Current Management of Locally Advanced Head and Neck Cancer: The Combination of Chemotherapy With Locoregional Treatments Voichita Bar-Ad,a Joshua Palmer,a Hushan Yang,b David Cognetti,c Joseph Curry,c Adam Luginbuhl,c Madalina Tuluc,d Barbara Campling,b and Rita Axelrodb This review will discuss the evolution of the role of chemotherapy in the treatment of locally advanced head and neck cancer (HNC), over the last few decades. Studies were identified by searching PubMed electronic databases. Surgery followed by radiotherapy (RT) or definitive RT are potentially curative approaches for locally advanced HNC. While chemotherapy itself is not curative, it can improve cure rates when given as an adjunct to RT. The benefit of combining chemotherapy with RT is related to the timing of the chemotherapy. Several prospective randomized trials have demonstrated that concurrent delivery of chemotherapy and RT (CRT) is the most promising approach, given that locoregional recurrence is the leading pattern of failure for patients with locally advanced HNC. Induction chemotherapy before CRT has not been shown to be superior to CRT alone and the added toxicity may negatively impact the compliance with CRT. Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT, has been successful as a strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal cancer. Systemic chemotherapy delivered concurrently with RT is used as a standard treatment for locally advanced HNC. Semin Oncol 41:798-806 & 2014 Elsevier Inc. All rights reserved.

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ead and neck cancer (HNC) represents about 9% of new cancer cases, with more than 500,000 new cases diagnosed worldwide each year.1–3 Smoking and alcohol abuse are considered major risk factors for HNC, which primarily affects the oropharynx, oral cavity, hypopharynx, and larynx.4 Recently, there has been a a

Department of Radiation Oncology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. b Department of Medical Oncology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. c Department of Otolaryngology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. d Department of Pathology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. Financial disclosures: none declared. Conflicts of interest: none declared. Address correspondence to Voichita Bar-Ad, MD, Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, 111 S 11th St, Philadelphia, PA 19107. E-mail: [email protected] 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.018

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tremendous increase in oropharyngeal cancer related to human papillomavirus (HPV) infection.5 At the time of diagnosis, the majority of patients present with locoregionally advanced disease. Surgical and radiotherapy (RT) treatments are associated with a 3-year overall survival of only 30%–50%; locoregional recurrences or distant metastases develop in 40%–60% of these patients.6,7 A variety of strategies have been attempted to improve outcomes by combining chemotherapy with surgery and RT, but the optimal schedule for integrating the systemic treatment into the management of HNC has yet to be determined. The results of several prospective randomized trials have changed the standard of care and clinical practice for the management of locally advanced HNC, over the last decades.

ADDITION OF CHEMOTHERAPY TO LOCOREGIONAL TREATMENTS IMPROVES SURVIVAL For several years, chemotherapy has been administered in neoadjuvant and adjuvant settings, before and after RT, respectively, and more recently,

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concurrently with RT. Meta-analyses of randomized trials have demonstrated that the benefit of combining chemotherapy with RT is related to the timing of the chemotherapy.8,9 The addition of chemotherapy to locoregional treatment for HNC is associated with an absolute survival benefit of 4.5% at 5 years. The benefit is significantly higher for concurrent chemoradiotherapy (CRT), while there is no definitive evidence of a benefit for using induction or adjuvant chemotherapy (see Table 1).8

