The use of systemic therapy as part of curative treatment and palliation is an evolving paradigm for squamous cell cancer of the head and neck (SCCHN), which historically has been treated with local modalities. At present, the treatment armamentarium includes traditional cytotoxic therapy, targeted biological agents, and emerging immunotherapeutics. This article discusses the use of all of these systemic approaches for the curative and palliative treatment of SCCHN.
Key points
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The use of systemic therapy for squamous cell cancer of the head and neck (SCCHN) has evolved, and cytotoxic therapy is now an integral component of the combined-modality treatment of locally advanced disease.
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An increasing understanding of the molecular basis of SCCHN has led to the development of agents targeting epidermal growth factor receptor, such as cetuximab and afatinib.
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Further advances are required for the treatment human papillomavirus–negative disease, which often is associated with a poor prognosis.
Systemic therapy for localized disease
Definitive Chemotherapy with Radiation
Meta-analyses evaluating the efficacy of multimodality approaches to the treatment of squamous cell cancer of the head and neck (SCCHN) have consistently supported concurrent chemoradiation (CCRT), reporting an improved overall survival (OS) of 8% to 11% in both surgically resectable and unresectable patients. However, higher locoregional dose density delivered with CCRT results, predictably, in a higher degree of regional toxicity, including severe mucositis with associated pain and diminished nutritional intake. Despite the demonstrated regional control and survival benefits, analysis of failure patterns has not demonstrated consistent decline in distant metastasis with CCRT in comparison with radiotherapy alone. Similarly, studies of induction chemotherapy, followed by chemoradiation, have failed to improve survival or decrease the risk of distant metastases.
Thus, for locally advanced cancers of the head and neck, definitive CCRT is the current treatment standard.
Long-term results of a trial evaluating the contribution of platinum-based chemotherapy added to radiotherapy demonstrated a significant improvement in locoregional control (LRC) and larynx preservation compared with either induction chemotherapy or radiation therapy alone. Locoregional failure has traditionally been the predominant manner of recurrence; nearly 90% of patients who present with distant metastasis also harbor concurrent locoregional cancer. CCRT has become an essential component of the treatment paradigm in patients with potentially curable disease. Disease-free survival (DFS) was demonstrated in the Radiation Therapy Oncology Group (RTOG) 91-11 study to be significantly prolonged in patients who received CCRT compared with radiotherapy alone (5-year OS and DFS were 22% and 27% vs 16% and 15%, respectively). There were disconcerting late deaths after CCRT that were not readily explained by tumor or treatment toxicity.
Single-Agent Platinum-Based Therapy
For patients in whom the primary site of malignancy is truly unresectable, OS after standard single-modality local radiotherapy was measured at less than 25%. A phase III randomized trial conducted by the Head and Neck Intergroup from 1982 to 1987 compared radiotherapy alone to CCRT with weekly cisplatin at 20 mg/m 2 . The median survival of 13 months did not differ significantly between the two treatment arms, and the CCRT regimen was not adopted. This study was followed in 1987 by an RTOG phase II trial evaluating the efficacy of concurrent radiation and high-dose cisplatin, using a dose of 100 mg/m 2 given every 21 days. This schedule yielded a complete response (CR) in 71% of patients, with a 4-year survival of 34%. The results suggested dose dependency of the observed improvement in response and survival, and the study was followed in 1992 by a second-generation trial by the Head and Neck Intergroup.
This phase III Intergroup trial compared radiotherapy alone with 2 different schedules of chemoradiotherapy in patients with locally unresectable disease. The first regimen used concurrent high-dose cisplatin and radiation (the RTOG regimen, 100 mg/m 2 on days 1, 22, and 43), and the second involved a split course of single-daily fractionated radiation and 3 cycles of concurrent infusional 5-fluorouracil (5-FU) plus bolus cisplatin (cisplatin at 75 mg/m 2 given every 4 weeks). With a median follow-up of 41 months, the 3-year projected OS for patients receiving high-dose cisplatin-based chemoradiation was 37% compared with 23% for those in the arm receiving radiotherapy alone ( P = .014). The addition of concurrent single-agent cisplatin at 100 mg/m 2 significantly improved survival over radiotherapy alone. Toxicities of grade 3 or greater occurred in 89% of patients receiving high-dose cisplatin, predominantly mucositis with dysphagia (43 of 95 patients), leukopenia (40 of 95 patients), and to a lesser extent nausea with vomiting.
