Andrew J. Johnsrud and Konstantinos Arnaoutakis Abstract
Systemic therapy in head and neck cancer has been an evolving field over the last several years. Its utility in the locally advanced setting as an induction treatment, as an integral part of combined modality therapy, and in the adjuvant setting is well documented. Systemic therapy in the more advanced setting has also been studied and evolved to introduce more novel approaches such as monoclonal antibodies against the epidermal growth factor receptor and immunotherapy, particularly checkpoint inhibitors such as PD-1 inhibitors. In this chapter, we review the current treatment options utilizing systemic therapy, as well as future directions including the utilization of targeted agents and immune therapy.
Keywords: systemic therapies, chemotherapy, head and neck cancer
26.1 Introduction
The role of systemic treatment (i.e., chemotherapy) in the management of head and neck squamous cell carcinoma (HNSCC) has been an evolving topic over the past few decades. Though historically its use has been limited to palliative settings, chemotherapy is now established as an essential component of multimodal treatment in the setting of both early and locally advanced disease. Its utility in this setting is most recognized as a radiosen- sitizing component given concurrently with radiotherapy.
Several agents have demonstrated activity against HNSCC, including platinum compounds (cisplatin, carboplatin), taxanes (docetaxel, paclitaxel), and antimetabolites (5-fluorouracil [5-FU], methotrexate). Cisplatin, a potent radiosensitizer, is established as a standard agent in combination with radiation or coupled with other chemotherapeutic agents. It remains a preferred option over other platinum agents such as carboplatin, which has demonstrated improved tolerability at the expense of less activity in HNSCC. In 2009, a large meta-analysis was updated including 87 trials and more than 17,000 patients, evaluating the benefit of chemotherapy in HNSCC given as concurrent chemora- diotherapy (CRT), induction chemotherapy (ICT), or adjuvant treatment. The included trials compared locoregional treatment plus chemotherapy versus locoregional treatment alone. The total observed benefit from chemotherapy was an absolute 4.5% higher 5-year survival, confirming the benefits of chemotherapy in locally advanced HNSCC. A more pronounced absolute benefit of 6.5% was observed in trials of concurrent CRT, whereas there was no clear survival benefit seen for ICT or adjuvant chemotherapy.1
The current treatment options utilizing systemic therapy will be reviewed here, as well as future directions including the utilization of targeted agents and immune therapy.
26.2 Induction Chemotherapy
The rationale behind the use of ICT prior to definitive therapy includes several considerations. One aim is to improve locoregional control, though in theory the additive systemic therapy may obviate the progression of metastatic disease and prevent distant relapses. It is indeed estimated that at least 50% of patients treated for locally advanced HNSCC will develop locoregional or distant relapse within 2 years of treatment despite receiving adequate local control with surgery and/or radiotherapy.2 It is also pertinent to consider that increased tumor volume and hypoxic tumor volume may have a deleterious effect on local therapies, particularly radiotherapy, considering its dependence on oxygen-derived free radicals. This is supported by several studies of laryngeal cancer, which have demonstrated an inverse relationship between tumor size and local control with radiotherapy.3,4,5 As such, in cases with relatively large tumor burden, ICT can be expected to reduce tumor volume and afford more adequate responses to locoregional therapy by enhancing radiosensitivity or resectability. Others have adopted the use of ICT as a basis for organ preservation, by inducing better responses to locoregional control with nonsurgical methods. By the same token, inadequate responses may permit salvage surgery to occur in a non- irradiated tissue environment and prevent complications such as fistula formation or poor wound healing.
