Radiotherapy for Head and Neck Squamous Cell Carcinoma State of the Art and Future Directions

Abstruse

During the by 20 years, treatments for head and cervix squamous cell carcinoma (HNSCC) take changed dramatically attributable largely to the appearance of novel approaches such as combined modality therapy likewise as improvements in surgical and radiotherapeutic techniques. Locally advanced affliction in particular, which engendered very high recurrence and mortality rates, is now associated with long-term disease-free survival in the majority of cases. This article volition focus on locally avant-garde HNSCC, which frequently remains a clinical challenge, review country-of-the-art therapy, and introduce promising novel therapies. The field continues to evolve rapidly with new testify during the past year clearly establishing the benefit of adjuvant chemoradiotherapy (CRT), equally well every bit early evidence showing improved survival with the use of an epidermal growth factor receptor inhibitor in combination with radiotherapy. At that place are varied regimens in use for patients with locally advanced disease, but at the aforementioned time the multitude of options can plague the clinician when trying to select the most appropriate one. This article will try to put the various approaches into perspective and propose an evidence-based treatment algorithm.

Principal

Head and cervix cancer has an estimated annual global incidence of 533 100 cases (Parkin et al, 2001) and is the fifth most mutual cancer worldwide with the great majority of cases beingness squamous prison cell carcinomas (HNSCC). There is strong geographical variance in incidence probable related to associated risk factors, with the highest reported rates being observed in some areas of France (Bas-Rhin, male person incidence 63.58 cases/100 000 people) and India/key Asia (Sankaranarayanan et al, 1998). The staging for HNSCC is shown in Table i. Treatment for locally advanced affliction (stages Iii, IVA, IVB), which makes up more than than l% of all cases, requires aggressive and concerted measures, and frequently remains a clinical challenge. Until recently, v-year survival rates were reported to exist below xxx% for patients with stage IVA/B disease (Vokes et al, 1993) and 40% for all locally advanced tumours (Laramore et al, 1992) even with early multimodality approaches (30% recur locally, 25% distally).

Table one Staging overview, for details of T and N staging, delight refer the AJCC staging manual

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Perspective

Current direction of locally advanced HNSCC (Tabular array 1) has evolved from poorly effective single modality therapy to an integrated, highly constructive multidisciplinary approach. Unlike early on phase HNSCC, all three modalities – surgery, radiotherapy, and chemotherapy – play vital and complementary roles. The diverse combination treatments have led to several competing approaches, each with distinct advantages and disadvantages, and initial treatment can vary significantly between institutions. Therefore, the post-obit paragraphs will examine each major approach, highlight important differences and advantages/disadvantages, and try to recommend a management flowchart based on the evidence. Treatments used for locally advanced disease tin be classified every bit follows:

1. i

   Surgery followed by adjuvant chemoradiotherapy (CRT) (or radiation)

2. two

   CRT upfront (with surgery every bit a salvage treatment)

3. iii

   Induction chemotherapy followed by definitive local therapy:

   1. a)

      CRT

   2. b)

      Other principal treatment options: radiotherapy, surgery (±adjuvant therapy)

4. iv

   epidermal growth factor receptor (EGFR) inhibition in combination with radiotherapy or CRT

Postoperative therapy: surgery followed by adjuvant CRT (or radiation)

Predictors of recurrence after surgical resection include involved margins of resection, extranodal/extracapsular spread, perineural invasion, and the presence of 2 or more than involved regional lymph nodes (Snowfall et al, 1982; Vikram et al, 1984; Kramer et al, 1987). Since locoregional failures remained the dominant trouble, adjuvant locoregional therapies such as radiation and subsequently CRT were added and adjuvant therapy is now considered standard of care for stage 3/IVA/B disease.

Adjuvant (postoperative) radiotherapy is well studied (Fletcher and Evers 1970; Snowfall et al, 1982; Vikram et al, 1984; Kramer et al, 1987). It decreases local failure rates and although only retrospective bear witness exists (Huang et al, 1992), there is broad consensus since the 1980s that it increases survival and a randomised prospective trial would be unrealistic at this point. Still even with adjuvant radiotherapy, in the presence of high-take a chance features, the adventure of local recurrence (27–61%), distant metastases (xviii–21%), and decease (five-year survival charge per unit 27–34%) remain unsatisfactorily high (Cooper et al, 1998).

Postoperative (adjuvant) CRT offered an arroyo that could heighten local control with radiosensitising chemotherapeutic agents. Several studies take demonstrated that concurrent CRT is a highly effective therapy for locally advanced HNSCC including tumours that are not amenable to surgery (El-Sayed and Nelson 1996; Brizel et al, 1998; Vokes et al, 1999; Jeremic et al, 2000; Adelstein et al, 2003; Vokes et al, 2003), justifying trials of concurrent CRT as postoperative (adjuvant) treatment.

