Early stage ovarian cancer

Stage and survival

More than 70% of patients present with advanced disease.

Only less than 40% of women with ovarian cancer are cured.

Early stage Stage 1 and 2

Low risk- stage 1a n 1b with grade 1 n 2

High risk- stage 1c, stage 1 with grade 3 and stage 2

Advanced stage- stage 3 n 4

Treatment Primary treatment for presumed ovarian

cancer consists of appropriate surgical staging and cytoreduction,

followed in most (but not all) patients by systemic chemotherapy

STAGING LAPAROTOMY

It is recommended that a gynecologic oncologist perform the surgery.

a vertical midline abdominal incision should be used

On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations

All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied.

In the absence of any suspicious areas, random peritoneal biopsies should be taken from

the cul de sac, pelvic side walls, paracolic gutters, and undersurfaces of the diaphragm (diaphragm scraping for Papanicolaou stain is an acceptable alternative).

Bilateral salpingo-oophorectomy (BSO) and hysterectomy should be performed with every effort to keep an encapsulated mass intact during removal.

Infracolic omentectomy

Lymph node dissection Para-aortic lymph node dissection should be performed

by stripping the nodal tissue

from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels.

The preferred method of dissecting pelvic lymph nodes is bilateral removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve

Mucinous tumors Primary invasive mucinous tumors of the

ovary are uncommon. Thus, the upper and lower GI tract should be carefully evaluated to rule out an occult GI primary with ovarian metastases

an appendectomy should be performed in patients with a mucinous ovarian neoplasm.

Fertility sparing surgery A unilateral salpingo-oophorectomy (USO)

(preserving the uterus and contralateral ovary) may be adequate for select stage I tumors (stage 1A and 1C, but not stage 1B)

and/or low-risk ovarian tumors (ie, early-stage, low-grade invasive tumors; ovarian LMP tumors).

Comprehensive surgical staging should still be performed to rule out occult higher-stage disease

Cytoreductive Surgery Cytoreductive surgery is the initial treatment

recommendation for patients with clinical stage II, III, or IV disease

A maximal effort should be made to remove all gross disease

Surgical cytoreduction is optimal if the residual tumor nodules are less than 1 cm in maximum diameter or thickness

Role of chemotherapy Adjuvant

Neoadjuvant

Evolution of chemotherapy in carcinoma ovary Similar to other malignancies, the

management of ovarian cancer has evolved from single agent to combination chemotherapy

Some of the first drugs used in ovarian cancer included single agent alkylating agents like melphelan, chlorambucil, cyclophpsphomide

This was the available agents till 1970s

Their response rate was very low 10-25%

Subsequently, clinical trials performed in the late 1970s demonstrated that cisplatin was an active chemotherapy in advanced or recurrent ovarian cancer with a single agent response rate in the range of 13–30% [Rossof et al. 1979; Thigpen et al. 1979].

Numbers of complete responses and overall response rates doubled compared with earlier single agent trials of non-platinum drugs

Subsequently, cisplatin became the primary chemotherapeutic agent defining the comparison arms for many clinical trials in ovarian cancer

Role of combination The next generation of research studies

evaluating combination chemotherapy with cisplatin plus cyclophosphamide revealed that the time to progression and the duration of survival were markedly improved compared with single agents [Decker et al. 1982].

Triplets added benefit? Adding doxorubicin to the cyclophosphamide

plus cisplatin doublet in women with optimally debulked stage III ovarian carcinoma

did not result in improved progression-free survival (PFS) (median, 22.7 months and 24.6 months) or OS (median, 31.2 months and 38.9 months) [Omura et al. 1989]

As a result, the standard combination chemotherapy in the late 1980s and early 1990s was cisplatin plus cyclophosphamide

Introduction of carboplatin Carboplatin was introduced in the 1990s as an

analog of cisplatin with similar single-agent activity in terms of response and survival rates, but with a significantly improved toxicity profile

The lower incidence of emesis, sensory neuropathy, oto- and nephrotoxicity favored carboplatin

however, myelosuppression was increased compared with cisplatin.