CRT, A STANDARD OF CARE FOR LOCALLY ADVANCED HNC Several prospective randomized trials have demonstrated that concomitant delivery of chemotherapy and RT is the most promising approach.6–12 The 6.5% absolute 5-year survival benefit (P o.0001) associated with CRT in the MACH-NC is due to a reduction in deaths related to HNC (hazard ratio [HR] 0.78 [95% confidence interval, 0.73–0.84], P o.0001) and there is no effect on non–cancerrelated deaths (HR 0.96 [0.82–1.12], P ¼ .62). The survival benefit of adding concurrent chemotherapy to RT in this meta-analysis appears to be similar, irrespective of whether the RT was delivered using a conventional fractionated schedule or an altered fractionated RT.8 The most effective chemotherapeutic drugs and their combination with RT have yet to be determined. Data regarding the type of drugs to combine concomitantly with RT in MACH-NC meta-analysis have suggested that cisplatin alone, cisplatin or carboplatin associated with 5-fluorouracil (5-FU), or other combination chemotherapy, including either a platinum compound or 5-FU, are associated with a similar survival benefit. In contrast, monochemotherapy with a drug other than cisplatin is associated with inferior treatment outcome and is not recommended in routine practice.8 Single-agent cisplatin is one of the most commonly used standard treatments in combination with RT. The majority of randomized trials of CRT use a dose of cisplatin of 100 mg/m2 every 3 weeks during the course of

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radiotherapy (cumulative dose of 300 mg/m2). Interestingly, the only negative trial of CRT with singleagent cisplatin in this meta-analysis used a cumulative dose of 140 mg/m2 (20 mg/m2, weekly for 7 weeks), suggesting that the cumulative dose of cisplatin may be important.8 However, the side effects related to high-dose cisplatin are significant and include peripheral neuropathy, hearing loss, marked nausea and vomiting, and renal dysfunction. Therefore, some patients are unable to receive a high-dose cisplatin regimen due to their reduced performance status and associated comorbidities. As an alternative to high-dose cisplatin, weekly cisplatin or weekly carboplatin and paclitaxel may be used. The most recently designed trials have moved towards weekly cisplatin 40 mg/m2 in an attempt to reduce the shortand long-term severe toxicity associated with highdose cisplatin (especially the ototoxicity and nephrotoxicity).4 To date no randomized comparisons have been performed between the high-dose cisplatin schedule and weekly lower dose regimens. The MACH-NC also has suggested that there is less benefit of CRT in older patients (470 years age). One of the reasons may be that older patients die more often from causes other than their HNC, which makes it more difficult to observe the benefit of CRT in these patients (“dilution effect”). An additional explanation may be related to an increase in noncancer deaths caused by the exacerbation of the comorbidities by combination of therapies in older patients.4,8

TAXANES, CISPLATIN AND 5-FU INDUCTION CHEMOTHERAPY VERSUS CISPLATIN, 5-FU INDUCTION CHEMOTHERAPY FOLLOWED BY DEFINITIVE RT WITH OR WITHOUT CONCURRENT CHEMOTHERAPY Several prospective randomized trials have demonstrated that CRT is the most effective approach for patients with locally advanced HNC, given that the leading pattern of failure for this group is the locoregional relapse.8,9 The MACH-HN has shown that CRT reduces the rate of loco-regional failure, an

Table 1. Survival Benefits When Chemotherapy Is Added to Locoregional Treatments for HNC: Results From the MACH-NC 2009 Analysis8 Study Design Adjuvant Induction Concurrent Total

No. of Studies

No. of Patients

Hazard Ratio (95% CI)

P Value

6 31 50 87

2,567 5,311 9,615 17,493*

1.06 (90.95–1.18) 0.96 (90.90–1.02) 0.61 (0.78–0.86) 0.88 (0.85–0.92)

.32 .18 o.0001 o.0001

5-Year Absolute OS (⫾ SD) –1.0% 2.4% 6.5% 4.5%

⫾ ⫾ ⫾ ⫾

2.2% 1.4% 1.0% 0.8%

n Because some trials had three arms or a 2-by-2 design; some trial arms were utilized twice. The meta-analysis used 17,493 patients to make 108 comparisons. Abbreviations: CI, confidence interval; OS, overall survival; MACH-NC, Meta-Analysis of Chemotherapy in Head and Neck Cancer.

