vagina.

*Stage III*: cancer has spread to the lower third of the vagina and/or pelvic sidewall, and includes cases with kidney involvement.

*Stage IV*: cancer has grown beyond the pelvis and involves tissue of the rectum, bladder, and/ or distal sites of metastasis.

The four main stages are then organized into sub-categories that further describe the extent of growth, adjacent tissue involvement, local organ participation, and metastasis to distal sites through the lymphatic system [66]. Present challenges to the optimal clinical staging of cervical cancer include complications associated with parametrial invasion, tumor location/size variation, and lymph node metastases, but developments in imaging are changing the tide [67, 68]. The ACS asserts that individuals diagnosed with cervical cancer from the early stages through late stage II actually have a survival rate greater than 50 percent. Cancers diagnosed at stage III and IV yield 30 and 15 percent survival rates, respectively. However, survival rates approach 100 percent if the cancer is caught early enough. The tools used in the process of staging and subsequent treatment of cervical cancer are numerous and will be mentioned only as they fit the scope of this review. Therefore, the sections below are not intended to represent a comprehensive discussion of these modalities.

distinguish between low-risk and high-risk HPV status without causing undue concern in patients with transient infection. However, the cost of cervical cancer screening programs, even

*Staging and Treatment Options:* Despite prevention initiatives to stay the tide of carcinogenesis caused by HR-HPV, thousands worldwide still require treatment. Currently, the most effective course of managing cervical carcinoma involves surgery and/or radiation. However, surgery provides the management team better insight into the extent of the disease because it allows the assessment of lymph node involvement [64, 65]. The surgical options available range from total removal of the cervix (radical hysterectomy) to less extreme options that preserve the fertility of the patient (radical trachelectomy), and are somewhat contingent upon disease progression. Other procedures such as chemotherapy, radiotherapy, or a combination thereof are routinely used, and their utilization depends on cancer stage as well. Factors further impacting the course of management include pregnancy; disease recurrence; fertility preser‐ vation; cervical location of the lesion; cancer type; age and general physical health. But the most important treatment determinant for cervical cancer is stage of disease, and years of clinical trials and case studies have formed the standard by which each stage is managed.

The staging of cervical cancer is based on the physical examination and is established by the International Federation of Gynecology and Obstetrics (FIGO). The World Health Organiza‐ tion reaffirms the FIGO organization of cervical carcinoma progression into four stages (I-IV):

*Stage II*: cancer found beyond the cervix in the vagina, but has not spread to the pelvic wall

*Stage III*: cancer has spread to the lower third of the vagina and/or pelvic sidewall, and includes

*Stage IV*: cancer has grown beyond the pelvis and involves tissue of the rectum, bladder, and/

The four main stages are then organized into sub-categories that further describe the extent of growth, adjacent tissue involvement, local organ participation, and metastasis to distal sites through the lymphatic system [66]. Present challenges to the optimal clinical staging of cervical cancer include complications associated with parametrial invasion, tumor location/size variation, and lymph node metastases, but developments in imaging are changing the tide [67, 68]. The ACS asserts that individuals diagnosed with cervical cancer from the early stages through late stage II actually have a survival rate greater than 50 percent. Cancers diagnosed at stage III and IV yield 30 and 15 percent survival rates, respectively. However, survival rates approach 100 percent if the cancer is caught early enough. The tools used in the process of staging and subsequent treatment of cervical cancer are numerous and will be mentioned only

in developed countries, may hamper the implementation of these new advances.

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**3. Current clinical treatmemts**

*Stage I*: cancer found only in the cervix.

cases with kidney involvement.

or distal sites of metastasis.

and excludes the lower third of the vagina.