Carboplatin vs cisplatin Alberts and colleagues conducted a phase III

randomized trial in stage III (suboptimal) and stage IV ovarian cancer, comparing cisplatin/cyclophosphamide versus carboplatin/cyclophosphamide [Alberts et al. 1992].

Both arms demonstrated a similar OS (17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively) and similar response rates including pathologic complete responses.

The regimen of carboplatin/cyclophosphamide had a significantly better therapeutic index compared with standard cisplatin/cyclophosphamide.

Multiple randomized studies conducted in advanced ovarian cancer and a meta-analysis of these studies confirmed that carboplatin (given as single agent or in combination regimens) had similar survival rates compared with cisplatin [Aabo et al. 1991], alone or in combination

Introduction of taxanes Paclitaxel introduced in 1990s

The GOG study- randomized 410 women with suboptimally debulked ovarian cancer to cisplatin (75 mg/m2) plus either cyclophosphamide (750 mg/m2) or paclitaxel (135 mg/m2 over 24 h).

The response rate (73 versus 60%, p = 0.01) PFS (18 versus 13 months, p<0.001) OS (38 versus 24 months, p<0.001) all

favored the cisplatin/paclitaxel arm [McGuire et al. 1996]

The second study was an intergroup European and Canadian randomized clinical trial with broader selection criteria compared with the GOG study.

In addition, paclitaxel was delivered as a 3-h rather than a 24-h infusion.

This study demonstrated an improved outcome in the paclitaxel group compared with the cyclophosphamide group [Piccart et al. 2000].

This benefit in survival (35.6 versus 25.8 months, p = 0.0016) was seen despite the fact that the study allowed crossover from the cyclophosphamide arm to the paclitaxel arm at progression.

PACLI/CISPLATIN VS PACLI/CARBO A non-inferiority trial conducted by the GOG in

patients with optimally debulked stage III ovarian cancer

randomized 792 patients to cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 over 24 h, or carboplatin area under curve (AUC) = 7.5 plus paclitaxel 175 mg/m2 over 3 h [Ozols et al. 2003].

The median PFS and OS were 19.4 and 48.7 months, respectively, for the cisplatin arm compared with 20.7 and 57.4 months, respectively, for the carboplatin arm.

The study met its primary non-inferiority end-point

the carboplatin arm was easier to administer and better tolerated compared with the cisplatin arm.

Similar results were seen by du Bois and colleagues in a phase III non-inferiority trial comparing paclitaxel plus cisplatin with paclitaxel plus carboplatin in patients with advanced ovarian cancer [du Bois et al. 2003].

Docetaxel Scottish Randomized Trial in Ovarian Cancer (SCOTROC1), compared

docetaxel/carboplatin with paclitaxel/carboplatin as initial chemotherapy for stage IC–IV ovarian and/or primary peritoneal cancers [Vasey et al. 2004].

The PFS, which was the primary end-point of the study, was similar in both groups (15.0 months versus 14.8 months p = 0.707).

The OS rates at 2 years were comparable in both arms.

More grade 3–4 neutropenia was associated with docetaxel while increased grade 2 or higher neurotoxicity was reported with paclitaxel.

So docetaxel plus carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.

Further attempts to improve the efficacy of the standard platinum/paclitaxel regimen by utilizing various triplet or sequential doublet chemotherapy failed to demonstrate improved outcomes in patients with advanced ovarian cancer [Bookman et al. 2009]

The Gynecologic Cancer Intergroup randomized 4312 women with stages III or IV ovarian cancer to a five-arm trial.

The reference carboplatin/paclitaxel arm was compared with the investigational arms

that incorporated gemcitabine, liposomal doxorubicin, or topotecan given concurrently or sequentially with carboplatin/paclitaxel

Each arm received at least four cycles of standard carboplatin/paclitaxel.

The primary end-point of this study was OS.

All arms had similar PFS and OS values.