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effect not observed for induction chemotherapy.8 However, induction chemotherapy provides a relatively more prominent effect on reducing the risk of distant metastases, compared to CRT, which indicates the need to use a relatively high-dose of chemotherapy to influence the incidence of distant metastases.8 Furthermore, taxane-based induction chemotherapy before definitive RT or CRT has been shown to be superior to the classical cisplatin and 5-FU (PF) regimen.13–16 Large phase III randomized trials confirm the significant clinical benefits of adding docetaxel to a cisplatin and 5-FU regimen (TPF) when compared to PF chemotherapy in a neoadjuvant setting, before definitive RT or CRT.13–15 The benefit associated with taxane-based induction chemotherapy in these individual studies appears to be more pronounced than was reported in the MACHHN meta-analysis.8,9,13–19 The TAX 323 clinical trial randomized 358 patients with unresectable, locally advanced HNC to receive four cycles of either cisplatin (100 mg/m2 on day 1) and 5-FU (1,000 mg/m2 per day, by continuous intravenous [IV] infusion on days 1-5) (PF) or cisplatin (75 mg/m2 on day 1), 5-FU (750 mg/ m2 per day, by continuous IV infusion on days 1–5), and docetaxel (75 mg/m2 on day 1) (TPF). Induction chemotherapy was followed by conventionally fractionated RT (once daily RT, 5 days per week, to a total dose of 66–70 Gy) or accelerated RT (one daily dose, 6 days per week, to a total dose 70 Gy) or hyperfractionated RT (twice daily, to a total dose of 74 Gy). All patients in the TPF arm received prophylactic antibiotics. The overall response rate was significantly higher for the TPF arm when compared with the PF induction chemotherapy regimen (72% v 59%, P ¼ .006). The patients in the TPF arm had a significantly longer progression-free survival of 11 months versus 8.2 months in the PF arm (P ¼ .006) and a median survival of 18.8 months in the TPF arm versus 14.5 months in the PF arm (P ¼ .02). However, grade 3 or 4 neutropenia developed in 77% of the patients in the TPF arm versus 53% in the PF induction chemotherapy arm. The rates of grade 3 or 4 nausea (11% v 5%), stomatitis (7% v 1%), vomiting (5% v 1%), hearing loss (3% v 0%), and toxic deaths were higher in the PF arm versus the TPF arm, although it may reflect the lower dose of cisplatin and 5-FU used in the TPF regimen.13 The TAX 324 clinical trial randomized 501 patients with unresectable, locally advanced HNC to receive three cycles of either cisplatin (100 mg/ m2 on day 1) and 5-FU (1,000 mg/m2 per day, by continuous IV infusion on days 1–5) (PF) or cisplatin (100 mg/m2 on day 1), 5-FU (1000 mg/m2 per day by continuous IV infusion on days 1–4), and docetaxel (75 mg/m2 on day 1) (TPF). Induction chemotherapy was followed by conventionally fractionated RT,

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with a total dose of 70–74 Gy delivered concurrently with weekly carboplatin (area under the concentration-time curve of 1.5). All patients in the TPF arm received prophylactic antibiotics. Neck dissection was performed after the end of CRT for initial N2/N3 disease or residual disease. The overall response rate was not statistically significantly higher for the TPF arm when compared with the PF induction chemotherapy regimen (72% v 64%, P ¼ .07). However, patients in the TPF arm had a significantly longer progression-free survival of 36 months versus 13 months in the PF arm (P ¼ .006) and a median survival time of 71 months v 30 months in the PF arm (P ¼ .004). However, grade 3 or 4 neutropenia developed in 83% of the patients in the TPF arm versus 56% in the PF induction chemotherapy arm, but there was not a statistically significantly higher incidence of neutropenic fever (12% v 9%). There was no difference in the number of toxic deaths between the two study arms, possibly because of the use of prophylactic antibiotics as well as granulocute-colony stimulating factor (G-CSF), as needed.14,15 The publication of the results of these two prospective randomized trials led the US Food and Drug Administration (FDA) to approve the use of docetaxel in combination with cisplatin, and fluorouracil (TPF) for induction treatment of patients with loco-regionally advanced HNC.

