ovarian carcinoma – Long journey of gyn&obs

OVARIAN CA

Incidence depend on geographical variation
- In general, EOC is most common and most lethal in industrialised countries
Most common – 7^th decade of life
Ovarian CA life time risk – 1:54, with 75% of cases diagnosed >55 years
Ovarian CA mostly occur in post-menopausal women
<1% affecting females under the age of 21 years (> 60% are of germ-cell origin)
Hereditary cancers (20%)usually in younger women – around 10 years earlier
Ovarian cancer has the highest mortality of all the gynaecological malignancies. Surgery during their lifetime for ovarian mass – 10%
- Pre-menapause – 90% benign
- Post menapuuse – 60% benign
80% of patients will present at advanced stage (2/3 of cases are diagnosed at stage III)
Overall 5-year survival rate is about 40%
- Stage I – 92%
- Stage II – 60%
- Stage III – 30%
- Stage IV – 5%
Five-year survival from ovarian cancer has increased significantly over the last decade. Improved chemotherapy regimens, Dedicated multidisciplinary teams and Radical surgery
Up to 20% of women with EOC have an inherited predisposition.
Routine screening (CA 125 & pelvic USS) – no proven value.
Diagnosis – by pelvic ultrasonography and serum CA 125.
Aim – Radical surgery to excise all macroscopic disease.

Aetiology

Reduced risk / Protective
- Breastfeeding
- Non-steroidal anti-inflammatory drugs
- Aspirin
- Combined oral contraception
- Factors that limit the number of ovulations

Increased risk
1. Endometriosis seems to be associated with higher risk of OC
1. Ovarian stimulation drugs do not appear to affect the risk of other than borderline tumours
1. Genetic factors
  1. Woman with a single affected relative – lifetime risk of developing ovarian CA à 3-4%
  1. Hereditary ovarian carcinomas are likely to represent about 20% of all ovarian cancers.
  1. Both BRCA and Lynch syndrome are inherited in an autosomal dominant pattern
  1. Lynch II – association with cancers at other sites, including the ovary and endometrium
  1. BRCA1 are responsible for approximately 5% of ovarian CA in women < 40 years
  1. Gene mutations – increased risk of ovarian carcinoma, include RAD51C and RAD51D,

Types	Risk of OC	Risk of BC	Other CA
BRCA 1 (chromosome 17)	40%	80%
BRCA 2 Chromosome 13)	20%	80%
HNPCC (Lynch TII)	12%		Endometrial
Peutz Jeghers	20% – sex cord stromal

Risk reducing surgery with BSO alone or with hysterectomy is recommended for BRCA 1/2 and Lynch syndrome mutation carriers respectively.
- RRBSO has been widely adopted as a key component of breast and gynaecological cancer risk- reduction for women with BRCA1 and BRCA2 mutations once they have completed their families after the age of 35 (C H sir 40)
- BSO is reducing risk for both ovarian and breast cancer but a small risk of primary peritoneal cancer is still present. (3%)
- The negative effects of surgical menopause should be discussed.
- Subsequent HRT is not found to increase the breast cancer risk.
- Annual ovarian & endometrial surveillance – for women that do not undergo surgery.
- Hereditary ovarian cancer syndromes reduce their risk of developing ovarian cancer by ever use of the COCP

Precursor lesions to epithelial ovarian cancer

In patient with Patients with BRCA mutation
precursor tubal lesions termed ‘p53 signatures’ have been found in 1/3 of all women and are believed to represent the initial events of serous carcinogenesis: DNA damage of secretory cells and p53 mutations
High-grade serous tubal intraepithelial carcinoma (STIC) not in the ovary but in the Fallopian tube &, particularly, in fimbria. Although not considered invasive lesions, STICS known to metastasise; it is likely that these lesions are the earliest phase of epithelial ovarian CA.

