Tumors staged up to T4a are considered to be resectable, and historically, surgery was the standard of care to treat LAHNSCC including oral cavity cancers (OCSCC). However, since it was noted that the risk of locoregional relapse after surgery alone in LAHNSCC exceeds 40 % [11], surgical resection was soon followed by postoperative radiation therapy (PORT). Nonetheless, subgroups of patients continue to have high risk of locoregional relapse after PORT and require further treatment – these include patients with either:

In 1996, the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative Group conducted a trial to study the role of concurrent chemoradiotherapy (CRT) in the postsurgical setting in this high-risk group of patients. This EORTC radiotherapy trial (22931) enrolled 334 patients with LAHNSCC after complete surgical resection. High-risk features were defined as T3 or T4 with any N stage (except T3N0 laryngeal cancer), positive surgical margins, extracapsular extension, perineural invasion, vascular invasion, or oral cavity/oropharyngeal primary sites with involvement of level IV or V lymph nodes. The patients were randomized to RT alone (66 Gy in 33 daily 2 Gy fractions) versus the same dose of RT with concomitant cisplatin (100 mg/m², on days 1, 22, and 43 of RT). With a median follow-up of 60 months, postoperative concurrent chemoradiotherapy (POCRT) significantly improved 5-year progression-free survival (PFS) by 13 %, locoregional control by 8–13 %, and overall survival (OS) by 13 %; locoregional control was seen as well as with chemoradiation [12].

The Radiation Therapy Oncology Group (RTOG) phase III 9501 trial “Radiation therapy with or without chemotherapy in treating patients with head and neck cancer that has been removed during surgery” offered the same treatment arms but differed slightly from the EORTC trial by the inclusion criteria. It included 459 patients on the two arms, but the high-risk features were limited to positive resection margins, involvement of two or more lymph nodes, and extracapsular nodal extension. Again adding chemotherapy to PORT improved locoregional control by 10 % [13]; however, the overall survival benefit improvement was different to the EORTC trial. It was concluded that patients with extranodal spread or involved surgical margins see an OS benefit with post-op chemoradiation, while those with other high-risk features show trends toward improved locoregional control and overall survival. A follow-up study 10 years later evaluated long-term differences in locoregional failure rates, disease-free survival, and overall survival. When selectively analyzing patients with positive resection margins and/or extracapsular spread of disease, the chemoradiation arm compared to radiation alone showed reduced locoregional failure rates at 21 % vs. 33 % and improved disease-free survival and overall survival at 18 % and 27 % vs. 12 % and 19 %, respectively. These studies helped develop the current standard of postoperative concurrent chemoradiation therapy in this group of patients that are at high risk for locoregional recurrence.

LAHNSCC definitive surgical treatments have short-term and long-term sequelae that result in drastic lifestyle changes with significant loss of speech and swallowing functions. Organ preservation treatments modalities aim to maximize or maintain the cure rate that could be achieved with surgical treatments, while minimizing the functional loss through organ preservation. Furthermore, given the lack of the good treatment options for recurrent disease, many efforts have been targeted at optimizing initial treatments and preventing locoregional recurrence. Multimodality treatment in the form of combined chemoradiation therapy can be utilized as an alternative to surgical resection in patients with advanced but resectable HNSCC. Organ preservation treatment strategies for potentially resectable disease include:

The story of organ preservation in HNSCC started more than 20 years ago with the famous Veterans Affairs Laryngeal Cancer Study. This trial enrolled 332 patients with stage III or IV laryngeal SCC, who were randomized to cisplatin and 5-FU induction chemotherapy followed by definitive RT, versus the control arm of total laryngectomy with PORT. Those who did not respond to induction chemotherapy or had locally persistent or recurrent disease underwent salvage laryngectomy. The trial resulted in similar 2-year survival rates for both treatment groups at 68 %, with 41 % of those treated with chemotherapy and RT alone surviving with a functioning larynx. Trends found in the VA trial included greater locoregional recurrence in the organ preservation arm (20 % vs. 7 %), while distant disease recurrence was less common (11 % vs. 17 %) [14].

