MANAGEMENT GUIDELINES GYNECOLOGIC CANCER 1.0 Carcinoma of ...
1.0 Carcinoma of Vulva and Vagina
2.0 Carcinoma of the Cervix
(squamous cell carcinoma, adenocarcinoma)
3.0 Carcinoma of the Endometrium
(adenocarcinoma, papillary serous carcinoma)
4.0 Uterine/Gynecological Sarcomas
(Mixed mullerian sarcoma, leiomyosarcoma)
5.0 Carcinoma of the Fallopian Tube
6.0 Epithelial Carcinoma of the Ovary
7.0 Non Epithelial Ovarian Cancer
(germ cell, sex cord tumors)
8.0 Trophoblastic Neoplasia (GTN)
9.0 Selected References
10.0 Appendix (Staging)
11.0 Summary (Common Gyn Cancers)
1.0 CARCINOMA OF VULVA AND VAGINA
• Local/regional disease managed by surgery and/or radiotherapy
• No standard role for systemic therapy (chemotherapy)
2.0 CARCINOMA OF THE CERVIX
• Common malignancy worldwide (incidence and death rate high in Latin America,
Africa, India, and Eastern Europe) although lower in Saudi Arabia (ninth most
common malignancy in Saudi females. Second among gyn malignancies behind
• Histology – primarily squamous cell carcinoma (SCC, 80-90%) and adenocarcinoma
(less than 10%).
• Follows a relatively orderly pattern of metastatic progression (eg, regional nodes,
paraaortic nodes, distant sites – lung, liver, bone).
• Prognostic factors: FIGO stage, clinical tumor diameter (greater or less than 4 cm),
lymph nodes metastases (regional, paraaortic), histologic features (lymph vascular
space invasion, deep stromal invasion, uterine body involvement, SCC better than
• FIGO staging most widely accepted (over TNM) – see appendix.
• FIGO staging based on careful clinical examination (pelvic, EUA) and specific
radiologic studies, (CT abdomen and pelvis, CXR) and procedures (cystoscopy,
sigmoidoscopy). MRI and PET scans are not used in routine management, although
one recent study (Rose et al, JCO 17:41-45, 1998) suggested that PET scanning may
accurately identify nodal metastases.
2.3 Initial Workup/Investigation:
• See 2.2 (to establish FIGO state).
• No specific markers
• Stage 1A, 1B1 and early IIA: Surgery (radical hysterectomy and pelvic node
• Stage 1B2 (lesion greater than 4 cm), IIB, III, IVA:
Radiotherrapy is the primary modality of treatment. Neoadjuvant chemotherapy
(chemotherapy given before radiotherapy) although producing high initial response
rates, has not improved survival, (one large study has, in fact, shown a decrease in
survival). Concurrent chemotherapy (chemoradiotherapy) does show a survival
advantage over XRT alone (cisplatin based, with or without other agents). Based
on these data it is recommended that patients with higher risk for relapse (patients
with pelvic lymphadenopathy and/or para-aortic lymphadenopathy) should receive
concurrent chemotherapy (cis-platin 40 mg/m2
iv q wk x 5 during the course of
radiotherapy). Adjuvant chemotherapy following radiotherapy is investigational.
• Stage IVB (metastatic) or recurrent disease outside of a radiation field can be
given a trial of chemotherapy. Treatment is palliative with the exception of
occasional individuals with isolated late pulmonary metastasis, central pelvic
recurrences after primary treatment with radiation therapy, or those who develop
central pelvic recurrences after radical hysterectomy. In selected circumstances these
situations may benefit from local management.
• Chemotherapy is for palliative intent for metastatic disease or recurrence outside a
radiation field. Therefore only patients with good PS (ECOG 2 or better)
symptomatic disease and good renal function to be selected. Local palliative
radiotherapy may be utilized to treat symptomatic bony metastases or other soft tissue
sites that have not responded to chemotherapy.
• Chemotherapy to consist of cisplatin (50 mg/m2
i.v. q 3 wk) as a single agent.
Although higher response rates have been reported with platinum combinations (eg,
ifosfamide, bleomycin, vinca) toxicity is high with no improvement in survival.
Higher than standard doses of cisplatin is also controversial and not recommended
outside of a study setting.