INDUCTION CHEMOTHERAPY FOLLOWED BY CONCURRENT CHEMORADIOTHERAPY (CRT) VERSUS CRT ALONE Recently, there has been renewed interest in the use of induction chemotherapy in HNC. Better locoregional tumor control and survival associated with concurrent chemoradiotherapy (CRT) have resulted in a shift in the pattern of treatment failure, with a higher incidence of distant relapse compared with loco-regional recurrence, especially in patients with advanced nodal disease at presentation.4 Even though induction chemotherapy has a limited impact on locoregional control, it seems more useful than concurrent chemotherapy in reducing distant disease relapse.8,17 By adding multi-agent induction chemotherapy to CRT, in a treatment paradigm known as sequential CRT, it may be possible to improve upon the result of CRT alone by providing optimal locoregional control and reducing distant disease relapse.18 The question of whether the use of induction taxane–PF chemotherapy prior to CRT additionally improves outcomes for HNC patients has been addressed in recent randomized trials. DeCIDE, a multi-institutional, randomized phase III study, was designed to compare induction TPF followed by CRT to CRT alone. The initial target

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accrual was 400 patients. However, only 122 patients were randomized to the induction chemotherapy arm of the study, while 138 were randomized to CRT alone. The majority of patients in this trial presented with N2 disease and 55% had primary oropharyngeal tumors. The 3-year cumulative incidence of distant failure was 10% for the TPF arm and 19% for the CRT-alone arm (P ¼ .025). The lower cumulative incidence of distant recurrence associated with induction chemotherapy in this study did not translate into a statistically significant improvement in 3-year overall survival, distant-failure free survival, or recurrence-free survival. There was, however, a trend toward improved overall survival with induction chemotherapy in the subset of patients with N2c or N3 disease (P ¼ .19).20 The PARADIGM, another phase III randomized study compared the use of TPF induction chemotherapy followed by CRT with a cisplatin-based CRT regimen alone, in patients with stage III–IVB HNC. In the control arm of this study, accelerated fractionation concomitant boost RT (an accelerated RT protocol in which patients receive 4 weeks of once-daily treatment, followed by 2 weeks of two fractions per day, with the afternoon fraction consisting of the boost) was administered with concurrent high-dose cisplatin. In the experimental treatment arm, three cycles of induction TPF followed by less intensive treatment with conventional fractionation RT (oncedaily RT treatment, 5 days per week) and concurrent weekly carboplatin AUC 1.5 were delivered for patients who achieved a complete pathological response at the primary site and a complete clinical response in the neck; all other patients received accelerated fractionation concomitant boost RT with concurrent weekly docetaxel. The primary study endpoint was 3-year survival. The trial was initially designed to include 300 patients. Unfortunately, only 145 patients were accrued due to early termination of the trial. More patients had febrile neutropenia in the induction chemotherapy followed by CRT arm than in the CRT-alone group. No difference was noted in 3-year overall survival between those patients treated with induction chemotherapy followed by CRT and those who received CRT alone.21 DeCIDE and PARADIGM were well-designed randomized trials with overall survival as the primary study endpoint. Furthermore, DeCIDE included only patients considered at high risk of distant metastases. Both trials terminated early as a result of slow accrual and did not demonstrate a survival advantage with the addition of induction TPF to CRT. The results could have been affected by the reduced sample size of the studies. Interestingly, the 3-year survival rates of more than 70% in the control arms of DeCIDE and PARADIGM trials were substantially higher than anticipated.20,21 This may be related to

