Download early stage cervical cancer

EARLY STAGE CERVICAL CANCER
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
EARLY STAGE CERVICAL CANCER
Executive Summary
Cervical Cancer is a pathology with a great impact in developing countries due to the limited
economic resources, screening opportunities, health services access, medical treatments and
monitoring difficulties. The incidence of cervical cancer is 14 per 100,000 inhabitants and a
mortality rate of 6.8 per 100,000 inhabitants; 87% of these deaths occur in developing countries,
Africa being the country with the highest incidence.
The available evidence shows that virtually all cases of invasive cervical cancer arise from
persistent infection by high risk serotypes of human papilloma virus (HPV). According to the
World Health Organization (WHO) there are 3 categories of invasive cervical carcinoma:
squamous, adenocarcinoma and other epithelial tumors. The most common histological type is
squamous, representing a 70 - 80% of the cases, followed by adenocarcinoma 10-15%.
The staging of invasive cervical cancer is clinical. This is in part due to the increased prevalence
of cervical cancer in resource-limited settings, where highly technical imaging studies and other
assays may not be readily available. The FIGO (International Federation of Gynecology and
Obstetrics) staging is as follows: Stage I tumors are confined to the cervix. Stage II tumors
extends beyond of the cervix without involving the pelvic walls; Stage III denotes extension to
the pelvic walls, which may cause hydronephrosis, or vaginal lower third invasion of the lower
third of the vagina. Stage IV denotes cancer that is distantly metastatic or invades the ladder or
rectal mucosa. Some authorities recommend surgical staging of cervical cancer through regional
lymphadenectomy, however, this intervention has not been proven to improve survival and is
generally not recommended outside the setting of clinical trials.
The stage specific five-year survival rates reported by the Cancer Joint American Committee
(CJAC) for 2000-2002 are 60 to 93% to 5 years for early stages of disease (FIGO stages IA, IB1
or IIA1), 16 to 58 % ,for locally advanced stages (FIGO stages IB2,IIA2, IIB, IIIA,IIIB or IVA)
and) 15% for advanced stages (FIGO stage IVB).
Survival from early stage cervical cancer appears comparable for patients treated either with
surgery or with radiotherapy. Most patients with smaller tumors are treated with primary surgery.
Acceptable treatment options for early stage cervical cancer include the following:
Stage IA1
• Cervical conization, or total hysterectomy, or cervical brachytherapy (this is often
considered in patients at high risk for surgical complications).
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Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Stage IA2
• Total hysterectomy plus pelvic lymphadenectomy.
• Teletherapy plus brachytherapy if there is a high surgical risk.
• Teletherapy plus brachytherapy (70-80 GY to point A), if there is a high surgical risk.
Stage IB1 - IIA1
• Radical hysterectomy + pelvic lymphadenectomy
• External radiation therapy+ brachytherapy (80-85 GY to point A), + Concurrent
chemotherapy with cisplatin.
• Radical hysterectomy and lymphadenectomy can be done by laparoscopic methods.
Surgical Management:
Patients with stage IA1 or IA2 who have lymphatic or vascular space invasion (LVSI) are treated
with radical surgery and lymphadenectomy. Further, preservation of normal appearing ovaries is
a reasonable option in patients undergoing surgery for early stage cervical cancer. Where it is
available, fertility sparing surgery appears to be a safe and reasonable option for selected patients
with early stage cervical cancer
Patients who undergo surgery for early stage cervical cancer are assigned to low,
intermediate or high risk for recurrence according to pathologic criteria:
Intermediate risk (risk of recurrence and death up to 30% after surgery alone):
• Presence of LVSI plus deep one third stromal invasion and tumor of any size
• Presence f LVSI plus middle one third stromal invasion and tumor size >/= 2 cm
• Presence of LVSI plus inner one third stromal invasion and tumor size >/= 5 cm
• No LVSI but deep or middle 1/3 stromal invasion and tumor size >/= 4 cm
High Risk (risk of recurrence and death of up to 50% after surgery alone):
• Positive surgical margins
• Pathologically confirmed involvement of the pelvic lymph nodes
• Microscopic involvement of the parametrium
Public Health Relevance
GLOBOCAN indicates that global cervical cancer prevalence in 2012 was 1,547,000 and labels
it as the fourth most common cancer in women (1). There were an estimated 528,000 new
incidences in 2012. About 85% (444,300) of all new cases in 2012 occurred in less developed
regions, and the remaining 15% (83,000) occurred in more developed regions. Highest-risk
regions include Eastern and Middle Africa. Cervical cancer is highly preventable and treatable, if
detected in early states. GLOBOCAN estimated that in 2012 there were 266,000 deaths from
cervical cancer. 87% of deaths (8.3 with an ASR per 100,000) occurred in less developed regions.