Cells of origin	Epithelial cell	Germ cell	Sex cord stromal cells	Metastatic
% of ovarian tumour	60 – 65%	30%	8%	5%
% of ovarian CA	90%	3-5%, >60% in children & adolescents	2-3%	5%
Age group	>20	0 – 25+	All ages	All ages
Types	Serous tumours Mucinous tumours Endometrioid Clear cell tumours Brenner tumours	Teratoma Dysgerminoma	Fibroma Granulosa cell tumours theca cell tumours Steriod cell tumour Leydig cell tumour	Breast Lung Colon Other sites

Tumor	Age	Locality	Macroscopy /microscopy	Behavior		Tumor marker	CT/RT
Germ cell 30% of ovarian tumors <5% of cancers
Dys germinoma	20-30yrs Commonest germ cell malignant tumor	Unilateral in 80-90% 10-15% BL	Solid tumours 75% present in stage I disease Minimal lymphocytic response-poor prognosis	All malignant but only30% spread Para arotic LN metastasis common than peritoneal surface deposits occur with gonadal dysgenesis & Androgen insensitivity Xn	AFP (-)		Radiosensitive (100%), 80% cure rate
Yolk sac/ Endodermal sinus tumor	Pre-pubertal /peak age 20 years 75% will come with pelvic pain	Mostly unilateral	Macroscopy- yellow colour- (white to Tan) Schiller-Duval body is pathognomonic	Malignant	AFP (+) α1-antitripsin (+) HCG (-)		Chemosensitive
Mature teratoma	10-20 years Commonest germ cell tumour	90% unilateral more in right side	Cystic (demoid cyst) Usually unilocular Cyst wall-epidermis contains all 3 germ layers If mature neural tissue present- cause limbic encephalitis	Benign 10-15% undergo torsion Can cause Infertility 1-2% can turn to squamous CA	HCG (–)
Immature teratoma	10-20 yrs Mean age 18yrs 2^nd commonest germ cell malignancy		Solid Minimally differentiated tissues Classified in a grading system according to maturity	Malignant If immature neuro-epithelial tissue+ bad prognosis	HCG (-)		Chemosensitive (bleomycin+etopiside+cisplatin) BEP Stage I, Grade I tumours does not need further therapy if removed
Mono dermal teratomas	10-20yrs	Unilateral Small Solid	Only one germ cell layer seen Struma ovary- T4 Carcinoid tumour	Struma- hyperthyroidism Carcinoid syndrome
Chorio Carcinoma					HCG (+)
Sex cord stromal
Granulosa cell tumour	Most PM Can affect children Can cause precaucious puberty	unilateral	85-95% present in stage I disease	5-25% malignant Can secrete oestrogen Associate with endometrial hyperplasia and adeno-CA of endometrium/breast Call Exner bodies pathognomic		Inhibin A Oestrogen Can go up	Surgery is main management 5year survival >90% Chemosensitive High rate of recurrence
Thecoma/ Fibro thecoma	Any age	unilateral	Solid lobulated tumour	Benign Associate with Meig’s Xn		Can secrete oestrogen
Sertoli-Leydig cell tumour	Any age	unilateral		Rarely malignant Cause masculization, Virilisation
Metastatic tumours
Metastasis to ovary	Mostly old age	Bilateral	Signet-ring mucin secreting cells in GI origin	1ry are GI- krukenberg Lung Breast

EPITHELIAL OVARIAN TUMOURS

Bilaterality is common
Five main types,
- High-grade serous carcinoma (HGSC) – 70%
- Endometrioid carcinoma (EC) – 10%
- Clear-cell carcinoma (CCC) – 10%
- Low-grade serous carcinoma (LGSC) – <5%
- Mucinous carcinoma (MC) – 3%
  - Primary mucinous cancers of the ovary are rare
  - Majority attributed to ovarian origin are in fact metastases from the intestinal tract
- Transitional (Brenner), mixed and undifferentiated tumours are very rare
Endocrine function may also occur
Paraneoplastic syndromes are a rare