As mentioned previously, several agents have demonstrated activity against HNSCC. Platinum-based regimens have generally shown the most anticancer activity and continue to be the most commonly used agents in the first-line setting. Many of the initial investigations in the 1980s and 1990s evaluating ICT followed by locoregional therapy could show a decrease in the rate of distant metastases, but were unable to consistently demonstrate a survival benefit. Cisplatin plus 5-FU became a standard regimen for ICT based on the observed high response rates and its ability to eliminate the need for surgical resection in some trials, though only a limited number of these were able to show a benefit in overall survival (OS).6.7.8 Though the previously described meta-analysis of chemotherapy in head and neck cancer (MACH-NC) revealed only a modest and statistically insignificant OS benefit from ICT (2.4%; p = 0.18), it should be considered that these trials included a heterogeneous collection of chemotherapy regimens, and when limited to those utilizing platinum and 5-FU, a statistically significant hazard ratio (HR) of 0.90 was obtained.1 Importantly, the analysis also demonstrated a meaningful reduction in the rate of distant metastasis, with an absolute difference of 4.3% (HR, 0.73; 95% confidence interval [CI], 0.61-0.88) at 5 years. Improvement in this parameter provided critical support for the idea that ICT can improve distant control, and implied a clear benefit for its addition to lo- coregional treatment. Though controversial and not universally accepted, these findings have continued to justify the investigation of ICT in HNSCC.
In the 1990s, taxane therapy (docetaxel or paclitaxel) began to garner immense interest as a new drug in the treatment for HNSCC. This was spurred in large part by a phase II trial which enrolled patients with recurrent, metastatic, or locally advanced incurable HNSCC to receive paclitaxel, noting an impressive response rate of 40%.9 The early success of taxane therapy inspired efforts to investigate its role in the setting of ICT. Ultimately, a benefit from the addition of a taxane to PF (cisplatin, 5-FU) regimens was demonstrated in three landmark phase III studies. The TAX323 study compared TPF (docetaxel, cisplatin, 5-FU) with PF as ICT in patients with locoregionally advanced, unresectable disease. In this study, 358 patients were randomized to receive TPF or PF followed by concurrent chemoradiation. At a median follow-up of 32.5 months, median progression-free survival PFS was 11.0 months in the TPF group compared to 8.2 months in the PF group (HR, 0.72; p = 0.007). Median survival was 18.8 months in TPF compared to 14.5 months with PF (p = 0.02).10 In the TAX324 study, 501 patients with locoregionally advanced disease were randomized to receive either PF or TPF. The TPF group achieved better locoregional control than in the PF group (p = 0.04). Median OS in the TPF group was 71 months, compared to 30 months in the PF group (p = 0.006). No significant difference was seen in the rate of distant metastases.11 Lastly, the GORTEC group for organ preservation randomized 213 patients with larynx and hypo- pharynx cancer requiring total laryngectomy, to receive three cycles of TPF or PF. Those who responded to chemotherapy received radiotherapy with or without additional chemotherapy, and those who did not respond to chemotherapy underwent total laryngectomy followed by radiotherapy with or without additional chemotherapy. The 3-year larynx preservation rate was 70.3% with TPF compared to 57.5% with PF (p = 0.03), showing a superior response rate and higher likelihood of larynx preservation with the TPF regimen.12 Together, these trials created a new standard for ICT by demonstrating that the inclusion of a taxane (TPF) was superior to the previously established PF regimen. A subsequent meta-analysis including 1,772 patients comparing PF with TPF supported this notion, showing an absolute survival benefit at 5 years of 7.4% (HR, 0.79; 95% CI, 0.70-0.89; p<0.001), as well as a significant reduction in progression, locoregional failure, and distant failure with the use of TPH compared to its PF counterpart as ICT.13 These findings came with an important criticism that they were comparing two experimental arms, as ICT was not established as a standard treatment. Moreover, questions remained based on the aforementioned MACH-NC metaanalysis, which failed to demonstrate a meaningful survival benefit from the use of ICT. It is worth noting, however, that these trials did not include TPF regimens.