• The efficacy should be assessed after no more than 3 cycles. If there is no significant
response, or improvement in symptomatology, it should be discontinued. Generally if
there is a response, chemotherapy can be continued until 2 cycles after the best
response or stable disease is obtained, or unacceptable toxicity or quality of life issues
• Small-cell carcinoma of the cervix is uncommon and should be treated with a
combination of XRT and chemotherapy (VP-16 and cis-platin).
• Investigational Protocols
A number of other chemotherapeutic agents have shown some activity (eg 5FU,
Taxol, Taxotere, Gemcitabine, Topotecan, Irinotecan, Vinorelbine) but their use
should at present be restricted to specific protocols.
2.5 Follow-up Schedule
• If no response to palliative chemotherapy patient should be given symptomatic and
supportive care (eg, palliative care) and referred to appropriate services or local
3.0 CARCINOMA OF THE ENDOMETRIUM
• The most common gynecological cancer in North America, although less common in
Saudi Arabia (third in incidence for gynecological cancers behind ovary and cervix).
• Predominantly a disease of post-menopausal women. Patients receiving long term
unopposed estrogen or tamoxifen (eg. Breast cancer) have an increased risk and may
need to be monitored.
• Histology: Endometrioid/endometrial adenocarcinomas most common type, and
most commonly associated with estrogen exposure or a precursor lesion (endometrial
hyperplasia). They are more likely to be hormone responsive. Other less common
lesions, (eg. Clear cell, papillary serous) associated with poor prognosis, hormone
unresponsiveness, less responsiveness to chemotherapy, and without identifiable
• Progression of disease often by local/lymphatic extension eg. to cervix, spread to
local organs (bladder, colon, adnexa), pelvic and para-aortic nodes. Peritoneal
extension less common (unlike ovarian carcinoma except for the papillary serous
type). Hematogenous metastases also less common.
• Prognostic factors: FIGO stage, histology (eg. adenocarcinoma versus papillary
serous), tumor grade, depth of myometrial invasion, lymphatic/vasc invasion. Well
differentiated (low grade) tumors are more likely to be hormone responsive than high
• FIGO staging most widely accepted. It is a surgical staging system (FIGO 1988), not
a clinical staging system (previously used but often under-staged patients). However,
clinical staging is still important for initial evaluation, prior to surgery and still
correlates fairly well with prognosis.
• See staging Table in Appendix
3.3 Initial Workup/Investigation
• Clinical assessment and fractional curettage.
• Chest X-ray
• Cystoscopy and sigmoidoscopy for locally advanced disease.
• CT scan or ultrasound of abdomen or pelvis.
• CA-125 occasionally helpful (papillary-serous or peritoneal disease).
• No specific markers.
• Stage 1A to 3A: surgery (TAH BSO) and/or radiotherapy.
• Stage 3B and 3C or gross residual disease (post surgery), or advanced disease
unsuitable for surgery or initial radiotherapy, should be considered for chemotherapy
or hormonal therapy, with or without subsequent pelvic radiotherapy. Only good
performance status patients with assessable/symptomatic disease should be
considered for chemotherapy. There is no role for adjuvant chemotherapy.
• Stage 4, distant metastases, or recurrence outside a radiation field considered for
hormonal or chemotherapy (again patients with good performance status and
assessable or symptomatic disease). Localised recurrences might be managed by
surgery and/or irradiation alone. Vaginal bleeding secondary to pelvic recurrence
may be palliated with radiotherapy.
• Hormonal therapy. Well differentiated tumors, and slowly progressive disease are
reasonable indicators. Medroxyprogesterone 100 mg po qid or 200 mg po
bid(response rate in the range 9-48%), or Megace 160 mg po od. There is no clear
dose response noted. Maximum clinical response may not be apparent for at least 3
months. Tamoxifen 20-40 mg per day has demonstrated activity (response rate 5-
46%), but is believed to be inferior to progestogens. Tamoxifen unlikely to be active
in patients failing to respond to progesterone and does not improve the response rate
when added to progesterone.
• Chemotherapy. Active single agents (response rate 20% or better) include
doxorubicin, epirubicin, cisplatin, carboplatin, 5-FU, and taxol. At present standard
chemotherapy to consist of doxorubicin 50 mg/m2
IV and cisplatin 50 mg/m2
every 3 weeks (with assessment after 3-4 cycles).
