Ovarian Carcinoma 203

39. Ovarian Carcinoma

39.1 General considerations

American joint Commission on Cancer/International Federation of Gynecology and Obstetrics Staging for Dvarian Cancer

Stage Definition

I Growth limited to the ovaries

A Growth limited to one ovary; no ascites; capsule intact;

no tumor on external surface

B Involvement of both ovaries; no ascites; capsule intact;

no tumor on external surface

C One or both ovaries, with surface tumor, ruptured capsule,

or ascites, or peritoneal washings positive for malignant cells

II Growth involving one or both ovaries with pelvic extension

A Involvement of uterus and/or fallopian tubes

B Involvement of other pelvic tissues

C Stage IIA or IIB with associated factors as in stage IC

III Peritoneal implants outside pelvis and/or positive

retroperitoneal or inguinal nodes; includes superficial liver

metastasis and spread to small bowel and omentum

A Grossly limited ot true pelvis; negative nodes; microscopic

seeding of abdominal peritoneum

B Implants of abdominal peritoneum, none > 2 cm in diameter;

negative nodes

C Abdominal implants > 2 cm and / or positive retroperitoneal

or inguinal nodes

IV Distant metastasis; includes parenchymal liver metastasis and

pleural effusions with positive cytologic findings

With the exception of radically operated patients with low-risk early ovarian cancer (stage IA or IB non-clear cell well differentiated or borderline tumors), multimodality treatment is the established standard approach. Surgery remains the cornerstone of diagnosis, pathological staging and treament, followed by chemotherapy either in the adjuvant setting or for advanced disease. Standard chemotherapy for previously untreated patients with advanced ovarian cancer consists of a combination of paclitaxel and a platinum compound. Patients with recurrent disease have a chance to respond to second- line therapy which is directly related to the progression-free interval: Those who have a progression –free interval > 6-12 months can be retreated with platinum and/or paclitaxel while others still can benefit from alternative chemotherapeutic agents. Palliation in advanced or recurrent disease might also be achieved with radiotherapy. At present there is no established role for high-dose chemotherapy, and intraperitoneal chemotherapy also has to be considered as experimental.

Literatrure: for review e.g.

BEREK et al, Ann. Oncol. 10 (Suppl 1) ( 1999): 87-92 (1998 consensus

statement)

BRIDGEWATER and RUSTIN, Oncology 57 (1999): 89-98 (management of non-epithelial ovarian tumors)

CHRISTIAN and THOMAS, Cancer Treat. Rev. 27 (2001): 99- 109 (role of chemotherapy)

204 Ovarian Carcinoma

COUKOS and RUBIN, Oncology 15 (2001): 1197- 1204 , 1207-1208 (gene therapy)

Du BOIS, Eur. J. Cancer 37 (2001): 1-7 HOFSTRA et al, Cancer Treat. Rev.26 (2000): 133-143 (intraperitoneal chemotherapy)

HOGBERG et al, Acta Oncol. 40 (2001): 340–360 (systematic overview of chemotherapy effects) KAYE, Eur. J. Cancer 37 (2001): 19 – 23 (future directions) MARKMAN, Semin. Oncol. 29 (Suppl 1) (2002): 9 – 10 (second line treatment) and Drugs 16 (2001): 1057 – 1065 (intraperitoneal drug delivery)

McGUIRE, Semin. Oncol. 27 (Suppl 7) (2000): 41-46 (high-dose

chemotherapy)

OZOLS, Semin. Oncol. 29 (Suppl 1) (2002): 32 – 42 (future directions)

and Semin. Oncol. 27 (Suppl 7) (2000): 47 –49 (consensus summary)

PICCART et al, Ann. Oncol. 12 (2001): 1195-1203 (role of platinum

drugs)

PIGNATA and MONFARDINI, Eur. J. Cancer 36 (2000): 817-820

(treatment of patients > 70 years of age)

THIPGEN, Semin. Oncol. 26 (Suppl 18) (1999): 29 – 33 (limited-stage

disease) and Semin. Oncol. 27 (Suppl 7) (2000): 11 – 16 (overview of

randomized trials)

39.2 First-line chemotherapy

39.2.1 Platinum + paclitaxel combinations

Literature: for review

OZOLS, Semin. Oncol. 27 (Suppl 7) (2000): 3 – 7 PICCART et al, Eur. J. Cancer 36 (2000): 10 – 12