Despite these criticisms, the enthusiasm for ICT and the success of these trials ultimately provided the basis for its measurement against concurrent CRT alone as definitive therapy for HNSCC. In a phase III trial conducted by Hitt et al, patients with locally advanced HNSCC were assigned to ICT with either docetaxel, cisplatin, and 5-FU (TPF) or cisplatin and 5-FU (PF) followed by concurrent chemoradiation (cisplatin + RT) or chemoradiation alone. The results showed a median PFS of 14.6, 14.3, and 13.8 months in the TPF + CRT, PF + CRT, and CRT groups, respectively (95% CI, 11-17.5; p = 0.56).14 They were unable to demonstrate statistically significant differences in time to treatment failure or in OS. In the PARADIGM trial, a phase III study, 145 patients with untreated, nonmetastatic head and neck cancer were randomized to receive ICT with TPF followed by concurrent CRT (weekly carboplatin + RT) or concurrent CRT alone (with standard two doses of cisplatin + RT). Three-year OS was 73% in the ICT+CRT group and 78% in the CRT alone group (HR, 1.09; 95% CI, 0.59-2.03; p = 0.77).15 The DeCIDE trial was a phase II trial comparing ICT with TPF versus CRT in patients with locally advanced HNSCC and high nodal stage disease (N2 or N3). At 3 years, no significant difference in OS was found, noting 72% in the induction arm and 69% in CRT arm (p = 0.69). There was a difference in rate of distant failure at 3 years with ICT (10 vs. 19%) but this difference was not statistically significant (p = 0.11).16 A meta-analysis in 2014 evaluating ICT followed by CRT concluded that ICT with TPF before CRT does not improve OS (HR, 1.008; 95% CI, 0.816-1.246; p = 0.94) and suggested only a mild, insignificant benefit in PFS (HR, 0.881; 95% CI, 0.723-1.073; p = 0.207).17 Of note, the slow rate of accrual in both studies led to premature termination after far less of the expected patients were enrolled (285 of expected 400 in PARADIGM, and 145 of expected 300 in DeCIDE). Therefore, though no difference in survival was noted between those treated with ICT followed by CRT and those receiving CRT alone, the deficiency of statistical power made it inherently difficult to detect any benefit to ICT.
In summary, the role of ICT prior to locoregional therapy in HNSCC remains controversial, and no consensus guidelines are available to guide its use. Despite the negative findings from these pertinent trials and meta-analyses, flaws in methodological design and heterogeneity in chemotherapy regimens employed limit any conclusive answer to the question of whether ICT has a definite role. Until stronger evidence is available, its use in locally advanced disease should be limited to unique scenarios and clinical trials, while concurrent CRT remains the standard of care. Some experts suggest considering ICT when delays in CRT therapy are expected, as a larynx-preserving approach, and in patients who are at high risk for distant relapse (such as those with N2c or low-neck disease). It is important to consider that in addition to the lack of efficacy achieved in the DeCIDE and PARADIGM trials, sequential treatment also caused more toxicity than CRT alone. In DeCIDE, severe adverse events were significantly higher in the ICT arm (47 vs. 28%, p = 0.002).16 In PARADIGM, the incidence of grade III-IV febrile neutropenia was 23 versus. 1%, and grade III-IV mucositis was 47 versus 16% in the ICT arm.15
26.3 Concurrent Chemoradiotherapy
The primary benefits of chemotherapy in the setting of nonmetastatic HNSCC stem from its utility as a radiosensitizing agent. Therefore, the focus has been on agents with known activity in head and neck cancer, as well as established radiosensitizing properties including cisplatin, cetuximab, and 5-FU. The use of radiotherapy has been established with two main strategies, including concomitant chemotherapy (single or multiagent) with continuous radiotherapy or multiagent chemotherapy with split-course radiotherapy. Other acceptable approaches now include radiotherapy with altered fractionation. As mentioned, historically, chemotherapy was used exclusively for unresectable disease. The demonstration that chemotherapy could improve locoregional control compared to radiotherapy alone ultimately led to its study in other groups of patients including those with resectable disease and with organ preservation intent, and as adjuvant