**3. Locally advanced cervical carcinoma management**

Advanced stages present a considerable challenge to achieving adequate treatment. This is compounded by the absence of modern treatment modalities and technologies that are avail-

**Studies Type Country Patients (N) Stage (rate percentage) at presentation**

IB (6.1%); IIA (20%); IIB (35.4%); IIIA (9.2%), IIIB (24.6%); IVA (3.1%)

IB (28.2%), IIA (6.4%), IIB (20.4%), IIIA (15.8%), IIIB (17.3%), IVA (7.4%)

IB (8.7%), IIA (6.8%), IIB (32.5%), IIIA (6.8%), IIIB (30.7%),

IVA (8.7%); IVB (1.9%)

Chirenje et al. [5] CS2 Zimbabwe 196 Stages IIB - IVA: (80.3%)

Musa et al. [4] R1 Nigeria 65 IA (1.5%) -

78 Cervical Cancer - Screening, Treatment and Prevention - Universal Protocols for Ultimate Control

Mlange et al. [6] CS2 Tanzania 212 IA (1.4%),

Sharma et al. [3] R1 India 227 IA (3.9%),

**Table 1.** Summary of rates of cervical carcinoma disease stage at presentation in LMICs.

LMICs face a double burden where patients for different reasons including health system factors presents at hospital with advanced diseases and at the same time there is a pronounced lack of infrastructure to take care of these patients. This leads to an overall poor survival rates.

Staging with full nodal evaluation remains a crucial aspect of the management of locally

able in high-income countries (HIC).

**2. Disease evaluation**

1

2

R = retrospective review.

CS = cross-sectional study.

advanced cervical carcinoma.

The standard of care for advanced cervical carcinoma is Radiation Therapy alone (in case of palliation), or in combination with cisplatin-based chemotherapy.

Overall survival is usually a function of disease-free interval rates, highlighting the scarcity of salvage therapy options in case of recurrence.

With limited options for salvage in cases of recurrences, disease-free interval rates directly correlate to Overall Survival and comorbidities of the patients.

Generally, management of cervical carcinoma includes definitive surgery for selected cases, upfront radiation therapy and chemo-radiation. Surgery and radiation therapy amount to the same effect yet with drastic differences in terms of debilitating toxicities, hence surgery alone is the treatment of choice for initial smaller lesions (<4 cm) with other treatment modalities offered as a salvage in case of recurrence.

A Gynecological Oncology Group (GOG 56) study confirmed the benefit of added hydroxyurea to radiation therapy, with a higher Progression Free interval, though no significant survival benefit was found [8]. This study was controversial in its setting and the recommendations were not applied widely. Hydroxyurea involves a high risk of myelosuppression, and prospects of considering it as a viable combination therapy to radiation were abandoned overtime. 5-Fluorouracil has also been considered as an alternative chemotherapy regimen for combination therapy. However, the few published studies failed to prove local disease control and

Locally Advanced Cervical Carcinoma Management http://dx.doi.org/10.5772/intechopen.74011 81

Based on a five-study analysis, cisplatin added to radiation therapy was confirmed to have a

A large systematic review of 18 trials combining radiation and chemotherapy for locally advanced cervical carcinoma proved the survival benefit of adding chemotherapy. Platinum based chemotherapy was not seen to be significantly different from non-platinum based chemotherapy (HR: 0.84 vs. 0.76, *p* = 0.48). Platinum-based regimens were also found to have a non-significant increased toxicity trend. However, single agent platinum offered an important alternative with

Historically, the GOG 120 compared different chemo-radiation regimens, combined with a brachytherapy boost. The arms had a cisplatin alone, a hydroxyurea alone and a cisplatin/5- Fluorouracil/Hydroxyurea components. The arms containing cisplatin had improved survival and disease down-staging was achieved. Subsequent studies removed hydroxyurea and compared upfront radiation therapy with concurrent cisplatin (with or without 5-Fluorouracil) with radiation therapy, which established the standard of care of adding chemotherapy to

regards to local disease control, adherence to treatment and ease of administration.

radiation therapy, as it was shown to increase survival and decrease recurrence risks.

The rationale behind adding cisplatin to radiation is that it acts as a radiosensitizer, by preventing the Non-Homologous End Joining pathway, which is paramount in the Double Strand Breaks repair. Double Strand Breaks in DNA are induced by high energy radiation therapy. Cisplatin is given on a weekly basis, a few hours before radiation therapy, and care needs to be taken for its administration. As a nephrotoxic agent, adequate hydration is to be ensured, before and after cisplatin infusion. Together with knowing prior the renal status of the patient, dosing can be altered to prevent toxicity. Carboplatin has been shown to provide a suitable alternative to cisplatin for patients who are not candidates to cisplatin infusion (**Table 2**).

Gemcitabine could also be a choice when cisplatin is contraindicated. However, in the absence of level I evidence, and with the increased toxicity risk associated with Gemcitabine, carboplatin remains the preferred choice in case of intolerance to cisplatin, and deranged renal

Radiation Therapy is provided by both External Beam Radiation (EBRT) and brachytherapy

survival benefit with an added 5-Fluorouracil regimen [9].

superior survival when compared to radiation alone.

function tests.

**5.2. Radiation therapy**

(BT) to increase local control.

## **4. Primary chemoradiation vs. surgery**

As cited above, the widely used treatment scheme for locally advanced cervical carcinoma consists of upfront radiotherapy concurrently with a platinum-based chemotherapy.

Surgery has been proven to not be superior to chemo-radiation, but carries twice a risk of increased toxicity rates.

Adverse features arising post-surgery could be similar to other advanced diseases, including high grade disease, lympho-vascular space invasion (LVSI), positive lymph nodes, prompting the use of multiple modalities of treatment with subsequent considerable toxicities.

The largest comparison study to date by Landoni, compared 343 patients with early disease, contemporarily included in the locally advanced stage (IB - IIA) disease, to undergo an extensive surgery with pelvic lymph node dissection, with a possibility of Radiation Therapy boost in the presence residual disease. This arm was compared with upfront Radiation Therapy. The comparison yielded no differences in survival, but showed considerable difference in toxicity rates [7].

Chemo-radiation has been proven to offer a high survival benefit which is greatly influenced by disease stage. Additionally, concurrent chemo-radiation decreases the recurrence risk.

Radiation consists of external beam radiotherapy session and a stage-variable boosting dose achieved by brachytherapy. Details on patient simulation, field size and dose specification are found below.
