Chemoradiation: The new paradigm for invasive cervical cancer

In recent years, cisplatin-based chemotherapy given concurrent with radiation has emerged as the new standard of care for treating locally advanced cervical cancer.

Screening and treatment of preinvasive lesions have cut the incidence of invasive cervical cancer in the United States by more than 90%. The second most common cancer among women worldwide, the disease afflicts 493,000 women each year and kills some 273,000.¹ Despite the dramatic drop in cervical cancer at home, however, more than 10,000 women in the US were expected to be diagnosed with it in 2006. The American Cancer Society estimates that 10,370 new cases were diagnosed in 2005, of whom 3,710 women died.²

Cervical cancer is clinically staged using the International Federation of Gynecology and Obstetrics (FIGO) system because for many patients surgery is not feasible or appropriate (Table 1).³ Cure rates are roughly equivalent for the options of primary surgery or radiation therapy for women with FIGO stage IA₁ to IIA cervical cancer. More advanced carcinomas (stages IIB to IVB-Figure 1) warrant primary treatment with radiation therapy. Usually, external beam radiation is delivered initially to shrink tumors and irradiate the parametrium and pelvic lymph nodes. Brachytherapy (local implant) is then administered to increase the radiation dose to the central residual tumor. Up until the last few years, the basic guidelines and technology of this approach to radiation therapy for cervical cancer had changed relatively little over the past few decades.

FIGURE 1. Advanced cervical cancer

Adding chemotherapy has several potential advantages. Several large randomized clinical trials have shown the effectiveness of chemoradiation in the treatment of cervical cancer. The National Cancer Institute (NCI) underscored the importance of these studies by issuing a rare clinical announcement suggesting that "strong consideration should be given to incorporation of concurrent chemotherapy with radiation therapy in women who require radiation therapy for the treatment of cervical cancer."⁴

Since then, chemoradiation has become the standard of care and cisplatin the most commonly used agent for several reasons-both theoretical and practical. Cisplatin has the best activity as a single agent in recurrent cervical cancer as shown by 20% to 30% objective response rates in multiple trials. Although adding other drugs to cisplatin can increase the objective response rate, doing so also increases toxicity without prolonging survival. Our purpose here is to review how cisplatin-based chemotherapy given with radiation has emerged as the new standard for the primary treatment of cervical cancer.

Biology of platinum-based chemoradiation

In theory, combining chemotherapy with radiation offers at least two advantages. First, chemotherapy can enhance the radiation's ability to kill local cervical tumors. Second, the combination is able to eradicate occult metastases outside the radiation field that would otherwise be untreated.

Tumor cytotoxicity intensifies when cisplatin is combined with radiation therapy, both in vitro and in vivo. One proposed explanation for this effect is that the drug stops cancer cells from repairing sublethal damage caused by radiation; another is that it preferentially sensitizes hypoxic cells. Animal studies suggest that the therapeutic gain is greatest when cisplatin is administered immediately before (rather than after) radiation, and that the combination of cisplatin and radiation is supra-additive regardless of whether the drug is given in a single dose before or in multiple doses during radiation.⁵

Clinical trials are ongoing to identify the ideal combination to successfully take advantage of these potential benefits. Study designs have chiefly included neoadjuvant chemotherapy (given prior to surgery or radiation) and concurrent chemotherapy and radiation (both given together).

Neoadjuvant chemotherapy

Most of the early randomized trials consisted of neoadjuvant chemo-therapy followed by radiation therapy. Typically two to four courses of chemotherapy were given to reduce the tumor size before proceeding with definitive radiation therapy. These regimens had a response rate of 40% to 70%, with up to 25% of patients achieving a complete response.

Despite the promising initial reports, however, no randomized trial has ever shown a benefit for neoadjuvant chemotherapy for cervical cancer. In fact, two of the randomized trials actually showed a significantly poorer outcome for patients who received neoadjuvant therapy.^6,7 A number of clinical and biologic factors might explain this poorer outcome, including chemotherapy-related mortality, decreased patient adherence toprotracted treatment schedules, and accelerated regrowth of resistant cancer cells. Despite encouraging tumor responses to various combination chemotherapy regimens, multiple trials have provided little or no evidence of clinical improvement.