While GLOBOCAN does not provide specifics about early stage cervical cancer, the data do
suggest that overall cervical cancer disproportionately impacts less developed regions.
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Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Requirements for diagnosis, treatment, and monitoring
Diagnostics: The diagnosis of cervical cancer is based on direct tissue biopsy. This can usually
be done by vaginal exam in an outpatient setting without anesthesia.
Histology: The diagnosis of invasive cervical cancer can be made by a pathologist based on
haematoxylin and eosin stains.
Imaging: Invasive cervical cancer is a clinically staged disease. Evaluation of the bladder and
rectum by use of cystoscopy and proctoscopy is advised when available. IVP is recommended
for patients at risk for ureteral obstruction; at many centers CT or MR is now substituted for this
evaluation. CT can be useful to evaluate tumor size, correlation with anatomic structures,
metastases and nodal involvement. Nuclear magnetic resonance gives high resolution of soft
tissues particularly for the cervix, parametrial invasion, bladder or rectal invasion, ureteral
obstruction, lymph node enlargement. PET-CT in particular allows for increased sensitivity in
assessing lymphatic invasion. Though not part of the clinical staging, evaluation for regional or
distant metastases using CT, MR or PET/CT may help guide treatment planning, Routine
imaging is not recommended for patients who have completed primary therapy.
Administration and Care of Patients: The administration of chemotherapy with a platinum
base requires that the patient to have regular access to clinical care and adequate venous access .
In developed countries administration is usually done in outpatient centers, although in another
environment, Patients can be treated in inpatient facilities. Patients should be encouraged to
increase fluid intake from the day before to the treatment. A minimum of 500ml of normal saline
should be administered intravenously one hour before cisplatin. Cisplatin doses of 40 mg/m2
should be diluted in normal saline and infused at a rate of 1 mg/min. Due to the risk of
dehydration and renal toxicity, IV hydration is highly recommended both pre- and postchemotherapy. Many physicians administer 500-1000ml or more normal saline intravenously as
post-hydration in this setting. Cisplatin is administered the first day of the external radiotherapy,
preferably 4 hours before the radiotherapy and repeated weekly for 4-6 cycles of treatment.
Overview of Regimens
Standard Regimens
Cisplatin 40 mg/m2 (maximum dose 70 mg) administered 1 mg/min, 6 Cycles, q week, on Days
1, 8, 15, 22, 29, 36.
Prescription: Cisplatin, available in vial of dry powder of 10 and 50 mg..
Adverse effects: leukopenia, thrombocytopenia, anemia, nausea, vomiting, nephrotoxicity,
ototoxicity, peripheral neuropathy, electrolyte imbalance, hypocalcemia, hypomagnesemia,
ocular toxicity and allergic reactions.
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Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Postoperative radiotherapy: Patients with prognostic factors high risk for relapsing
· Pelvic lymph nodes involved.
· Microscopic tumor involvement of the section lines.
· Microscopic tumor involvement, lower than 3 mm to the section line.
· Deep stromal invasion, more than the 50%.
· Lymphatic invasion.
· Vascular invasion.
· Cervical Cancer handled with no surgical oncology.
· Parametrial commitment.
RADIOTHERAPY: Radiotherapy planning involves simulation or evaluation of tumor burden
with the imaging using the radiotherapy treatment unit or X-ray equipment. Radiation therapy is
applied using the four fields technique.
Anterior and posterior areas:
· Upper limit: the gap between L4-L5. In patients with histerolinfadenectomía in
absence of nodal involvement, the limit may be reduced to L5 - S1.
· Lower limit: the lower edge of the obturator foramina lateral limits: 2 cm outside the bone
pelvic wall, according to the parametrial involvement.
Lateral fields:
· Anterior limit: middle portion of the pubic symphysis.
· Posterior limit: S2-S3 (rectal half).
· Upper and lower limits: the same limits are preserved of anterioposterior fields.
Pelvic area with central protection:
For overprint from 4500 - 5040 cGy, protecting the medium line with a rectangular lead of 4 x
10 cm.
Teletherapy: megavoltage energy is used (cobalt or accelerator).
White volume: the tumor volume is included along with pelvic nodal disease. Two to four fields
are used (antero - posterior and/or laterals). Therapy involves 180 cGy – 200 cGy fractionation
for five times a week to complete a cumulative dose of 4400 – 5040 cGy.
Brachytherapy: It can be administered by intrauterine catheter, ovoid or intravaginal cylinder
and a low or high dose rate can be used. Isotopes used include: 226-Radium, 137-Cesium, and
192-Iridium.