The first trial to suggest a marked do good of postoperative CRT over radiation lonely in patients with locally advanced disease with loftier-run a risk features was a smaller trial by Bachaud et al published in 1996 (Table 2a) (Bachaud et al, 1996). In club to ostend the Bachaud trial, ii similarly designed, multicentre, randomised stage Iii trials of adjuvant radiation vs CRT were reported in 2004 (Bernier et al, 2004; Cooper et al, 2004) also in patients with stage III, IVA/B disease and high-risk features for recurrence. The RTOG 9501 and the EORTC 22931 (summarised in Table 2) were able to produce level 1 evidence of a articulate benefit for adjuvant CRT, at the toll of a pregnant increase in acute toxicities. Inclusion criteria and the type of radiotherapy varied somewhat between the two trials (Table ii), but overall they were coordinated to employ similar treatment protocols, making the results appear very robust. Both trials support the benefit of CRT over radiations alone in patients with high-adventure features. Although only the EORTC trial showed a significant survival reward for CRT, the RTOG trial trended in the same direction and showed a significant increment in progression-free survival.

Tabular array 2a Postoperative therapy: randomised trials of adjuvant chemoradiotherapy vs radiotherapy lonely in locally advanced HNSCC

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Likewise consistent in both trials was an increase in acute class Iii and Iv toxicities in the combined therapy arm (Table 2) including toxic deaths. On the other mitt, at that place was no difference in astringent long-term handling-related toxicities. Strong consideration should, therefore, be given to handling of these patients in centers with expertise in combined modality treatment and a well-established supportive care system. A positive correlation of treating institution expertise and patient survival supports this belief (Benasso et al, 1997).

Although we can conclude that postoperative CRT in patients with locally advanced disease with high-chance features is now standard of care (Tabular array 2a), for patients without high-risk features, the testify of a benefit of CRT over radiation lone is less clear with no randomised trials addressing this question. The Intergroup trial 0034 (Laramore et al, 1992) (see Tabular array 2b) may give some insight, simply clearly was non intended to address this particular question equally it used sequential chemotherapy and radiotherapy in comparison to radiations alone. This trial did enroll a significant portion of intermediate take chances patients (phase Three illness) without loftier-adventure features and did non find a difference in local command, disease-costless, and overall survival. Interestingly, distal failures were decreased presumably due to the higher doses of systemic chemotherapy compared with concomitant CRT. Despite the enrollment of lower take a chance patients, overall local control rates were lower than in the more than recent EORTC and RTOG trials. These trials were reported 12 years apart and make comparisons difficult due to stage migration and full general improvements in supportive care and therapeutic modalities.

Tabular array 2b Postoperative therapy: randomised trial of adjuvant sequential chemotherapy+radiotherapy vs radiotherapy solitary in locally advanced HNSCC

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Even though adjuvant concomitant CRT as reported in these two landmark trials is a major step, information technology needs to be noted that the locoregional failure rate remains unsatisfactorily high at thirty%. Attempts have been made to farther improve the radiosensitising properties of chemotherapy using doublet and triplet combinations (see beneath) with the hope of further improving survival. Many centres have adopted this approach, based on stage 2 evidence indicating safety, feasibility, and potentially improved efficacy, but this remains an unanswered question until phase III data become available.

The optimal fourth dimension frame to start adjuvant treatment postsurgery has non been studied sufficiently. Limited evidence and clinical experience with the fourth dimension needed for patients to recover advise that it should be inside four–six weeks postsurgery.

Definitive/concomitant CRT and organ preservation

During the by decade, an attractive alternative to initial surgery has evolved. Originally pioneered for inoperable patients, upfront concomitant CRT has emerged as a definitive treatment selection comparable to upfront surgical management in resectable patients. Given its advantage with regards to organ preservation and excellent reported local control and survival rates, CRT is increasingly used and has become the dominant treatment modality in many centres (Hoffman et al, 2004). The decision betwixt upfront surgery followed by chemoradiation vs upfront chemoradiation with the option of save surgery remains controversial and depends on many factors, including local expertise, goals for organ preservation, operability, resectability, and patient preference. No adequate randomised trial has examined this question and, given inherent biases in patient pick and power to stage patients in a comparable fashion, it is unlikely that we will have a definitive answer in the about future. Both approaches piece of work well, can coexist, and allow matching of treatments to a patient's disease and preferences.