In 2000, a large meta-analysis of over 60 trials further solidified our understanding of the role of chemotherapy added to local treatment. The Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) studied 63 trials that included more than 10,000 patients. This study came to the conclusion that chemotherapy plus radiation, compared to radiation alone, led to a 4 % absolute survival benefit and a 12 % reduction in risk of death from head and neck cancer. Chemotherapy treatments included in the analysis consisted of concurrent as well as neoadjuvant treatments. Several years later, an update to the analysis that included an additional 24 trials of mostly concurrent chemotherapy showed an absolute survival benefit of 4.5 % at 5 years. A significant difference was seen with the timing of chemotherapy (adjuvant, induction, or concurrent), with concurrent chemotherapy showing a more pronounced benefit of adding radiation [15, 16]. These studies again validated concurrent chemoradiation therapy as the standard of care.

Another important chapter in the organ preservation treatment story for HNSCC patients was written in 2003 by another famous trial, “Phase III trial to preserve the larynx: induction chemotherapy and radiation therapy versus concomitant chemotherapy and radiation therapy versus radiation therapy” (RTOG 9111). RTOG 9111 was designed to compare CRT concurrently, induction cisplatin/FU followed by RT (sequential therapy, identical to the VA trial), or RT alone. Long-term results revealed concurrent cisplatin/RT resulted in a 13.6 % absolute benefit in 5-year laryngeal preservation compared with 17.9 % for induction chemotherapy and RT. Locoregional control was superior with CRT (68.8 %) versus induction chemotherapy/RT (54.9 %) or RT alone (51 %). There was no statistically significant OS difference between the CRT and induction chemotherapy arms. The results of this trial set CRT as the standard of care for stage III to IV laryngeal cancers [17].

In 2006, a randomized study compared radiotherapy alone with radiotherapy plus cetuximab in patients with locoregional advanced HNSCC (oropharyngeal, hypopharyngeal, and laryngeal SCC) [18]. Results showed a significant improvement in OS in the concurrent bio-Rt arm, as well as improved locoregional control. Unfortunately, cetuximab is also known to increase the cytotoxic effects associated with radiation therapy.

Cetuximab (Erbitux®, C-225) is a chimeric monoclonal IgG1 subclass antibody with a binding affinity to epidermal growth factor receptor (EGFR) that exceeds the natural ligand epidermal growth factor (EGF). Cetuximab is FDA approved for the treatment of relapsed non-resectable or metastatic HNSCC as a single agent or in combination with chemotherapy. In multiple phase II clinical trials, the objective response rate (ORR) of single-agent cetuximab in relapsed/metastatic HNSCC patients who failed platinum-based palliative chemotherapy was 10–13 %; median time to progression was 2.3–2.8 months, and (OS) was 5.2–6.1 months [19].

Despite the clinical efficacy of cetuximab in HNSCC, its exact mechanism(s) of action remains uncertain. Cetuximab does not induce HNSCC cells apoptosis or lysis in vitro unless lymphocytes are added to the culture; an observation supports the hypothesis that an immune-mediated mechanism might contribute to the antitumor effect of cetuximab. While EGFR signaling blockade is likely to play a role in the clinical responses seen in patients receiving cetuximab, the immune complexes formed on the surface of tumor cells treated with this agent provide an additional mechanism of action [20]. Evidence in support of the role of immune-mediated responses in cetuximab therapy is provided by the lack of correlation between level of EGFR expression and clinical responses to cetuximab. López-Albaitero et al. reported a correlation between certain FcgR genotypes and natural killer (NK) cell-dependent cytotoxicity of HNSCC cells in vitro [21]. These data suggest that cetuximab may induce tumor cell killing through an immune-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and not simply through blockade of EGFR signaling; this effect is limited by the tumor-mediated immunosuppression that inhibits NK cells and other effector cells. HNSCC tumors are highly immunosuppressive and are characterized by marked and persistent elevation of inhibitory regulatory T cell (Tregs). In an ongoing pilot study, Gopalji and Miller hypothesized that Tregs, which are elevated in HNSCC, can be suppressed with cyclophosphamide, and this suppression can lead to improved antitumor responses mediated by cetuximab [22].