*Imaging:* One of the most important aspects of cervical cancer treatment is identifying and evaluating abnormal tissue morphology using radiological technologies such as magnetic resonance imaging (MRI), x-ray computed tomography (CT scan), and positron emission tomography (PET). Because the effectiveness of these devices depends on clinical expertise and equipment, diagnostic imaging possesses several inherent discrepancies [64]. However, many researchers have begun studies that will help to improve these methods and/or to enable clinicians to draw better conclusions. Advancements in the functionality of diagnostic imaging are making it easier than ever to assess and exploit tumor parameters such as cellularity, blood flow, and glucose metabolism. Recent studies are showing that the glucose analogue, fluorinelabeled fluoro-2-deoxy-D-glucose (FDG), is particularly useful in gauging tumor metabolic activity. When combined with PET (FDG-PET), FDG is considered to have high sensitivity in detecting primary cervical tumors [69]. Additionally, combining PET and CT is becoming more acceptable as a way to eliminate the guesswork involved in evaluating metastasis to lymph nodes [70]. However, MRI is the preferred imaging method in managing cervical cancer due to the high quality of anatomic resolution it provides in the pelvis; this enhances its ability to evaluate primary tumor volume [67, 71]. New developments in MRI technology such as diffusion-weighted MRI (DWI) compare normal and abnormal tissues based on the Brownian motion of water molecules, the movement of which impacts cellular membrane integrity. However, these features may not be as distinct or reliable in excessively necrotic tumors. Another derivative of MRI is dynamic contrast-enhanced MRI (DCE-MRI), which provides an unprecedented appraisal of tumor vasculature through contrast distribution over time. Therefore, DCE-MRI may prove to be distinctly helpful in ascertaining a tumor's unique response to therapies [67, 72].

*Surgery:* Surgery is the advised treatment for cervical carcinoma at stages I and II. The preferred procedure, radical hysterectomy (RH), has a 75 to 80 percent cure rate according to the NCI and is the gold standard of treatment. RH is the complete removal of the uterus, cervix, and upper portion of the vagina, and involves measuring metastasis to the parametrial and pelvic lymph nodes [73, 74]. Other procedures, such as total and subtotal hysterectomies, do not require the removal of the vagina and cervix, respectively. At the early phase of stage I, less invasive techniques labeled *excisional* therapies selectively remove pathologic tissue [75, 76]. Large loop loop excision of the transformation zone (LLETZ) and cold knife conization procedures are classified as excisional therapies and are used without great risk of the cancer recurring. Conical biopsies, or the removal and microscopic examination of presumably abnormal tissue, may suffice in some situations. *Ablative* therapies such as laser and cryosur‐ gery are utilized in expunging carcinomas *in situ* of lesser risk. This distinction between therapies is supported by studies showing that lesions from more progressed carcinomas return at a higher rate when treated with ablative techniques as compared to excisional ones [76]. In some instances, neither excision nor ablative therapies are suitable for the grade of disease, and hysterectomy is recommended. Indeed, patients not interested in fertility loss or those with lymph and vascular space involvement (LVSI) should elect for RH (RH). Nonethe‐ less, for nulliparous women radical trachelectomy, or the removal of the uterine cervix only, with lymphadenectomy is always an option up to late stage I (Ib1) [77-79]. According to the ACS, RH is always optional for those diagnosed with early stage squamous cell cervical carcinoma, but it is strongly suggested for adenocarcinoma cervical cancer.

CRT), which better concentrates radiation to specific regions of interest. BT involves the placement of a radioactive device in the uterus or vagina. Low or high-doses of radiation are given over long or short periods of time, respectively, and in accordance with the Manches‐ ter triple source system. Also, BT is a highly specialized method of radiotherapy requiring costly equipment and extensive technical training, as device positioning is very important in

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Maximum dose toleration by adjacent tissues such as vaginal tissue is a major limiting factor in all radiotherapy procedures. Therefore, many strategies attempt to radiosensitize the appropriate tissues (*See Neoadjuvant and Combination therapies,* below) before exposing them to radiation. Intensity modulated radiation therapy (IMRT) offers a unique advantage through the virtual mapping of tumors so that the delivery of radiation is focused and minimal tissue damage occurs to the surrounding vital structures. Supplemental techniques to improve the localization of radiation such as hyperthermia, neutron therapy, and hypoxic cell sensitizers still need refinement, and are not routinely utilized [85, 86]. Despite potential high levels of toxicity necessitating close patient monitoring, RT is a powerful tool in managing cervical cancer. The side effects of RT that have caused the greatest concern include hematologic imbalances, GI distress, GU complications due to hydronephrosis, and secondary malignancy. Future improvements in the field of RT to treat cervical cancer must first rectify the issues of maximum dose tolerance by exploiting radiosensitizing methods in order to compensate for