• Papillary-serous carcinoma of the endometrium is more aggressive and stage for stage
has a lower survival than the more common adenocarcinoma. Its behaviour is more
analogous to epithelial ovarian cancer. Optimal treatment is not clear although
pretreatment with chemotherapy (cyclophosphamide 500 mg/m2
IV and cisplatin 50
IV Q 3 weeks x 3) prior to pelvic radiotherapy has been advocated by some
institutions and will be carried out at KFSH&RC.
3.5 Follow-up Schedule
• If no response to palliative systemic therapy (hormonal or chemotherapy) patient
should be given symptomatic and supportive care and referred to appropriate
services or local institutions.
4.0 UTERINE/GYNECOLOGIC SARCOMAS
• Uncommon, therefore management more anecdotal.
• Histology – homologous type (endometrial stromal sarcoma, leiomyosarcoma,
supportive tissue sarcomas); heterologous (malignant mixed mullerian tumor or
mixed mesodermal tumor – MMT, adenosarcoma, etc).
• Extensive local growth a common clinical presentation. Distant spread common by a
variety of mechanisms – nodal and peritoneal with MMT; hematogenous (eg. Lung,
liver, bone) spread with most. Generally poor prognosis.
• No official staging system. Usual to use the FIGO system of endometrial cancer.
4.3 Initial Work-up/Investigations
• Chest X-ray and CT scan or ultrasound of abdomen and pelvis.
• CA-125 may be elevated for MMT with peritoneal spread.
• Surgery important if possible (curative for small numbers versus palliative to control
pain, bleeding, etc).
• Radiotherapy – role unclear (as numbers small and distant failure is common). MMT
or stromal sarcoma may have better local control with post-op adjuvant pelvic XRT.
However, survival not influenced.
• Chemotherapy – limited role. No role for adjuvant chemotherapy following initial
surgery or radiotherapy. Leiomyosarcoma – doxorubicin likely as useful as drug
combinations (eg. Ifosfamide does not add substantially when combined with
doxorubicin). Endometrial stromal sarcoma therapy is unclear. MMT may be treated
with cisplatin or ifosfamide (the advantage of the combination is not clear – presently
a GOG trial). However, there is no survival advantage.
5.0 CARCINOMA OF THE FALLOPIAN TUBE AND PERITONEAL CANCER
• Uncommon as primary site.
• Managed the same as epithelial ovarian cancer.
• Frequently involved as secondary site from other gynecologic and gastro-intestinal
6.0 EPITHELIAL CARCINOMA OF THE OVARY
• Epithelial cancers are the most common ovarian malignancies (commonest gyn
cancer in Saudi Arabia, 7th
in incidence among adult malignancies). They are usually
asymptomatic until they present with a more advanced stage.
• This group of tumors has the highest fatality to case ratio of all gynecologic
• Histology – Serous histologic type most common. Less common types are mucinous,
endometrioid, clear cell carcinomas, etc.
• An important group of tumors to distinguish is tumor of low malignant potential or
borderline tumors. These lesions tend to remain confined to the ovary for long
periods of time and generally are associated with a good prognosis. They tend to
occur in younger women more often than invasive epithelial tumors. After
appropriate surgical therapy systemic treatment is usually left until disease relapse, (ie
adjuvant therapy not of significant benefit). If relapse occurs, repeat surgery needs to
• Prognostic features: histology (clear cell carcinomas worst prognosis), tumor grade
(high grade tumors have a worse prognosis), stage, dense adhesions and large
growing ascites (for early stage tumors), residual disease left after surgery (greater
than 1 - 2 cm a poorer prognosis), age, prior therapy (eg. Platinum resistant or not),
and newer features (eg. Ploidy – diploid better; p53 gene expression).
• FIGO staging most widely accepted (see Appendix).
6.3 Initial Work-up/Investigations
• Clinical examination including assessment of the pelvis.
• CA-125 (useful in assessing response to therapy as well as follow-up).
• Chest X-ray.
• CT scan or ultrasound of the abdomen.