This series of randomized phase III studies established carboplatin/paclitaxel as the standard chemotherapy regimen

Adjuvant chemotherapy in early stage Patients with grade 3 tumors and extension

beyond the ovarian capsule or into the abdominal wall or peritoneum (stage IC or II) demonstrated a relapse rate of 20%

two randomized European trials

International Collaborative Ovarian Neoplasm Trial 1 [ICON-1]

Adjuvant ChemoTherapy in Ovarian Neoplasm Trial [ACTION]

compared platinum-based adjuvant chemotherapy with observation following surgery in early-stage ovarian cancer.

Overall survival at 5 years was 82% in the chemotherapy arm and 74% in the observation arm

Such patients include those with stage I, grade 3, stage IC, or any stage II disease

although subset analysis revealed that the benefit appeared to be restricted to those patients who did not undergo adequate surgical staging

Adjuvant chemotherapy Observation in patients with stage IA or IB,

grade 1 tumors

because survival is greater than 90% for this group with surgical treatment alone

Stage 1A or 1B grade 2 observation/ chemotherapy

Stage 1A or 1B grade 3, stage 1C n above need adjuvant chemotherapy

How many cycles of chemotherapy? GOG study -3 vs 6 cycles of pacli/carbo

The relapse rate and progression-free survival were not statistically different between these two treatment arms

33% reduction in the risk of recurrence in patients who received six cycles compared to three cycles

administration of six cycles of adjuvant carboplatin plus paclitaxel chemotherapy can still be considered a reasonable approach for high-risk, early stage patients

Adjuvant chemotherapy Intravenous chemotherapy- stage 1 and 2

Intraperitoneal/iv chemotherapy- optimally debulked stage 3 disease

Its role in stage 2 controversial

For earlier-stage disease recommended cycles are 3 to 6

For patients with advanced-stage disease 6 to 8 cycles of chemotherapy are recommended

PRIMARY CHEMOTHERAPY/PRIMARY ADJUVANT THERAPY REGIMENS

Paclitaxel 175 mg/m2 IV over 3 hours followed by carboplatin4 AUC 5-7.5 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (category 1)

Dose-dense paclitaxel 80 mg/m2 IV over 1 hour Days 1, 8, and 15 and carboplatin4 AUC 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (category 1)

Docetaxel 60-75 mg/m2 IV over 1 hour followed by carboplatin4 AUC 5-6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (category 1)

PRIMARY CHEMOTHERAPY/PRIMARY ADJUVANT THERAPY REGIMENS FOR STAGE II-IV Intraperitoneal (IP)/Intravenous (IV) Regimen

Paclitaxel 135 mg/m2 IV continuous infusion over 3 or 24 h Day 1

Cisplatin 75-100 mg/m2 IP, Day 2

Paclitaxel 60 mg/m2 IP Day 8.

Repeat every 3 weeks x 6 cycles. (category 1)

These regimens have different toxicity profiles.

The docetaxel/carboplatin regimen is associated with increased risk for neutropenia

Intravenous paclitaxel/carboplatin regimen is associated with sensory peripheral neuropathy

dose-dense paclitaxel is associated with increased anemia

The IP paclitaxel/cisplatin regimen is associated with leukopenia, infection, fatigue, renal toxicity, abdominal discomfort, and neurotoxicity

Postoperative Radiation Therapy The role of radiation therapy in the treatment

of patients with primary ovarian cancer has changed markedly over time

Because the entire peritoneal cavity is at risk for metastatic dissemination, the radiation treatment technique must encompass the whole peritoneum

IP Isotopes or WAR

EBRT Princess Margaret Hospital in Toronto and GOG compared

pelvic radiation with observation or single-agent chemotherapy (melphalan)

Pelvic failures were reduced in those receiving radiotherapy.

However, upper abdominal recurrence was a major contributor to overall recurrence

survival was statistically similar among the three arms evaluated.

This suggested that ovarian cancer is responsive to radiation, but to be effective, the treatment field needs to include the entire abdominopelvic cavity.