*Chemotherapy:* Chemotherapy is the principal treatment option for recurrent and metastatic cervical cancer, and it is recommended by the ACS for the management of late stage I of cervical cancer or higher. Chemotherapy can be curative or palliative. In early cervical disease, chemotherapy can be curative, but may also be given in more advanced stages (stage IV and recurrence) to alleviate the ravaging effects of the cancer itself and its related symptoms. Chemotherapy may also be given in the later stages to postpone the toxicities associated with it until absolutely necessary. Thus, designing optimal regimens suited for each case is essential to attaining both patient comfort and treatment success. Chemotherapy can also be given adjunctively to strengthen the effects of primary treatment, or provided post-operatively [87]. In fact, the ways in which chemotherapy can be administered are numerous, ranging from single, doublet, triplet, or quartlet-agent regimens to combined chemoradiation routines. However, a few agents such as cisplatin, paclitaxel, and ifosfamide are distinguished for being somewhat autonomously potent [88]. The success of single-agent chemotherapy generally depends on histology. For example, although cisplatin is most effective for treating squamous cell carcinomas (SCC), paclitaxel has been shown to improve the median survival of non-SCC type patients as compared to others who did not receive paclitaxel [89]. Furthermore, paclitaxel yielded a response rate (RR) of 33 percent, surpassing other single agents in non-SCC type

Cisplatin, a platinum-based agent, is the accepted standard of chemotherapy for cervical cancer, and it improves survival in chemoradiation recipients as compared to the use of other chemotherapeutic drugs [90-94]. However, its adequacy in improving survival and quality of life in palliative management has been questioned. Some tumor cells acquire resistance to

the systemic and potentially oncologic risks associated with radiation.

treatment success [84].

cervical cancer treatment [88, 89].

Surgery is immensely valuable for determining lymph node status, which is strongly corre‐ lated to survival [80]. The risk of lymph node metastasis is increased by 10 percent if tumor invasion reaches between 3 and 5 mm beyond the primary lesion. If this occurs, the NCI recommends that a modified RH comprising pelvic lymph node dissection be performed even in early disease stages. Furthermore, if metastasis to the lymph nodes or parametria is found, their removal is indicated as well as radiotherapy or chemo radiotherapy post-operatively. Post-surgery radiotherapy is also indicated if the tissue collected during surgery has a positive margin, which alludes to residual cancer and commonly occurs in late stage I. Though it is advisable to use radio and chemotherapies in stage II, some experts also support hysterectomy following these procedures. In summation, surgery yields its most potent benefits in the earlier stages of cervical carcinoma, though this fact can be viewed as a great limitation in the case of advanced disease. Other limitations of surgery include pelvic sepsis and thrombosis as well as vesicovaginal fistulas. However, opting for surgery in the management of cervical cancer may prevent vaginal stenosis, spare ovarian function, and protect local organs from future complications. There is no doubt that surgery is vital in the prospective treatment planning of the patient following operation because it allows the delineation of tumor metastasis [65]. However, surgical options are contingent upon early detection, and thus time will always be one of the most important factors in predicting a prognosis. Fortunately, advances in the field of surgery have given patients better alternatives that are less invasive (i.e. laparoscopic surgery), and these procedures, together with non-invasive therapies, will continue to benefit those for whom preventive measures have failed.

*Radiotherapy:* More advanced cervical cancer (stage IIb and higher) is treated with radiother‐ apy (RT), chemotherapy, or a combination of the two. However, surgery and RT both aim to completely eradicate malignancy and have equally positive results in attenuating disease in the initial phases. RT is generally substituted for surgery when circumstances render an operation less than optimal as in the case of elderly patients, obese patients, or patients with several co-morbidities [80, 81]. Usually younger patients elect for surgery in order to preserve sexual function and to avoid side effects such as vaginal dryness and narrowing caused by scar tissue (as described by the ACS). Elderly patients (65+ years), who account for 20 percent of cervical cancer cases, usually choose the less invasive RT [82]. Cancer cells are more susceptible to radiation than are normal cells because radiation uses high-energy particles to target and kill rapidly dividing cells through DNA damage. In general, there are two main types of radiation therapy: external beam radiation, and internal (implant) radiation usually referred to as intracavitary brachytherapy (BT). External beam radiation therapy (EBRT) is aimed wholly at the pelvis, much like a regular x-ray, and is often accompanied by cispla‐ tin chemotherapy. The chemotherapy is added to enhance the effectiveness of the radia‐ tion and to treat metastasis to lymph nodes [83]. The selectivity of EBRT for cervical sites is enhanced by combining its use with a CT scan via 3-D conformal radiation therapy (3-D CRT), which better concentrates radiation to specific regions of interest. BT involves the placement of a radioactive device in the uterus or vagina. Low or high-doses of radiation are given over long or short periods of time, respectively, and in accordance with the Manches‐ ter triple source system. Also, BT is a highly specialized method of radiotherapy requiring costly equipment and extensive technical training, as device positioning is very important in treatment success [84].