• Appropriate surgery is extremely important. It is useful for making the diagnosis,
carrying out appropriate exploration and staging, and in attempting to perform
maximum debulking (as the extent of residual disease is an important prognostic
factor). The role of second look surgery should be considered investigational.
However in some situations interval debulking may have a useful role (eg young
patient with good PS who could not be optimally debulked initially but who has a
significant response after chemo – usually 3 cycles, its usefulness presently being
examined through GOG and EORTC trials).
• Radiotherapy. Many institutions utilize radiotherapy for early stage disease. If it is
utilized it is important to use whole abdominal-pelvic radiotherapy. Because of the
extent of the treatment field late toxicities include the GI tract as well as bone
marrow. However, not generally utilized at KFSH&RC.
• Chemotherapy. At present chemotherapy is advocated as adjuvant treatment for
patients with stage 1 poorly differentiated disease up to advanced stage disease.
Patients with maximum debulking are likely to accrue the most benefit (less than 1
cm maximum diameter residual disease). At present the most common front line or
initial chemotherapy consists of the use of a platinum drug and taxol. It is now clear
that a taxol and platinum combination is superior to a cychophosphamide and
• The standard regimen at this institution consists of taxol 175 mg/m2
IV given over 3
hours and carboplatin 350 mg/m2
IV given every 4 weeks. In planned adjuvant
treatment settings 6 cycles of chemotherapy are utilized. For elderly patients and
some palliative situations single agent carboplatinum in the range of 300 – 350 mg/m2
every 4 weeks could be utilized. One reported study (Mogensen Gyn Onc 1992) has
suggested that high CA-125 levels following the 3rd
cycle of induction chemotherapy
may be a good predictor of treatment failure.
• Disease relapse. If the patients don’t respond to initial platinum based therapy, or
relapse within 6 months of ending a platinum based combination, they are likely
platinum resistant. Those patients will be treated with single agent Liposomal
Doxorubicin ( Caelyx). If patients relapse longer than 6- 12 months following their
initial platinum based chemotherapy, they should be retreated with the initial
• Alternative chemotherapy regimens for relapse. There is no clear consensus
regarding the most appropriate salvage regimen particularly in the platinum resistant
situation. These patients should be considered for investigative therapies if they are
available. However other drugs that have shown some usefulness include oral
etoposide (50-100 mg/m2
for 14 or 21 days every 4 weeks), and tamoxifen (20 mg
bid). If patients are considered “platinum resistant” but have not received prior
taxane therapy (eg previous therapy with cyclophosphamide and cis-platin) they
should receive taxol (175 mg/m2
iv q 3 weeks). Other alternatives have included
5FU/leucovorin, hexamethylmelamine, topotecan, taxotere, gemcitabine (although the
later 4 agents not presently available at KFSH&RC and should be used only in a
protocol setting or if these agents can be supplied from another source).
7.0 NON-EPITHELIAL OVARIAN CANCER
• Non-epithelial cancers are less common than their epithelial counterparts.
• Germ cell tumors should be considered an important entity as they occur
predominantly in younger women and are highly curable with appropriate therapy
(surgery and chemotherapy).
• Histologic typing of ovarian germ cell tumors – dysgerminoma, teratoma, endodermal
sinus tumor, embryonal carcinoma, choriocarcinoma, and others.
• In contrast to epithelial ovarian cancers, the germ cell malignancies tend to grow
more rapidly and may become symptomatic at an earlier stage. Large tumors and
high grade are adverse prognostic features.
• Sex cord – stromal tumors are an uncommon group of ovarian tumors. The most
common varieties are the granulosa cell tumors and the Sertoli Leydig tumors. These
tumors often present at lower stages. The granulosa cell tumors often secrete
estrogen. The Sertoli Leydig tumors may secrete androgens. Experience with
chemotherapy in these lesions is much more limited (although platinum based
combinations have been advocated; platinum alone or BEP). There is no benefit to
• Staging systems should be similar to that of epithelial ovarian cancer.
7.3 Initial Work-up/Investigation
• Work-up again should be similar to that of epithelial ovarian cancer with the
exception of the markers involved. CA-125 does not have any significant usefulness
in this group of tumors. For the germ cell tumors a serum BhCG and AFP should be
determined and are useful markers for response and follow-up.