therapy after surgical resection in those with high-risk features. In 1992, Merlano et al randomized 157 patients with untreated, unresectable HNSCC to receive either cisplatin plus 5-FU plus radiotherapy or radiotherapy alone, and showed an increase in the frequency of complete response (43 vs. 22%, respectively; p = 0.037), increased PFS at 5 years (21 vs. 9%, respectively; p = 0.008), and increased 5-year survival benefit (24 vs. 10%, respectively; p = 0.01) in the combined treatment group.18 This study represents a turning point in the interest in concurrent CRT for HNSCC. In 2003, a phase III study by Adel- stein et al assigned 295 patients to radiotherapy alone, radiotherapy with concurrent cisplatin, or split-course radiotherapy given with 5-FU and cisplatin. Surgical resection was available to all three arms if appropriate after treatment was completed. Three-year OS for patients who received radiation alone was 23%, compared to 37% for those who received radiotherapy + cisplatin (p = 0.014), and 27% for those who received split-course radiotherapy given with 5-FU and cisplatin (p = not significant).19 This study established concurrent CRT with cisplatin as the standard of care for locally advanced, unresectable head and neck cancer. The meta-analysis by Pignon et al again highlighted the favorable results seen with this approach. Albeit with variable chemotherapy regimens, concurrent CRT showed an absolute survival benefit of 8% compared with radiation alone.1
Given that epidermal growth factor receptor (EGFR) is highly expressed in most HNSCC, and inversely associated with prognosis, EGFR inhibitors have garnered much interest in the treatment of HNSCC. In a study by Bonner et al, 424 patients were randomized to receive radiotherapy alone or radiotherapy with weekly cetuximab. The median duration of locoregional control was 24.4 months in those treated with cetuximab plus radiotherapy compared to 14.9 months in those treated with radiotherapy alone (HR, 0.68; p = 0.005). OS was 49 months compared to 29.3 months in those treated with combined therapy versus radiation alone, respectively (HR, 0.74; p = 0.03).20 These findings led to the FDA approval for the use of cetuximab in combination with radiotherapy for patients with advanced head and neck cancer. It is important to note that the use of cetuximab with concurrent radiotherapy has not been compared directly with cisplatin, and indications for its use at this time remain limited to the treatment of patients whose age, performance status, or comorbidities preclude the use of cisplatin-based treatment.
Panitumumab, another monoclonal antibody against EGFR, was studied in the phase II CONCERT-2 study. A total of 152 patients with locally advanced HNSCC were randomized to receive CRT with two cycles of cisplatin 100 mg/m2 during radiotherapy or to radiotherapy plus panitumumab (three cycles of 9 mg/kg every 3 weeks). Locoregional control at 2 years was 61 versus 51% in the CRT (cisplatin) group versus radiotherapy plus panitumumab group, respectively. The two groups showed no difference in OS.21
A few trials have investigated the utility of using concurrent CRT with the addition of EGFR inhibition to standard chemotherapy, without showing any significant advantage to date from the inclusion of EGFR inhibition. The RTOG-0522 trial compared cetuximab + cisplatin + radiotherapy to cisplatin/ra- diotherapy alone. At 3 years, there was no improvement noted in PFS (61.2 vs. 58.9%; p = 0.76), OS (72.9 vs. 75.8%; p = 0.32), or distant metastasis (13 vs. 9.7%; p = 0.08) in the cetuximab group compared to cisplatin/radiotherapy alone group, respectively.22 In the CONCERT-1 trial, a phase II study, 150 patients with locally advanced HNSCC were randomized to receive CRT with high-dose cisplatin, or CRT plus panitumumab. They failed to show any benefit in locoregional control at 2 years in the pani- tumumab + CRT group compared to CRT alone.23 In a similar fashion, the addition of erlotinib (a tyrosine kinase inhibitor [TKI] acting on EGFR) to CRT did not show any improvement compared with CRT alone.24
26.4 Adjuvant Chemoradiation
The decision to provide adjuvant radiation or chemoradiation is based on pathologic features. The use of chemoradiation has been studied in two main trials, which together have provided some clarification of the indications for its use.