Concomitant CRT

Concomitant CRT attempts to capitalise on radiosensitising backdrop while delivering systemically active agents. Sensitising effects though are not selective for neoplasm cells, and next normal tissue inside the field is also subject to more than effective and more toxic radiation. Consistently, CRT trials study an increased incidence of form 3 and iv acute toxicities with mucositis and dermatitis existence the most prominent. On the other hand, astringent long-term side effects are not increased in comparison to radiation lonely, and nigh all patients recover from the intense treatment. As mentioned, handling should preferentially be done at experienced centres that accept an advisable support infrastructure (Benasso et al, 1997).

Multiple phase Two trials using intensive CRT regimens take shown long-term survival rates of 60–70%, without surgery, for locally advanced HNSCC (Kies et al, 2001; Adelstein et al, 2002; Machtay et al, 2002; Vokes et al, 2003). Phase Ii trials need to be interpreted with circumspection due to their inherent biases, but the consistency of the results and the big number of patients treated with this arroyo is reassuring. Meta-analysis of early on randomised, only generally underpowered, trials suggested an accented survival benefit of approximately 8% at 5 years for CRT over radiation also (NNT=13; 13 patients need to be treated to salvage i life) (El-Sayed and Nelson, 1996; Pignon et al, 2000). More contempo trials furthermore propose fifty-fifty more robust survival benefits with an absolute take chances reduction of death at 3 years of 14–25% (NNT=4–7; betwixt 4 and 7 patients demand to be treated to salve one life) (Brizel et al, 1998; Adelstein et al, 2003).

Based on suggestive phase Two bear witness, contempo trials often at present investigate combination chemotherapy. Commonly used agents include cisplatin, 5-FU (Table ii), taxanes, hydroxyurea, and gemcitabine (Vokes et al, 2003; Milano et al, 2004). Concomitant CRT is among the near efficacious locoregional control measures, but at the same time, these contempo trials reveal a shift in the pattern of failure towards afar disease especially in patients with advanced nodal stage. Induction chemotherapy attempts to subtract distal failures has been advocated now that local control is achieved in nearly patients (encounter below).

Even though some controversy remains, at that place is an increasingly meliorate divers part for surgical management of certain patients afterwards CRT (Argiris et al, 2004). Cervical lymph node autopsy (ND) fifty-fifty after a complete response (CR) to CRT is advisable in patients with N2-N3 illness to optimise locoregional illness control (Lavertu et al, 1997; Argiris et al, 2004). Too, all patients with residual lymph node enlargement on imaging should undergo ND, even though many specimens volition only show necrosis. In patient with higher LN status (N2 and higher), upwards to 35% of specimen volition harbour residue microscopic tumour (Stenson et al, 2000). In a contempo trial, this arroyo was able to improve progression-free survival (Argiris et al, 2004). In contrast, patients with N0-1 disease and a CR to treatment did not benefit. A selective lymph node dissection is feasible four–12 weeks after CRT and is associated with an excellent safety profile (Stenson et al, 2000).

Organ preservation

Given that concomitant CRT increases locoregional control, and thereby avoids surgical resection of important anatomical structures, it was postulated that CRT may offer superior organ preservation in comparison to surgery, radiation, or sequential chemotherapy and radiation. Initially, two trials using sequential chemotherapy and radiation in comparison to surgery with adjuvant radiations reported improved organ preservation with no difference in survival (Table three) (VA Laryngeal cancer report group, 1991; Lefebvre et al, 1996, 2004), establishing sequential treatment as a standard approach. At effectually the same fourth dimension, CRT emerged every bit a highly efficacious handling and a large Intergroup trial was therefore initiated. Intergroup trial 91–xi had as a primary finish point larynx preservation in resectable patients with stage 3 or IV (just excluding T₄) illness (Table 3) (Forastiere et al, 2003). The three treatment arms compared sequential chemotherapy and radiation, concurrent CRT, and radiotherapy alone. Laryngectomy was reserved for patients who did non respond to induction chemotherapy or with residual or recurrent disease following completion of radiotherapy on all iii artillery. Laryngeal preservation, the primary end point of this trial, was superior in the concomitant CRT arm compared to both sequential CRT (88 vs 75% 2-yr laryngeal preservation rate, P=0.005) and radiotherapy solitary (88 vs 70% 2-yr laryngeal preservation, P<0.001). On the other manus, astute high-grade toxicities were more common in both artillery involving chemotherapy. Similar to other CRT trials, late toxicities and swallowing part at 2 years were equivalent between the three artillery. As a secondary outcome, CRT achieved the highest locoregional control rate. Survival was not significantly dissimilar between all 3 treatment arms, while both chemotherapy artillery showed lower distant failure rates compared to radiotherapy lonely. In conclusion concurrent CRT should be considered standard of intendance in this patient population. Sequential CRT is not more than efficacious, simply more toxic than radiotherapy, and should therefore not be routinely used.