Patients receiving high-dose cisplatin are at risk of auditory toxicity, for which they may be monitored with serial comprehensive hearing tests during the course of therapy. This approach is warranted for such symptoms as diminished auditory acuity or tinnitus. Patients receiving CCRT with cisplatin also require regular assessment and repletion of volume status, particularly during high-dose therapy, to minimize renal complications from potential insults, including direct cisplatin-induced nephrotoxicity and prerenal insufficiency secondary to diminished oral fluid and nutritional intake. Patients typically receive liberal amounts of intravenous fluid immediately surrounding each cisplatin administration (approximately 2.5 L), and frequently require additional intravenous hydration during the course of each 21-day cycle. Many continue to benefit from intravenous hydration for several weeks after formal completion of the course of therapy.
For patients unable to tolerate high-dose cisplatin at baseline, or for those who require a dose alteration during the course of definitive CCRT, an acceptable consideration is transition to a weekly cisplatin dosing schedule using either 30 mg/m 2 or 40 mg/m 2 (category 2B as per National Comprehensive Cancer Network guidelines). This regimen has been shown to achieve a high rate of LRC and survival (demonstrated 2-year OS of 67% with a median relapse-free survival time of 31 months). However, no randomized phase III trials compare high dosing with weekly dosing in the definitive locally advanced setting.
Agents Targeting Epidermal Growth Factor Receptor Combined with Radiation
The epidermal growth factor receptor (EGFR) is expressed at very high levels in most SCCHN. EGFR is activated by several ligands including the epidermal growth factor (EGF), or transforming growth factor α, resulting in a signal transduction cascade leading to tumorigenic activity such as resistance to apoptosis and transcription of proangiogenic proteins. The RTOG 90-03 trial demonstrated that high EGFR expression measured by immunohistochemistry was associated with a higher risk of both locoregional recurrence and death in comparison with tumors with EGFR expression below the median. Preclinical data show synergy between EGFR inhibition and radiation, prompting further study of this class of agents.
Cetuximab
Cetuximab is an immunoglobulin G1 (IgG1) EGFR-targeting monoclonal antibody which, like cisplatin, has been demonstrated to improve both LRC and survival when added to definitive radiation therapy in the treatment of patients with locally advanced head and neck cancer. When cetuximab was initially investigated, CCRT had not yet been established as the standard of care, so EGFR-targeted therapy was initially compared with radiotherapy alone rather than with cisplatin-based CCRT. A phase III randomized clinical trial conducted by Bonner and colleagues randomized patients to either radiotherapy alone or radiotherapy plus cetuximab (400 mg/m 2 loading dose followed by 7 weekly doses at 250 mg/m 2 ). The primary end point was local tumor control, and OS was included within the secondary end points. The updated median OS at long-term follow-up in 2009 was reported as 49.0 months (95% confidence interval [CI] 32.8–69.5) in the combined-modality arm, compared with 29.3 months (95% CI 20.6–41.4) for those receiving radiotherapy alone. This result appears to represent a significant improvement over historical data. Development of the common cetuximab-associated acneiform rash of grade 2 or greater severity was associated with a significant improvement in OS compared with those who developed either no rash or a grade 1 rash (hazard ratio [HR] 0.49, 95% CI 0.34–0.72; P = 002), suggesting that this toxicity may serve as an early indicator of outcome. However, in the absence of level 1 evidence from a phase III noninferiority trial demonstrating equivalence, cisplatin remains the agent of choice for fit patients receiving chemoradiation for locally advanced SCCHN.
Cetuximab constitutes a form of targeted therapy using a mechanism markedly different from that of traditional cytotoxic therapy, so it was hypothesized that its combination with platinum-based CCRT might act synergistically to improve survival in the locally advanced setting. This question was addressed in RTOG-0522, a phase III clinical trial that compared results of cisplatin-based CCRT with or without cetuximab. Published in 2014, results failed to meet either the primary end point of improved progression-free survival (PFS) or the secondary end points of prolonged OS, improved LRC, and decreased incidence of distant metastasis. Furthermore, patients receiving the added cetuximab had a greater number of high-grade toxicities, primarily an increase in grade 3 to 4 acneiform rash and radiation dermatitis. Thus there would seem to be no benefit from cetuximab and platinum-based therapy with radiation in the curative setting.
