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Agreed 2012 Review 2015
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MEDICAL PROTOCOL
ONCOLOGICAL MANAGEMENT OF OVARIAN CANCER
These guidelines have been developed by members of the Gynaecological Oncology
Guidelines Group, for approval by the Merseyside and Cheshire Gynaecological
Cancer Network Group.
1. Background .................................................................................................................................... 3
2. Prognostic Factors ........................................................................................................................... 3
3. Abbreviated Staging System (FIGO 1997) ....................................................................................... 4
4. Diagnosis/Referral ........................................................................................................................... 4
5. Pre‐Treatment Assessment ............................................................................................................. 5
6. Referral to the Multidisciplinary Team ........................................................................................... 7
Referral of Patients Presenting as an Emergency with Suspected Ovarian Cancer ....................... 8
7. Surgery for Ovarian Carcinoma ....................................................................................................... 9
Staging ........................................................................................................................................... 10
Optimal debulking ......................................................................................................................... 10
Primary cytoreduction .................................................................................................................. 11
Splenectomy ................................................................................................................................. 11
Bowel resection ............................................................................................................................ 11
Lymphadenectomy ....................................................................................................................... 12
Surgery in Stage I EOC ................................................................................................................... 13
Second‐look Laparotomy .............................................................................................................. 13
Interval Debulking Surgery ............................................................................................................ 13
Neo‐adjuvant chemotherapy followed by surgery‐NACT‐S .......................................................... 15
Recurrent Ovarian Cancer ‐ Salvage Surgery ................................................................................ 15
Minimal Access Surgery ................................................................................................................ 16
8. Post‐operative Management ‐ Chemotherapy ............................................................................. 17
Early Stage Disease ....................................................................................................................... 17
Advanced Disease ......................................................................................................................... 19
2nd line Chemotherapy for Advanced Disease .............................................................................. 22
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Intraperitoneal Chemotherapy ..................................................................................................... 24
9 Post‐operative Management ‐ Radiotherapy ................................................................................ 25
Adjuvant radiotherapy .................................................................................................................. 25
Consolidation radiotherapy .......................................................................................................... 25
Palliative radiotherapy .................................................................................................................. 25
10. HRT .............................................................................................................................................. 26
11. Palliative Care and Nursing care ................................................................................................. 26
12. Follow up ..................................................................................................................................... 27
13. Maintenance of quality ............................................................................................................... 27
14. Clinical Trials ............................................................................................................................... 28
15. Women with a family history ...................................................................................................... 29
References ........................................................................................................................................ 30
Appendix 1: FIGO staging 2010……………………………………………………….………………………………………………34
Appendix 2: Chemotherapy regimes……………………………………………………………………………………………….36
Agreed 2012 Review 2015
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1. Background
Ovarian cancer is the fourth commonest cause of cancer death in women.
Approximately 200 cases are diagnosed in women in Mersey annually under the age
of 70, and 15% of cancers arise in patients under the age of 55. The role of surgical
debulking has been well established for the last twenty years, but with the
introduction of more effective cytotoxic chemotherapy the relative timing of surgery
and chemotherapy has been called into question (1). Primary debulking to no visible
disease, where feasible, remains the standard treatment. Where this is not possible,
interval debulking surgery has been defined as a further attempt following
chemotherapy, while neoadjuvant chemotherapy followed by surgery (NACT-S) is
the term applied to the strategy of early introduction of chemotherapy in potentially
resectable cases. Radiotherapy has a more limited role primarily in palliation of
advanced disease.
Chemotherapy therefore has a central role in management and platinum based
chemotherapy has been established as the most active effective against ovarian
cancer for over 15 years; more recently two randomised trials have demonstrated
the valve of incorporation of paclitaxel as a first line agent. The standard combination
for patients is now the combination of these two drugs (2), and carboplatin has in
most cases replaced cisplatin in view of its reduced nephro- and neuro-toxicity.
Guidelines have been issued by NICE (Reports 3 and 55). For patients with impaired
renal function or elderly patients then single agent carboplatin may be the most
appropriate treatment.
Clinical trials are exploring the role of second line chemotherapy, with surgery in
selected cases.
2. Prognostic Factors
Many attempts have been made to classify ovarian tumours, usually with the aim of
determining prognosis more accurately. Stage (Figo I-IV) and grade (G1-G3) are the
principal independent variables. Several other factors are listed below which may be
of adverse prognostic significance.
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Adverse Prognostic Factors in Ovarian Tumours
Clear Cell Histology
Mucinous vs. Serous
Lymphatic Invasion
Poor Performance Status
Poor Biochemical or Haematological Status
3. Abbreviated Staging System (FIGO 2010) – See Appendix 1.
The FIGO staging system, updated in 2010, is currently in use. This system
incorporates cyst rupture in Stage I as an adverse prognostic factor.
In early disease, histological grade, even though there are problems with
reproducibility among pathologists, may be a better prognostic indicator than stage.
4. Diagnosis/Referral
The Merseyside & Cheshire Cancer Network requires that cancer guidelines are IOG
compliant. Patients with a high index of suspicion for ovarian cancer should be
referred to a Sector MDT for surgical management at the Gynaecological Oncology
Centre. It is recognised there may be individual factors to suggest that non-surgical
or local treatment may be preferable.
Patients whose treatment should be delivered under the care of members of the
specialist gynaecological oncology team at the centre should include the following:
Women with complex adnexal masses or imaging consistent with disseminated ovarian
cancer, with a risk of malignancy index3 (*RMI) greater than 250. If the cancer is thought
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to be metastatic to the ovary, discussion between the Multidisciplinary Team meeting
and the referring unit is appropriate to decide on management on an individual basis.
Patients to be considered for interval debulking surgery.
Patients in randomised trials including a surgical component.