Table 3 Chemoradiotherapy vs other modalities for organ preservation in locally advanced HNSCC

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In other anatomical locations, no comparable level i evidence for CRT exists. The earlier EORTC 24891 trial (Lefebvre et al, 1996, 2004) included hypopharynx tumours just merely used sequential CRT. Even so, based on the superior locoregional command rates in comparison to radiotherapy alone in locally advanced unresectable patients, CRT is likely to be at the very to the lowest degree a reasonable choice for organ preservation in full general.

An evolving role for consecration chemotherapy

The administration of induction chemotherapy prior to definitive local therapy remains controversial. The involvement in systemically active chemotherapy arose from the observation that, with highly effective local control measures, the majority of patients, who failed therapy, would recur at a distant site. This was presumably from micrometastatic disease that local therapy or lower dose chemotherapy as function of chemoradiation would non adequately treat. This theoretical statement has been tested in several trials that have been unable to show a consequent survival do good (1987; Schuller et al, 1988; 1991; Paccagnella et al, 1994; El-Sayed and Nelson 1996; Domenge et al, 2000; Pignon et al, 2000). (Tabular array 4a). Design issues as well as concerns that less effective local therapy in the past may have decreased the power to bear witness a survival benefit, remain. Nevertheless, induction chemotherapy continues to be an ongoing surface area of research with several centres around the globe continuing to investigate this approach, which can produce CR rates in 30–65% of patients and overall response rates of 70–85% (Hitt et al, 2003; Knecht et al, 2003; Knecht et al, 2003; Gustin et al, 2004; Nadeem et al, 2004; Vermorken et al, 2004).

Table 4a Randomized trials of induction (Neoadjuvant) chemotherapy vs no induction chemotherapy in locally advanced HNSCC

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Ii European studies have shown evidence of a survival do good with induction chemotherapy: the Italian GSTTC report (Gruppo di Studio sui Tumori della Testa) (Domenge et al, 2000) demonstrated increased cure rates in a subset of nonoperable patients and the French GETTEC trial (Groupe d'Etude des Tumeurs de la Tete et du Cou), which was closed early (Paccagnella et al, 1994). A large meta-analysis past Pignon et al (2000) furthermore showed a 5% increase in survival only for trials using a cisplatin/fluorouracil (v-FU) combination, reaching statistical significance (P=0.05).

More than recently, two trials compared a triplet combination of a taxane (docetaxel or paclitaxel), cisplatin, and 5-FU (TPF) with doublet cisplatin/5-FU (PF) (Hitt et al, 2003; Vermorken et al, 2004). Consistent in both randomised trials, TPF was well tolerated and significantly more effective in detail in the recently reported EORTC 24971 trial past Vermorken et al (2004), where a significant difference in overall survival was seen. The trials are not fully published, but the data from both trials are consequent suggesting that a triplet combination (TPF) including a taxane has potential to sally as a standard choice for induction chemotherapy in the futurity.

Still induction chemotherapy cannot be considered standard of care due to the lack of convincing phase III evidence, only lower level show suggests that it is reasonably safe and may benefit patients at high risk for distal failure as indicated by advanced nodal involvement. The triplet combination of a taxane, cisplatin, and 5-FU seems to have a high degree of activity and acceptable toxicity (Table 4b) (Hitt et al, 2003; Knecht et al, 2003; Vermorken et al, 2004).

Table 4b Randomized trials of comparing PF vs TPF induction (neoadjuvant) chemotherapies

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Induction chemotherapy and concomitant CRT

The combination of induction chemotherapy and concomitant CRT appears to be of detail involvement due to their complementary effects with the erstwhile leading to a reduction of afar disease and the latter achieving locoregional control. Results of induction chemotherapy followed by CRT are encouraging (Hainsworth et al, 2002; Machtay et al, 2002; Haraf et al, 2003; Vokes et al, 2003) (Table 4b) and propose a reasonable toxicity profile, lower distal failure rates, and improved survival in comparison with historical controls using the same CRT regimen (Vokes et al, 2003).

In summary, there is a possibility that consecration chemotherapy may improve survival in locally advanced HNSCC in combination with CRT every bit suggested by lower level evidence. Adequate phase III show is non available currently, and until farther data become available, induction chemotherapy should not be used routinely in HNSCC exterior a clinical trial, just may be appropriate given its well-established safety profile in high-risk situations.