Panitumumab
Additional EGFR inhibitors investigated in the locally advanced setting include panitumumab, which differs from cetuximab in that it is fully humanized and is based on an IgG2 isotype (potentially affecting its mechanism of action). A phase II randomized trial of CCRT with or without panitumumab in patients with stage III, IVA, or IVB disease (CONCERT-1) reported disappointing results in 2012. The 2-year LRC rate (95% CI) was found to be 61% (50%–71%) for CCRT plus panitumumab, versus 68% (54%–78%) for CCRT alone. PFS events occurred in 40% of the panitumumab group and 35% of the standard CCRT arm, whereas death occurred in 36% of the patients in the experimental arm compared with 24% in the control arm. Like RTOG-0522, this was considered a negative study. The addition of panitumumab demonstrated no increase in efficacy compared with standard platinum-based CCRT alone. Toxicities worsened along with the addition of this EGFR-inhibitor in a manner similar to those noted with the addition of cetuximab: grade 3 or higher adverse events (AEs) occurred in 85% of patients in the experimental arm versus 68% in the control arm, primarily mucosal inflammation (55% vs 24%), radiation skin toxicity (28% vs 13%), dysphagia (40% vs 27%), and acneiform rash (11% vs 0%).
As already noted, no formal completed phase III study compares cisplatin-based CCRT with radiotherapy plus EGFR-inhibitor therapy for locally advanced disease. RTOG 10-16 has pursued this question with cetuximab, and a phase II randomized trial (CONCERT-II) has recently been conducted comparing panitumumab plus radiotherapy with standard high-dose platinum-based CCRT. LRC was the primary end point, with results revealing a 2-year LRC rate of 61% among patients assigned to standard CCRT compared with 51% among patients assigned to panitumumab plus radiotherapy. Secondary end points included OS, which also favored the CCRT group (HR 1.59, 95% CI 0.91–2.79). AEs of grade 3 or higher were again notable for greater skin toxicity in the experimental arm, with such AEs affecting 85% of the panitumumab arm versus a slightly lower 81% of the standard CCRT arm. The patients receiving cisplatin-based therapy experienced more neutropenia and febrile neutropenia, whereas grade 3 or higher neutropenia was absent in the panitumumab arm. The study revealed a significant worsening of outcome for those patients receiving panitumumab in lieu of standard platinum-based CCRT.
Lapatinib
Lapatinib is an oral agent that targets multiple transmembrane receptors within the EGFR family, and has been investigated as a potential agent in the treatment of head and neck cancers. It is a selective and potent inhibitor of the tyrosine kinase domains of HER2 and EGFR, with preclinical data demonstrating the potential inhibition of HER2 in SCCHN cell lines and within xenograft mouse models. In addition, breast cancer cell lines treated with lapatinib have decreased levels of phosphorylated Akt and ERK1/2, with termination of proliferative signals, consequent growth arrest, and apoptosis.
Two phase II studies demonstrated modest clinical activity of single-agent lapatinib, one in the recurrent/metastatic setting and the other as induction therapy before definitive chemoradiation. A phase II study of definitive chemoradiotherapy with or without oral lapatinib (1500 mg daily) in patients with stage III to IVB squamous cell carcinoma of the head and neck, followed by maintenance lapatinib or placebo, suggested a statistically significant investigator-assessed improvement in complete response rate (CRR) in the lapatinib arm compared with placebo (50% vs 24%, P = .009). With independent assessment, however, the improvement in CRR did not achieve statistical significance (53% vs 36%, P = .093). Other reported outcomes included improved PFS with addition of lapatinib to 35.3 months (compared with 12.1 months in the control arm; HR 0.74, P = .184) and an HR for OS of 0.9 ( P = .382). Although the latter measures did not meet statistical significance, the HPV-negative population experienced an improved PFS in favor of the addition of lapatinib (median PFS = not reached vs 10.3 months). Recent and currently ongoing trials include a phase II study (RTOG 3501: TRYHARD trial) combining lapatinib with platinum-based CCRT in patients with human papillomavirus (HPV)-negative (HPV(−)) disease, and a phase II study combining lapatinib with carboplatin and paclitaxel in the induction setting before surgery followed by risk-guided adjuvant therapy.