The EORTC trial randomized 167 patients with stage III or IV head and neck cancer to receive either radiotherapy alone or radiotherapy combined with cisplatin after undergoing surgery with curative intent. They demonstrated improvement in both PFS at 60 months (47 vs. 36%; HR, 0.75; p = 0.04) and 5-year OS (53 vs 40%; p = 0.02) in the combined therapy group compared to radiotherapy alone. The cumulative incidence of local or regional relapses was significantly lower in the combined therapy group (p = 0.007).25 The RTOG trial employed the same two study arms, comparing combined CRT with cisplatin to radiotherapy alone after surgical resection in 231 patients with high- risk disease. At 45.9 months, the combined treatment group showed an improvement in locoregional control compared to radiotherapy alone (HR, 0.61; 95% CI, 0.41-0.91; p = 0.01), and longer disease free survival (DFS; HR, 0.78; 95% CI, 0.61-0.99; p = 0.04). Unlike the EORTC trial, no significant difference in OS was found in the RTOG trial.26
Though similar in their methodology, each of these trials employed slightly different definitions of high-risk pathologic features, which may explain some of the differences in their results. The RTOG defined high-risk disease to include the presence of multiple positive nodes, extracapsular extension of tumor, or a positive margin. The EORTC trial definition of high-risk disease included positive margins, extracapsular extension of nodal disease, vascular embolism, or perineural disease; for oral cavity or oropharyngeal tumors, high risk was defined as positive nodes at level IV or V. A pooled analysis of the two trials was carried out for clarification of these definitions, and concluded that the subsets of patients from both trials who benefited from combined therapy approach had either positive margins or extracapsular extension.27 Hence, patients with either or both of these features are considered to have a clear indication for adjuvant CRT. On the other hand, radiotherapy alone is usually recommended for patients at intermediate risk of recurrence, such as those with T3-T4/N0 disease, multiple positive nodes (without extracapsular extension), perineural or lymphovascular invasion, or oropharyngeal cancers with cervical nodes at level IV or V.
As expected, the addition of chemotherapy to radiotherapy in this setting comes with an increased incidence of adverse events. In the aforementioned trials, serious adverse events were increased in the combined-treatment groups by as much as 43% in RTOG26 and 20% in EORTC.25 Moreover, an updated result of the RTOG trial at 10-year follow-up failed to show a statistically significant survival benefit, even when limited to subset analysis of patients with positive margins or extracapsular extension.28
26.5 Adjuvant Chemotherapy
A role for adjuvant chemotherapy has been undetermined, with relatively few trials executed largely due to the successes of concomitant radiotherapy dating back to the 1970s. These early studies have compared postsurgical management for HNSCC with or without chemotherapy, and failed to establish any efficacy.29,30,31 Moreover, the recent MACH-NC meta-analysis failed to demonstrate a survival benefit in this subset of patients.1 One trial analyzed 442 patients with completely resected tumors or the oral cavity, oropharynx, hypopharynx, or larynx, who were then randomized to receive either three cycles of cisplatin and 5-FU, followed by postoperative CRT, or postoperative CRT alone. Patients with both high-risk and low-risk treatment volumes were included. They were unable to show any significant difference in locoregional failure, DFS, or OS, but did show a decreased incidence of distant metastases in the chemotherapy arm (15 vs. 23%; p = 0.03).31 Nevertheless, adjuvant chemotherapy alone has not been consistently shown to provide a clinical benefit and therefore is not indicated for postoperative HNSCC patients.
26.6 Metastatic or Incurable Recurrent Disease
Systemic therapy remains the mainstay of treatment in metastatic or incurable recurrent HNSCC. As described previously, several agents have shown activity in HNSCC and are available for use. Combination chemotherapy versus single-agent chemotherapy has been evaluated extensively, and although the multiagent approach tends to demonstrate higher response rates, these do not translate into significant survival benefits. Moreover, increased toxicities often a limit its use. A metaanalysis in 1994 analyzed trials comparing cisplatin plus 5-FU to single-agent therapy in this setting. It demonstrated a significant improvement in response with combination therapy, but only a 2-week difference in median survival (odds ratio, 0.43; 95% CI, 0.29-0.63) and increased toxicities for those who received combination therapy.32 This approach should therefore be limited to patients with good performance status who may better tolerate increased treatment-related toxicity. Methotrexate has been used frequently as single-agent therapy due to its ease of administration, favorable toxicity profile, and low cost. Despite showing efficacy in early-stage disease, the use of taxanes has not proven to be beneficial in metastatic disease. Trials comparing paclitaxel versus methotrexate33 and cisplatin plus paclitaxel versus cisplatin plus 5-FU34 have failed to show any survival benefit from the addition of taxane therapy. In the phase III EXTREME trial, 440 patients with metastatic disease were assigned to receive cisplatin or carboplatin/ 5-FU/cetuximab or cisplatin or carboplatin/5-FU. They were able to show that the addition of cetuximab increased the response rate from 20 to 36% (p <0.001), and prolonged PFS from 3.3 to 5.6 months (HR, 0.54; p<0.001) as well as median OS from 7.4 to 10.1 months (HR, 0.80; p = 0.04).23 This remains the standard approach in patients able to tolerate combination chemotherapy.