Patients with an isolated elevated Ca125 measurement should not be referred solely on
this basis. This can be due to many other conditions, including endometriosis,
adenomyosis, benign ovarian cysts, Meig's syndrome, ovarian hyperstimulation
sydrome, fibroids, pancreatitis, chronic liver disease, colitis, diverticulitis, renal disease,
systemic auto-immune conditions, and malignancies of lung, breast and gastrointestinal
tract.
However, patients who do not clearly fall into any of the above should be discussed
individually in the sector MDT before definitive management is finally decided. It should
be remembered that MDT meetings are not exclusively pathology review meetings but
should be designed to incorporate prospective discussion of as many patients as
possible before definitive management is decided.
Unexpected post surgical diagnosis of ovarian malignancy.
* RMI = U x M x CA125, where U is the ultrasound score and M is the menopause score.
The ultrasound score is based on the following features suggestive of malignancy: multiloculated cysts, evidence
of solid areas, evidence of metastases, ascites, bilateral lesions. U=0 when no features are recorded; U = 1 if 1
feature is recorded; U=3 if 2 or more features are recorded.
The menopause score (M) of 1 or 3 is given to pre- and post menopausal patients respectively(3).
5. Pre-Treatment Assessment
A thorough pre-operative work up is required in all cases of suspected ovarian
cancer. The 2011 NICE guidance4 gives clear recommendations as to the
assessment of women, and this has been mirrored in these guidelines.
Examination and assessment
A thorough abdominal and pelvic (vaginal and rectal) examination Relevant present and past medical history and examination, performance
status (WHO)
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Family history – first degree relatives with ovarian, breast or colon cancer
FBC, U+E, LFT, CA125
Group and save if surgery is expected as the primary treatment
Tumour markers
Measure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care.
In women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer.
Imaging
Perform an ultrasound of the abdomen and pelvis as the first imaging test in secondary care for women with suspected ovarian cancer, if this has not already been done in primary care.
If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated.
Do not use MRI routinely for assessing women with suspected ovarian cancer.
Tissue diagnosis
If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases.
Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without
a tissue diagnosis (histology or cytology) only: in exceptional cases, after discussion at the multidisciplinary team and
after discussing with the woman the possible benefits and risks of starting chemotherapy without a tissue diagnosis.
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Methods of tissue diagnosis other than laparotomy
If surgery has not been performed, use histology rather than cytology to obtain a tissue diagnosis. To obtain tissue for histology:
o use percutaneous image-guided biopsy if this is feasible o consider laparoscopic biopsy if percutaneous image-guided biopsy is
not feasible or has not produced an adequate sample.�� o Use cytology only if histology is not appropriate.
N.B. Laparoscopy and cyst aspiration is NOT routinely recommended when ovarian cancer
is suspected. Negative cytology does not safely exclude the diagnosis, and cyst leakage
may disseminate and upstage the cancer.
6. Referral to the Multidisciplinary Team
Multidisciplinary clinic assessment at the outset of treatment is beneficial for strategic
planning of the clinical management. Decisions regarding further investigations,
primary treatment and planning of future management are best undertaken in the
MDT setting.
National Cancer Standard 1A-211 (1*): The Network board should agree the network’s guidelines in ovarian cancer which should include: the network guidelines for patients with suspected ovarian cancer who present as an emergency, whereby they may be stabilised and then transferred to a named specialist team for definitive treatment. These guidelines should be distributed to all consultant gynaecologists and all consultant surgeons on general surgical take in the network.
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7. Surgery for Ovarian Carcinoma
In summary:
Standard surgery involves total abdominal hysterectomy, bilateral salpingo
oophorectomy, omentectomy and para aortic node assessment
The aim of surgical treatment is for maximal tumour debulking (to <1cm
disease), and with that outcome, more radical surgery such as bowel
resections are justified.
Should optimal debulking not be considered possible after preoperative
assessment, neo-adjuvant chemotherapy with surgery after 3 cycles should
be considered.
Primary surgery or interval debulking surgery after 3 cycles of chemotherapy
carry a similar prognosis
Salvage surgery should only be undertaken in selected cases or as part of a
randomised controlled trial
The current clinical consensus is based on the concept of radical cytoreductive
surgery. This followed the observation that patients with minimal or no residual
disease after primary surgery had a better survival than those with gross residual
disease.
The 2011 NICE guidelines on ovarian cancer4 have not specifically recommended
either primary surgery or primary chemotherapy, but advised the aim of surgery at
any stage should be the complete resection of all macroscopic disease. The main
change in local practice following the NICE guidance is the use of preoperative CT
staging for all suspected ovarian cancers. If after preoperative staging optimal
debulking is not considered possible, primary chemotherapy with consideration for
surgery after 3 cycles is likely to be a better approach; the EORTC 55971 data
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suggests improved morbidity but no change in overall survival with this approach in
advanced stage ovarian cancer.
There are a number of indications for surgery:
Diagnosis
Staging
Primary cytoreduction
Interval and secondary cytoreduction
Palliative and salvage surgery
Staging
Accurate staging procedures are important in the determination of the future
management of any patient with ovarian carcinoma. Therefore, the incision used
should be of a suitable type (i.e. vertical) and size to allow adequate exploration of
the entire abdominal cavity. A sample of any ascites present should be sent for
cytological analysis and in the absence of ascites, peritoneal washings are
performed. The abdominal contents, peritoneal surfaces and retroperitoneal spaces
should then be carefully and systematically examined to determine the extent of any
macroscopic disease. Infracolic omentectomy is routinely indicated for staging
unless there is inoperable carcinomatosis.
Optimal debulking
Debulking, or cytoreductive surgery, by which is meant the removal of as many
tumour deposits as completely as possible, is a concept which was first applied 30
years ago to ovarian cancer with peritoneal metastases5. Complete debulking of all
macroscopic disease is desirable. “Optimal Debulking” has been defined in different
ways at different times in the literature, but currently is generally understood to mean
cytoreduction to less than 1cm disease, which should be achievable with acceptable
morbidity in 60% or more of patients.