Molecular classification of ovarian cancer

Theory of ‘incessant ovulation’ has now been replaced by genetic
Much serous ovarian CA arises in the fimbrial end & disseminates within the peritoneal cavity.
It is likely that high-grade serous cancer, Fallopian tube cancer and primary peritoneal cancer are different phenotypes of the same biological disease entity
p53 is mutated in almost all serous ovarian cancer
Germ-line BRCA mutations detected in 17% of all high-grade serous cancer
BRCA testing in every patient with high-grade serous cancer is indicated
BRCA mutations in ovarian cancer may also benefit from a newer class of drugs – poly ADP ribose polymerase inhibitors

	TYPE 1	TYPE 2
Eg	clear-cell mucinous endometrioid low-grade serous cancer	High-grade serous cancers
Features	slow growing indolent Can detect earlier by USS	Fast growing
Treatment	Less well to chemotherapy harder to treat	Highly chemo-sensitive

High grade serous tumours
Commonly present at advanced stage
Serous tumours seem to arise from dysplastic epithelium in the distal fallopian tube
Strongly associated with p53, BRCA 1 & 2 mutations and homologous recombination deficiency
Tend to be highly chemo-sensitive
Low grade serous
KRAS, BRAF, NRAS, HER2 mutations
Usually have a borderline component
Less chemo-sensitive
Endometrioid tumours
Commonly low grade
Low grade tumours behave like endometrioid endometrial cancers
High grade counterparts resemble the high grade serous ovarian cancers.
Associated with CTNNB1, PTEN gene mutation and lynch syndrome
Appear to arise from endometriotic cysts
Usually present at early stages
Can be bilateral
Accompanied by synchronous endometrial cancer
Clear cell tumours
Associated with ARID1A, CTNNB1 and PTEN mutations.
Commonly arise on the background of endometriosis
Usually unilateral
Poor response to chemotherapy and poor prognosis.
Mucinous ovarian tumours
Most of them are metastatic to the ovary from the GIT, usually the appendix.
Associated with KRAS AND HER2 mutations
Largely borderline with a small proportion being malignant and resistant to conventional chemotherapy.

BORDERLINE OVARIAN TUMOURS

Found in younger age women
Histological features that is intermediate between benign and malignant tumour
Can spread beyond the ovary to produce non-invasive implants in the omentum or peritoneum
Can have late recurrences
It is probable that they represent premalignant disease for low grade ovarian carcinomas.
Main treatment – surgery with the extent of this being debatable & tailored to fertility concerns.
Primary peritoneal cancer is histologically indistinguishable from metastatic serous ovarian cancer and is diagnosed in the absence of any clear ovarian primary

SEX-CORD STROMAL TUMOURS

From the hormone producing cells of the ovary and stromal fibroblasts
May be associated with an oestrogenic, androgenic or (more rarely) progestogenic effect.
Functional activity does not correlate with the appearance of the cell.
Many of these tumours are benign
Meigs syndrome à Fibromas + ascites and right hydrothorax
7% of all malignant ovarian tumours

Granulosa cell tumours

Most of the clinically malignant forms are granulosa cell tumours
Granulosa cell tumours account for 70% of sex cord-stromal tumours
Present at the sixth decade and less commonly in young or pre-pubertal women
Usually unilateral and can secrete sex hormones, mainly oestrogen
Excess of oestrogen can lead to endometrial hyperplasia and cancer in the older group or precocious puberty in the pre-pubertal group
Fertility sparing surgery is suggested for younger women while chemotherapy (bleomycin, etoposide and cisplatin), is used for advanced disease or recurrences.

GERM-CELL TUMOURS

In germ cell tumours – elevations of α-FP and hCG.
Commonest ovarian malignancy in the first two decades of life
Yolk sack tumour, embryonal carcinoma, polyembryoma, nongestational choriocarcinoma & teratoma are treated with the chemotherapy (BEP – bleomycin, etoposide and cisplatin)
Cure rates approaching 100% in early stage and 75% in advanced disease.