less, for nulliparous women radical trachelectomy, or the removal of the uterine cervix only, with lymphadenectomy is always an option up to late stage I (Ib1) [77-79]. According to the ACS, RH is always optional for those diagnosed with early stage squamous cell cervical

Surgery is immensely valuable for determining lymph node status, which is strongly corre‐ lated to survival [80]. The risk of lymph node metastasis is increased by 10 percent if tumor invasion reaches between 3 and 5 mm beyond the primary lesion. If this occurs, the NCI recommends that a modified RH comprising pelvic lymph node dissection be performed even in early disease stages. Furthermore, if metastasis to the lymph nodes or parametria is found, their removal is indicated as well as radiotherapy or chemo radiotherapy post-operatively. Post-surgery radiotherapy is also indicated if the tissue collected during surgery has a positive margin, which alludes to residual cancer and commonly occurs in late stage I. Though it is advisable to use radio and chemotherapies in stage II, some experts also support hysterectomy following these procedures. In summation, surgery yields its most potent benefits in the earlier stages of cervical carcinoma, though this fact can be viewed as a great limitation in the case of advanced disease. Other limitations of surgery include pelvic sepsis and thrombosis as well as vesicovaginal fistulas. However, opting for surgery in the management of cervical cancer may prevent vaginal stenosis, spare ovarian function, and protect local organs from future complications. There is no doubt that surgery is vital in the prospective treatment planning of the patient following operation because it allows the delineation of tumor metastasis [65]. However, surgical options are contingent upon early detection, and thus time will always be one of the most important factors in predicting a prognosis. Fortunately, advances in the field of surgery have given patients better alternatives that are less invasive (i.e. laparoscopic surgery), and these procedures, together with non-invasive therapies, will continue to benefit

*Radiotherapy:* More advanced cervical cancer (stage IIb and higher) is treated with radiother‐ apy (RT), chemotherapy, or a combination of the two. However, surgery and RT both aim to completely eradicate malignancy and have equally positive results in attenuating disease in the initial phases. RT is generally substituted for surgery when circumstances render an operation less than optimal as in the case of elderly patients, obese patients, or patients with several co-morbidities [80, 81]. Usually younger patients elect for surgery in order to preserve sexual function and to avoid side effects such as vaginal dryness and narrowing caused by scar tissue (as described by the ACS). Elderly patients (65+ years), who account for 20 percent of cervical cancer cases, usually choose the less invasive RT [82]. Cancer cells are more susceptible to radiation than are normal cells because radiation uses high-energy particles to target and kill rapidly dividing cells through DNA damage. In general, there are two main types of radiation therapy: external beam radiation, and internal (implant) radiation usually referred to as intracavitary brachytherapy (BT). External beam radiation therapy (EBRT) is aimed wholly at the pelvis, much like a regular x-ray, and is often accompanied by cispla‐ tin chemotherapy. The chemotherapy is added to enhance the effectiveness of the radia‐ tion and to treat metastasis to lymph nodes [83]. The selectivity of EBRT for cervical sites is enhanced by combining its use with a CT scan via 3-D conformal radiation therapy (3-D

carcinoma, but it is strongly suggested for adenocarcinoma cervical cancer.

296 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

those for whom preventive measures have failed.

Maximum dose toleration by adjacent tissues such as vaginal tissue is a major limiting factor in all radiotherapy procedures. Therefore, many strategies attempt to radiosensitize the appropriate tissues (*See Neoadjuvant and Combination therapies,* below) before exposing them to radiation. Intensity modulated radiation therapy (IMRT) offers a unique advantage through the virtual mapping of tumors so that the delivery of radiation is focused and minimal tissue damage occurs to the surrounding vital structures. Supplemental techniques to improve the localization of radiation such as hyperthermia, neutron therapy, and hypoxic cell sensitizers still need refinement, and are not routinely utilized [85, 86]. Despite potential high levels of toxicity necessitating close patient monitoring, RT is a powerful tool in managing cervical cancer. The side effects of RT that have caused the greatest concern include hematologic imbalances, GI distress, GU complications due to hydronephrosis, and secondary malignancy. Future improvements in the field of RT to treat cervical cancer must first rectify the issues of maximum dose tolerance by exploiting radiosensitizing methods in order to compensate for the systemic and potentially oncologic risks associated with radiation.