26.7 Novel Agents and Future Directions
The past few decades have yielded promising therapies in the treatment of early-stage and locally advanced HNSCC, most of which now involve multimodal therapy including systemic treatment with chemotherapy. Despite these advancements, many patients will develop local or distant failure after treatment. Ongoing efforts to improve outcomes will rely on further understanding of the biology of HNSCC and novel ideas for more targeted therapies. EGFR activity plays a central role in the development and progression of HNSCC, and its overexpression has been associated with poor outcomes. Several agents have been developed with anti-EGFR activity including monoclonal antibodies to EGFR (cetuximab, panitumumab) and TKIs (afatinib, dacomitinib, gefitinib, erlotinib, lapatinib, and vandetanib). As described previously, cetuximab concurrent with radiotherapy has been approved for use in the treatment of locally advanced HNSCC based on results of a phase III trial by Bonner et al,20 and in recurrent/metastatic disease based on the EXTREME trial.36 Panitumumab has been similarly investigated in the SPECTRUM trial, a phase III trial which randomized 657 patients with recur- rent/metastatic HNSCC to receive cisplatin and 5-FU with or without panitumumab. No significant difference was demonstrated in OS, the primary endpoint, but a modest increase in PFS of 1.2 months was observed in the panitumumab group (5.8 vs. 4.6 months; p = 0.004).35 At this time, there is no indication for the use of panitumumab in head and neck cancer.
Afatinib, a TKI which interrupts EGFR signaling, has been compared with methotrexate in recurrent/metastatic HNSCC in the phase III LUX-Head & Neck1 trial showing improved PFS in the afatinib group (2.6 vs. 1.7 months; HR, 0.80; p = 0.030) but no benefit in OS.37 Less mature trials involving other TKI agents have shown largely negative results. Buparlisib, a phosphoinosi- tide 3-kinase inhibitor, has been investigated as a potential option. The BERIL-1 study was a multicenter, phase II trial which randomized 158 patients with recurrent or metastatic HNSCC to receive buparlisib and paclitaxel versus placebo and paclitaxel for second-line treatment. The buparlisib/paclitaxel group showed improvement in PFS (4.5 vs. 3.5 months; HR, 0.65; p = 0.01), OS (10.4 vs. 6.5 months; HR, 0.72; p = 0.04), and overall response rate (ORR; 39.6 vs. 13.9%; p<0.001).38
Immune therapy has garnered a great deal of interest in the treatment of both solid and hematologic malignancies based on the premise that tumors can be recognized as foreign and eradicated by effective immune responses. While an understanding of the interplay between tumor and immune cells remains rather rudimentary, this field is rapidly evolving and preclinical advancements have continued to reveal new insights which propel their integration into clinical practice. It is hypothesized that a normal host employs immune surveiiiance, where premalignant cells are continually sought and destroyed by a healthy immune system, precluding the establishment or progression of advanced disease. Accordingly, tumor progression depends on the acquisition of traits that allow cancer cells to evade immune surveillance and effective immune responses. A recent therapeutic approach involves modulation of T-cell activation, a process requiring a critical combination of T-cell receptor co-stimulation, as well as inhibitory stimulation to preserve appropriate, controlled activity levels in the normal host. Inhibition of these checkpoints has been confirmed to promote anticancer immune activity. One such checkpoint inhibitor, pembrolizumab, is a monoclonal antibody directed against programmed cell death-1 (PD-1), a cell surface receptor that plays an important role in downregulating the immune system. Data from the phase Ib KEYNOTE-012 trial demonstrated the efficacy of pembrolizumab in the treatment of recurrent or metastatic HNSCC, showing an ORR of 18%.39 A pooled analysis of the trial was later presented after long-term follow-up of patients enrolled in KEYNOTE-012, showing an ORR of 17.7%. Median follow-up duration in responders was 12.5 months. Median duration or response had not yet been reached at the time of data cutoff, and among responders 76% had ongoing responses.40 Based on these results, pembrolizu- mab was granted accelerated FDA approval for the treatment of recurrent/metastatic HNSCC in August 2016. Another anti- PD-1 monoclonal antibody, nivolumab, has been approved for use based on the CHECKMATE-141 trial, a phase III trial exploring the use of nivolumab in patients with recurrent/meta- static HNSCC. In this trial, 361 patients were randomized to receive nivolumab or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The results showed an improvement in OS (HR, 0.70; p = 0.01) in the nivolumab group compared to those who received standard therapy.41