Dysgerminoma

Commonest germ-cell malignancy
75% – Present with stage I disease.
10-15% is bilateral with contralateral involvement usually being microscopic.
5-10% occurs in phenotypic females with abnormal gonads (androgen insensitivity syndrome or gonadal dysgenesis).
Malignant germ cell tumours
Dysgerminoma occur mainly in adolescence & early adulthood & can be B/L in up to 20%.
Produce high levels of LDH.
60% are confined to one ovary at diagnosis,
Fertility sparing surgery with unilateral salpingo-oophorectomy or even ovarian cystectomy in selected cases is an option.
Spread through the lymphatic system
Highly radiosensitive, platinum based chemotherapy is preferable due to fertility preservation.

Teratomas

Derived from two or three embryonic layers

Mature cystic teratoma

commonest ovarian germ-cell tumour
Usually benign
Most are unilateral 15–20% are bilateral.
Commonest ovarian tumours leading to torsion.
Classical appearance on plain abdominal X-ray(Due to hair/teeth)
Malignant transformation – 2 % (squamous carcinoma commonest)
Struma ovarii – tumours are predominantly composed of thyroid tissue.

Immature teratoma

Second commonest germ-cell malignancy
20% of ovarian malignancies in females under 20 years of age.
Virtually all are unilateral
Currently classified (grading system) based on
- Degree of differentiation
- Quantity of immature tissue.

Primary ovarian carcinoid tumours

Variants of monodermal teratomas
Usually favourable prognosis.

Secondary carcinoids (not associated with a monodermal teratoma)

Usually metastatic from the gastrointestinal tract
Poor prognosis

Embryonic markers

Most ovarian yolk sac tumours – AFP, normal levels do not exclude

TYPE	AFP	β-Hcg	LDH
Yolk sac tumours	↑
Dysgerminoma	No
Pure dysgerminoma	No	No	No
Chorio carcinoma		↑
Teratoma		No
Embryonal carcinomas	May ↑	↑
Poly-embryoma	↑	↑

GONADOBLASTOMA

Rare tumour
Consists of admixed germ-cell and sex-cord stromal elements.
Usually in the second decade of life
Rarely occurs in normal ovaries.
80% occur in phenotypic females who are virilised
20% in phenotypic males with developmental abnormalities of the external genitalia.
The most common karyotypes are 46XY and 45XO/46XY (mosaic).

SECONDARY OVARIAN MALIGNANCIES

10% are metastases from some other organ
Many cases the ovarian metastases are detected before the primary tumour.
Most common metastatic cancers
- Colon
- Stomach
- Breast
- Female genital tract.
Metastatic gastric or (less commonly) colonic cancer – Bilaterally enlarged ovaries that contain signet-ring cells on microscopic assessment –Krukenberg

PRIMARY PERITONEAL CARCINOMA

Highly malignant tumour arising from the peritoneum
Signs and symptoms very similar to those of primary epithelial ovarian cancer.
Rare benign and borderline variants
Share many similarities with ovarian CA & clinically managed in a similar manner.

PRIMARY FALLOPIAN TUBE CANCER

Rare cancer
0.3% of all female genital tract cancers.
The classical presenting triad consists of
- A prominent watery discharge (hydrops tubae profluens)
- Pelvic pain
- A pelvic mass.
Share many similarities with primary epithelial ovarian CA (histological appearance & clinical behaviour) & clinically managed in a similar manner.

RARE OVARIAN TUMOURS

Include primary small-cell carcinoma and various types of sarcoma
All having a poor prognosis.
Lymphoma / extramedullary leukaemia may manifest initially as an ovarian tumour.

CLINICAL MANAGEMENT OF OVARIAN CANCER

Clinical assessment

Most women – Non-specific symptoms.
A complete history and examination are essential to
- Make the diagnosis
- Identify patients with secondary ovarian malignancy
- Assess fitness for surgical and non- surgical management

Spread (epithelial ovarian cancer)

Transcoelomic spread
- commonest pattern
- The cells disseminate and implant along the peritoneal surfaces following the circulatory path of peritoneal fluid
Lymphatic spread
- Common
- To pelvic (96%) and para-aortic nodes (4%)
- May occur in apparent early-stage disease
Haematogenous spread
- Uncommon at the time of diagnosis
- Liver and lung are the preferred sites.

