MEDICAL PROTOCOL ONCOLOGICAL MANAGEMENT OF OVARIAN … · MEDICAL PROTOCOL ONCOLOGICAL MANAGEMENT OF OVARIAN ... Offer cytotoxic chemotherapy for suspected advanced ovarian cancer

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


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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


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).


21 | P a g e

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


22 | P a g e

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.


23 | P a g e

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


24 | P a g e

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.


25 | P a g e

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


26 | P a g e

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


27 | P a g e

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


28 | P a g e

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.


29 | P a g e

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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1995;332(10):629-34.

17. Vaccarello L, Rubin SC, Vlamis V, Wong G, Jones WB, Lewis JL, et al.

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19. Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, et al.

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24. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB,

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based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-

OVAR-2.2 trial. Lancet 2003;361(9375):2099-106.

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

advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft

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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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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


35 | P a g e

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.


36 | P a g e

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

Documents

MEDICAL PROTOCOL ONCOLOGICAL MANAGEMENT OF OVARIAN … · MEDICAL PROTOCOL ONCOLOGICAL MANAGEMENT OF OVARIAN ... Offer cytotoxic chemotherapy for suspected advanced ovarian cancer