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There is however an increasing body of evidence to indicate that while operative
management for advanced stage disease is capable of contributing to an improved
outcome, it only does so when all macroscopic disease is completely removed6. This
should be readily achievable in 22-25% of cases of stage 3 or 4 disease7.
Randomised trials are not available, but comparative studies indicate that each 10%
improvement in the total debulking rate is associated with a 5.5% improvement in
median survival8. Total debulking rates in excess of 80% have been described9. This
latter approach involves an ultraradical approach including extensive bowel
resection, splenectomy, and radical stripping of the peritoneum, including the
diaphragm, at the expense of increasing postoperative morbidity and mortality. There
is a move towards more radical surgery within the UK and this is developing within
the Mersey cancer network.
Primary cytoreduction
Standard primary surgery comprises total abdominal hysterectomy, bilateral
salpingo-oophorectomy, infracolic omentectomy and tumour debulking. Surgical
staging is also mandatory and includes cytology washings in apparent early stage
disease, and retroperitoneal node assessment.
Splenectomy
Metastasis of ovarian carcinoma to the spleen is uncommon and usually occurs late
in the course of the disease. It may be an appropriate measure but only when there
is no significant disease left elsewhere in the abdominal cavity.
Bowel resection
There are occasions when resection of bowel at primary laparotomy is necessary to
afford symptomatic relief or to prevent bowel obstruction. It is less clear however
whether bowel resection performed in order to achieve optimal debulking is
beneficial. Potter et al found that extensive surgical procedures, in particular bowel
resection, though achieving clearance of all macroscopic disease, did not improve
survival over those who did not have such surgery and were left with macroscopic
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disease10. Other authors however, are achieving a significant improvement in
survival with multiple bowel resections7,8,9,11. Bowel resection if leading to complete
removal of all visible disease needs to be considered (dependent on patient choice
and patient fitness), but given the morbidity attendant with bowel resection it would
seem inappropriate to perform such procedures unless no other macroscopic
intraperitoneal disease was to remain or where certain palliative benefit would not
ensue.
Lymphadenectomy
Retroperitoneal palpation of node chains should always be carried out, but removal
of lymph nodes is only indicated where this would potentially affect the stage of
disease or result in the removal of bulky disease. Selective lymphadenectomy of
pelvic and para-aortic nodes is recommended by the GOG in patients with no gross
residual disease regardless of stage, gross residual disease limited to the pelvis or
those in whom the largest diameter of any gross residual disease outside the pelvis
is 1 cm. In cases where stage IIIc disease is diagnosed prior to cytoreduction, the
presence of positive retroperitoneal lymph nodes would not influence staging though
assessment of retroperitoneal disease may still be helpful if there is any question of
attempting optimal debulking. Selective removal should not otherwise be justified
unless undertaken as part of a research protocol.
The question of systematic lymphadenectomy has been examined in a randomised
trial11. There was no overall survival advantage, however a modest progression free
survival improvement in the lymphadenectomy arm was offset by increased
morbidity. We do not currently recommend systematic lymphadenectomy to our
patients, and this is in line with the current NICE guidance (CG 122)4.
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Surgery in Stage I EOC
Stage I EOC is relatively more frequent in women who may wish to retain fertility. In
such circumstances it is possible to simply remove the affected ovary and to carry
out surgical staging. On the basis of the available evidence, removal of a single
abnormal ovary with careful examination of the entire abdominal cavity is all that is
required in selected stage Ia EOC, where the woman wishes to retain her fertility.
Washings and omental biopsy are required for stage confirmation. There is no
evidence to justify lymphadenectomy or representative biopsies, although some
clinicians would choose to perform para-aortic node sampling in these
circumstances. A thorough and careful discussion with the patient is required
regarding optimal staging, the risks of recurrence and the possibility of further
surgery if limited surgery is considered. In those women not requiring fertility, the
standard recommendation is still for a total abdominal hysterectomy, bilateral
salpingo oophorectomy and omentectomy in cases of suspected ovarian cancer or
all stages.
Second-look Laparotomy
This describes an operation performed after the completion of primary
chemotherapy, the aims of which were to assess disease status (i.e. response to
chemotherapy) and to resect any residual tumour.
On the basis of the available evidence, second-look laparotomy has no place as part
of the routine management of patients with ovarian carcinoma, though in the context
of ongoing clinical trials (eg DESKTOP 3) there is a role for secondary debulking of a
localised recurrence.
Interval Debulking Surgery
The concept of interval debulking surgery arose following the disappointing results
achieved with second-look laparotomy. According to the hypothesis of Goldie and
Coldman14, the development of resistance to chemotherapy would be a function not
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only of the initial number of cells present but also of time. Thus it was proposed that
the failure of secondary surgery to affect survival 6 months after the initial
laparotomy might simply reflect the development of resistant clones of cells. If this
theory were to hold true then surgery should be performed as soon as chemotherapy
has produced the necessary cytoreduction, which would usually be after 2 or 3
cycles of chemotherapy.
There exist 2 prospective randomised trials regarding intervention debulking surgery
(IDS). The first of these studies was carried out in the West Midlands of the United
Kingdom and included 79 patients with bulky residual disease after primary
surgery15. They were randomised to either IDS or standard chemotherapy alone. No
significant difference in survival was found to justify the increased morbidity,
although the number of patients in the study means that the power for detecting
small differences was low.
The second prospective trial of IDS is that of the EORTC Gynaecological Cancer Co-
operative Group reported in 1995 by van der Burg16. A total of 425 women were
enrolled into the study of whom 319 were subsequently randomised and the
published report alludes to 278 patients for whom follow-up data was available.
