Cervical Cancer

Chemoradiation Therapy for Locally Advanced Disease

An updated RTOG trial (RTOG 90-01) for advanced cervical cancer (stage IB or IIA with tumor ≥ 5 cm or with biopsy-proven pelvic lymph node involvement and stages IIB–IVA disease) compared extended-field radiotherapy (EFRT) vs pelvic radiotherapy with concomitant 5-FU and cisplatin(Drug information on cisplatin) in women with locoregionally advanced carcinomas of the uterine cervix. The addition of chemotherapy to irradiation improved 5-year survival from 55% to 79% and disease-free survival from 46% to 74% for stage IB/IIA disease by reducing the rates of both local recurrence and distant metastases. For stage III/IVA disease, chemoradiotherapy improved 5-year survival from 45% to 59% and disease-free survival from 37% to 54% (Figures 1 and 3).

GOG 123 randomized patients with stage IB bulky cervical cancer to receive either local treatment alone (external and intracavitary irradiation followed by hysterectomy) or local therapy plus weekly cisplatin. The combination of concurrent weekly cisplatin and irradiation significantly reduced the relapse rate and improved survival by 50%. The 3-year survival rate was significantly improved from 74% to 83% with the use of chemotherapy; this improvement was primarily due to a reduced risk of local recurrence (21% vs 9%).

On the other hand, a small Australian gynecologic group randomized study with 76 patients and a Canadian randomized study of 127 patients with stages IB–IIB carcinoma of the cervix treated with chemotherapy and irradiation or irradiation alone showed no significant difference in tumor control or survival. A possible explanation for the discrepancy in the results between the five US trials and the National Cancer Institute of Canada study has been analyzed by Lehman and Thomas. A review of 4,069 patients with invasive carcinoma of the cervix treated in Ontario, Canada, between 1992 and 2001 documented a significant increase in 3-year survival in patients treated with concurrent chemotherapy-radiotherapy (CT-RT; 75.9%) compared with those treated with irradiation alone (71.1%).

Current treatment recommendations

Concurrent CT-RT (usually cisplatin-based) with or without adjuvant hysterectomy is standard treatment for bulky stage IB2 cervical cancer. An alternative approach is radical hysterectomy followed by tailored postoperative CT-RT.

The use of adjuvant hysterectomy is controversial for stage IB2 cervical cancer, since dose-intense external pelvic and intracavitary irradiation plus chemotherapy may obviate the need for adjuvant surgery. The GOG trial suggests that adjuvant hysterectomy reduces the recurrence rate but does not affect survival.

The use of weekly cisplatin for six cycles or 5-FU and cisplatin every 3 weeks for two cycles concurrently with radiotherapy is the standard treatment approach for bulky stage IB2 cervical cancer.

Stages IIA–IVA disease

The most important prognostic factor associated with pelvic tumor control and survival is the bulk of pelvic disease within each stage. For stage IIB, bulky disease is variously defined as bilateral or lateral parametrial infiltration or central bulky disease greater than 4 cm. For stage IIIB, bulky disease is defined as bilateral sidewall involvement, lower-third vaginal involvement, or hydronephrosis.

In the previous GOG experience, in which para-aortic lymph node staging had been mandated, multivariate analysis testing revealed para-aortic lymph node involvement to be the most powerful negative prognostic factor, followed by pelvic lymph node involvement, larger tumor diameter, young age, advanced stage, and lower performance status for patients with negative para-aortic lymph nodes. Five-year survival rates for radiotherapy alone vary from 80% for stage I, 60% for stage II, and 45% for stage III disease, with corresponding pelvic tumor control rates of 90%, 80%, and 50%, respectively.

CT-RT. A GOG phase III trial (GOG 120) compared standard pelvic EBRT/intracavitary brachytherapy plus hydroxyurea vs weekly cisplatin vs hydroxyurea, 5-FU, and cisplatin. Both the weekly cisplatin and the 5-FU–cisplatin–hydroxyurea arms produced significantly improved survival and relapse rates compared with hydroxyurea alone. Two-year progression-free survival rates were significantly improved from 47% to 67% and 64% with weekly cisplatin-irradiation and 5-FU–cisplatin–hydroxyurea–irradiation compared with hydroxyurea and radiotherapy (Figure 1). The improved outcome was due to the reduced rates of pelvic failure and lung metastases. Because of an improved therapeutic ratio, weekly cisplatin is the favored regimen. Updated results of this trial confirm the original observations.

GOG 165 compared standard radiation therapy plus concurrent weekly cisplatin vs concurrent protracted venous infusion of 5-FU (225 mg/m²/d over 5 weeks) as radiation sensitizers. In a randomized trial, 294 patients with advanced cervical cancer were enrolled to compare cisplatin and cisplatin plus topotecan(Drug information on topotecan) (Hycamtin). Patients who received topotecan had outcomes that were statistically superior to those of patients who received cisplatin alone, with median overall survival of 9.4 months and 6.5 months (P = .017), median progression-free survival of 4.6 months and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. This study confirms the efficacy of pelvic radiotherapy with weekly cisplatin. The study was closed prematurely when a planned interim analysis indicated that the 5-FU arm had a 35% higher rate of treatment failure. An editorial published with the article highlighted the future difficulties with randomized trials for this population.