While immune therapy has been established as a safe and effective approach in the treatment of recurrent/metastatic disease, it is conceivable that its greatest utility may exist in the management of early or locally advanced disease. For example, preclinical data have demonstrated a synergistic effect with the combination of checkpoint inhibitors and radiotherapy. In murine models, it has been observed that their concurrent administration can result in antitumor immune responses both in the radiation field and outside of it. This synergism is known as the abscopal effect.42 PD-1 blockade has also been shown to induce rejection of persistent tumors in mouse models as adjuvant treatment after completion of radiotherapy. It is important to note that human papillomavirus (HPV) positivity, a favorable prognostic factor in HNSCC, engenders better responses to radiation, chemotherapy, or both. Interestingly it has been shown that HPV-positive tumors are more infiltrated by CD8 T-cells than HPV-negative tumors, and may have a particularly robust response to immune therapy. This is the result of checkpoint inhibitors induced by active exposure to tumor-specific antigens during radiation- or chemotherapy-induced cell death. The role for systemic treatment in HPV-positive HNSCC remains unclear and needs to be addressed in future trials.
In conclusion, the past several decades of research have unveiled a critical role for systemic therapy in the treatment of head and neck cancer. It can be expected that continued progress with novel, targeted agents and the rapidly growing field of immunotherapy will continue to provide new insight into this disease, and that these developments will augment complex, multimodality approaches with the hope of increasing cure rates by enhancing systemic treatment.
References
[1] Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group.
Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): an
update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92(1):4-14
[2] Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet. 2008; 371(9625):1695-1709
[3] Lee WR, Mancuso AA, Saleh EM, Mendenhall WM, Parsons JT, Million RR. Can pretreatment computed tomography findings predict local control in T3 squamous cell carcinoma of the glottic larynx treated with radiotherapy alone? IntJ Radiat Oncol Biol Phys. 1993; 25(4):683-687
[4] Stadler P, Becker A, Feldmann HJ, et al. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 1999; 44(4):749-754
[5] Dunst J, Stadler P, Becker A, et al. Tumor volume and tumor hypoxia in head and neck cancers. The amount of the hypoxic volume is important. Strah- lenther Onkol. 2003; 179(8):521-526
[6] Wolf GT, Fisher SG, Hong WK, et al. Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324(24):1685-1690
[7] Domenge C, Hill C, Lefebvre JL, et al. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC). Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC). Br J Cancer. 2000; 83(12):1594-1598
[8] Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst. 1994; 86 (4):265-272
[9] Forastiere AA, Shank D, Neuberg D, Taylor SG, IV, DeConti RC, Adams G. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer. 1998; 82(11):2270-2274
[10] Vermorken JB, Remenar E, van Herpen C, et al. Long-term results of EORTC24971/TAX323: Comparing TPF to PF in patients with unresectable squamous cell carcinoma of the head and neck. Preliminary results of a modern integrated approach. J Clin Oncol. 2011; 29 suppl 15:5530
[11] Posner MR, Hershock DM, Blajman CR, et al. TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007; 357(17):1705-1715
[12] Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 2009; 101(7):498-506
[13] Blanchard P, Bourhis J, Lacas B, et al. Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction Project, Collaborative Group. Taxane-cisplatin-fluo- rouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol. 2013; 31(23):2854-2860