The previously mentioned clinical trials, and many others, support the widely accepted practice of using concurrent chemo/biotherapy with concomitant RT as an equivalent alternative to surgical resection in locally advanced resectable HNSCC. A nonsurgical approach can minimize potential functional loss through organ preservation; however, definitive CRT still has significant short-term and long-term toxicities that may drastically affect the patient’s quality of life. Over 40 % of HNSCC patients who received definitive CRT suffer from acute grade 3–4 complications (leukopenia, anemia, mucositis, and dysphagia) [13, 23, 24]. Moderate to severe long-term complications of CRT also occur in a significant percentage of patients who will suffer from complications including xerostomia, increased muscular fibrosis, dysphagia, feeding tube dependence, and speech changes. Perhaps the most worrisome CRT effects are speech and swallowing changes. To further characterize these complications and their effects on patient lifestyles, the RTOG 9111 trial prospectively evaluated speech and swallowing function. Findings show that CRT has a 26 % chance of having diet limitations to soft foods or liquids or require percutaneous gastrostomy tube 1 year out [25]. A pooled analysis on three RTOG CRT protocols revealed that post-CRT neck dissection, advanced T stage, older age, and laryngeal or hypopharyngeal primary sites increased the risk of late toxicities [26].

With the turn of the millennium and the introduction of the taxoids paclitaxel (Taxol) and docetaxel (Taxotere) as effective single-agent chemotherapies for HNSCC, the potential of induction chemotherapy as organ-preserving treatments has been rejuvenated. Multiple clinical trials have been initiated evaluating induction chemotherapy using platinum, 5-florouracil, and a taxane followed by RT only or CRT [27–32]. One of the most important trials in this setting was TAX 324. In 2007, the TAX 324 study group presented data comparing induction chemotherapy with docetaxel plus cisplatin and 5-FU versus cisplatin and fluorouracil alone followed by concurrent chemoradiation with weekly carboplatin. The study included patients with stage III and IV HNSCC, who either had unresectable disease or were candidates for organ preservation treatment. The primary endpoint of the trial was survival, and the addition of docetaxel to induction chemotherapy led to a significantly improved 5-year survival at 52 % compared to 42 %. Comparisons of toxicities between the two treatment arms showed that while rates of neutropenia and febrile neutropenia were higher in the docetaxel arm, treatment delays due to hematologic adverse events were more common in the non-docetaxel group [28, 29].

To evaluate the benefit of adding induction chemotherapy prior to concurrent CRT, the PARADIGM study in 2013 employed the same induction chemotherapy regimen with docetaxel, cisplatin, and 5-FU and compared outcomes of induction plus concurrent CRT to concurrent CRT alone. Included patients had unresectable disease or low surgical curability and also consisted of candidates for organ preservation therapy. No difference was noted in survival rates; however, the trial was relatively short with a median follow-up of 49 months and 21 months in the induction chemotherapy and concurrent CRT alone arms, respectively. The authors suggested that differences in survival could, therefore, have gone undetected [27]. Certainly these studies do not provide enough support to change the standard of care given higher toxicities with increased treatment; however, encouraged by a meta-analysis showing a reduction in distant metastasis rates [33], induction chemotherapy has remained an avid interest of research.

Recently in 2014, clinicians at the University of Chicago published results from a phase III trial evaluating induction chemotherapy of docetaxel, cisplatin, and 5-FU plus concurrent chemoradiation with concurrent CRT alone in patients with N2 or N3 HNSCC (i.e., disease with local metastasis to cervical lymph nodes). The authors had hypothesized that patients with local metastasis were at the highest risk for distant metastases [30] and would benefit the most from induction chemotherapy. However, this trial again did not show a difference in disease outcome measure in OS, disease-free survival, or recurrence-free survival [31].

In a slightly different application of induction chemotherapy, a trial in Shanghai published in 2012 found no survival difference between induction chemotherapy followed by surgery and postoperative radiation compared to upfront surgery and postoperative radiation alone [34]. This trial consisted of locally advanced SCC originating in the oral cavity and given the scope of this book will be discussed in more detail later in this chapter.

In summary of our discussion of resectable yet locally advanced HNSCC, the goal of treatment, is foremost, the achievement of the best chance at a cure without recurrence. A second goal of treatment is organ preservation, which implies function preservation. Even nonsurgically treated patients frequently develop a decline in function from toxicities of therapy, adding additional complexity to treatment. In potentially resectable disease, a choice can be made surgery and chemoradiation therapy as primary treatments. Ultimately, the selected treatment is the result of a discussion between the patient and the oncologist, radiation oncologist, and surgeon, taking into account available resources, skill sets, and support services.