Outcome measures showed a significant survival advantage for patients undergoing
IDS with a 6 month median survival advantage and 56% vs 46% being alive at 2
years. However, of the 127 patients undergoing surgery only 83 had residual tumour
>1cm diameter at IDS and hence could potentially benefit from secondary
cytoreductive surgery, and only 37 of these patients underwent cytoreduction to
<1cm at IDS. This would suggest that if there is indeed a survival advantage it may
only apply to a small sub-group of patients, but the authors concluded that the
overall increase in morbidity was acceptable in view of the 6 month median survival
advantage. A confirmatory trial carried out by GOG and reported at ASCO 2002
(Rose PG et al) showed no survival benefit from IDS. The explanation proffered is
the overall patient population had been managed with more aggressive surgical
approaches common in North American practice. The 10-year results of the EORTC
study contain a persisting survival advantage in the IDS arm. Taken with Rose’s
data, this suggests that optimal debulking surgery may confer a survival advantage
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irrespective of whether it is delivered as a single operation or staged as a primary
laparotomy followed by IDS.
Neo-adjuvant chemotherapy followed by surgery-NACT-S
In this approach, patients with histologically or cytologically positive ovarian
carcinoma are treated with primary cytotoxic chemotherapy prior to a definitive
attempt at tumour debulking. This requires a reasonable certainty of the diagnosis,
such as an ovarian mass present and an elevated serum CA125.
The EORTC randomised trial 55971 compared NACT-S with the standard primary
surgery followed by platinum-based chemotherapy, while the NCRI CHORUS study
is similar, but with less stringent entry criteria, and a requirement for
histology/cytology only after randomisation. EORTC 55971 was published in
September 2010, and reported no improvement in survival with neo-adjuvant
chemotherapy, but a lower postoperative mortality, shorter operation time, less
haemorrhage, venous complications and infections.
In the light of the EORTC trial and the recent NICE guidance, practice within the
network has shifted. Primary surgery is still offered to those patients in whom
complete surgical excision is felt feasible, but if on pre-treatment CT scan complete
debulking of the tumour is not felt possible, primary treatment is now chemotherapy
(after image guided or laparoscopic tissue biopsy confirmation of disease), with
consideration of surgery at MDT after 3 cycles of chemotherapy.
Recurrent Ovarian Cancer - Salvage Surgery
Salvage surgery is a term which can be used to describe attempts to carry out
secondary cytoreduction in patients who develop recurrent disease after a disease-
free interval. Little published work exists. Vacarello et al17 performed a retrospective
review of 57 patients developing recurrent disease after a negative second-look
laparotomy. Recurrence was diagnosed a mean interval of 20 months from second-
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look surgery and 38/57 patients underwent a laparotomy with attempt at further
cytoreduction. Patients who underwent cytoreduction to <0.5cm residual disease had
a significant survival advantage.
The DESKTOP trial18 was an exploratory study based on data from a retrospective
analysis of hospital records from 25 collaborating institutions.
Two hundred and sixty-seven patients were included. Complete resection was
associated with significantly longer survival compared with surgery leaving any
postoperative residuals [median 45.2 vs. 19.7 months; hazard ratio (HR) 3.71; 95%
confidence interval (CI) 2.27–6.05; P < .0001]. Variables associated with complete
resection were performance status, FIGO stage at initial diagnosis, and absence of
ascites > 500 ml. A combination of PS, early FIGO stage initially or no residual
tumour after first surgery, and absence of ascites could predict complete resection in
79% of patients.
Only complete resection was associated with prolonged survival in recurrent ovarian
cancer.
These findings are interesting but, being based on retrospective data, should be
interpreted with caution. The prospective study (AGO-DESKTOP II) identified the
criteria for selecting the right patients for cytoreductive surgery in recurrent ovarian
cancer, so leading the way for the prospective randomised trial of surgery in
recurrent ovarian cancer (DESKTOP III).
Our policy is to recommend salvage surgery only for strictly selected patients or
within a trial setting, such as DESKTOP III. The indications must be critically
evaluated in each individual case.
Minimal Access Surgery
The role of MAS in the management of ovarian carcinoma other than laparoscopic
assessment for initial diagnosis has yet to be properly defined.
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8. ROLE OF SYSTEMIC CHEMOTHERAPY IN THE MANAGEMENT
OF OVARIAN CANCER
In summary:
• Do not offer adjuvant chemotherapy to women who have had optimal surgical
staging and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
• Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant
chemotherapy consisting of six cycles of carboplatin.
• Discuss the possible benefits and side effects of adjuvant chemotherapy with
women who have had suboptimal surgical staging and appear to have stage I
disease
See Appendix 2 for chemotherapy regimes
8.1 Early Stage Disease- Adjuvant Chemotherapy
In women with apparent stage I disease, chemotherapy can be given in certain
circumstances, such as poorly differentiated tumours and in certain histological sub-
types (for example, clear cell carcinomas). This is done to treat residual disease that
is suspected but may not, in fact, exist. Therefore some women without residual
disease will receive chemotherapy with its associated risks. Currently NICE
technology appraisal guidance 55 (NICE, 2003) recommends a choice of either
platinum based compound on its own or in combination with paclitaxel but does not
stipulate the number of cycles to be given. It is logical that reducing the number of
cycles of chemotherapy is likely to reduce toxicity but could compromise
effectiveness.