WAR

which is given by the open-field technique via anterior and posterior ports shaped to encompass the entire peritoneal cavity as well as pelvic and paraaortic lymph nodes

Radiation can permanently eradicate ovarian epithelial tumors

But tumoricidal dose depend on size

Schray and associates reported pelvic irradiation of 50Gy

< 2 cm- LR was 16%

> 2cm – LR was 45%

This data suggest that for large tumors tumoricidal dose exceeds 50-60 Gy

< 2 cm may be 45-50Gy For microscopic disease it may be lower

WAR Trials..

The data indicate that when whole abdominal fields are used, the limited tolerance of the liver, kidneys, and spinal cord would practically rule out eradication of visible tumor masses in the upper abdomen, regardless of tumor size.

For pelvic fields, the tolerance of the intestines, rectum, and bladder would restrict the delivery of tumoricidal doses to tumors of less than 2 cm in size.

This analysis suggests that only patients with minimal or microscopic residua would be candidates for cure by radiotherapy.

Chemotherapy versus Radiation Currently, the only completed phase III trials

in the literature comparing abdominopelvic radiation with chemotherapy have used single-agent non-platinum-containing regimen

attempts to complete phase III trials of abdominopelvic irradiation and platinum-containing standard regimens have been unsuccessful because of poor patient accrual

Whole Abdominal Radiotherapy as Consolidation Therapy 40% to 60% of patients achieving a pathologic

complete response after chemotherapy ultimately recur

unrecognized microscopic residual disease has been implicated most often

Two recent trials Austria and norway

Stage 3 disease with complete response after adjuvant chemo WAR or observation

WAR was associated with improved PFS but no OS advantage

Treatment fields Encompass the whole of abdominal cavity

WAR is given either by open field technique or by moving strip technique

Open field technique- anterior and posterior port shaped to encompass the entire peritoneal cavity

Superiorly- above the domes of diaphragm

Inferiorly -below the obturator foramen

Laterally beyond the peritoneal reflection

The total dose- 30 Gy in 20 fractions

1.2-1.5Gy per day

Kidneys are shielded at 20Gy

Liver at 25Gy

Paraaortic – additional 15Gy

Pelvis- additional 20-25 Gy

Moving strip technique Developed in an era in which radiation therapy

equipment could not adequately encompass the entire abdomen in a single portal.

The patient's abdomen was marked with 12 to 14 “strips,” each 2.5 cm in height

4 strips are treated at a time

This hypofractionation technique delivered daily fractions of 225 to 300 cGy, accumulating in total abdomen doses of 2250 to 3000 cGy..

The kidneys and liver are usually shielded by partial thickness lead blocks to restrict the dose to 15 Gy

Additional dose of 20Gy in 10 fractions is given to pelvis

Martinez technique

Open field technique was preferred

As a matter of convenience, treatment time, technical ease

possible reduction in late (chronic) effects

toxicity

Late toxicity

RADIOISOTPOES

The radioisotope most commonly used for treating ovarian cancer is phosphorus-32 (32P) in the form of chromic phosphate colloid (32P-CP).

The 32P isotope is a pure beta emitter and has a half-life of 14.3 days.

Its beta particles have a mean energy of 0.69 Mev and tissue penetration of 3 to 5 mm.

The fact that there is no gamma emission provides significant safety to the treating staff.

The standard dose of 32P is 15 mCi given in a single IP application

Several prospective randomized trials have looked at 32P versus chemotherapy, and all have shown equivalent survival rates

GOG trial randomized 205 patients with stage I to IIA (high risk) to 15 mCi intraperitoneal 32P versus 3 cycles of cyclophosphamide and cisplatin.

With a median follow-up of 6 years, there was no statistically significant difference in overall 5-year survival rates (84% chemotherapy arm versus 76% 32P arm).

The authors concluded that chemotherapy is better because of the better progression-free interval

NCCN GUIDELINES

Prognostic factors FIGO stage

volume of residual disease after cytoreductive surgery

histological subtype

histological grade

Age

malignant ascites