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the recent increase in the incidence of human papilloma virus (HPV)-associated HNC, which has a better prognosis following treatment. The patients in these trials were not stratified according to HPV status even though more than half of the patients presented with primary oropharyngeal tumors. Despite the study limitations, results from DeCIDE and PARADIGM trials suggest no survival advantage with the addition of induction chemotherapy to CRT.20,21 The addition of induction chemotherapy to CRT was compared to CRT alone in two additional studies.22,23 An Italian group reported a higher rate of complete response associated with TPF followed by CRT when compared to CRT alone.22 A Spanish group accrued only patients with N2 and N3 disease and compared induction TPF or PF followed by CRT with high-dose cisplatin versus CRT alone.23 This study also was terminated early due to slow accrual and did not show a survival improvement with the addition of induction chemotherapy to CRT, although induction chemotherapy appeared to reduce the cumulative incidence of distant metastases.23 A recent meta-analysis has evaluated the efficacy and toxicity of induction chemotherapy using taxane–PF regimens and has identified differences in outcomes for different subsets of HNC patients.24 Five randomized trials representing 1,772 patients and their individual data were included in the analysis.13,15,16,22,23,25 When compared with induction PF regimens, taxane–PF regimens are associated with significant increases in progression-free survival and decreases in rates of locoregional failure and distant metastases. Taxane–PF induction chemotherapy improves overall survival when compared with PF induction chemotherapy, with an absolute benefit at 5 years of 7.4% (42.4% v 35%, respectively). Taxane–PF induction chemotherapy also improves progression-free survival with an absolute benefit at 5 years of 7.1% (35.5% v 28.4%, respectively). The locoregional failure rates are lower for the taxane–PF induction chemotherapy group than for the PF group (51.6% v 44.2%, respectively), with an absolute decrease of locoregional failures of 7.4% at 5 years favoring the taxane–PF group. Taxane–PF induction chemotherapy is associated with a lower rate of distant failures than PF, with an absolute decrease of distant failures of 6.4% at 5 years (13.7% v 20.1%, respectively).24 Considering that in the MACH-NC meta-analysis, PF induction chemotherapy was not associated with a difference in terms of locoregional control,8 but the induction taxane–PF regimens were associated with reduced locoregional failure rates when compared with PF induction chemotherapy,24 it may be hypothesized that taxane–PF induction chemotherapy followed by concurrent CRT may be superior to concurrent CRT

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alone. These data suggest that concomitant and induction chemotherapies are complementary for HNC treatment. However, the decrease in locoregional failures associated with taxane–PF induction chemotherapy (an absolute decrease of locoregional failures of 7.4% at 5 years)24 is lower than that associated with platinum-based concurrent CRT in the MACH-NC analysis (an absolute decrease of locoregional failures of 13% at 5 years).8 Moreover, there are concerns regarding the routine ability of delivering optimal local treatment thereafter. It is challenging to add high-dose concurrent cisplatin to RT, or even deliver RT without interruption, following induction taxane–PF chemotherapy. Only 73% of the patients analyzed in taxane–PF individual patient data meta-analysis started RT in the taxane–PF group.24 Among the trials, two studies used RT alone,13,25 two used concurrent cisplatin every 3 weeks16,23 and one used concurrent carboplatin.14,15 Only 50% of patients received the concurrent chemotherapy during the RT as planned in taxane–PF individual patient data meta-analysis.25 The latter concern expressed in this meta-analysis24 is comparable with the TREMPLIN larynx preservation study recently published, showing that only 43% of patients received concurrent high-dose cisplatin as planned following induction TPF chemotherapy.26 Intensifying induction chemotherapy may negatively influence the compliance with CRT, which appears to be the most important component of the sequential strategy.8 Clinicians should continue to use their best judgment, based on the available data, in the decision on how to treat patients. Future randomized studies of induction chemotherapy in HNC should probably include only patients considered at high risk of cancer-related death (such as those with HPV-negative tumors, advanced tumor or node stage) who are likely to benefit from treatment escalation with induction chemotherapy followed by CRT.18,19

CRT VERSUS INDUCTION CHEMOTHERAPY FOLLOWED BY DEFINITIVE RADIOTHERAPY OR CHEMORADIOTHERAPY FOR LARYNGEAL AND HYPOPHARYNGEAL ORGAN PRESERVATION Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT has been a successful strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal squamous cell carcinoma.10,11,25,27,28 Until the early 1990s, total laryngectomy followed by conventional RT was considered the standard treatment for locally advanced laryngeal and