*Chemotherapy:* Chemotherapy is the principal treatment option for recurrent and metastatic cervical cancer, and it is recommended by the ACS for the management of late stage I of cervical cancer or higher. Chemotherapy can be curative or palliative. In early cervical disease, chemotherapy can be curative, but may also be given in more advanced stages (stage IV and recurrence) to alleviate the ravaging effects of the cancer itself and its related symptoms. Chemotherapy may also be given in the later stages to postpone the toxicities associated with it until absolutely necessary. Thus, designing optimal regimens suited for each case is essential to attaining both patient comfort and treatment success. Chemotherapy can also be given adjunctively to strengthen the effects of primary treatment, or provided post-operatively [87]. In fact, the ways in which chemotherapy can be administered are numerous, ranging from single, doublet, triplet, or quartlet-agent regimens to combined chemoradiation routines. However, a few agents such as cisplatin, paclitaxel, and ifosfamide are distinguished for being somewhat autonomously potent [88]. The success of single-agent chemotherapy generally depends on histology. For example, although cisplatin is most effective for treating squamous cell carcinomas (SCC), paclitaxel has been shown to improve the median survival of non-SCC type patients as compared to others who did not receive paclitaxel [89]. Furthermore, paclitaxel yielded a response rate (RR) of 33 percent, surpassing other single agents in non-SCC type cervical cancer treatment [88, 89].

Cisplatin, a platinum-based agent, is the accepted standard of chemotherapy for cervical cancer, and it improves survival in chemoradiation recipients as compared to the use of other chemotherapeutic drugs [90-94]. However, its adequacy in improving survival and quality of life in palliative management has been questioned. Some tumor cells acquire resistance to cisplatin, and so non-platinum chemotherapy or higher doses of cisplatin, in these cases, are indicated [81, 91]. In the cases of cisplatin resistance or disease recurrence, non-platinum-based agents such as topotecan, vinorelbine, irinotecan, paclitaxel, mitomycin c, and ifosfamide are sometimes combined with cisplatin. Topotecan and 5-fluorouracil (5-FU), among other combinations, seem to produce an additive effect with cisplatin to reduce its toxicity, increasing its RR from 20 to 50 percent [90, 91, 95]. Similarly, when paclitaxel is combined with cisplatin, a high RR of 46 percent is reached for late stage IV cervical cancer and is accompanied by decreased hematologic complications. However, a Gynecologic Oncologic group study reported that consistent, weekly schedules of cisplatin alone are less toxic than cisplatin combined with other agents, particularly 5-FU [92, 96]. Sanazol and tirapazamine are relatively new chemotherapeutic agents that specifically target and destroy hypoxic tissue by dissociat‐ ing into free radicals that cause DNA damage. Therefore, drug selectivity for hypoxic tissue will result in greater cytotoxicity among malignant cervical cells [81]. Multiple-agent regimens may also include the use of antibodies targeting a tumor's peculiar characteristics. For example, if a particular tumor markedly over-expresses EGFR-1, it would be appropriate to include Cetuximab in treatment, or Bevacizumab in the case of extreme vascularity [95].

**4. Molecular therapies in development**

may be constructed in a variety of ways, as described below [100].

*Therapeutic Immune Strategies:* The development of the prophylactic vaccine has forever changed the course of HPV-mediated cervical disease. Nevertheless, it is clear that there is still an immense need for therapeutic options, especially in developing countries where the positive, yet costly measures of preventative initiatives remain to be implemented. In contrast to prophylactic vaccines that target the L1 and L2 proteins and are protective against HPV infections, therapeutic vaccines would ideally target molecules such as E6 and/or E7 postinfection, which are directly linked to HPV-mediated carcinogenesis [99]. Therapeutic vaccines