39.2.2.1 Paclitaxel + cisplatin (TP)

Paclitaxel 135 mg/m² i.v. (3 h or 24 h inf) d 1

Cisplatin 75 mg /m² i.v.(1 mg/min) d 1 or 2

To be repeated every 3 weeks ( 6 cycles)

Literature:

McGUIRE et al, N. Engl. J. Med. 334 (1996): 1-6 (phase III trial GOG 111 comparing cisplatin plus either paclitaxel 24 h inf or cyclophosphamide)

MUGGIA et al, J. Clin. Oncol. 18 (2000): 106 – 115 (phase III trial GOG 132 comparing cispalatin vs paclitaxel vs cisplatin + paclitaxel 24 h inf) PICCART et al, J. Natl. Cancer Inst. 92 (2000): 699 – 708 (randomized Intergroup trial of cisplatin + paclitaxel 3 h inf vs cisplatin + cyclophosphamide )

39.2.1.2 Paclitaxel + carboplatin

Paclitaxel 175 mg/m² i.v. (3 h inf) d 1

Carboplatin AUC = 5 (-6) i.v.(1 h inf) d 1

To be repeated every 3 weeks ( at least 6 cycles; outpatient treatment)

Literature:

INTERNATIONAL COLLABORATIVE OVARIAN NEOPLASM

(ICON) GROUP, Lancet 360 (2002): 505 – 515 (multinational

randomized trial ICON3: paclitaxel + carboplatin vs standard CT)

NEIJT et al, J. Clin. Oncol. 18 (2000): 3084 –3092 (phase III study of paclitaxel + cisplatin vs paclitaxel + carboplatin)

Ovarian Carcinoma 205

39.2.2 Carboplatin + cyclophosphamide

Carboplatin 300mg/m² i.v.(1 h inf) d 1

Cyclophosphamide 600 mg/m² i.v. (short inf) d 1

To be repeated every 4 weeks ( for 6 cycles)

Literature: ALBERTS et al, J. Clin. Oncol. 10 (1992): 706 – 717 SWENERTON et al, J. Clin. Oncol. 10 (1992): 718 – 726

39.2.3. Carboplatin

Carboplatin 300 – 400 mg/m² i.v.(1 h inf) d 1 or

AUC = 5 i.v. ( 1 h inf) d 1

To be repeated every 3 weeks ( 6 cycles)

Litetature:

EISENHAUER et al, Cancer Treat. Rep. 70 (1986): 1195-1198 INTERNATIONAL COLLABORATIVE OVARIAN NEOPLASM (ICON) GROUP, Lancet 360 (2002): 505 – 515 (multinational randomized trial ICON3; paclitaxel + carboplatin vs standard CT) MANGIONI et al, J. Natl. Cancer Inst. 81 (1989): 1464 – 1471

TAYLOR et al, J. Clin. Oncol. 12 (1994)L 2066 – 2070

39.3. Salvage therapy

39.3.1 Platinum – sensitive relapse

In patients with recurrences after a therapy-free interval of > 6 – 12 months a

second treatment with platinum- based chemotherapy is warranted.

Literature: e.g.

ALBERTS, Semin. Oncol. 26 (Suppl 1) (1999): 8 – 14 (review)

MARKMAN et al, J. Clin. Oncol. 9 (1992): 389 – 393

39.3.2. Platinum – resistance

Patients with platinum- resistant ovarian cancer can benefit from therapy

with altretamin (hexamethylmelamin), topotecan, oral etoposide, ifosfamide,

liposomal doxorubicin, taxanes, gemcitabine, oxaliplatin, or other standard

or investigational regimens, e.g.

39.3.2.1. Topotecan

Topotecan 1.0 – 1.5 mg/m² i.v.(30 min inf) d 1-5

To be repeated every 3 weeks

Literature:

BOOKMAN et al, J. Clin. Oncol. 16 (1998): 3345 – 3352 GORE et al, J. Clin. Oncol. 19 (2001): 1893 –1900 (3rd-line activity after one platinum-based regimen and paclitaxel) and Eur. J. Cancer 38 (2002): 57 – 63 (randomized comparison of i.v. vs oral topotecan)

McGUIRE et al, J. Clin. Oncol. 18 (2000): 1062 – 1067 (first- line salvage therapy in platinum- sensitive relapse)

RODRIGUEZ and ROSE, Gynecol. Oncol. 83 (2001): 257 – 262 (improved therapeutic index of 1mg/m² d x 5 topotecan)