Combination Cytotoxic Therapy
Multiagent systemic regimens as a component of definitive CCRT in the locally advanced and unresectable setting have been studied, reporting excellent outcomes. Although cisplatin remains the current standard of care, phase III trials in favor of the concurrent chemoradiotherapy approach have been conducted with multiagent regimens. The phase III Intergroup trial compared standard radiotherapy and 2 different schedules of CCRT in patients with unresectable disease. The results of this study favored the single-agent cisplatin arm (versus cisplatin and infusion of 5-FU), although the radiation therapy schedule deviated significantly from the standard at that time.
An additional phase III randomized trial of 2 cisplatin-based CCRT regimens for locally advanced disease (cisplatin vs cisplatin plus 5-FU) concluded that the outcomes were similar (primary end point of recurrence-free survival at 2 years was 94% in the cisplatin arm versus 88% in the in the cisplatin/5-FU arm; P = .86). The toxicity profile differed considerably between the two arms, suggesting that the choice of regimen may hinge on this difference.
Carboplatin/5-fluorouracil
Citing the overall poor results of radiotherapy alone for locally advanced oropharyngeal carcinomas, the French Head and Neck Oncology and Radiotherapy Group (GORTEC) initiated in 1994 a phase III randomized clinical trial evaluating the benefit of CCRT with a combination of carboplatin and 5-FU compared with radiotherapy alone. The 5-year results were reported in 2004. OS was 22% in the multiagent CCRT arm compared with 16% in the radiotherapy arm ( P = .05). DFS was also improved in the CCRT arm (27% vs 15%; P = .01), as was the rate of LRC (48% vs 25%; P = .002). Late grade III or IV toxicities were not increased in the CCRT arm when compared with the arm receiving radiotherapy alone (56% vs 30%; P not significant), although there was a trend toward increased toxicity.
Hemoglobin (Hgb) level in patients before treatment was found to be one of the most important factors for shortened survival, with an Hgb level of less than 12.5 g/dL associated with a 92% rate of death within 2 years (OR 10.36, 95% CI 3.07–34.97; P <.0001). This factor was found to be more prognostic than either the presence of stage IV disease (vs stage III) or randomization to the radiotherapy arm. Based on the hypothesis that correction of anemia would decrease tumor hypoxia and thus enhance response to therapy, a review of 5 randomized controlled trials (1397 patients) was undertaken, which concluded that the addition of erythropoietin to CCRT actually results in an adverse effect on outcomes.
Platinum plus paclitaxel
To further explore the role of multiagent CCRT in the locally advanced setting, the RTOG conducted a 3-arm randomized phase II trial (RTOG 97-03) comparing outcomes with 3 doublet regimens in combination with radiotherapy. Eligible patients had stage III or IV squamous cell carcinoma (SCC) of the oral cavity, oropharynx, or hypopharynx, and received either weekly cisplatin (20 mg/m 2 ) plus paclitaxel (30 mg/m 2 ), cisplatin (10 mg/m 2 ) plus fluorouracil (400 mg/m 2 continuous infusion for the final 10 days of treatment), or hydroxyurea (1 g every 12 hours) plus fluorouracil (800 mg/m 2 /d infusion with each fraction of radiation).
The investigators reported an estimated 2-year DFS of 51.3% and OS of 66.6% for the arm receiving CCRT with weekly cisplatin plus paclitaxel. The number of patients in this arm who completed the scheduled radiotherapy was 83%, and 66% received both drugs for the entire prescribed course. The CR rate in the platinum-taxane arm was 82%, with only 27.5% (95% CI 17.4–37.6) of patients experiencing locoregional failure at 2 years (compared with 41.1% and 40.8% in the other 2 arms, respectively). Analysis of first-failure patterns revealed a lower percentage of patients with persistent local disease in the platinum-taxane arm, and a decreased number of patients with regional nodal relapse. The incidence of grade 3 or greater toxicity in this arm was measured at 87%, which proved very similar to the 89% reported by the Head and Neck Intergroup with high-dose single-agent cisplatin-based CCRT. Overall, all 3 approaches with multiagent CCRT were feasible.