• Surgery should be considered first line treatment in these diseases. Conservative
surgery (eg fertility sparing) is advocated for germ cell tumors of low stage although
more extensive surgery is required for high-stage tumors to leave minimal residual
• All patients with germ cell tumors (with exception of Stage I well-differentiated
dysgerminoma – resected; or Stage I mature teratoma – resected) should receive
• Radiotherapy. At present there is no clearly defined role at KFSHRC.
Dysgerminomas sensitive to both XRT and chemotherapy.
• Chemotherapy. Chemotherapy regimens for germ cell tumors have been variable.
Usually platinum based combinations including etoposide and bleomycin are the most
common. VAC (vincristine, actinomycin D, cytoxan) regimens have also had
extensive use in the past. At this institution the germ cell tumors are treated
primarily by a modified BEP regimen (Bleomycin 30 u IV day 1, VP16 166 mg/m2
IV daily x 3 days, Cisplatin 33 mg/m2
daily x 3 days every 3 weeks). For adjuvant
treatment (resected disease) 3 cycles of BEP or 4 cycles of EP are utilized. For
patients with residual disease, 4 cycles of BEP are utilized. Recurrent or resistant
disease is treated with VeIP (Vinblastine 0.11 mg/kg iv days 1 and 2, Ifosfamide 1.2
iv days 1-5, Platinol 20 mg/m2
iv days 1-5, Mesna 400 mg/m2
iv pre and of 4
and 8 hr post ifosfamide x 5 days). Carboplatin should not be used to replace cis-
8.0 TROPHOBLASTIC NEOPLASIA (GTN)
• Gestational trophoblastic tumors are rare but highly curable tumors arising from the
products of conception in the uterus.
• The histologic subtypes range from a hydatidiform mole, to invasive mole
(chorioadenoma destruens), to choriocarcinoma.
• The probability of cure depends on the histologic type, the extent of spread of the
disease, the level of the beta-HCG titer, the duration of disease from the initial
pregnancy event to start of treatment, the specific sites of metastases, the nature of the
antecedent pregnancy, and the extent of prior treatment. See table Relating
Prognostic Factors (Appendix).
• The most common antecedent pregnancy is that of a hydatidiform mole. After
evacuation patients with a plateau of the Beta-HCG over 3 weeks, an increasing level
of Beta-HCG, or persistent elevation of Beta-HCG after 16 weeks of follow-up
should be considered as having gestational trophoblastic neoplasia and should
undergo the appropriate management.
• Various staging systems have been developed, although most commonly an
assessment of the various risk factors to divide patients into good prognosis to
moderate and poor prognosis groupings are used for a decision of the actual
treatment modality (see table in appendix).
8.3 Initial Workup/Investigation
• Pelvic ultrasound is the preferred method of diagnosis in addition to an elevated Beta-
• Initial diagnostic/therapeutic intervention should consist of a suction D and C.
• Chest x-ray to rule out lung metastases.
• Moderate to high risk patients should have a CT abdomen (eg liver) and CT brain.
• After evacuation Beta-HCG should be determined weekly until 3 negative titers have
been obtained. This should be followed by monthly tests for 6 months with effective
contraception practiced during this duration. After evacuation of a molar pregnancy,
Beta-HCG titers usually disappear within 8-10 weeks. Persistence or increasing titers
need to be investigated for the potential of recurrent or metastatic disease.
• Treatment depends on the risk group of the disease. After appropriate evaluation low
risk disease is usually treated with single agent methotrexate or actinomycin. In this
regard various regimens of methotrexate have been reported with no clear comparison
amongst the various regimens. At our institute methotrexate 1 mg/kg/IM/Q weekly
has been utilized with the addition of Beta-HCG monitoring. This is continued until
3 normal marker values have been obtained.
• Intermediate or high risk disease is usually managed with combination chemotherapy.
Again, various regimens have been reported with the EMA-CO being the most
commonly reported. At our institution a modified BEP chemotherapy regimen has
been utilized (Bleomycin 30 units iv day 1, VP16 166 mg/m2
iv daily x 3 days,
Cisplatin 33 mg/m2
iv daily x 3 days).