ICON1 (JNCI 2003) and ACTION (2003) trials have confirmed the survival gain of
adjuvant chemotherapy in early stage disease. ACTION was for patients with Stage
IA or B, G2/3 and all Stage IC patients, while ICON1 comprised the less well defined
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group where investigators were uncertain about optimum management. The
combined data19 have effectively shown an 8% survival benefit at 6 years in favour of
adjuvant platinum based chemotherapy (disease free survival 11%), and a meta-
analysis with two additional trials showed an overall hazard ratio of 0.72 in favour of
adjuvant chemotherapy. The benefits of the treatment have to be viewed against the
good survival of the overall group following surgery alone (80% at 10 years). Degree
of differentiation is the most powerful prognostic indicator in stage I ovarian cancer
and should be used in decisions on therapy in clinical practice20. However, in Stage
1a and 1b grade 1 tumour, where the risk of relapse is slight, an observation policy
may be appropriate.
Review of Winter-Roach et al., (2009)21 investigated the role of adjuvant therapy with
mainly platinum-containing regimens in terms of survival advantage and compared
those to withholding chemotherapy until disease progression. Women who received
adjuvant therapy had a considerable advantage in overall survival (HR=0.71 [95%CI:
0.53 to 0.93] P=0.015) and progression-free survival (HR=0.67 [95%CI: 0.53-0.84]
P=0.00046) at an average follow up of 10 years. In particular, those women who had
been adequately staged gained no survival advantage from immediate adjuvant
chemotherapy (HR=1.22 [95%CI: 0.63-2.37] P=0.56) whereas women who had been
inadequately staged did (HR=0.63 [95%CI: 0.46 to 0.85] P=0.0031).
Bell et al22 compared six vs. three cycles of adjuvant carboplatin and paclitaxel in
women with early stage ovarian cancer (N=457). After an average follow-up of 6.8
years, there were no statistically significant differences in the risk of death (HR=1.02
[95%CI: 0.66-1.57] P=0.94) or the rate of disease recurrence (HR=0.76 [95%CI:
0.51-1.13] P=0.18). The higher number of treatment cycles was associated with
significantly increased morbidity.
The systematic review21 included evidence from the Adjuvant Chemotherapy in
Ovarian Neoplasm (ACTION) trial which has now been updated by Trimbos et al23.
The results showed that, even with observation, optimally surgically staged patients
had a significantly better prognosis compared with patients who had been non-
optimally staged: cancer-specific survival (risk of death: HR 3.28 [95%CI: 1.47-7.33]
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(P=0.002); recurrence-free survival (risk of death: HR 1.91 [95%CI: 1.17-3.11]
P=0.009). In non-optimally staged patients only, adjuvant chemotherapy provided
significantly improved cancer-specific survival (risk of death: HR 0.58 [95%CI: 0.35-
0.95] P=0.029) and recurrence free survival (risk of death: HR 0.60 [95%CI: 0.41-
0.87] P=0.007) when compared with observation. The authors concluded, therefore,
that the benefit of adjuvant chemotherapy appeared to be limited to patients with
non-optimal staging who, perhaps, had a greater risk of unidentified residual
disease. The results of Bell et al.22 were re-analysed in a more recent report (Chan
et al., 2010) after a median follow-up of 91 months. They reported that only women
with serous cancer derived a significant benefit from six cycles compared with three
cycles of adjuvant carboplatin and paclitaxel chemotherapy (HR=0.33 [95%CI: 0.14-
0.77] P=0.007). Although interesting, the original study was underpowered for sub-
group analyses which, in any event, have been performed post hoc.
8.2 Advanced Disease- First line chemotherapy
The revised NICE guidelines take into account the published results of ICON3, which
shows that single agent carboplatin is an effective treatment if given at a dose of
AUC6 based on a calculated GFR. Platinum agents remain the most effective in the
treatment of this disease with a survival benefit estimated at 6 to 24 months and
some evidence that this benefit is greater in stage III than in stage IV patients.
For patients who are medically fit, the combination of a platinum compound and
paclitaxel is considered the standard first line chemotherapy, based on the 2 positive
trials (GOG III and OV10), and this forms the basis of the NICE guidelines. Very
occasionally consolidation pelvic radiotherapy may be advised, usually in cases of
stage 2 disease where the residual volume of tumour is small. In some cases of
Agreed 2012 Review 2015
20 | P a g e
ovarian cancer, adenocarcinoma may be found in the endometrium, and pelvic
radiotherapy advised as the possibility of co-existing endometrial cancer cannot be
excluded. A further indication may be palliation of pelvic symptoms in advanced
disease.
Four randomised controlled trials (RCTs) provide the main evidence base for the
consideration of paclitaxel as first-line therapy in ovarian cancer.
The GOG111 trial compared combination treatments of paclitaxel (135
mg/m2)/cisplatin (75 mg/m2) and cisplatin (75 mg/m2)/cyclophosphamide (750
mg/m2) in 410 women. All had severe disease (as defined by the International
Federation of Gynaecology staging system, FIGO stage III or IV) and sub-optimal
tumour reduction following surgery. No statistically significant difference in overall
tumour response (that is, complete and partial response) was found (relative risk =
1.19, 95% CI = 0.95 to 1.5). Median progression free survival was statistically
significantly longer for patients receiving the paclitaxel/cisplatin combination (18
months vs 13 months, relative risk = 0.7, 95% confidence interval [CI] = 0.5 to 0.8, p
value < 0.001). Overall survival was also statistically significantly longer in these
patients (38 months vs 24 months, relative risk = 0.6, 95% CI = 0.5 to 0.8, p <
0.001). Estimates from updated longer-term study results suggest that the death rate
is 30% less among those treated with the paclitaxel containing regimen (relative
hazard: 0.7, 95% CI = 0.57 to 0.87). No statistically significant difference in
performance scores was found between the two groups.
The OV10 trial also compared the combinations of paclitaxel (175 mg/m2)/cisplatin
(75 mg/m2) and cisplatin (75 mg/m2)/cyclophosphamide (750 mg/m2). A statistically
significant overall tumour response in favour of the paclitaxel combination was found
(relative risk = 1.92, 95% CI = 1.52 to 2.42). Median progression-free survival for the
paclitaxel combination was longer (15.3 months vs 11.5 months, hazard ratio = 0.74,
95% CI = 0.63 to 0.88, p value = 0.0005). Overall survival was also statistically
significantly higher in this group (35.6 months vs 25.8 months, hazard ratio = 0.73,
95% CI = 0.60 to 0.89, p value = 0.0016).