Combining chemotherapy and radiation

On the other hand, preliminary reports of chemotherapy given simultaneous with radiation to treat patients with locally advanced cervical cancer were promising enough to prompt further investigation. The most commonly used agents included cisplatin, fluorouracil (5FU), mitomycin, and hydroxyurea. Larger Phase II trials of chemoradiation provided the rationale for further studies. There have now been six large randomized, multicenter controlled trials that evaluated cisplatin-based chemoradiation (Table 2). These were reported by the Gynecologic Oncology Group (GOG), Radiation Therapy Oncology Group (RTOG), Southwest Oncology Group (SWOG), and the National Cancer Institute of Canada (NCIC).^8-13

GOG #85. The first trial randomized patients with stages IIB to IVA cervical cancer to radiation concurrent with either cisplatin/5FU or hydroxyurea. The cisplatin/5FU regimen showed a superior overall survival (P=0.018) and reduced risk of dying by 26%.⁸

GOG #120. Results of the second trial-which randomized stage IIB to IVA patients to radiation con-current with either cisplatin/5FU/hydroxyurea, weekly cisplatin, or hydroxyurea-confirmed the observations of GOG #85. Both platinum-based regimens showed a superior overall survival (P<0.01), reducing the risk of dying by 39% to 42%.⁹

RTOG #9001. The third trial randomized patients with stages IB₂ to IVA to radiation alone or concurrent with cisplatin/5FU. Survival was better in the chemoradiation arm (P=0.004), reducing risk of death by 41%.¹⁰ This study suggested that chemoradiation is the treatment of choice not only for stages IIB to IVA, but also for stage IB₂ and IIA disease.

GOG #123. The fourth trial randomized patients with bulky stage IB cervical cancer to radiation alone or concurrent with weekly cisplatin. The women receiving chemoradiation survived longer (P=0.008) and were 46% less likely to die.¹¹ This study agreed with what RTOG #9001 had suggested, that chemo-radiation is best for bulky stage IB disease.

SWOG #8797. The fifth trial was an intergroup study involving SWOG, GOG, and RTOG. Patients with stages IA₂ to IIA disease and pelvic node metastases, positive parametrial involvement, or positive surgical margins at the time of primary radical surgery were randomized to postoperative radiation therapy with or without concurrent cisplatin/5FU. Survival rates were much higher for those receiving chemoradiation (P=0.01), with a 51% reduction in risk of death.¹² Study results suggested that chemoradiation is the treatment of choice for selected high-risk postoperative patients with stages IA₂ to IIA disease.

NCIC. In striking contrast, in the sixth trial, in which researchers randomized patients with stage IB₂ to IVA cervical cancer to either cisplatin-based chemotherapy given concurrent with radiation or to radiation alone, they found that 5-year survival did not differ significantly (62% vs. 58%, respectively) for chemoradiation versus radiation alone. Although this study did not find significant clinical differences, all outcomes slightly favored chemoradiation.¹³ Investigators speculate that the negative results in this trial were due to the lack of surgical staging prior to treatment, increased cisplatin-induced anemia in the chemoradiation group, or statistical chance.^14,15

Five impressive trials and one outlier. These six studies had different eligibility criteria, but in total included a broad spectrum of clinical presentations: (1) patients with locally advanced tumors^8-10,13; (2) bulky early-stage cancers¹¹; and (3) postradical hysterectomy cases with high-risk pathologic factors.¹² The first five trials each showed an increase in survival rate of 30% to 50%. Representing more than 1,800 patients, these studies formed the basis for the NCI's consensus statement.

In contrast, the sixth randomized trial alone failed to find a statistical benefit to cisplatin-based chemo-radiation. Even so, the collective results emphatically support the clinical benefit of using cisplatin-based chemoradiation in cervical cancer (Figure 2). Furthermore, a meta-analysis of approximately 3,000 randomized patients in 19 studies confirmed the benefit.¹⁶ The investigators reported a highly significant reduction in the rate of distant metastases in chemoradiation patients-an effect that wasn't apparent in the individual trials. This observation strongly suggests that cisplatin is effective as a systemic cytotoxic agent and acts synergistically with radiation. Early-stage cervical cancers appeared to derive the greatest benefit from chemoradiation. Overall, the authors estimated a survival benefit of 12% directly attributable to chemoradiation.¹⁶

Is chemoradiation more toxic?

