Treatment Advances in Locoregionally Advanced and Stage IVB/Recurrent Cervical Cancer: Can We Agree That More Is Not Always Better?

Although relatively rare in the developed world, cervical cancer is the fourth most common cancer among women worldwide with over 527,000 cases in 2012. Primary and secondary prevention efforts will be most impactful, but research aimed at improving outcomes and individualizing therapies is also critical. Developments in individualizing this therapy to the population most likely to benefit may allow evidence-based triage of therapies, even in resource-limited areas, and improve outcomes overall. Accompanying this editorial are two articles helpful for treatment decision making. Rose et al evaluated data from over 2,000 women treated for locoregionally advanced cervix cancer and developed a nomogram that proposes to stratify women by prognostic risk. Kitagawa et al report on a large randomized phase III trial (RCT) comparing standard of care cisplatin and paclitaxel (PT) to carboplatin and paclitaxel (CT) seeking to investigate whether the latter, more tolerable, regimen was noninferior to PT. In 1999, the National Cancer Institute recommended that treatment for locally advanced cervical cancer (stage IB2-IVA) should include the addition of cisplatin-based chemotherapy to radiation as demonstrated by five RCTs showing a decrease in the risk of death of 40%. Despite significant improvements with the addition of cisplatin to radiation (chemoradiotherapy [CRT]), local recurrences still hover around a rate of 20% and 3-year overall survival (OS) ranges from 67% to 74% depending on the study (Table 1). To further decrease the rate of recurrences, which are almost universally lethal, treatment strategies have included combining another cytotoxic therapy with CRT, addition of targeted therapies with CRT, neoadjuvant chemotherapy, and consolidation cytotoxic therapy after CRT. With the exception of the Duenas-Gonzalez et al study evaluating RT with cisplatin and gemcitabine followed by two cycles of cisplatin and gemcitabine as compared with CRT, no other strategy has demonstrated improvement in response rate (RR) and survival over CRT alone. The concept of using adjuvant chemotherapy is currently being evaluated in an international phase III RCT comparing CRT with CRT plus four cycles of CT (NCT01414608). It is important to note that early trials with patients receiving radiation alone demonstrated that approximately 50% of patients never had recurrences and for these patients, additional treatment adds only harm. Furthermore, with the addition of sensitizing cisplatin, the rate of recurrence drops an additional 15%. Maximizing the gain of additional treatment for the 35% who will recur and sparing toxicity for the other 65% is critical to maximizing OS and quality of life. Although prognostic factors for recurrence have been previously evaluated to help guide identification of patients at risk for recurrence, the extent to which these factors may continue to apply with the widespread use of CRT is not defined. Rose et al present an analysis of locally advanced cervical cancer patients treated on phase III RCT of RT alone versus CRT and nomograms were constructed for 2-year progression-free survival, 5-year OS, and pelvic recurrence. The nomograms provide improved risk stratification, by weighting each characteristic rather than a simple additive risk model and offer an opportunity to better estimate an individual patient’s risk and target more aggressive therapies (adjuvant CT for example) to those at highest risk. Although these nomograms are validated for their predictive abilities, we must consider them within the context of individual patients. Patient treatment preferences, goals of care, comorbidities, and many other factors sit outside predictive models, but play an equal role in developing best treatment plans for our patients. Integration of this information is key. We must also consider the context of the studies that were included to create the nomograms. In this case, these six trials span 26 years from first study launch to last study closure. During this time, protocol mandated radiation treatment length decreased from 10 to 8 weeks and all studies mandated 2or 4-field external beam and assigned dose based on anatomic landmarks (80 Gy to Point A, for example, in Table 1). These techniques are still widely used in certain parts of the world and the nomograms may be most applicable where current techniques mirror the included studies. In the developed world, where much of radiation for cervix cancer has transitioned to three-dimensional conformal therapy, intensity-modulated radiation therapy, and volumetric dosing, we wonder if this nomogram is as applicable. In contrast to the management of patients with earlier-stage disease, treatment of stage IVB/recurrent cervical cancer is generally noncurative. For such patients, we have progressed over the past 30 years from a model of best supportive care to doublet cytotoxic therapy with or without bevacizumab, with concordant improvements in JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 19 JULY 1 2015