Symptoms

In early disease (confined to the ovary)
- Are asymptomatic
- Pressure symptoms
  - Urinary frequency
  - Constipation
  - Pelvic pain/pressure,
  - Dyspareunia
- Symptoms of a cyst accident – rarely

(Abdominal pain/Pelvic pain radiating to inner aspect of the leg / vomiting)

– Torsion – Severe pain associated with vomiting

– Rupture – Small cyst – Asymptomatic / Few signs

Large cyst – Signs of peritonitis (Irritant- Endometrioma / Dermoid)

– Signs of shock (Extensive rupture / Haemorrhage)

-Hemorrhage

In advanced-stage disease

Symptoms are usually (metastases affecting the bowel and mesentery, and ascites)

Persistent abdominal bloating
- Pelvic and abdominal pain
- Early satiety
- Symptoms due to pressure effects in the pelvis may also occur
  - Changes in bowel habit – Constipation -misinterpreted as IBS
  - Urinary frequency or urgency
- Loss of appetite, nausea, weight loss, abdominal distention and discomfort due to ascites and or large abdomino-pelvic mass
- Abnormal vaginal bleeding (pre / post-menopausal women) is a less common
Unfortunately, symptoms in ovarian cancer are so vague à delays in presentation à subsequent delay in diagnosis.

Clinical signs

Supraclavicular, axillary and inguinal nodes
Breast examination
Chest examination (pleural effusion)
Abdominal examination
- Liver size
- Solid, irregular mass is highly suspicious
- Particularly associated with an upper abdominal mass (omental cake)
Per-vaginal examination (Detailed)
Per-rectal examination

Investigations

To assess the likelihood of malignant disease
To plan the extent of surgery
To assess fitness for anaesthesia and surgery

Tumour markers
- CA125
- Carcinoembryonic antigen (CEA) – 1ry gastrointestinal malignancy
- AFP, LDH and β-hCG – young women <40 years (germ-cell tumours commonest in the 1^st two decades of life)

Immunohistochemistry

Ck-7 useful to differentiate 1ry ovarian Ca from metastatic colorectal CA of the ovary. (elevated in 96% OF OVARIAN ADENO Ca and only 25% of metastatic colorectal CA)
CDX-2 expression found in up to 100% of intestinal CA —in 1ry ovarian CA
Ultrasonography abdominal and pelvis
- For the diagnosis and characterization of ovarian pathology
- Liver – Parenchymal metastases increase the likelihood of non-ovarian primary
- kidneys – Hydronephrosis
Doppler – no benefit
3-D sonography can show higher sensitivity and specificity over 2-D scan
Chest imaging (CXR)
- To assess the possibility of Stage IV disease
- presence of pleural effusion
CT scan (abdomen and pelvis) – Extent of upper abdominal disease
- Choice for preoperative staging
- Can guide choice between primary surgery or chemotherapy
- Should cover the pelvis, the upper abdomen, the base of the lungs or the entire thorax if chest X-ray is suspicious
- Assess response of chemotherapy either prior interval debulking surgery or commonly after three cycles
- When recurrence is suspected CT is still the modality of choice à positron emission tomography (PET)/CT emerging as the optimal imaging technique particularly in patients with negative CT
MRI (pelvis) – Assist surgical planning in a fixed pelvic mass
- To determine adherence to large bowel / to the pelvic sidewalls.
UGIE / Colonoscopy
- If symptoms
- Tumour marker / CT suggest a 1ry gastrointestinal malignancy.
EUA/endometrial biopsy – If AUB
Oestrogen secreting tumor
2ry deposit in ovary with 1ry endometrial CA
Synchronous tumor