Epidermal growth factor receptor inhibition in combination with radiotherapy or CRT

The EGF receptor as well every bit its primary ligand TGF-α are expressed in approximately 80% of HNSCC (Grandis et al, 1996; Grandis et al, 1998) and play an important role in the biology of this disease (Barrandon and Greenish 1987; Grandis et al, 1998; O-charoenrat et al, 2000; Veikkola et al, 2000; Ang et al, 2002). A multitude of agents inhibiting EGFR are in various stages of evolution and encouraging unmarried agent activity has been reported in recurrent or metastatic HNSCC (Cohen EE et al, 2003; Soulieres et al, 2004). Despite the loftier efficacy of electric current treatments, EGFR inhibitors hold hope in 2 important ways: (ane) to further improve efficacy for patients at take chances for recurrence and (2) to decrease treatment-related toxicities by replacing more toxic cytotoxic drugs without jeopardising survival.

A phase III multicentre trial (Bonner et al, 2004) enrolled 424 patients with stage III/Iv HNSCC randomising them to receive radiotherapy with or without concomitant cetuximab, a humanised monoclonal antibiotic directed against the EGFR, as a main treatment. Overall, the regimen was well tolerated, with an increase in class iii cutaneous toxicity from xviii to 34% and some mild increases in allergic reactions. Even though only preliminary data are available, a marked increase in median overall survival from 28 months with radiations alone to 54 months with the add-on of cetuximab was reported. Locoregional command was significantly improved in the cetuximab arm as well (48 vs 56% at 2 years, P=0.02).

These reports are very encouraging; however, the major difficulty in interpreting and using these data is that it remains unclear how radiotherapy plus cetuximab compares to CRT as the reported trial used a control arm that would be considered inferior in light of contempo evidence discussed above. Given the immature nature of the data and in item the disability to compare to electric current standards of intendance, it is prudent to expect until further information becomes bachelor. Still it is reasonable to consider this regimen in patients with poor functioning status, who are not good candidates for CRT or surgery.

Another written report of the combination of gefitinib with CRT (5-FU, hydroxyurea, and twice daily radiotherapy), following induction chemotherapy and followed by gefitinib maintenance, provided insights into a potential role for EGFR inhibitors (Cohen EW et al, 2004). In comparison to previous similarly designed trials, this treatment was at least as efficacious as a comparable taxane-containing regimen (paclitaxel, 5-FU, hydroxyurea, and radiotherapy) (Vokes et al, 1999) and meliorate tolerated. Some other trial exploring the combination of gefitinib and radiation with or without cisplatin is currently ongoing and demonstrates that the combination of gefitinib with cisplatin and radiotherapy appears feasible.

Conclusion

Treatment for locally advanced HNSCC has improved dramatically during the past decade, allowing a word of cure in many patients, and an prove-based algorithm to guide treatment can be created (Effigy i). In detail, CRT has established itself equally a central treatment modality either upfront equally definitive therapy or every bit an adjuvant to surgery, due to its excellent local control rates, increased survival, and college rates of organ preservation. For the future, the integration of EGFR inhibitors is poised to play an increasingly important curative role while potentially decreasing toxicity. Still it may be even more of import to consolidate our current knowledge and abilities and enforce quality standards to allow as many patients as possible to benefit from already first-class handling approaches.

Figure 1

Evidence-based treatment algorithm for direction of locally avant-garde HNSCC.

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Change history

• xvi November 2011

  This newspaper was modified 12 months later initial publication to switch to Creative Commons licence terms, as noted at publication

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Acknowledgements

We give thanks Michelle Scheuer for help in training of the manuscript.

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Affiliations

1. Department of Medicine, Section of Hematology/Oncology, Pritzker School of Medicine, The University of Chicago, Chicago, 60637-1470, IL, U.s.a.

   T Y Seiwert & E Due east Westward Cohen

2. Cancer Research Center, Academy of Chicago, Pritzker School of Medicine, The Academy of Chicago, Chicago, 60637-1470, IL, USA

   East E Due west Cohen

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Correspondence to E East Westward Cohen.

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Seiwert, T., Cohen, E. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 92, 1341–1348 (2005). https://doi.org/10.1038/sj.bjc.6602510

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• Received: 17 January 2005

• Accustomed: 04 February 2005

• Published: 20 April 2005

• Effect Engagement: 25 April 2005

• DOI : https://doi.org/10.1038/sj.bjc.6602510

Keywords

• head & cervix cancer
• chemoradiotheraphy
• squamous jail cell carcinoma (HNSCC)
• epidermal growth cistron receptor (EGFR)

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