• Recurrent or resistant disease has been managed by a number of reported salvage
regimens. At our institution a VeIP regimen every 3 weeks has been utilized
(Vinblastin .11 mg/kg IV on days 1+2, ifosfamide 1.25 g/m2
daily x 5 days, Mesna
IV pre and q4 and 8 hrs post ifosfamide daily x 5 days, and cisplatin 20
IV daily x 5 days).
• Patients with central nervous system metastases should be treated with whole brain
radiotherapy and intrathecal methotrexate (2 x week x 6) along with the initiation of
systemic chemotherapy. Approximately 50-60% of patients will achieve sustained
remission using this treatment approach. Patients with CNS mets with hemorrhage
should be assessed by neurosurgery.
8.5 Follow-up Schedule
• The length of follow-up with adequate contraception is not entirely clear but should
be for a minimum of 1 year. In general all recurrences likely to occur within 3 years
with 85% before 18 months.
9.0 References (selected)
Society of Gynecologic Oncologists Clinical Practice Guidelines. Oncology.12(1):119-
National Cancer Institute PDQ – Treatment. Cervical Cancer, Endometrial Cancer,
Uterine Sarcoma, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Gestational
Trophoblastic Tumor. 1998.
Cervical Cancer. NIH Consensus Statement. 14(1). April 1996.
National Cancer Registry. The Kingdom of Saudi Arabia. 1994 Report.
J S Berek and N F Hacker (Ed). Practical Gynecologic Oncology. 2nd
& Wilkins. 1994.
COSA-NZ-UK Endometrial Cancer Study Groups. Adjuvant medroxyprogesterone
acetate in high risk endometrial cancer. Int J Gyn Cancer.8(5):387-391,1998.
VT De Vita, S Hellman, SA Rosenberg. Cancer: Principles and Practice of Oncology.
DM Gershenson and WP McGuire (Ed). Ovarian Cancer. Churchill Livingstone. 1998.
M Markman. Recurrence within 6 months of platinum therapy: An adequate definition
of “platinum refractory” ovarian cancer? Gyn Onc.69:91-92, 1998.
WP McGuire and RF Ozols. Chemotherapy of advanced ovarian cancer. Sem Onc
O Mogensen. Prognostic value of CA 125 in advanced ovarian cancer. Gyn Onc 44:207-
C Trope and G Kristensen. Current status of chemotherapy in gynecologic cancer. Sem
Onc. 24(5), Supp 15:515-22, 1997.
PG Rose, LP Adler, M Rodriguez et al. PET for evaluating para-aortic nodal metastases
in locally advanced cervical cancer before surgical staging: A surgicopathologic study. J
Clin Oncol.17:41-45, 1999.
10.0 APPENDIX (STAGING)
11.0 SUMMARY OF COMMON GYNECOLOGIC CANCERS –
1. Ca Cervix:
a. Locally advanced/primary treatment:
XRT + cisplatin 40 mg/m2
iv q wk x 5
Cisplatin 50 mg/m2
iv q 3 wk
2. Ca Endometrium (Adenocarcinoma):
Systemic therapy palliative
a. Hormonal: Medroxyprogesterone 400 mg po qd
b. Chemotherapy: Adriamycin 50 mg/m2
Cisplatin 50 mg/m2
iv q 3 wk
3. Epithelial Ca Ovary:
a. Primary therapy after surgery:
Taxol 175 mg/m2
iv and carboplatin 350 mg/m2
q 4 wk x 6 cycles
b. Relapse >12 mo: Repeat Primary Therapy
c. Relapse <12 mo or PD on Taxol/carboplatin =
• Liposomal Doxorubicin 50 mg/m2 IV q 4 weeks
• Etoposide 50-100 mg/m2
/d po x 14-21 d
q 28 days
• Tamoxifen 20 mg po BID
4. Germ Cell Ca Ovary
a. Primary Therapy (adjuvant) =
BEP q 3 wk x 3 or EP q 3 wk x 4
b. Primary Therapy (disease residium):
BEP q 3 wk x 4
c. Relapse: VeIP q 3 wk
5. Invasive Mole/Choriocarcinoma:
a. Low-risk = MTX 1 mg/kg/IM q 1 wk
(until 3 normal B-HCG)
b. hi-risk = PEB q 3 wk x 4
c. Resistant = VeIP