Radical surgery or definitive radiotherapy is effective treatment for many women with nonbulky, early-stage cervical cancer (stage IB1 to IIA). However, for women with bulky, early-stage (IB2) or late-stage disease (stage IIB to IVA), treatment results are unsatisfactory.[1,2] The patterns of failure are characterized by an increase in both local and distant metastases related to increasing tumor size. However, the main cause of failure is uncontrolled disease within the pelvis. Local failure can be reduced with higher doses of radiation, but this also causes an increase in complications.[3,4]
Our previous study demonstrated that strategies to augment tumor shrinkage prior to intracavitary brachytherapy are necessary to improve local control and increase survival because of the geometric limitation of intracavitary brachytherapy. Strategies to enhance the efficacy of irradiation, such as hyperbaric oxygen,[6,7] hypoxic cell sensitization, neutron therapy, and hyperthermia,[10,11] have been attempted, especially in late-stage disease, but have shown little or no success in most studies. Many investigations are currently being conducted to identify more effective treatments.
Chemotherapy combined with radiation is the logical choice to improve local control as well as reduce distant failure. The use of chemotherapy with radiation therapy in locally advanced cervical cancer evolved as encouraging results were reported in trials investigating chemoradiotherapy in squamous cell cancer of the head and neck, esophagus, lung, and anal canal. The utility of cytotoxic chemotherapy in patients with advanced cervical cancer has been the subject of extensive clinical investigations, with variable results. These studies can be categorized as: (1) neoadjuvant chemotherapy administered prior to radiation; (2) concurrent chemotherapy in which both chemotherapy and radiotherapy are administered together; and (3) adjuvant chemotherapy in which radiation is followed by chemotherapy.
The rationale of combining chemotherapy and radiotherapy has been reviewed previously. Despite the controversy concerning its efficacy, the use of chemotherapy with irradiation appears to be increasing rapidly. Recently, the National Cancer Institute (NCI) distributed a clinical announcement to physicians recommending the use of concurrent cisplatin(Drug information on cisplatin) (Platinol)-based chemoradiotherapy for the treatment of cervical cancer. This article presents an overview of the results of phase III randomized trials of combined chemoradiotherapy in locally advanced cancer of the cervix.
Neoadjuvant chemotherapy has been used prior to local regional radiotherapy for advanced cervical cancer. The theoretical rationale for the use of cytoreductive systemic agents prior to radiation therapy includes the following factors:
(1) Access of chemotherapy to the tumor may be optimal before local treatment interferes with tumor vascularity;
(2) The efficacy of radiation treatment may be improved by reduced cancer cell numbers and improved oxygenation; and
(3) Distant relapse may be reduced by effects on micrometastases.
Therefore, the potential exists for neoadjuvant chemotherapy to both improve local cancer control and reduce distant metastasis.
Numerous studies of the combination of chemotherapy and radiation therapy for advanced cancer of the cervix appear in the literature, but most are uncontrolled phase II trials involving small numbers of patients. Conclusions cannot be drawn about the relative merits of these regimens without data from a large, well-designed phase III trial.
Reports From Phase III Trials
Ten phase III trials of neoadjuvant chemoradiotherapy in advanced cancer of the cervix have been reported (see Table 1).[18-27] All were single-center trials except for those reported by Sundfør et al and Tattersall et al. Many of the trials were small, with fewer than 100 patients in each arm. Cisplatin-based chemotherapy was utilized in all these trials. In general, two or three courses were administered before radiation treatment. Complete response rates achieved with neoadjuvant chemotherapy prior to radiotherapy ranged from 0% to 26% (average, 7%). Complete response rates for radiotherapy alone and for neoadjuvant chemotherapy followed by radiation treatment ranged from 33% to 89%, and 42% to 85%, respectively. Median follow-up in these studies ranged from 1.3 years to 5.0 years.
None of these trials demonstrated a significant difference in survival with neoadjuvant chemotherapy compared to radiotherapy alone. Two studies reported a decreased survival rate and increased treatment complication rate with neoadjuvant chemotherapy.[20,25] This was due partially to the death of several patients in one study from bleomycin(Drug information on bleomycin) (Blenoxane)-associated pulmonary toxicity.
The failure of neoadjuvant chemotherapy to improve local control indicates that partial regression after neoadjuvant chemotherapy was not translated into better local control by subsequent radiotherapy. The possibility of cross-resistance between cisplatin-based drugs and radiation has also been proposed, but requires further exploration. Accelerated repopulation of clonogenic cells in the tumor may provide another possible explanation for the failure of neoadjuvant chemotherapy.
As ineffective chemotherapy may prejudice response to radiation simply by delaying its initiation, neoadjuvant therapy is potentially risky. Until regimens are developed that produce a high complete response rate, neoadjuvant chemotherapy is unlikely to be beneficial.[28-31]
Using chemotherapy during radiation treatment as a radiation sensitizer is an attractive approach. With this strategy, the entire treatment course is not prolonged and, thus, the effects of tumor proliferation are minimized. Unfortunately, these same mechanisms apply to normal tissue and result in greater toxicity.
We analyzed nine phase III trials of concurrent chemoradiotherapy for cervical cancer (Table 2).[32-40] Seven of the nine trials were primarily radiotherapy trials, with or without concurrent chemotherapy, for late-stage disease. Two other trials utilized surgery as the primary approach for the treatment of patients with early-stage disease; one employed preoperative chemoradiotherapy for bulky stage IB disease, and the other employed postoperative chemoradiotherapy in patients with high-risk factors.
Radiation With Concurrent Hydroxyurea
Of the seven trials using primary radiation therapy, the first two[32,33] evaluated the concurrent use of hydroxyurea. Hydroxyurea was advocated as a radiation sensitizer in earlier studies by Piver et al. In 1979, the Gynecologic Oncology Group (GOG) published the results of a randomized, prospective trial favoring concurrent hydroxyurea over radiation therapy alone. However, hydroxyurea has not been incorporated into general use because of its greater hematologic toxicity and uncertainty about its real benefit. Moreover, half of the patients in the 1979 GOG trial were inevaluable due to protocol violations. The 3-year disease-free survival in this trial was only 13% in the control arm and 26% in the hydroxyurea arm.
Nevertheless, on the basis of these data, three subsequent GOG trials of concurrent chemoradiotherpy used hydroxyurea as a control arm (Table 3).[41-43] First, Stehman et al compared hydroxyurea with misonidazole and reported no survival advantage for misonidazole. Next, Whitney et al compared hydroxyurea with cisplatin-based combination chemotherapy and showed survival benefits for the cisplatin combination.
When Rose et al were designing their trial, the results of the hydroxyurea vs cisplatin-based combined chemotherapy trial were not available. Therefore, in a three-armed study, they compared treatment with radiation plus hydroxyurea, radiation plus weekly cisplatin, and radiation plus hydroxyurea, cisplatin, and fluorouracil(Drug information on fluorouracil) (5-FU). These investigators found that the relapse-free survival rate was significantly higher in both regimens containing cisplatin. In addition, patients treated with hydroxyurea had significant hematologic toxicity: Grade III or IV neutropenia occurred in 24.5% of patients receiving hydroxyurea and 3.6% of patients receiving cisplatin/5-FU. Concurrent weekly cisplatin alone was a more effective, less toxic regimen than radiation plus hydroxyurea.[42,43]