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hypopharyngeal squamous cell carcinoma. However, total laryngectomy requiring a permanent stoma has a negative impact on patient quality of life, causing loss of natural voice, social isolation, loss of employment, and depression.25 The major patterns of failure for these patients are locoregional recurrences and distant metastases, which occur in 40%–60% of patients.27,28 Induction chemotherapy using a PF protocol followed by RT in patients who respond to chemotherapy was shown to be a successful strategy for laryngeal preservation in potentially resectable laryngeal and hypopharyngeal squamous cell carcinoma. Two large prospective randomized trials from the Veterans Affairs Laryngeal Cancer Study Group (VALCSG) and the European Organization for Research and Treatment of Cancer (EORTC) compared this treatment with total laryngectomy and postoperative RT in patients with potentially resectable laryngeal and hypopharyngeal squamous cell carcinoma, respectively. Laryngeal preservation rates were 64% (at 2 years) and 42% (at 3 years) for the respective subsites without compromise of disease control or survival rates.27,28 In the VALCSG trial, the estimated 2-year overall survival was 68% in each arm. More local recurrences and fewer distant metastases were reported in the chemotherapy group than in the surgery group.27 In the EORTC trial 10-year update, treatment failures at local and regional sites occurred at the same frequencies in the immediate surgery group (12% and 19%, respectively) and in the induction chemotherapy group (14% and 19%, respectively). The 3-, 5-, and 10-year estimates of functional larynx in patients who were treated in the induction chemotherapy group were 42%, 35%, and 26%, respectively.28,29 The Radiation Therapy Oncology Group (RTOG) 91-11 trial compared three treatments: induction chemotherapy with PF followed by RT, concurrent CRT with high-dose cisplatin, and RT alone.10,11 The study accrued patients with stage III or IV laryngeal cancer (T1 and high-volume T4 primary tumors excluded). No upfront total laryngectomy followed by postoperative RT arm was included into this study design. Three larynx organ preservation approaches were compared. The results of this study were published in 2003 after a median follow-up of 3.8 years and they suggested the superiority of the concomitant CRT regimen in terms of laryngeal preservation and locoregional control. At 2 years, the proportion of patients who had an intact larynx after RT delivered concurrently with high-dose cisplatin (88%) was statistically significantly different when compared with induction chemotherapy (using PF combination) followed by RT (75%, P ¼ .005) or RT alone (70%, P o.001). However, severe toxicity was more frequent with the concurrent schedule, and no differences in overall survival were

Combination of chemotherapy with locoregional treatments

observed.10 An updated analysis of this study was performed after a median follow-up for surviving patients of 10.8 years. The laryngeal preservation rates at 10 years were 67.5% versus 81.7% versus 63.8% in the induction, concomitant, and RT alone arms, respectively; 80% of laryngectomies were performed during the first 2 years of follow-up. The significant advantage of concomitant cisplatin and RT for larynx preservation and improved local control (compared with the induction and RT alone treatment groups) persists. However, for the composite end point of laryngectomy-free survival, there is no difference between the concomitant arm (23.5%) at 10 years versus the induction arm (28.9%) (P ¼ .68). Laryngectomy-free survival is significantly worse for the RT alone group (17.2%) versus both the induction and concomitant groups. Chemotherapy given concomitantly or as induction showed similar benefit for achieving distant control (7% to 8% difference compared with RT alone), but neither comparison reached statistical significance. Overall survival did not differ in any of the treatment comparisons, with 5- and 10-year overall survival estimates of 58% and 39% for induction, 55% and 28% for concomitant, and 54% and 32% for RT alone benefit.11 The finding that induction PF did not add to treatment with RT alone for achieving locoregional control or larynx preservation was consistent with previous trials of induction PF and the updated MACH-NC analysis, which demonstrated no effect of induction PF on local control.8 Finally, the long-term results of Intergroup RTOG 91-11 show that for the composite end point of laryngectomy-free survival, induction and concomitant treatments have similar efficacy. However, locoregional control and larynx preservation were significantly improved with concomitant treatment compared with induction or RT alone.11 Strategies for additional investigation should include the use of a more efficacious induction chemotherapy regimen. The Groupe Oncologie Radiotherapie Tete et Cou (GORTEC) 2000-0112 trial investigated TPF induction chemotherapy compared with PF induction chemotherapy followed by RT for larynx preservation in patients with T3 and selected T4 laryngeal or hypopharyngeal cancer. Patients who responded to chemotherapy received RT with or without additional chemotherapy. Patients who did not respond to chemotherapy underwent total laryngectomy followed by RT with or without additional chemotherapy. The primary endpoint was a 3-year larynx preservation rate. Patients who received an induction TPF regimen achieved a statistically significantly superior 3-year larynx preservation rates (70.3%) when compared with those who received the PF induction regimen (57.5%, P ¼ .03) with an absolute difference of

