• 6/30/2008
  • web-based article
  • Bhuvanesh Singh and David G. Pfister
  • Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3114-3116

Integrated chemotherapy and radiation therapy have become the standard of care for most patients with advanced stage laryngopharyngeal cancers. The concurrent administration of these two modalities is the approach recommended by most experts at present.1 This strategy achieves higher rates of locoregional control compared to when chemotherapy is given as induction treatment before, or as an adjuvant after, radiation therapy.2-6 However, the benefits from concomitant chemoradiotherapy treatment are tempered by higher rates of treatment-related sequelae, especially in the short term. This issue is of particular concern in patients that fail to respond and who have to endure the adverse effects of treatment.

Based on observations that response to chemotherapy predicts radiation response, initial combined modality trials used response to induction chemotherapy to select patients for subsequent organ preservation treatment with definitive radiation, reserving laryngectomy for chemoresistant patients.5,6 However, with a shift to concomitant administration of chemotherapy and radiation therapy, the opportunity for treatment selection based on initial response was lost.3 To maximize the potential value of induction chemotherapy in terms of patient selection while minimizing the delay in the start of concomitant treatment, Urba et al has promulgated an approach in larynx cancer in which one cycle of neoadjuvant chemotherapy is delivered to select patients for subsequent concomitant chemoradiotherapy.7 Their published work suggests that this approach offers advantages for survival improvement over historical controls. The group recently expanded their observations to oropharyngeal cancers, reporting 3-year overall survival of 67% (95% CI, 53.5% to 80.6%) and disease-free survival of 80.5% (95% CI, 68.9% to 92.1%) that was superior to historical controls.8

The use of induction chemotherapy primarily in select patients for subsequent therapy is not without issues. For example, the results of Radiation Therapy Oncology Group trial 91-11 demonstrated that among patients who had less than a partial response at the primary site to induction chemotherapy but refused recommended total laryngectomy, durable disease control was still possible with radiation therapy alone. Similarly, it can be difficult to assess response after just one cycle of chemotherapy, raising the possibility that patients who would have done well with radiation-based treatment alone are triaged to unnecessary surgery.9 Finally, newer triplet induction chemotherapy regimens combining cisplatin and fluorouracil with a taxane have proven to be more efficacious than cisplatin and fluorouracil alone.10-12 By focusing on a short course of induction therapy for patient selection purposes, the potential therapeutic benefit of a more prolonged course on distant control may be compromised.

Not surprisingly, there has been a growing interest in defining molecular subgroups that predict disease behavior to select treatment. The work from Kumar and colleagues13 reported in this issue of the Journal aims to define pretreatment molecular markers that predict response to chemotherapy in a clinical trials data set. This well designed study has the clear benefit of identifying markers that may be clinically applicable. The investigators chose to look at established markers individually and in combination based on biologic principles, leading to the identification of prognostically significant molecular predictors.

The genetic analysis of cancers reached a crescendo with the completion of the Human Genome Project along with the development of high throughput genome-wide analytic techniques. These analyses have helped to shape our understanding of human malignancies generally, and head and neck cancers specifically. Global genomic analyses have identified molecular subsets of head and neck squamous cell carcinoma (HNSCC), which may have prognostic implications.14-21 The challenge has been to reproduce prognostic gene signatures. For example, two independent groups have reported gene signatures that predict outcome in breast cancers using gene arrays, one including 70 genes and the other 76 genes.22-25 Interestingly, although both sets of genes have been validated in independent patient cohorts, there is relatively little overlap between the gene sets. Similarly, the use of individual and combined markers to predict outcome in HNSCC has shown conflicting results, as is well illustrated by the variable correlation between p53 status and outcome reported by different investigators.26-32