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Live, vector-based vaccines, bacterial and viral, can generate very robust cell-mediated and adaptive immune responses, and because of this they are preferred over peptide/protein vaccines. Specifically, bacterial vectors function well when they are packaged with antigen (genes or proteins), thereby alerting antigen-presenting cells (APCs) to initiate an immune response. Though several bacterial vectors have been tested, *L. monocytogenes* is a prototypic example. Simply, *L. monocytogenes* stimulates antigen-specific CD8+ and CD4+ T cell responses following its evasion of immune destruction by releasing *Lm* toxin to avoid phagosomal lysis. However, the most appealing factor of the *L. monocytogenes* vector is that the immune response can be easily controlled by antibiotics should the body react adversely to *Lm* [101-104]. With regards to viral vectors, a few viruses, such as the vaccinia virus, adenovirus, vesicular stomatitis virus, and alphavirus, have distinguished themselves and show great promise. In fact, researchers have discovered that when an adenovirus vector is used to deliver calreticulin and HPV E7 antigens, the size of E7-expressing tumors in mice decrease [105]. A highly anticipated viral vaccine candidate is the TA-HPV vaccine, consisting of both HPV16 and HPV18 E6 and E7 antigens and a vaccinia virus vector. TA-HPV is safe and efficient in stimulating either a specific CTL response or a serological response, which might depend on the epigenetic patterns of each individual [106]. Similarly, the MVA E2 vaccine is also packaged with the vaccinia virus, and uses the bovine papillomavirus E2 protein to repress E6 and E7 transcription. MVA-HPV-IL2, currently undergoing a phase III clinical trial for CIN 2-3 treatment, utilizes a modified vaccinia Ankara viral vector, and uniquely contains HPV16 E6 and E7 DNA as well as IL-2 [99, 107]. The co-expression of a cytokine with HPV antigens induces a stronger immune response by stimulating dendritic cell maturation, though the refinement of viral vector tools must include solutions for overcoming pre-existing immunity. To rectify this, Cox-2 inhibitors are presently being tested to offset such immune interferences, thus allowing greater exploitation of a potentially powerful treatment. However, safety factors remain a high priority when viral vectors are considered, and these vectors must be properly constructed for use in both immunocompetent and immunocompromised individuals [100].

In peptide-based vaccines, antigens from HPV are directly administered to elicit a response from dendritic cells (DCs) *via* toll-like receptor (TLR) activation [108]. The peptide vaccine platform is ideal for mass production, but the breadth of its efficacy is limited by the expression of only one major histocompatibility complex I (MHC I) phenotype; protein-based vaccines are not encumbered in the same way. However, if the specific immunogenic epitopes on

*Combination Therapies:* Multidisciplinary treatment might be indicated throughout any of the stages of cervical carcinoma, mainly depending on its aggressiveness. In fact, it is quite common for treatment schedules to include chemotherapy, radiation therapy, and surgery [81]. The concurrent use of chemotherapy and radiation therapy is reported by the NCI to reduce cervical cancer mortality by 30 to 50 percent, particularly in late stage II. Alternatively, neoadjuvant therapy, defined as a specific sequence for delivering any treatment before a definitive therapy such as surgery or radiotherapy, may be employed. Neoadjuvant therapy is intended to prime the target tissue, thus making it more susceptible to primary treatment [71, 93]. Neoadjuvant chemotherapy (NACT) is often administered before radiation in order to radiosensitize solid tumor cells and to decrease tumor size and hypoxic cell numbers. In few instances, NACT could potentially provide patients with the option of surgery even though it may have been unfeasible prior to NACT. Moreover, researchers are finding that patients who receive sequential NACT-RH have a 10 to 15 percent survival advantage five years after treatment [97]. In cases when surgery does not completely remove all traces of abnormal tissue as anticipated, chemotherapy or radiation must be given post-operatively to inhibit local and distal metastasis through the lymphatic system. Hence, there is no doubt that concurrent chemotherapy and radiation therapy can improve survival in women with locally advanced cervical cancer or recurrent cancer [93, 98]. Radiation treatment alone does not contain cancer in 35 to 90 percent of patients, but chemotherapy given with radiation treatment yields much higher survival rates. The chemotherapeutic drugs most commonly used with radiation are cisplatin, 5-FU, mitomycin C, and hydroxyurea, though cisplatin produces the largest increase in survival by reducing mortality and recurrence [93, 94]. Many times, the sensitizing effects of drugs are needed to accentuate the value of other treatment methods, as is the case with histone deacetylase inhibitors, decitabine and valproic acid, that radiosensitize tumors for RT [81]. Thus, researchers may build and forge new applications through trials that study combination therapies.