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12.8% favoring the TPF regimen. The induction TPF regimen showed higher rates of laryngeal preservation, likely due the better response rate associated with TPF (80% v 59% for PF; P ¼ .002). Following the results of this study, induction TPF is considered a standard treatment option by European investigators for laryngeal and hypopharyngeal cancer.25 Unfortunately, the findings were not reported separately for these two biologically different primary sites, larynx versus hypopharynx, so the specific benefit for laryngeal cancer remains uncertain.

POSTOPERATIVE CRT The concomitant use of the systemic chemotherapy and RT in the postoperative setting has been tested in two randomized phase III trials.30,31 Patients with high-risk surgical and pathological features were assigned to RT alone versus RT concurrently with high-dose cisplatin 100 mg/m2 every 3 weeks. High-risk features were represented by the presence of a positive margin, nodal extracapsular spread, lymphovascular invasion, perineural invasion, and multiple positive lymph nodes. CRT significantly reduced the risk of locoregional recurrence, as compared with RT alone, but no benefit in overall survival was noted in the RTOG 9501 study.30 The progression-free survival and overall survival were significantly longer in patients receiving CRT in the EORTC 22931 study.31 Both trials reported a significant increase in severe acute treatment-related toxicity in the CRT group, including mucositis, hematologic toxicity, and muscular fibrosis. A pooled analysis of data from both trials showed that two risk factors were associated with a significant benefit from concurrent CRT: extracapsular extension and positive surgical margins.32

TARGETED THERAPY IN THE TREATMENT OF LOCALLY ADVANCED HNC A recent innovation for the treatment of HNC has been the development of the monoclonal antibody cetuximab, which targets the epidermal growth factor receptor. A recent randomized phase III trial has demonstrated that cetuximab in combination with RT improves locoregional control and overall survival in patients with locally advanced HNC. Four hundred twenty-four patients were randomized to receive RT alone versus cetuximab plus RT. Cetuximab was initiated 1 week before RT, with a loading dose of 400 mg/m2, followed by 250 mg/m2 weekly throughout RT. The study demonstrated that locoregional control, and progression-free and overall survival rates were significantly improved with the combination of RT and cetuximab. Treatment with

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other or could improve the outcome. There were fewer local treatment failures in CRT arm than in RT plus cetuximab arm. Overall toxicity of both CRT and RT plus cetuximab arms was substantial following induction chemotherapy. However, treatment compliance was higher in the RT plus cetuximab arm.26 A direct comparison of cetuximab plus RT and cisplatin plus RT is only now being undertaken in patients with HPV–related cancers of the oropharynx (RTOG 1016 trial).

