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Standard Of Care In Management of Locally Advanced Cervical Cancer

Dr. Heba Abdallah Gomaa

Radiation Oncologist, KAMC

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OCMU Wednesdays nights (Didactics)

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Am I undertreating ?

Am I Using The Optimal Treatment ?

Am I over treating ?

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Definition of LACC ?��

. The 2018 International Federation of Gynecology and Obstetrics staging system (summarized in Table 1), while remaining a clinical staging system, has incorporated precise measurements of tumor size and specific information about lymph node involvement to allow for more clinically relevant staging when this information can be obtained. The size criteria for 2018 FIGO stage IB have changed, and stage IB1 disease is defined now as less than or equal to 2 cm in maximum diameter, stage IB2 as greater than 2 cm and less than or equal to 4 cm, and stage IB3 as greater than 4 cm in maximum diameter.�There have been multiple studies showing an increase in disease recurrence in the presence of positive lymph nodes at various stages of local tumor extension, as well as a reduced overall survival. Consequently, stages IIIC1 and IIIC2 have been added to the 2018 FIGO staging classification and manifest as pelvic and para-aortic lymph node enlargement, respectively.�

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Locally advanced IB3, II, III, IVA Deeply invasive cervix-only disease larger than 4 cm, disease that invades beyond the uterus, into regional lymph nodes, and into adjacent organs.

Radiation therapy for FIGO

Stages IB3 and IIA2

Although feasible, surgery as initial treatment is not encouraged for

patients with Stage IB3 and IIA2 disease since 80% of them require PORT or CCRT.54 It is well known that the addition of adjuvant radiotherapy

to surgery increases morbidity and thus compromises quality of life.102,103 Additionally, combined modality treatment will unnecessarily overburden the surgical and radiation facilities, which are already inadequate in low-resource countries. Therefore, CCRT is the standard of care for Stage IB3 and IIA2 disease. CCRT includes external radiation and intracavitary brachytherapy.

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Why MDT ?

1. Date of radiation start. Chemotherapy should be coordinated to start within 5 days.

2. Dates for subsequent cycles of chemotherapy and how often patients will be seen by their oncologist for chemotherapy clearance.

3. Plan for brachytherapy including where and when it will be performed.

4. Consideration for the presence of the gynecologic oncologist at brachytherapy. In some practices, the gynecologic oncologist is present at the first fraction to place a Smit sleeve.

5. Dates and types of repeat imaging. MRI prior to or with brachytherapy is often used to plan brachytherapy for at least the initial fraction.

6. Plan to manage hematologic toxicity, including transfusion and growth factor support for neutropenia.

C.H. Holschneider et al. / Brachytherapy 18 (2019) 123e132

The multidisciplinary team should develop a plan for the following:
involvement of a broad multidisciplinary team including gynaecological oncologist, radiation oncologist, radiologist, pathologist, medical oncologist, urologist, and plastic surgeon. A structured program for multidisciplinary diagnostic work-up, treatment, and follow-up must be present in centres responsible for the treatment. Participation in clinical trials is encouraged. Early involvement of palliative care specialist is encouraged. Patient should be carefully counselled regarding treatment options, risks and consequences
Some centres routinely use an intrauterine stent — a Smit sleeve which is fixed with stitches to the cervix or upper vagina. The stent stays in place for the whole course of BT and is removed after the last BT session. The intrauterine stent carries a small metal ring that facilitates the localization of the cervical os in the radiographs and prevents uterine perforations.

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Under treated?��Microinvasive squamous cell carcinoma of the uterine cervix.� - deeper invasion cannot be appreciated in available necrotic fragments.

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Under treated?

The delineation of para-aortic nodal involvement is particularly important, as this upstages disease from stage IIIC1 to IIIC2 with significant reduction in 5-year survival and a resultant change in treatment.

the presence of central lymph node necrosis is highly specific for involvement, with a positive predictive value of 100% in the pelvis.

Necrotic nodes have central low attenuation at CT and high T2-weighted with associated low T1-weighted signal intensity at MRI. Importantly, there may be poor central FDG uptake at PET/ CT. This is a potential pitfall, and these lymph nodes may be missed if not correlated with reference CT images.

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HYDROURETER is IIIB

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Over treated ?��Radiotherapy Intent: The Crux of the Matter�

When the initial objective of radiation therapy is palliation, new ground rules must be applied:

Possible serious complications or even slowly self-limiting adverse effects of treatment are no longer acceptable.

Overall treatment time must be short. Cost must be minimized. Convenience of treatment must be considered.

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Locally advanced cervical cancer is defined as clinically visible tumor exceeding 4 cm or invading beyond the cervix, extending to the pelvic sidewalls, vagina, bladder, rectum, or involving pelvic and/or para-aortic lymph nodes. Just more than half of invasive cervical cancer cases involve regional or distant metastases at diagnosis.

The current standard of care for locally advanced cervical cancer is external beam radiation therapy and concurrent weekly cisplatin, with the entire course of treatment completed within 56 days.