Ten BOKKEL HUININK et al, Semin, Oncol. 24 (Suppl 5) ( 1997): 19 – 25 (review)

206 Ovarian Carcinoma

39.3.2.2 paclitaxel

Paclitaxel 135-175mg/m² i.v.(3 h inf) d 1

To be repeated every 3 weeks ( 6 – 10 cycles or until progression)

Literature:

EISENHAUER et al, J. Clin. Oncol. 12 (1994): 2654-2666 (European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose vs low dose and long vs short infusion) GORE et al, J. Clin. Oncol. 19 (2001): 1893-1900 (3^rd – line activity after one platinum-based regimen and topotecan) PICCART et al, J. Clin. Oncol. 18 (2000): 1193-1202 (randomized phase II study of the EORTC comparing paclitaxel and oxaliplatin)

39.3.2.3 Etoposide

Etoposide 50 -100mg/m² p.o. d 1- 4

To be repeated every 3-4 weeks ( until progression)

Literature:

HOSKINS and SWENERTON, J. Clin. Oncol. 12 (1994): 60 – 63 OZOLS, Drugs 58 (Suppl 3) (1999): 43 – 49 (review)

39.3.2.4 Gemcitabine

Gemcitabine 800-1250mg/m² i.v. d 1, 8, 15

To be repeated every 4 weeks . Also in combination with cisplatin, carboplatin or

paclitaxel.

Literature:

LUND, et al, J. Natl. Cancer Inst. 86 (1994): 1530 – 1533 MARKMAN, Semin. Oncol. 29 (Suppl 1) (2001): 9 – 10 (review) ORLANDO and MANDACHAIN, Semin. Oncol. 28 (Suppl 10) ( 2001): 62 –69 (review)

39.3.2.5 Ifosfamide and ifosfamide – containing combinations

Ifosfamide 1200-2400mg/m² i.v. (30 min-2 h inf) d 1-5

With mesna uroprotection

To be repeated every 3-4 weeks

Literature:

MARKMAN et al, J. Clin. Oncol. 10 (1992): 243-248 MARKMAN, Gyn. Onocl. 70 (1998): 272-274 SUTTON, Gynecol. Oncol. 51 (1993): 104-108

Ifosfamide 1000mg/m² i.v. (cont inf) d 1-7

With mesna uroprotection

To be repeated every 4 weeks .

Literature:

DORVAL et al, J. Infus. Chemother. 6 (1996): 47- 49

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Ifosfamide + Paclitaxel

Ifosfamide 1500mg/m² i.v. (1 h inf) d 2-5

With mesna uroprotection

Paclitaxel 175 mg/m² i.v. ( 3 h inf) d 1

To be repeated every 3 weeks .

Literature:

KLAASSEN et al, Anti-Cancer Drugs 9 (1998): 359-361

Ifosfamide + mitoxantrone

Ifosfamide 2000mg/m² i.v. (30min inf) d 1-3

With mesna uroprotection

Mitoxantrone 10 mg/m² i.v. ( 30 min inf) d 1

To be repeated every 3 weeks .

Literature:

NARDI et al, Cancer Chemother. Pharmacol. 38 (1996): 298-301

39.3.2.6 pegylated liposomal doxorubicin (Doxil)

Doxil 50mg/m² i.v. (1 h inf) d 1

To be repeated every 4 weeks (until progression or up to 1 year).

Literature:

GORDON et al, J. Clin. Oncol. 19 (2001): 3312-3322 (randomized phase III study of pegylated liposomal doxorubicin vs topotecan in recurrent ovarian carcinoma)

JOHNSTON and GORE, Eur. J. Cancer 37 (Suppl) (2001): 8 – 14 (overview of phase II studies) MUGGIA and HAMILTON, Eur. J. Cancer 37 (Suppl) (2001): 15 – 18 (overview of phase III studies)

39.4 Intraperitoneal chemotherapy

Literature: for review e.g.

MARKMAN, Drugs 16(2001): 1057-1065 and Oncology 15 (2001): 93-98, 103 – 105

OZOLS et al, Ann. Oncol. 10 (Suppl 1) (1999): 59 – 64

Patients who may potentially benefit from intraperitoneal chemotherapy include those with small volume intraperitoneal disease at the intiation of initial chemotherapy and individuals with microscopic and very small volume macroscopic cancer after the completion of front-line systemic treatment. Cisplatin, carboplatin, mitoxantrone or paclitaxel are suitable for this mode of administration.