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2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Review of Benefits and Harms
Benefits
Peters 2000/GOG protocol 109: In this study, 268 patients at high risk for recurrence after radical
surgery for stage IA2, IB or IIA disease were randomized to receive pelvic radiotherapy or pelvic
radiotherapy plus four cycles of chemotherapy with cisplatin and 5-fluorouracil. Twenty-five
patients (9%) were considered ineligible; 243 patients were evaluated: 116 in the radiotherapy
arm and 127 in the radiotherapy and chemotherapy arm. Patients were enrolled between 1991
and 1996 . The average length of follow up was 42 months. Compared to patients treated with
RT and chemotherapy, patients treated with RT alone were found to have lower progression free
survival at four years (63 vs. 80%), lower overall survival at four years (71 vs. 81%), and
decreased grade 3 or 4 toxicity
Studies of chemo-radiotherapy in the setting of patients at moderate risk for recurrence, such as
GOG 263, are ongoing. Outside of the setting of a clinical trial, most of these women are treated
with radiotherapy alone.
Harms and Toxicity Considerations
General
Based on GOG 109, treatment of women at high risk for recurrence after surgery for early stage
cervical cancer is recommended. Due to the increased toxicity of chemotherapy and a lack of
proven benefit, women at intermediate risk for recurrence are treated with radiotherapy alone. In
addition, based on trials involving women treated primarily with radiotherapy and chemotherapy
for advanced stage disease, treatment with cisplatin alone can be recommended to reduce the
toxicity seen with the addition of 5-fluorouracil
Common
Cisplatin is highly emetogenic, prophylactic antiemetics are necessary to reduce nausea and
vomiting in all patients.[2] Mild peripheral neuropathy is common with cisplatin. Patients should
be followed carefully and dose reduction or discontinuation may be required for moderate or
severe symptoms. Ototoxicity is observed with cisplatin and is more common with increasing
dose and number of cycles. Audiometry should be considered to monitor patients with toxicity;
vestibular defects are less common.
Serious
Renal toxicity caused by cisplatin can be significant and may result in electrolyte abnormalities.
Hypomagnesemia, hypocalcemia and hypokalemia should be followed and deficits repleted.
Intravenous hydration both before and after administering cisplatin is necessary to reduce the
incidence of renal toxicity.[3]
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2014 Review of Cancer Medicines on the WHO List of Essential Medicines
Systematic Reviews
Petrelli F, et al. Radiotherapy with concurrent cisplatin-based doublet or weekly cisplatin for
cervical cancer: A systematic review and meta-analysis. Gynecologic Oncology.
2014;134(1):166–171. doi:10.1016/j.ygyno.2014.04.049.[4]
Background: Treatment with weekly cisplatin (CDDP) plus radiotherapy (RT) is the
standard regimen for stage IB to stage IVA cervical carcinoma (CC). We performed a
systematic review and meta-analysis of published studies to evaluate whether CDDPbased doublet therapy improves survival compared to weekly CDDP plus RT in patients
with CC. Materials and Methods: We conducted a systematic search for randomized
and nonrandomized studies in PubMed, EMBASE, Web of Science, Scopus, and the
Cochrane Register of Controlled Trials. We then carried out a meta-analysis by using the
fixed- or random-effects models. The primary endpoints were overall survival (OS) and
progression-free survival (PFS), reported as odds ratios (ORs) and 95% confidence
intervals (CIs). Results: Four randomized trials and 4 retrospective studies that included
a total of 1500 patients matched our selection criteria. Meta-analysisshowed that for
locally advanced CC, concurrent RT and with CDDP-based doublet chemotherapy
significantly improved the OS (OR, 0.65; 95% CI, 0.51-0.81; p=0.0002), PFS (OR, 0.71;
95% CI, 0.55-0.91; p=0.006), and rate of locoregional relapse (OR, 0.64; 95% CI, 0.470.89; p=0.008), compared to RT with concurrent weekly CDDP alone. Conclusions: In
patients with CC, platinum-based doublet chemotherapy plus concurrent RT was
associated with improvements in the OS and PFS of 35% and 30% patients, respectively,
compared to RT plus weekly CDDP. Therefore, platinum-based combination therapy plus
RT should be the preferred treatment over weekly CDDP plus RT for stage IB-IVA CC.
Scatchard K et al. Chemotherapy for metastatic and recurrent cervical cancer (Review).
