Carcinoma of the Uterine Cervix

NM 111

M N T ab le 4. 4 Recommendations for the Use of Systemic Therapy in Endometrial Carcinoma

Patient Characteristics
Advanced or recurrent disease Advanced or recurrent receptor-positive and/or grade 1 or 2 Stage Ill-IVA

Recommendations
Chemotherapy (cisplatin/doxorubicin/ paclitaxel) Hormonal therapy (oral progestins or megestrol acetate) Surgery followed by chemotherapy

and overall survival compared with doxorubicin/cisplatin. Hormonal therapy with progestins is appropriate for those with disease features suggesting hormonal responsiveness. Chemotherapy for patients with stage III-IVA disease should be considered following surgery. Carcinoma of the Uterine Cervix Carcinoma of the uterine cervix remains a common disease, although the majority of cases are diagnosed before invasion, with cure the expected result, at least in the United States. In 2003, a projected 12,200 invasive cases with 4,100 deaths are expected, a marked reduction from the almost 60,000 deaths from this disease in 1950. The majority of cases are squamous carcinomas (80%-85%); hence, most of the data on management apply most reliably to this histologic type. The approach to other histologies is based on the assumption that histology does not alter therapeutic choices, at least in the case of systemic therapy. For invasive cases, management is dictated by the extent of disease at diagnosis as expressed in the FIGO staging system (Table 4.5). Chemotherapy has a defined role in two situations: the management of advanced (stage IVB) or recurrent disease as the primary therapy, and the management of locoregionally advanced (stage IIB, III, or IVA) disease in conjunction with radiation.

112 =II
II= Table 4.5

The Role of Chemotherapy in Gynecologic Cancer

FIGO Staging System for Carcinoma of the Cervix Stage Stage 1

IA

Description The carcinoma is strictly confined to the cervix

Invasive cancer identified only microscopically. All gross lesions even with superficial invasion are stage IB cancers Inv as io n is lim ite d to m e as ur ed strom al inv as io n with maximum depth of 5.0 mm and no wider than 7.0 mm* Msdanmoaa.m i eriv o agtrn m a ns f nre 3 n u i s et 0 e ot h o r depth and no wider than 7.0 mm Measured inv asion o f strom a gre ater than 3 mm and no greater than 5 mm and no wider than 7 mm Clinical lesions confined to the cervix or preclinical lesions greater than stage IA Clinical lesions no greater than 4.0 cm in size Clinical lesions greater than 4.0 cm in size

IA1 IA2 IB IBI IB2

Stage 11
IIA IIB

Vaginal or parametrial extension Extension to the upper two-thirds of vagina

Extension to parametria, but not to pelvic sidewall

Stage111
IIIA 11 18

Pelvic sidewall extension, lower vaginal involvement, or hydronephrosis

Extension to the lower one-third of vagina Extension to pelvic sidewall or hydronephrosis

Stage IV Mucosal involvement of bladder or rectum, or distant disease IVA Mucosal involvement of bladder or rectum
IVB Involvement of distant organs * The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. Vascular space involvement, either venous or lymphatic, should not alter the staging.

MN Advanced or Recurrent Disease In patients with advanced or recurrent disease, a number of cytotoxic drugs have minimal to moderate activity (response rates of 10%-15%), but several agents or groups of agents have shown consistent activity in the range of response rates of better than 15%. The most intensely studied agent is cisplatin, which demonstrated a response rate of 23% among 815 patients studied by the GOG in trials of sin-

Carcinoma of the Uterine Cervix

MU 113

gle-agent cisplatin. Activity does not appear to depend on dose and schedule as long as at least 50 mg/m2 is used every 3 weeks. In the absence of major antiemetics (metoclopramide, ondansetron, and granisetron), infusion over 24 hours rather than at 1 mg/min yields less nausea and vomiting. Carboplatin appears to have a slightly lower response rate in the range of 15% to 20%, although this agent has never been directly compared to cisplatin in a phase III trial in cervix carcinoma. Other active agents used as monotherapy include ifosfamide, vinorelbine, paclitaxel, topotecan, and irinotecan. I fosfamide, in several smaller trials, produced responses in up to 33% of patients not previously exposed to chemotherapy. Phase 2 trials of vinorelbine have reported response rates of 18% in patients with prior radiation, and 45% when used as neoadjuvant therapy. Paclitaxel, topotecan, and irinotecan have all shown responses of approximately 17% to 20% among patients who have been treated with radiation. It is important to note that responses to single-agent therapy usually result in responses of relatively brief duration, except for the 5% to 10% who achieve a complete response. Although such therapy should be considered as an option and so presented to the patient, expectations of benefit must be tempered. A few large randomized trials of combination chemotherapy versus single agents have been conducted. GOG Protocol 110 randomized patients with advanced or recurrent disease to receive cisplatin alone, cisplatin/dibromodulcitol, or cisplatin/ifosfamide. Response rates were 19%, 22%, and 33%, respectively. No significant difference was noted in the response rates between cisplatin alone and cisplatin/dibromodulcitol. However, the combination of cisplatin/ifosfamide produced a significantly improved response rate and progression-free survival but at the cost of increased hematologic, renal, and neurologic toxicity. No difference in overall survival was noted. GOG 169 randomized patients with stage IVB, recurrent, or persistent dis-

of

Summary Chemoradiation Trials for Cervical Cancer

Protocol
GOG 85 (SW G 8695)