5-Fluorouracil plus hydroxyurea
As one of the regimens used in RTOG 97-03, patients received a single 5-FU dose of 800 mg/m 2 with each fraction of radiotherapy rather than a prolonged infusion. In contrast to standard continuous daily treatment, this was an every-other-week regimen. Hydroxyurea was administered at 1 g twice per day throughout the course of treatment. The 2-year OS for this group was estimated at 69% (range 59.0%–79.8%), which was slightly higher than that for the platinum-taxane arm, and 2-year DFS was estimated at 49%, which was comparatively slightly lower. Although these outcomes were similar (including estimated survival), the rate of estimated locoregional failure was reported to be 41% (95% CI 29.6–51.9), which compared unfavorably with the 28% reported in the platinum-taxane group. Hematologic toxicity of grade 3 or higher in the 5-FU plus hydroxyurea group was reported in 44% of patients. In view of the similar rates of OS and DFS when compared with platinum-based therapy, this is an acceptable and recommended CCRT regimen along with cisplatin-paclitaxel and carboplatin–5-FU for the definitive treatment of locally advanced SCCHN. Additional trials have investigated the backbone of 5-FU, hydroxyurea, and hyperfractionated radiation with taxanes, cetuximab, and bevacizumab. These combinations are active, but at the expense of elevated acute toxicity.
Considerations for the Definitive Treatment of Locally Advanced Human Papillomavirus–Positive Disease
Patients with human papillomavirus–positive (HPV(+))-associated SCCHN have different patterns of disease progression, and a better prognosis. Investigators from the Eastern Cooperative Oncology Group (ECOG) conducted a planned analysis of a prospective trial of induction chemotherapy followed by chemoradiation to determine the impact of HPV status on prognosis. This study was one of the first to establish the superior prognosis of HPV(+) patients, with a 2-year survival of 95% ( P = .005). An additional retrospective analysis published in 2010 explored the association between tumor HPV status and survival among stage III or IV patients with oropharyngeal cancer treated with cisplatin-based CCRT, and found tumor HPV status to be a strong and independent prognostic factor for survival. After adjustment for age, tumor and nodal stage, race, tobacco exposure, and treatment randomization, there was a 58% reduction in the risk of death over a 3-year period (HR 0.42, 95% CI 0.27–0.66).
HPV(+) patients typically present with oropharyngeal malignancy at a younger age than those who are HPV(−), making the long-term toxicities of definitive therapy for those with potentially cured disease of even greater importance than for patients whose cancer is caused by substance abuse. As HPV(+) disease now represents at least 60% of new diagnoses of squamous cell oropharyngeal cancers, amelioration of toxicity has received considerable attention.
One area of recent investigation has aimed to determine whether the standard dose of radiotherapy during CCRT may be safely lowered in HPV-associated disease without adverse outcomes. ECOG 1308 was a phase II trial evaluating reduced-dose intensity-modulated radiation therapy (IMRT) in HPV-associated resectable oropharyngeal SCCs among patients who derived a clinical complete response (cCR) to platinum-based induction chemotherapy. The investigators hypothesized that reduced-dose IMRT given at 54 Gy (representing a 23% reduction to the standard dose) with ongoing weekly cetuximab could maintain a high rate of LRC and a 2-year PFS of at least 85% in patients with stage III, IVa, or IVb HPV(+) disease who had achieved a cCR to induction chemotherapy with paclitaxel (90 mg/m 2 on days 1, 15, 18), cisplatin (75 mg/m 2 on day 1), and cetuximab. At a median follow-up of 23 months, lower-dose radiotherapy had achieved a PFS of 84% and a 2-year survival rate of 95%. In patients with a less than 10-year smoking history and T1-3 N0-2b disease, the PFS was 96%. Patients with lower PFS and OS included those with greater than 10-pack-year smoking history, T4 stage, and advanced N2c nodal stage. Late toxicities with this approach were reported as minimal. These results demonstrated that reduced-dose IMRT in patients with chemoresponsive disease can produce very high tumor control rates, although this does not represent a current standard of care. Phase III comparative studies are warranted.
Although EGFR expression is not predictive of sensitivity to EGFR inhibition, the lower EGFR expression noted in p16-positive tumors has raised questions regarding the activity of cetuximab in HPV(+) disease. RTOG 1016, a phase III trial of radiotherapy plus cetuximab versus cisplatin and radiotherapy in HPV(+) oropharynx cancer, has completed accrual and should demonstrate how the HPV(+) population responds to cetuximab and radiation. If substitution of EGFR-directed therapy for cisplatin affords comparable DFS and OS (with lower toxicity), there will be a strong argument for its use.
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