There is a downside. The additive effects of cisplatin and radiation can also lead to significantly higher treatment-related toxicity. These limiting side-effects may lead to delays in radiation therapy and missed chemotherapy cycles.¹⁷ Anemia is second only to tumor stage in prognostic significance in the treatment of cervical cancer with irradiation. Although the mechanisms underlying this correlation are unclear, they may be linked to tumor hypoxia and resulting radio-resistance, as well as angiogenesis induction, increased tumor aggressiveness, and a greater potential for metastasis. The average hemoglobin (Hgb) level during radiation therapy (rather than pre-therapy) appears to be more predictive of poor outcome, but fortunately, transfusion can overcome this problem.¹⁵

The GOG attempted to perform a Phase III trial (protocol #191) to determine the effectiveness of erythropoietin for maintaining Hgb levels during chemoradiation. However, this study was closed prematurely due to an increased risk of thromboembolic events in the treatment arm. Acute hematologic and gastrointestinal side-effects are consistently increased with concurrent chemoradiation. Fortunately, these therapy-induced toxicities don't tend to last long and resolve with medical management. Late complications lead to damage that can be difficult to reverse and may permanently impair quality of life. There's currently not enough data, however, to establish whether chemoradiation increases late toxicity.¹⁶

Cost-effectiveness of cisplatin-based chemo

Obviously, chemoradiation increases the cost of treatment. Chemothera-peutic agents, concomitant medications, chemotherapy administration, laboratory testing, physician visits, adverse event management, and time lost from work due to treatment delays do add up. However, studies show that cisplatin-based chemoradiation is cost-effective compared to standard therapy using radiation alone. Cost per year of life gained varied from $2,384 to $28,770 based on published survival rates.¹⁸ These figures are well below the benchmark of $40,000 to $75,000 that health-care economists and ethicists consider acceptable. There's also an expected economic benefit from the decrease in disease recurrences and subsequent medical care.

Where do we go from here?

Cisplatin-based chemoradiation has become the new standard of care for locally advanced cervical cancer. However, questions remain about the usefulness of other chemotherapeutic agents, drug combinations, and regimens. If we accept the importance of platinum-based therapy, is it possible to make further progress in the chemotherapy regimen?

Other single agents. 5FU has no proven advantages over cisplatin (GOG #165), and hydroxyurea has been abandoned due to bone marrow toxicity and the lack of any discernible benefit. On the other hand, carboplatin has an extremely low toxicity and a promising response rate.¹⁹ Although this drug has essentially replaced cisplatin in the treatment of ovarian cancer, no controlled trials have yet compared carboplatin versus cisplatin as radiation sensitizers of cervical cancer.

Combination therapy. Cisplatin is relatively nonmyelosuppressive, and another alternative to consider is primary combination chemotherapy during radiation. The GOG is currently studying a variety of agents in stage IB₂ to IVA cervical cancer patients. Protocols #9803 and #9804 are Phase I/II trials evaluating concomitant cisplatin and paclitaxel, a drug combination that has shown activity in recurrent cervical cancer.²⁰

Other open Phase I studies pair cisplatin with gemcitabine (protocol #9912) or cetuximab (protocol #9918) during primary radiation. The GOG will be activating protocol #219 in 2006. This Phase III trial will randomize stage IB₂ to IVA cervical cancer patients to weekly cisplatin and radiation versus cisplatin, tirapazamine, and radiation.

Primary treatment. The optimal treatment of bulky stage IB cervical cancer remains unresolved. GOG protocol #141 randomized 288 patients to radical hysterectomy with or without neoadjuvant vincristine and cisplatin. Preliminary analysis suggests that neoadjuvant chemotherapy was not beneficial, but the trial was closed early. More recently, GOG protocol #201 was opened to randomize stage IB₂ cervical cancer patients to radical hysterectomy followed by tailored chemoradiation versus primary chemoradiation. Both postoperative and primary regimens include weekly cisplatin during radiation. Unfortunately, this trial was closed in 2004 due to insufficient accrual.

Based on the overwhelming evidence cited above, we can say that the standard of care for stage IB₂ to IVA disease is platinum-based chemoradiation. Patients who benefited were women with locally advanced cervical cancer ordinarily treated by primary radiation therapy. Postoperative patients with high-risk features also benefited. For these patients, it cut the overall risk of death from cervical cancer by 30% to 50%. Weekly cisplatin achieves results similar to the other regimens with less toxicity and is the current regimen of choice. Although there was more toxicity compared to radiation alone, it was manageable. Further studies are necessary to define the best drug combination, improve patient selection for primary or postoperative chemoradiation, explore novel treatment strategies, and optimize management-such as the use of supportive treatments aimed at overcoming tumor hypoxia.²¹

The cumulative results from the randomized trials discussed here represent a major advance in the management of women with cervical cancer and have established a new paradigm for therapy. In North America, patients with locally advanced cervical cancer should receive cisplatin-based chemotherapy concurrent with radiation therapy. h

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