Imaging guided biopsy may be obtained at the same time and diagnosis can be established.
Cytology of ascitic or pleural fluid is informative but not diagnostic
Laparoscopy is increasingly used preoperatively for purposes of biopsies and assessment of tumour respectability
Basic investigations
- Full blood count
- PT/INR
- B.urea, S.creatinine & S.electrolytes
- Liver function tests (including total protein and albumin)
- ECG
- 2D ECHO
- To assess fitness for anaesthesia and surgery
- After chemo to exclude cardiac dysfunction

Staging of primary ovarian cancer

Based on findings at laparotomy
Accurate staging is of paramount importance
Prognosis
Requirement for adjuvant treatment.

previous staging

Technique for surgical staging

A midline incision extending above the umbilicus
- Adequate access for thorough surgical staging
A systematic exploration of all peritoneal surfaces and viscera
- Ascites or peritoneal washings for cytology
  - Decision making with regard to adjuvant treatment
  - (Washings may be positive in apparent stage Ia disease)
- TAH/BSO
  - High incidence of bilateral tumours (metastatic or primary)
  - Metastases to the uterus
  - Endometrium – site of a coincidental 1^ry CA – endometrioid carcinoma
- Omentectomy
  - Major site of abdominal metastases
  - An infra-colic omentectomy is most universally performed
  - Supra-colic procedure may be preferable
To achieve adequate cytoreduction of gross omental disease
- Peritoneal biopsies of all suspicious areas
- Assessment of pelvic and para-aortic lymph nodes
- Assessment of upper abdomen à diaphragm, liver, spleen, lesser sac & morrison’s pouch
- Appendectomy – Not universally accepted – currently under consideration
  - Commonly the site of metastases in advanced-stage disease
  - Site of occult disease in a significant proportion of apparent stage I disease
  - Ovary may be a site of secondary disease in the rare case of an appendiceal primary and may be associated with pseudomyxoma peritoneii.
  - It should be removed if it appears abnormal at laparotomy.
  - Appendectomy in mucinous cystadeno CA ?????

SURGICAL AND NON-SURGICAL MANAGEMENT OF OVARIAN CANCER

Primary surgery: early epithelial ovarian cancer

Aim – identify occult metastases through meticulous systematic exploration.
Standard surgical procedure – Staging laparotomy, cytology, TAH + BSO, Infra-colic omentectomy. ????? LN
Fertility wish
- Adequate staging procedure while minimising the risk to future fertility.
- Frozen section may be useful – Heterogeneity and size of ovarian malignancies result in under-diagnosis in a considerable proportion of cases.
- Delaying a sterilising procedure until the final histopathology is available
- If initial procedure involve complete surgical staging and conservation of uterus and contralateral ovary following careful inspection àA decision at multidisciplinary team à regarding completion of surgery and adjuvant treatment
Laparotomy is currently the gold-standard surgical procedure for the diagnosis and staging of early ovarian cancer.
The role of laparoscopy is undefined

Primary surgery: advanced epithelial ovarian cancer

Cytoreductive surgery
- Goal of surgery in ovarian cancer (Complete debulking)
- TAH/BSO, complete omentectomy & resection of all metastases. ????? LN
- Complete cytoreduction – Removal of all visible cancer deposits
- Optimal cytoreduction – no residual disease >1 cm
- Interval cytoreduction
Resectability of disease depends on
- Skill of the surgeon
- Site of disease.
Optimal cytoreduction is unlikely if there is extensive disease in the liver parenchyma, porta hepatis or root of the small bowel mesentery.