Divergent findings are not uncommon when assessing individual molecular markers, reflecting the genetic complexity of HNSCC. To overcome these issues, several studies have attempted to define molecular prognostic groups based on global genomic profiles. Several studies have used comparative genomic hybridization (CGH) to categorize prognostic subgroups in HNSCC. Three of these studies define individual prognostic markers among a background of complex genetic aberrations identified by CGH using well defined statistical methods.14,21,33 These studies identified amplifications at 11q13 and 3q26-27 as markers of outcome. The 11q13 amplification has been well studied, with well characterized oncogenes including cyclin D1, EMS1, and TAOS1 as putative targets for 11q13 amplification.34,35 Amplification at 3q26.3 has also been a topic of significant analysis, with several putative genes (including PIK3CA, PKC-, LAMP3, and eIF-5A2) identified at this locus.36-40 Similarly, gene array studies have delineated putative prognostic subsets that predict outcome.15-17,29 Overall, studies using DNA-based assessment have been more reproducible than those that profile using mRNA-based gene arrays. Moreover, even though they are provocative, none of these studies have been validated sufficiently to allow use in routine clinical practice.

Given the significance of response to chemotherapy in HNSCC, several studies have used this as a surrogate end point for defining molecular markers. Predictably, the literature on genome-based assessment of factors predicting response to platinum-based treatment is limited. Studies using CGH suggest that increased chromosomal instability may contribute to tumors containing or acquiring genetic changes that confer treatment resistance in HNSCC, but do not reproducibly identify specific events that predict treatment response. Gene expression array analyses have identified factors that may predict response to chemotherapy. In an interesting study, 45 genes were identified that predicted cisplatin response.18 The accuracy of these markers was 83%, with a positive predictive value of 78% and a negative predictive value of 100% in ovarian and lung cancers. Other studies have also identified prognostic signatures, but there is limited overlap between studies in the gene sets, calling their significance into question.41,42 Moreover, limited information is available for gene sets predicating chemoresponse in HNSCC.15,29

In contrast to specific or combined molecular markers, the definition of patient subgroups by biologic parameters has been much more reliable in predicting outcome. In vitro chemosensitivity testing has been shown by some investigators to be an independent predictor of outcome,43-45 although a technology assessment done by the American Society of Clinical Oncology would suggest that chemopredictive assays are not ready for routine use.46 The presence of human papillomavirus (HPV) in oropharyngeal cancers also predicts outcome. Like cervical cancers, HPV appears to play a causative role in the development of HNSCC.47 A meta-analysis of published trials, including 5,046 HNSCC cancer specimens, shows a 26% prevalence of HPV, with the vast majority being HPV type 16 (HPV-16).48 The predominant location of HPV-associated tumors is in the oropharynx, with a predilection for nonsmokers (up to 50% of cases). Similar to cervical cancers, detection of HPV in HNSCC is associated with sexual history, implicating direct exposure as a cause for infection.49 In addition, immunosuppression has been suggested to increase the risk for infection and development of HPV-related HNSCC.50 Of specific interest, HPV-positive tumors have improved outcomes relative to HPV-negative cases.51 The outcome advantage is maintained in patients treated with chemoradiotherapy, suggesting that HPV status may be a predictor of treatment response.52 This assertion is validated by the studies from Worden et al54 and Kumar et al,13 suggesting that HPV status should be considered in the selection of patients for concomitant chemoradiotherapy. Recent work indicates that the genetic composition of HPV-positive and HPV-negative cancers may be different, suggesting putative molecular markers that may have predictive value.20,53 Kumar and colleagues report an association between p16 and HPV status, suggesting that p16 may serve as a surrogate marker for HPV infection.13,54 Weinberg and colleagues combined the HPV status with the p16 expression level to develop a prognostic categorization for oropharyngeal tumors and showed that it was a treatment response predictor.52,55

Despite these promising findings, the key question that remains is whether any of the putative predictors can be used to individualize treatment selection. Unfortunately, unlike the example of kinase mutations in other solid tumors, the predictive value of individual or combined molecular markers remains insufficient for routine clinical use in HNSCC. Even more importantly, the inherent genetic differences that predict response to chemotherapy remain unidentified, which may not only serve as treatment selectors, but also as therapeutic targets. The current work suggests that combining the epidermal growth factor receptor (EGFR) expression status with HPV status may predict chemoradiotherapy treatment response. Given the success of EGFR targeting in combination with radiation in HNSCC, could targeting EGFR in HPV-negative, EGFR overexpressing cases improve control? These and other possibilities merit investigation.

1. published online ahead of print at www.jco.org on May 12, 2008
2. The author(s) indicated no potential conflicts of interest.

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