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The GOG132 trial included comparison of combination paclitaxel (135 mg/m2
)/cisplatin (75 mg/m2) with cisplatin (100 mg/m2) alone. All 424 women had FIGO
stage III or IV disease and suboptimal tumour reduction following surgery. No
statistically significant difference in overall tumour response (that is, complete and
partial response) was found between the group receiving cisplatin alone and those
receiving the paclitaxel/cisplatin combination (relative risk = 0.97, 95% CI = 0.86 to
1.09). However, unlike GOG111 and OV10, no statistically significant differences
were found in progression-free survival (14.1 months vs 16.4 months, hazard ratio =
1.06, 95% CI = 0.86 to 1.30), and overall survival (26.6 months vs 30.2 months,
hazard ratio = 0.99, 95% CI = 0.80 to 1.23). The difference between the findings of
the trial and those reported for the GOG111 and OV10 studies may be explained by
the extent of patient cross-over between treatments before the disease progressed.
However it is unlikely that this is sufficient to explain such markedly different findings.
ICON3, compared a combination of paclitaxel (175 mg/m2)/carboplatin (5 AUC) with
either carboplatin (5 AUC) alone or a combination of cyclophosphamide (750
mg/m2)/doxorubicin (75 mg/m2)/cisplatin (75 mg/m2) (CAP). The trial differs from the
others, in that patients had a wider range of residual tumour following surgery (54%
had optimally reduced tumours), and a smaller proportion (80%) had FIGO stage III
and IV disease. After more than 3 years of follow up, no statistically significant
difference was found between the groups receiving the paclitaxel/platinum
combination or carboplatin alone, in terms of progression-free survival (17.1 months
vs 16.1 months, hazard ratio = 0.94, 95% CI = 0.84 to 1.05, p value = 0.24) or overall
survival (37.6 months vs 36.1 months, hazard ratio = 0.96, 95% CI = 0.84 to 1.09, p
value = 0.53). The follow up with ICON424 again suggested an improvement in
survival with the addition of paclitaxel.
The NICE guidelines (January 2003) quote meta-analysis data carried out both by
the MRC and industry, which show a non-significant disease free benefit for the
Paclitaxel/platinum combination, but a hazard ratio of 1.0 for survival in advanced
disease (Stages III/IV) population. Two further randomised trials have suggested that
carboplatin at doses AUC 5-7 in combination with the taxanes is as effective as
cisplatin25,26. Myelosuppression is, however, greater than with cisplatin, and may
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lead to greater dose reductions, and an impaired ability to tolerate second line
therapy.
The choice of treatment for first-line chemotherapy for ovarian cancer should be
made after discussion between the clinician and the patient about the risks and
benefits of the options available. In choosing between treatment with a platinum-
based compound alone or paclitaxel in combination with a platinum-based
compound, this discussion should cover the side-effect profiles of the alternative
therapies, the stage of the woman’s disease, the extent of surgical treatment of the
tumour, and disease-related performance status.
8.3 Advanced Disease- Second line Chemotherapy
Many patients with advanced ovarian cancer will develop recurrent/progressive
disease. Second line chemotherapy is less effective, although patients who relapse
more than 6 months after platinum response may benefit from a further trial of the
same drug in the first instance.
The results of ICON4 demonstrated a survival benefit of 3 months and disease free
survival benefit in patients with relapsed platinum-sensitive (Patients who respond to
platinum initially but relapses ≥ 12 months) and partially sensitive disease (Patients
who respond to platinum initially but relapses between 6 and 12 months) treated with
carboplatin + paclitaxel compared to single agent carboplatin. However, 75% of the
patients had a platinum free interval of 12 months or more.
NICE has recommended that Paclitaxel in combination with platinum based
chemotherapy can be considered in those patients whose disease relapses more
than 6 months after first line platinum bases chemotherapy. Women who have
received paclitaxel as first line may receive it as a part of second line or subsequent
treatments (NICE TA91 2005). Retreatment with paclitaxel however is associated
with 20% incidence of grade 3&4 neuropathy and this should be considered when
planning treatment.
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CALYPSO (Eric Pujade-Lauraine et al), a multicenter phase III study compared
efficacy and safety of carboplatin-pegylated liposomal doxorubicin (PLD) and
carboplatin-paclitaxel in relapsed platinum-sensitive ovarian cancer patients.
Patients with recurrent ovarian cancer > 6 months after first-line or second-line
platinum-based therapy who had been pretreated with a taxane were randomized by
stratified blocks to either carboplatin (AUC5) + PLD (30 mg/m2) d1 q4 wk, or
Carboplatin(AUC5) + Paclitaxel (175 mg/m2) d1 q3 wk x ≥ 6 cycles. With median
follow-up of 22 months, PFS for the Carboplatin/PLD arm was statistically superior to
the Carboplatin/Paclitaxel arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005);
median PFS was 11.3 versus 9.4 months, respectively. Overall severe
nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation
(15% v 6%; P < .001) occurred more frequently in the Carboplatin/Paclitaxel arm.
More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions
(18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the
Carboplatin/Paclitaxel arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%),
nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) were observed in
the Carboplatin/PLD arm. Carboplatin/PLD was reported to be superior in PFS and
had better therapeutic index over standard Carboplatin/Paclitaxel.