Cochrane Reviews. 2013:1–63.[5]
Background: Cervical cancer is the second most common cancer among women up to
65 years of age and is the most frequent cause of death from gynaecological cancers
worldwide. A woman's risk of developing cervical cancer by 65 years of age ranges from
0.69% in developed countries to 1.38% in developing countries. Although screening by
Pap smear should mean early detection at a curable stage for most women, many still
present with advanced or metastatic disease with a worse prognosis. The addition of
platinum-based chemotherapy to radiotherapy has improved outcome compared to
radiotherapy alone; however, 30% to 50% fail to respond to treatment or develop
recurrent disease. There are no standard treatment options for these patients, although
platinum-based chemotherapy is frequently used and trials are on-going. Objectives: To
compare different types and combinations of cytotoxic chemotherapy for the treatment of
metastatic/recurrent cervical cancer. Search Methods: We searched the Cochrane
Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of
Controlled Trials (CENTRAL, Issue 1, 2012), MEDLINE (1950 to January 2012) and
EMBASE (1980 to January 2012). The reference lists from these and those of review
articles were also checked. Selection Criteria: All randomised controlled trials (RCTs)
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2014 Review of Cancer Medicines on the WHO List of Essential Medicines
involving chemotherapy for metastatic/recurrent cervical cancer. Trials involving
radiotherapy, chemoradiotherapy, intra-arterial chemotherapy, biological agents or
immunomodulators were excluded.
Data Collection and Analysis: Three review authors independently reviewed trials for
inclusion and data extraction and assessed risk of bias. Main Results: There were no data
comparing best supportive care with chemotherapy. Cisplatin-based regimens are the
most widely used and therefore we have concentrated on these trials. In terms of response
rates some non-platinum regimens are equivalent but toxicity is higher. The most
common cisplatin regimen was 50 mg/m(2) day 1 q21days. Higher doses had similar
survivals. There was no direct comparison between single-agent cisplatin and carboplatin.
Overall survival (OS) and progression-free survival (PFS) were not adequately reported
and quality of life (QoL) outcomes were incompletely documented. Combination
regimens were more toxic than single agents, but in the limited reported data this did not
appear to adversely affect QoL.No significant difference in response rate by site of
recurrence was found, although there was a trend towards improved response when the
main site of disease was beyond the previously irradiated pelvis. Authors’ Conclusions:
Combination cisplatin-based chemotherapy could be a viable option for patients of good
performance status with recurrent/metastatic cervical cancer, but further trials that report
adequate survival and QoL data are sought. Response rates and improvements in survival
are low. Cisplatin-based combinations have significant toxicity. Outcomes are poor and
novel cytotoxic/biological agents and optimal scheduling need further investigation.
Future trials need to stratify for and perform planned subgroup analysis with respect to
previous treatment and site of recurrence.
Recommendations
The reviewers recommend the incorporation of early stage cervical cancer treatment options into
the WHO Model List of Essential Medicines, and recommend specifically that cisplatin be added
to the core Essential Medicines List.
Additions proposed for Section 8.2 of the EML
Cisplatin*
*Carboplatin is currently in the WHO Essential Medicines List for Adults (2013, 18th Edition).
Next to Carboplatin in the WHO List is a symbol that states that the listing of the drug indicates
“similar clinical performance within a pharmacological class. The listed medicine should be the
example of the class for which there is the best evidence for effectiveness and safety. In some
cases, this may be the first medicine that is licensed for marketing; in other instances,
subsequently licensed compounds may be safer or more effective. Where there is no difference
in terms of efficacy and safety data, the listed medicine should be the one that is
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2014 Review of Cancer Medicines on the WHO List of Essential Medicines
generally available at the lowest price, based on international drug price information sources.
Not all square boxes are applicable to medicine selection for children — see the second EMLc
for details. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and
safety and when consistent with WHO clinical guidelines. National lists should not use a similar
symbol and should be specific in their final selection, which would depend on local
availability and price.” The present proposal calls for the explicit addition of Cisplatin to the
EML given its distinct use in the treatment of a number of cancers.
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References
Citations
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3. Portilla D, Safar AM, Shannon ML, Penson RT. Cisplatin nephrotoxicity. In: UpToDate,
Post TW (Ed), UpToDate, Waltham, MA, 2014.
4. Petrelli F, et al. Radiotherapy with concurrent cisplatin-based doublet or weekly cisplatin
for cervical cancer: A systematic review and meta-analysis. Gynecologic Oncology.
2014;134(1):166–171. doi:10.1016/j.ygyno.2014.04.049.
5. Scatchard K et al. Chemotherapy for metastatic and recurrent cervical cancer (Review).
Cochrane Reviews. 2013:1–63.
Additional Literature Referenced Throughout*
*Note that the references in the present document need revisions. Please find additional literature
below that has been referred to by the authors.
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