FUTURE DIRECTIONS Figure 1. HPV-related tonsillar squamous cell carcinoma. This is a poorly differentiated carcinoma, non-keratinizing, with basaloid and focally spindle cell morphology (hematoxylin and eosin [ H&E],. 20x magnification).

the combination regimen decreased the risk of locoregional progression by 32% and the risk of death by 26%. However, the rates of distant metastases were similar in the two study groups. In an unplanned analysis, the survival benefit was increased in patients with primary oropharyngeal tumors (tonsil and tongue base) and in those receiving a concomitant boost RT schedule (an accelerated RT protocol in which patients receive 4 weeks of once-daily treatment, followed by 2 weeks of two fractions per day, with the afternoon fraction consisting of the boost). The concomitant boost radiotherapy was the most common schedule used in this study (56%). The addition of cetuximab to RT was associated with similar rates of grade 3 or 4 toxic effects in the two study groups, with the exception of the incidence of acneiform rash and infusion reactions, which were significantly higher in the combination cetuximab plus RT group than in the group receiving RT alone.33 The interpretation of the results of the cetuximab plus RT trial is relatively complicated, since chemotherapy was not part of the study, making it difficult to assess whether the combination of cetuximab and RT is as effective as CRT. Moreover, subset analyses suggested that the benefit of cetuximab was limited to patients with oropharyngeal cancer. The RTOG has evaluated RT plus cisplatin with or without cetuximab and has found no improvement in any outcome with the addition of cetuximab for patients with locally advanced HNC treated with definitive CRT.34 A recent phase II randomized trials compared RT plus high-dose cisplatin versus RT plus cetuximab following three cycles of induction TPF in stage III–IV laryngeal and hypopharyngeal cancer. There is no evidence that one treatment was superior to the

Recent advances in our understanding of the epidemiology, etiology, and subsequent changes in prognosis and survival of patients with HNC have been striking. Two separate pathways may be involved in the development of oropharyngeal cancer, one mostly driven by tobacco and alcohol and the other by HPV-induced genomic instability.35,36 Molecular evidence suggests that HPV, particularly HPV-16, plays a significant role in the pathogenesis of oropharyngeal squamous cell carcinoma; HPV viral oncogenes E6 and E7 are frequently overexpressed in oropharyngeal cancer.5,37 A case control study describes how oropharyngeal cancer is significantly associated with oral HPV-16 infection. HPV DNA was detected in 72% oropharyngeal tumor specimens and 64% of the patients were seropositive for HPV-16 E6, HPV-16 E7, or both.5 Patients with HPV-positive tumors appear to have peculiar histological features (see Figure 1) and unique gene expression profile with minimal molecular and cytogenetic alterations (see Figures 2 and 3) and a more favorable outcome after therapy.38 Patients with oropharyngeal cancer related to HPV infection have

Figure 2. HPV-related tonsillar squamous cell carcinoma. In situ hybridization for high-risk HPV subtypes showing positive staining in the tumor cells (10x magnification).

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REFERENCES

Figure 3. HPV-related tonsillar squamous cell carcinoma. Invasive non-keratinizing squamous cell carcinoma, p16 immunohistochemistry stain (10x magnification).

a favorable prognosis and have high survival rates in the 70%–90% range.38 Furthermore, HPV-related oropharyngeal cancer affects younger patients who generally are very healthy and may have a better tolerance to therapy. These patients are typically non-smokers and often have primary disease in the tonsils or base of tongue. In contrast, patients diagnosed with HPV-negative tumors, which show several molecular and cytogenetic changes (p53 mutations, loss of p16INK4a, p15INK4b, cyclin D1 overexpression, or an increase copy number of EGFR and chromosome 7) appear to have less favorable outcomes.35,36,39 The HPV status was not obtained in most of the studies discussed in this review and the smoking status was not uniformly recorded. It is reasonable to assume that many of the patients with oropharyngeal cancer enrolled in some of these trials have HPVrelated oropharyngeal cancer and thus are likely to do very well with any treatment. Several newly designed studies targeting this population will focus on de-escalating the intensity of the current treatment, by reducing the total dose of RT, limiting the irradiated volumes or by replacing the standard chemotherapy with less toxic agents.

CONCLUSIONS Concurrent CRT is used as a standard treatment in the definitive and postoperative setting for locally advanced HNC. Historical data do not account for the rising incidence of HPV related cancers and their improved prognosis. This represents a subset of HNC patients that may benefit from de-escalated therapy.

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