A randomized study of patients with stages IIIB–IVA cervical cancer was presented at ASCO 2009. The study had two arms: (1) a standard regimen of weekly cisplatin with pelvic radiation therapy and (2) concurrent radiation therapy and weekly cisplatin (40 mg/m²) plus weekly gemcitabine(Drug information on gemcitabine) (Gemzar, 125 mg/m²), followed by two additional cycles of higher-dose cisplatin and gemcitabine after radiation therapy was completed. This study enrolled more than 500 patients worldwide, most notably in developing countries. There was a significant survival advantage with the addition of gemcitabine and post–radiation therapy chemotherapy (3-year progression-free survival rate, 65% vs 74%; overall survival HR = 0.68). Neutropenia and anemia rates were higher in the gemcitabine group. This study did not clarify whether the addition of gemcitabine or the post-radiation chemotherapy, or both, was the reason for the survival improvements.

Current treatment recommendations. In view of the multiple randomized trials documenting a survival benefit with concurrent CT-RT, the use of concurrent weekly cisplatin or cisplatin–5-FU every 3 weeks with irradiation is standard therapy for stages IB2–IVA cervical cancer (Figure 1). Further prospective studies should be explored to determine the role of gemcitabine and post–radiation therapy chemotherapy.

Five of six large randomized clinical trials demonstrated a significant survival benefit for patients treated with concurrent CT-RT, using a cisplatin-based regimen, with a 28% to 50% relative reduction in the risk of death. In addition, the results of a meta-analysis of 19 randomized clinical trials of concurrent CT-RT involving 4,580 patients showed that concurrent CT-RT significantly improved overall survival (HR = 0.71; P < .001) as well as progression-free survival (HR = 0.61; P < .0001). In line with these results, concurrent CT-RT is currently recommended as standard therapy (Table 3).

TABLE 3Large randomized studies of concurrent chemoradiotherapy in cervical cancer

A meta-analysis from all randomized trials reaffirms the benefits of concurrent CT-RT. On the basis of 13 trials that compared CT-RT vs the same radiation therapy, there was a 6% improvement in 5-year survival with CT-RT (HR = 0.81; P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after CT-RT. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83; P < .017) and non–platinum-based (HR = 0.77; P < .009) CT-RT, but no evidence of a difference in the size of the benefit by radiation therapy or chemotherapy dose or scheduling was seen. CT-RT also reduced local and distant recurrence and disease progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and gastrointestinal toxicities were increased with CT-RT, but data were too sparse for an analysis of late toxicity. This meta-analysis clearly demonstrates the benefit of concurrent CT-RT and suggests further exploration should continue with additional adjuvant chemotherapy and non–platinum-based CT-RT.

On the basis of the promising responses and acceptable toxicity reported in the phase I/II study, a phase III GOG trial for advanced cervical cancer (stages IB2–IVA) is randomizing patients to undergo pelvic radiotherapy plus cisplatin weekly or pelvic radiotherapy, cisplatin, and tirapazamine (a hypoxic cell sensitizer).

For patients without para-aortic lymph node metastases, pelvic external irradiation (4,000 to 5,000 cGy) should be used, followed by intracavitary LDR brachytherapy (4,000 to 5,000 cGy) to point A, for a total dose of 8,000 to 9,000 cGy to point A. Noteworthy, in a study at the Norwegian Radium Hospital by Vistad et al of 147 patients, the estimates of physician-assessed intestinal, bladder, and vaginal grade 3/4 morbidity were 15%, 13%, and 23%, respectively, whereas the prevalence of patient-reported severities of the same symptoms were 45%, 23%, and 58%, respectively. The study underscores the importance of incorporating patient assessment in the analysis of treatment morbidity.

Adjuvant radiotherapy following radical hysterectomy

Node-negative disease. Local failure rates approach 20% following radical hysterectomy and pelvic lymphadenectomy when pelvic lymph nodes are not involved but the primary tumor has high-risk characteristics (primary tumor > 4 cm, outer-third cervical stromal invasion, and capillary-lymphatic space invasion). A GOG trial randomized these intermediate-risk patients with node-negative disease to receive pelvic EBRT (5,100 cGy/30 fractions) or no further therapy following radical hysterectomy–pelvic lymphadenectomy. Postoperative irradiation produced a significant 44% reduction in recurrence; the recurrence-free rate at 2 years was 88% with irradiation vs 79% without it. Survival analysis awaits further follow-up.

Node-positive disease. For patients with positive pelvic lymph nodes following radical hysterectomy–pelvic lymphadenectomy, pelvic radiotherapy reduces the pelvic failure rate from approximately 50% to 25% but does not affect survival, since distant metastases are still seen in 30% of patients. GOG/Southwest Oncology Group 8797 randomized these high-risk patients with node-positive disease (or patients with positive surgical margins) to undergo pelvic EBRT (4,930 cGy/29 fractions) vs pelvic EBRT plus concurrent 5-FU and cisplatin for four cycles following radical hysterectomy–pelvic lymphadenectomy. A significant improvement in disease progression-free and overall survival was seen for concurrent 5-FU–cisplatin and radiation therapy compared with radiation therapy alone (4-year survival, 81% vs 71%).

• Current treatment recommendations—At present, the use of adjuvant pelvic radiotherapy should be considered for patients with negative nodes who are at risk for pelvic failure and remains the standard postoperative treatment for patients with positive lymph nodes. Treatment consists of external pelvic irradiation (45 to 50 Gy), with specific sites boosted with further external beam or intracavitary irradiation as needed.

Since the combination of radical surgery and irradiation has greater morbidity than either modality alone, complete preoperative assessment is crucial to minimize the need for both.

Since concurrent CT-RT following radical hysterectomy provides a significant benefit in node-positive, high-risk cervical cancer, it should be part of the postoperative treatment plan. Postoperative CT-RT following radical hysterectomy should be strongly considered for patients with negative nodes but positive margins or parametrial invasion, middle-third or greater stromal invasion, and lymphovascular space invasion for tumors 5 cm or larger.