Brachytherapy is integral for patients who undergo curative-intent treatment. With a median follow-up of 4.3 years the EMBRACE-I study showed a local control rate of >90% in patients who received the standard of care.

Studies have demonstrated that cause-specific survival and overall survival (OS) are worse in patients who do not receive brachytherapy or if treatment extends beyond 56 days.

Patients should be referred to facilities with expertise and adequate resources to treat cervical cancer.

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Why Peer Review in radiation oncology? �

Peer review in radiotherapy is defined by The Royal College of Radiologists as ‘a formal review by another expert of the delineated contours used to produce a radiotherapy plan.

Reasons for this variability may include differing levels of experience with particular tumor sites, seniority in post, individual stylistic conventions and use of different protocols between centers. Although this variation can never be completely eradicated e given that each volume delineated requires clinical judgement.
American Society for Radiation Oncology conducted a nationwide survey related to peer review, 2009. The results showed that 83% of radiation oncologists were involved in the process, and among those, 90% changed their radiation plans because of peer review, with approximately 7% to 10% of plans being changed.

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Benchmark an excellent overall survival, based on improved local, nodal and systemic control, as well as reduction of morbidity and improvement of quality of life.

The publication of the GEC-ESTRO recommendations one decade ago was a significant step forward for

reaching international consensus on adaptive target definition and dose reporting in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Since then, IGABT has been spreading, particularly in Europe, North America and Asia, and the guidelines have proved their broad acceptance and

applicability in clinical practice. The first EMBRACE study (EMBRACE I) was a prospective observational study including external beam (45–50 Gy) and MRI-based IGABT. The study closed in 2015 with the accrual of 1416 patients. The GEC-ESTRO GYN network also carried out a retrospective collection of data (retroEMBRACE) on 852 patients from 12 centres, treated with IGABT before the start of EMBRACE I [11]. In 2016, The EMBRACE II study was launched as a prospective interventional study with specific treatment interventions based on the outcome results of the retroEMBRACE and EMBRACE I studies.

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Completion of the radiotherapy protocol within the stipulated�time is an important goal as it has a direct correlation on the outcome.�� The current recommendation�is to complete the entire protocol of EBRT and brachytherapy�within 8 weeks.

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Concurrent Chemotherapy

Several radiosensitizers have been evaluated in the treatment of locally advanced cervical cancer, including cisplatin, 5-fluorouracil (5-FU), hydroxyurea, gemcitabine, and mitomycin C.
Across five initial studies, concurrent cisplatin-based chemoradiation reduced the risk of death between 30% and 50%, which led to a National Cancer Institute (NCI) clinical alert in 1999 and established the current standard for radiosensitization.
Chemotherapy is thought to augment the efficacy of radiation by cell-cycle specific cytotoxicity, cell synchronization to a more radiosensitive phase, decreasing tumor repopulation, and inhibiting repair of radiation-induced cell damage.
For patients who are suboptimal candidates for cisplatin, such as those with pre-existing chronic renal failure or significant baseline neuropathy, weekly carboplatin dosed by area under the curve two should be considered. In patients with renal dysfunction caused by malignant ureteral obstruction, re-establishment of urinary flow with ureteral stenting should be pursued before treatment, as normalization of renal function may restore candidacy for cisplatin.

Ongoing research is focused on improving outcomes further by adding additional systemic agents to cisplatin and radiation. The addition of gemcitabine to cisplatin chemoradiotherapy followed by adjuvant gemcitabine/cisplatin chemotherapy was explored in a phase III study and showed improved survival outcomes with the addition of gemcitabine, but at the cost of increased toxicity.

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Immuno-chemoradiotherapy strategy as a new standard of care

newly diagnosed, high-risk (FIGO 2014 stage IB2–IIB with node-positive disease or stage III–IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously.

Keynote-A18 reported a statistically significant and clinically meaningful improvement in PFS with the addition of pembrolizumab to CRT following by maintenance pembrolizumab compared to CRT alone. The US Food and Drug Administration (FDA) has granted priority review with target decision date of January 20, 2024.

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Our purpose is to develop a fast, effective, and independent intracavitary brachytherapy implant insertion method that does not need sleeve insertion, anesthesia or conscious sedation, and that can be performed at the front edge of the simulation table (CT or MRI), using finger guidance without a need for speculum or cervical dilatation.�

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Side Effects (should be consented)

Acute effects (i.e., diarrhea, bladder irritation, fatigue) occur to some degree in most patients undergoing radiation and are typically magnified by concurrent chemotherapy. However, acute effects can often be managed with medications and supportive care, and they generally resolve soon after completion of radiation.
late side effects may include potential injury to bladder, rectum, bowel, and pelvic skeletal structures. The risk of major complications (eg, obstruction, fibrosis/necrosis, and fistula) is related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the normal tissue that is irradiated.

In addition, patient-related conditions (ie, inflammatory bowel disease, collagen-vascular disease, multiple abdominal/pelvic surgeries, history of pelvic inflammatory disease, diabetes) influence determination of radiation dose and volumes.