Ultra-radical surgery in ovarian cancer

Complex surgical procedures (radical and ultra-radical surgery) – complete removal of all cancer deposits in addition to standard TAH + BSO.
Marked improvement in progression-free and overall survival
Major morbidity around 1–3%
Operative mortality 1%
Prognosis depends on
- Extent of residual disease
- Patient’s age
- Volume of ascites
- Performance status
In planning management, these factors must be taken into consideration

TIMING OF SURGERY – PRIMARY SURGERY VS INTERVAL DEBULKING SURGERY AFTER NEOADJUVANT CHEMOTHERAPY

Best survival following
- No residual disease after surgery
- Respond to platinum (platinum sensitive’ patients)
Primary surgery followed by chemotherapy VS surgery after neoadjuvant chemotherapy (chemotherapy where three or four cycles are given pre-surgery) in patients with large tumour burden and poor performance status
- Similar survival outcomes.
- Interval debulking – lesser morbidity & reduced number of major resections
Initial surgery has involved biopsy only, with no attempt at cytoreduction of advanced disease, it is reasonable to consider definitive surgery after three cycles of chemotherapy, with three further cycles being given following surgery.

CHEMOTHERAPY

complete staging at surgery has no statistically significant improvement in recurrence-free survival and overall survival in women receiving adjuvant chemotherapy
Low-grade stage IA and IB (adequately staged) – very good prognosis & no need adjuvant treatment
Early-stage with poor prognostic factors (degree of differentiation / cyst rupture) may benefit from adjuvant treatment (substantial risk of micrometastases).
High-risk early-stage disease and for advanced-stage ovarian cancer, the recommended standard treatment is
- Combination with carboplatin and paclitaxel(six cycles)
- Carboplatin alone – In less fit patients
- Adjuvant chemotherapy with platinum – initially responds in 70%
In stage IV cancer and in those with residual disease after surgery – Carboplatin/taxel with bevazicumab (maintenance up to 12 months) significant improvement in survival over standard chemotherapy.

Relapse

At least half will relapse within 18 months (treatment at relapse is palliative)
platinum-sensitive(progression-free interval of at least 12 months since platinum-based therapy) or partially sensitive cases
- Carboplatin & taxel are first choice for relapse six or more months after completing previous chemotherapy
In platinum-resistant cases (an agent without cross-resistance is required)
- Alkylating agents (liposomal doxorubicin)
- Gemcitabine
- Anthracyclines
- Topoisomerase inhibitors (etoposide, topotecan)
- Others (tamoxifen)
Bevazicumab (antiangiogenic agent) – commonly used in recurrent CA (first relapse)
Single-agent regimens are preferred due to ease of administration and low toxicity.
Second-line chemotherapy for platinum resistant cases (combinations different to carboplatin with or without taxol) is indicated, if
- Recurrent disease.
- Progressive platinum-resistant disease.
- Refractory disease.
Response rates for second-line therapy much lower than primary treatment with (15-35% vs 80%), although better response rates are found in women with longer disease-free intervals before recurrence.
Intraperitoneal chemotherapy after complete cytoreduction – significant improvement in survival. But high toxicity rates. At present, role is unclear.
Increasing use of supportive factors [granulocyte colony-stimulating factor (G-CSF)]in chemotherapy, patients
- Receive more cycles of chemotherapy
- Receive more lines of chemotherapy
- Five to six years of survival is achievable in a minority.
Pelvic radiation alone is not as effective as adjuvant treatment – occasionally used to palliate isolated pelvic recurrence (bleeding mass at the vaginal vault)
It is reasonable to manage patients with symptom-based follow-up rather than serial measurements of CA125 (rising CA125 levels in asymptomatic patients does not improve survival in comparison to re-treatment with chemotherapy when the patient becomes symptomatic of recurrence)

Recurrence

platinum refractory. – disease that failed to respond
- pegylated liposomal doxoru- bicin hydrochloride (PLDH)
- paclitaxel alone and topotecan are the alternatives to PLDH.
platinum- resistant – Recurrences within 6 months
- pegylated liposomal doxoru- bicin hydrochloride (PLDH)
- paclitaxel alone and topotecan are the alternatives to PLDH.
partially sensitive to platinum. – occurs within 6 – 12 months disease
- paclitaxel or gemcitabine along with a platinum compound is recommended.
- pegylated liposomal doxorubicin hydrochloride (PLDH)
sensitivity to platinum – recurrence occurs after 12 months –
- paclitaxel or gemcitabine along with a platinum compound is recommended.