Gynecologic Cancer Inter Group trial (Jacobus Pfisterer et al) of the
Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group, the
National Cancer Institute of Canada Clinical Trials Group, and the European
Organisation for Research and Treatment of Cancer Gynaecological Cancer Group
evaluated Gemcitabine-Carboplatin with Carboplatin alone in platinum-sensitive
recurrent ovarian cancer patients. With a median follow-up of 17 months, median
PFS was 8.6 months for gemcitabine-carboplatin (95% confidence interval [CI] 7.9-
9.7 months) and 5.8 months for carboplatin (95% CI 5.2-7.1 months; hazard ratio
[HR] 0.72 [95% CI 0.58-0.90; P = 0.0032]). The response rate for the gemcitabine-
carboplatin group was 47.2% (95% CI 39.9-54.5%) and 30.9% for carboplatin group
(95% CI 24.1-37.7%; P = 0.0016). The HR for overall survival was 0.96 (95% CI
0.75-1.23; P = 0.7349). Patients treated with gemcitabine-carboplatin reported
significantly faster palliation of abdominal symptoms and a significantly improved
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global quality of life. Gemcitabine-carboplatin treatment significantly improves the
PFS of patients with platinum-sensitive recurrent ovarian cancer. Combination of
Gemcitabine and carboplatin can be considered in patients where further taxane
therapy is not appropriate.
NICE has recently reported that liposomal Doxorubicin, Caelyx or Topotecan
(Gordon AN et al. 2001) should be considered as options for the second line (or
subsequent) treatment of women with advanced ovarian cancer, where the disease
is initially resistant or refractory to first line platinum based combination
chemotherapy, or has become resistant after successive courses of platinum based
combination therapy (NICE TA91 2005). In this setting the complete response rate is
less than 10% and overall response rate about 20%, with no clear evidence of a
survival gain. Other agents which may be considered are doxorubicin (Omura 1991),
or the oral alkylating agents cyclophosphamide and chlorambucil. Inclusion into
appropriate clinical trials should be considered.
8.4 Intraperitoneal chemotherapy
There has been increasing interest in the role of intraperitoneal chemotherapy, with
improved survival rates reported in individual trials27 and also in the 2011 Cochrane
review28. However, there remain issues regarding the ideal dosing regime,
appropriate comparisons with standard chemotherapy regimes in trials29 and
concern about significant toxicity of intraperitoneal chemotherapy. Its use is currently
only recommended within a randomised controlled trials such as the PETROC trial.
8.4 Chemotherapy protocols
For full details of chemotherapy regimens and doses please refer to CCO
Chemotherapy protocol document.
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9 Post-operative Management - Radiotherapy
Adjuvant radiotherapy
Whilst the general opinion is that ovarian cancer is not radiosensitive, there is some
evidence that long term survival may be achieved in some patients with small
volume residual disease following surgery. The greatest experience comes from
Toronto where whole abdominal radiotherapy was used. However the toxicity of
such treatment is considerable.
Currently, the vast majority of centres recommend adjuvant chemotherapy if
proposing adjuvant treatment. Whole abdominal radiotherapy is not used at CCO.
Consolidation radiotherapy
Pelvic radiotherapy may be considered as consolidation treatment after
chemotherapy for solitary pelvic relapse. It can be given if there is a good response
to chemotherapy after relapse, where there is small volume pelvic disease only.
Palliative radiotherapy
This can be used in patients with local pelvic symptoms such as pain, bleeding or
discharge. It can also be used for distant metastatic sites such as bone or brain
according to symptoms.
10. HRT
There have been 2 prospective studies of HRT in women with bilateral
oophorectomy for ovarian cancer. Our policy is that there is no evidence for an
excess adverse effect of HRT in ovarian cancer patients, including those of
endometrioid histology, and the indications for HRT are the same as for women
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without a prior diagnosis of ovarian cancer. Patients should be referred to their
general practitioner for relevant leaflets and counselling.
11. Palliative Care and Nursing care
Palliative care input is appropriate to consider at all stages of the patient’s cancer
journey. Please refer to the separate palliative care guideline for detailed advice.
All women with a diagnosis of a Gynaecological Cancer should be offered the
support of, and have access to a Clinical Nurse Specialist (CNS), in order to facilitate
the woman’s needs throughout the Cancer Journey, including those of her partner or
carer.
The skills of the C.N.S. as a consultant, practitioner and educator can be drawn upon
at all stages throughout their illness, from the pre-diagnosis to the terminal stage –
incorporating the Specialist Palliative Care Services provided in the hospital and the
community setting. Bereavement Support will also be available, if appropriate.
Important aspects of the role are to provide advice, support, information and to
effectively incorporate appropriate resources. The C.N.S. will be receptive to the
social, physical, psychological, cultural, sexual and spiritual needs of the patient. The
aim of the patient support is to assist with the improvement in the quality of their
lives, allowing them to become more empowered; to help take control and enhance
their self esteem.
The C.N.S. works closely with Surgeons, Oncologists, Radiotherapists, Consultants
in Palliative Medicine and others (Nurses & P.A.M.s).
They will undertake a number of key responsibilities including:
Linking with other professionals who can help the patients throughout the system
A resource for information and support to the patient carer and other H.C.P.s
Liaison point for other health care professionals in primary and secondary care
Teacher and Educator
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Researcher
Standards and Audit Co-ordinator
Co-ordinate Care Services
12. Follow up
Standard: Four monthly for years 1 and 2, six monthly to 3 years.
Discharge after 3 years with open access to CNS in the event of new
symptoms or concerns.
CNS holistic assessment is carried out 6 weeks after the completion of
primary treatment.
Follow up of borderline tumours is similar if greater than stage 1a disease or
managed by conservative surgery. For stage 1 disease managed by hysterectomy
and bilateral oophorectomy, patients may be discharged with an open appointment
in the event of new symptoms or concerns.