Eligible Patients
Stages IIB-IVA Negative para-aortic nodes No intraperitoneal disease Stages IIB-IVA, or Stage IB and IA with positive pelvic nodes or tumor > 5cm Stages IIB-IVA Negative para-aortic nodes No intraperitoneal disease Stages IA2, IB, IIA with positive pelvic nodes, positive parametria, or positive surgical margins Negative para-aortic nodes Stage IB2 Negative pelvic and para-aortic nodes

Treatment Arms
I: pelvic EBRT, brachytherapy 5-FU/cisplati II: pelvic EBRT, brachytherapy

3 Year Survival (%)

-

67 57 75 63 65

RTOG 9001

hydroxyurea I: pelvic EBRT, brachytherapy 5-FU/cisplatin

extended-field EBRT, brachytherapy I: pelvic EBRT, brachytherapy weekly cisplatin II: pelvic EBRT, brachytherapy 5-FU/cisplatin/hydroxyurea III:pelvic EBRT, brachytherapy hydroxyurea I: pelvic EBRT 5-FU/cisplatin II: pelvic EBRT

II:

GOG 120

SW OG 8797 (GOG 109, RTOG 91 12) GOG 123

65 47 87 77

I: pelvic EBRT, brachytherapy weekly cisplatin extrafascial hysterectomy II: pelvic EBRT, brachytherapy extrafascial hysterectomy

83 74
(median follow-up

35.7 mo) GOG, Gynecologic Oncology Group; SWOG, Southwest Oncology Group; RTOG, Radiation Therapy Oncology Group; EBRT, external beam radiation therapy.

114 II=

The Role of Chemotherapy in Gynecologic Cancer

ease to receive either cisplatin alone or cisplatin/paclitaxel. The majority of patients had received radiation therapy. Preliminary results document significantly improved response rate (19% vs. 36%, respectively) and progression free-survival (2.8 months vs. 4.8 months, respectively). No difference was noted in median survival. Although the combination incurred more frequent neutropenia and anemia, no significant differences were noted in patient-reported quality of life. Randomized trials comparing various chemotherapeutic combinations have not shown a clear benefit. GOG 149 compared cisplatin and ifosfamide with or without bleomycin for the treatment of advanced, recurrent, or persistent disease showed no difference in response, progression-free interval, survival, or toxicity. Currently, the GOG has completed a comparison of topotecan/cisplatin versus cisplatin alone and is conducting a phase 3 randomized trial of cisplatin plus either paclitaxel, or vinorelbine. Until additional results are available, the current data suggest that cisplatin/paclitaxel or cisplatin/ifosfamide may offer patients higher response rate and superior progression-free survival, though with increased toxicity.

Locoregionally Advanced Disease The role of chemotherapy in the treatment of cervical cancer has changed dramatically in the last several years, with the concurrent use of platinum-based therapy with radiation becoming the standard of care for treatment of locally advanced cervical cancer (IIB-IVA). Five randomized phase 3 trials were published in 1999 and 2000 (Table 4.6). Although these trials treated different groups of patients with differing regimens of chemotherapy and radiation, all showed statistically significant overall survival advantage for concurrent platinum-based chemotherapy. Survival was improved in patients with locally advanced cervical cancer (stages IBIVA), as well as those with stage I-IIA disease with poor prognostic factors such

It
!I

116 I

The Role of Chemotherapy in Gynecologic Cancer

S UM T ab l e 4 .7 Recommendations for the Use of Chemotherapy in Carcinoma of the Cervix Patient Characteristics Stage IVB or recurrent disease Stages IIB, Ill, IVA Recommendations Chemotherapy (combination of cisplatin plus ifosfamide or cisplatin plus paclitaxel) Radiotherapy with concomitant chemotherapy (cisplatin/5-fluorouracil or weekly cisplatin)

as positive surgical margins, parametria, or pelvic nodes. Chemoradiation appears to decrease the risk of death by approximately 30% to 50%. Though the single best chemotherapy regimen has not been defined, both weekly cisplatin alone and the combination of cisplatin/fluorouracil both appear effective with acceptable toxicity. NMI Summary Chemotherapy should be considered in two situations: advanced or recurrent disease as the primary treatment, and locoregionally advanced disease in combination with radiotherapy (Table 4.7). In advanced or recurrent disease, combination therapy with cisplatin/paclitaxel or cisplatin/ ifosfamide may result in a longer progression-free survival and a higher response rate than cisplatin alone, though overall survival has not shown to be significantly increased. In locoregionally advanced disease, concurrent cisplatin/fluorouracil or weekly cisplatin should be given concurrently with radiation.

fur

10
on.*

Uterine Sarcomas Uterine sarcomas account for fewer than 5% of cancers of the corpus of the uterus. In the United States, this translates into approximately 1,000 cases per year. Although multiple histologic types are seen, the GOG experience observes that 60% will be malignant mixed mullerian tumors, 30%