[14] Hitt R, Grau JJ, Lopez-Pousa A, et al. Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-FU or docetaxel/cis- platin/5-FU followed by chemoradiotherapy (CRT) vs. CRT alone as first line treatment of unresectable locally advanced head and neck cancer (LAHNC). J Clin Oncol. 2009; 27 suppl 15:6009
[15] Haddad RI, Rabinowits G, Tishler RB, et al. The PARADIGM trial: a phase III study comparing sequential therapy to concurrent chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2012; 30 suppl 15:5501
[16] Cohen EE, Karrison T, Kocherginsky M, et al. DeCIDE: A phase II randomized trial of docetaxel, cisplatin, 5FU induction chemotherapy in patients with N2 N3 locally advanced squamous cell cancer of the head and neck. J Clin Oncol. 2012; 30 suppl 15:5500
[17] Budach W, Boelke E, Kammers K, Gripp S, Matuschek C. Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy as treatment of unresected locally advanced head and neck squamous cell cancer (HNSCC): A meta-analysis of randomized trials. J Clin Oncol. 2014; 32(suppl 15):6012
[18] Merlano M, Benasso M, Corvo R, et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst. 1996; 88(9):58:3-589
[19] Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules ofconcurrent chemoradiother- apy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003; 21(1):92-98
[20] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med. 2006; 354(6):567-578
[21] Giralt J, Trigo J, Nuyts S, et al. Panitumumab plus radiotherapy versus chemo- radiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015; 16(2):221-232
[22] Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014; 32 (27):2940-2950
[23] Mesia R, Henke M, Fortin A, et al. Chemoradiotherapy with or without pani- tumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015; 16(2):208-220
[24] Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol. 2013;31(11):1415-1421
[25] Bernier J, Domenge C, Ozsahin M, et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350(19):1945-1952
[26] Cooper JS, Pajak TF, Forastiere AA, et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004; 350(19):1937-1944
[27] Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (# 22931) and RTOG (# 9501). Head Neck. 2005; 27(10):843-850
[28] Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/ intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. IntJ Radiat Oncol Biol Phys. 2012; 84(5):1198-1205
[29] Taylor SGIV, IV, Applebaum E, Showel JL, et al. A randomized trial ofadjuvant chemotherapy in head and neck cancer. J Clin Oncol. 1985; 3(5):672-679
[30] Rentschler RE, Wilbur DW, Petti GH, et al. Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcino- mas-a prospective, randomized study. J Clin Oncol. 1987;5(2):278-285
[31] Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. IntJ Radiat Oncol Biol Phys. 1992; 23(4):705-713
[32] Browman GP, Cronin L. Standard chemotherapy in squamous cell head and neck cancer: what we have learned from randomized trials. Semin Oncol. 1994; 21(3):311-319
[33] Vermorken J, Catimel G, Mulder PD, et al. Randomized phase II trial of weekly methotrexate (MTX) versus two schedules of triweekly paclitaxel (Taxol [trade]) in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). [abstract]. Proc Am Soc Clin Oncol. 1999; 18:395
[34] Gibson MK, Li Y, Murphy B, et al. Eastern Cooperative Oncology Group. Randomized phase III evaluation ofcisplatin plus fluorouracil versus cispla- tin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005; 23 (15):3562-3567
[35] Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. SPECTRUM investigators. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013; 14 (8):697-710
[36] Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N EnglJ Med. 2008; 359(11):1116-1127
[37] Machiels JP, Haddad RI, Fayette J, et al. LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015; 16(5):583-594
[38] Soulières D, Faivre S, Mesia R, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017; 18(3):323-335
[39] Uppaluri R, Zolkind P, Lin T, Nussenbaum B, Paniello R, Rich J. Immunotherapy with pembrolizumab in surgically resectable head and neck squamous cell carcinoma. Paper presented at: the American Society ofClinical Oncology Annual Meeting; June 3-7,2016; Chicago, IL
[40] Mehra R, Seiwert TY, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow up in KEYNOTE-012. Paper presented at: the American Society of Clinical Oncology Annual Meeting; June 3-7,2016; Chicago, IL
[41] Ferris RL, Blumenschein G, Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016; 375 (19):1856-1867
[42] Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005; 11(2, Pt 1):728-734