13. Maintenance of quality
Guidelines will be reviewed every 3 years
These guidelines conform to:
Improving outcomes in Gynaecological Cancers NHS Executive 1999
Department of Health Peer Review measures
14. Clinical Trials
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The cancer network is committed to an active involvement in research, both at a
local, national and international level. Please refer to CCO live clinical trials database
for current trials in Gynae Oncology.
15. Women with a family history
If you feel that your patient would benefit from a genetic counselling referral please
discuss referral with a member of the network genetics team or consult their
guidelines.
Referral guidelines
The family must be at increased risk (as defined below):-
The patient must be a first degree relative of an affected family member in any one of
the following situations.
The family contains 2 or more individuals on the same side of the family with ovarian
cancer who are first degree relatives of each other. (If 2 close relatives on the same
side of the family – please discuss with a member of the genetics team).
OR
The family contains one individual with ovarian cancer at any age and one individual
with breast cancer diagnosed under the age of 50 years, who are first degree
relatives of each other.
OR
The family contains one individual with ovarian cancer at any age and two individuals
with breast cancer diagnosed under the age of 60 years who are connected by first
degree relationships.
OR
The family contains one individual with one of the known cancer predisposing genes.
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OR
The family contains three individuals with colorectal cancer with at least one case
diagnosed before 50 years and one case of ovarian cancer connected by first degree
relationships.
All above situations are associated with at least a 10% lifetime risk of ovarian cancer.
Action
Individuals assessed to be at a 10% or greater lifetime risk of ovarian cancer may be
offered annual transvaginal ovarian ultrasound and CA125 tumour marker blood test.
Screening should start at age 30 years or 5 years before the age of onset of the first
ovarian cancer in the family.
Individuals should also be advised to perform monthly breast self examination.
Annual clinical breast examination and mammography as per the cancer genetics
guidelines on breast cancer should be considered.
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13. Finn CB, Luesley DM, Buxton EJ, Blackledge GR, Kelly K, Dunn JA, et al. Is
stage I epithelial ovarian cancer overtreated both surgically and systemically?
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16. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G,
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Surgical staging and treatment of early ovarian cancer: long-term analysis from a
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24. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB,
et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-
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25. du Bois A, Lück HJ, Bauknecht T, Meier W, Richter B, Kuhn W, Quaas J,
Pfisterer J. First-line chemotherapy with epirubicin, paclitaxel, and carboplatin for
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Gynäkologische Onkologie Ovarian Cancer Study Group. J Clin Oncol. 1999
Jan;17(1):46-51.
26. Ozols RF. Paclitaxel plus carboplatin in the treatment of ovarian cancer. Semin
Oncol. 1999 Feb;26(1 Suppl 2):84-9.
27. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ,
Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and
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28. Jaaback K, Johnson N, Lawrie TA. Intraperitoneal chemotherapy for the initial
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Intraperitoneal chemotherapy in patients with advanced ovarian cancer: the con
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30. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, Ovary and
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Appendix 1
Abbreviated Staging System (FIGO 2010)
The FIGO staging system, as updated in 201030, is currently in use. This system
incorporates cyst rupture in Stage I as an adverse prognostic factor.
In early disease, histological grade, even though there are problems with reproducibility
among pathologists, may be a better prognostic indicator than stage.
Primary tumor (T)
TNM FIGO
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 I Tumor limited to the ovaries (1 or both)
T1a IA Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface; no malignant cells
in ascites or peritoneal washings
T1b IB Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface; no
malignant cells in ascites or peritoneal washings
T1c IC Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on
ovarian surface, malignant cells in ascites or peritoneal washings
T2 II Tumor involves 1 or both ovaries with pelvic extension
T2a IIA Extension and/or implants on the uterus and/or tube(s); no malignant cells in ascites or
peritoneal washings
T2b IIB Extension to other pelvic tissues; no malignant cells in ascites or peritoneal washings
T2c IIC Pelvic extension (T2a or T2b) with malignant cells in ascites or peritoneal washings
T3 III Tumor involves 1 or both ovaries with microscopically confirmed peritoneal metastasis
outside the pelvis
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T3a IIIA Microscopic peritoneal metastasis beyond the pelvis (no macroscopic tumor)
T3b IIIB Macroscopic peritoneal metastasis beyond the pelvis > 2 cm or less in greatest dimension
T3c IIIC Macroscopic peritoneal metastasis beyond the pelvis > 2 cm in greatest dimension
and/or regional lymph node metastasis
Regional lymph nodes (N)
TNM FIGO
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 IIIC Regional lymph node metastasis
Distant metastasis (M)
TNM FIGO
M0 No distant metastasis
M1 IV Distant metastasis (exclude peritoneal metastasis)
Notes:
The presence of nonmalignant ascites is not classified. The presence of ascites does not affect staging unless malignant cells are present.
Liver capsule metastasis is T3/stage III; liver parenchymal metastasis, M1/stage IV. Pleural effusion must have positive cytology for M1/stage IV.
Agreed 2012 Review 2015
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Appendix 2 – Chemotherapy Regimes
Adjuvant chemotherapy
STAGE OF DISEASE CHEMOTHERAPY
Low risk (Stage Ia,Ib, Gd1, 2) Surveillance
High risk (Stage Ic, Gd3) Carboplatin single agent x 6 cycles OR
Carboplatin/Paclitaxel x 6 cycles
Chemotherapy in advanced epithelial ovarian cancer
First line Carboplatin/Paclitaxel OR Carboplatin
Second Line
options
Single agent Carboplatin x 4-6 cycles
Single agent Cisplatin x 4-6 cycles
Carboplatin/ Gemcitabine x 6 cycles
Carboplatin/Liposomal Doxorubicin x 6cycles
Weekly Paclitaxel
Third Line
options
Paclitaxel x 6 cycles
Liposomal Doxorubicin x 6cycles
Topotecan x 4 cycles
Gemcitabine x 6 cycles
Etoposide x 6 cycles
top related