13 Applications in Head and Neck Cancer
Deepak Khuntia, Anne M. Traynor, Paul M. Harari, and Jean Bourhis
D. Khuntia, MD
Assistant Professor, Department of Human Oncology, Univer- sity of Wisconsin, 600 Highland Avenue, K4 312-3684, Madi- son, WI 53792, USA
A. M. Traynor, MD
Assistant Professor, Department of Medicine, University of Wisconsin, 600 Highland Avenue, K4 312-3684, Madison, WI 53792, USA
P. M. Harari, MD
Jack Fowler Professor, Department of Human Oncology, University of Wisconsin, 600 Highland Avenue, K4 312-3684, Madison, WI 53792, USA
J. Bourhis, MD
Professor, Head of Radiation Oncology Department, Institute Gustave-Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France
13.1
Introduction
Head and neck (H&N) cancer refers to a heteroge- neous group of epithelial tumors involving the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, salivary glands, and paranasal sinuses. In this chapter we focus discussion primarily on squa- mous cell carcinoma of the H&N, particularly can- cers involving the oral cavity, pharyngeal axis, and larynx. In 2006 there will be approximately 43,000
cases of H&N cancer diagnosed in the United States with over 500,000 cases worldwide (American Cancer Society 2005). Tobacco and alcohol use are major risk factors for the development of H&N cancer. For selected H&N tumors, data also impli- cates Epstein-Barr virus (EBV) and human papil- loma viruses (HPV) in the pathogenesis ( Gillison et al. 2000).
Historically, patients with early-stage disease (stages I–II) are effectively treated with single modality therapy using radiation (RT) or surgery alone. Patients with more advanced-stage disease (stage III–IVb) have generally received combined modality therapy with surgery and radiation; how- ever, advanced-stage H&N cancer patients com- monly experience significant functional and cos- metic deficits that adversely impact both speech and swallowing capacity. In addition, ultimate disease- free survival is modest for advanced stage patients, with 5-year survival rates on the order of 20–40%.
Over the past decade, the integration of systemic chemotherapy (CT) has been shown to improve out- come for several cohorts of advanced stage H&N cancer patients. For the future, there is also reason for optimism that new molecular targeted therapies will further enhance the therapeutic approach in advanced H&N cancer.
In this chapter we review the rationale and clini- cal results for chemoradiation in the management of locoregionally (LR) advanced H&N cancer patients.
13.2
Randomized Trials with Definitive Chemoradiation
13.2.1 Oropharynx
Primary anatomic subsites of the oropharynx include the tonsil, base of tongue, upper posterior pharyngeal wall, and soft palate. Though surgery
CONTENTS
13.1 Introduction 187
13.2 Randomized Trials with Definitive Chemoradiation 187
13.2.1 Oropharynx 187 13.2.2 Larynx 188 13.2.3 Hypopharynx 189 13.2.4 Nasopharynx 190
13.3 Induction Chemotherapy 191
13.4 Induction Chemotherapy Followed by Concurrent Chemoradiation 192
13.5 Adjuvant Chemoradiation after Primary Surgery 193
13.6 Toxicity 193 13.7 Conclusion 194 References 195
alone may be curative for some of these patients, RT is generally preferred in light of the reduced func- tional morbidity. For stage-III and stage-IV disease, randomized trials have recently validated a role for the addition of concurrent CT with RT. Potential dis- advantages to concurrent chemoradiation regimens include increased acute and late toxicity (Holsti and Mantyla 1988; Calais et al. 1999). The acute toxicities, namely mucositis, can be quite severe such that patients may require treatment breaks that can compromise ultimate outcome.
A major trial validating the use of chemoradiation for oropharyngeal tumors comes from the Groupe d’Oncologie Radiothérapie Tête Et Cou (GORTEC).
In this trial, 226 patients were randomized between RT alone (70 Gy in 35 fractions) versus the same RT and three cycles of carboplatin (70 mg/m2) and 5- fluoruracil (600 mg/m2; Calais et al. 1999; Denis et al. 2004). Like cisplatin, carboplatin is a radiosen- sitizer, but it offers fewer acute toxicities, including less nausea, ototoxicity, and diminished need for hydration. In the most recent update of this trial, 5- year overall survival was improved from 16 to 22%
in favor of the chemoradiation arm (Denis et al.
2004). Local control was also improved with CT (see Table 13.1). Pretreatment hemoglobin, stage, and
treatment were found to be of prognostic signifi- cance. Severe late morbidity rates were reported as similar in both arms; however, feeding tube depen- dence, swallowing function, and laryngeal function were not rigorously assessed.
Few other randomized trials exist that focus solely on oropharyngeal cancer patients; however, multiple trials, including a variety of H&N tumor subsites, have been conducted to evaluate the role of concurrent CT with RT. Several of these trials iden- tify a survival benefit for combined chemoradiation vs RT alone and are summarized in Table 13.1.
13.2.2 Larynx
Patients with advanced-stage tumors of the larynx can be managed with partial laryngectomy, total laryngectomy, RT alone, or combined RT and CT.
The choice of therapy depends on a variety of fac- tors, including anatomic extent of disease, patient preference, and local practice patterns. In the U.S., patients receiving radiotherapy often receive induction-CT based on the landmark Veterans Affairs Laryngeal Cancer Study (Department of
Table 13.1. Summary of selected chemoradiation randomized trials
Reference Primary Arms LC (%) OS (%)
Al Sarraf (1998) et al. NP RT
CRT
26 PFSa 66 PFSa
46a 76a
VA Larynx (1991) L Induction CTÆ CRT
Surgery/RT
80b 93b
68 (NS)b 68b Forastiere (2003) et al. L Induction CTÆ CRT
CRT RT
61c 78c 56c
55 (NS)c 54c 56c Calais (1999, 2000) et al. OP RT
CRT
42a/25c 66a/48c
31a/16c 51a/22%c Brizel (2000) et al. L, HP, OP, OC Hyperfractionated RT
Hyperfractionated CRT
44b 70a
34b 55b
Adelstein (2003) et al. Unresectable: L;
HP; OP; OC
RT CRT
Split-course CRT
23b 37b 27b Bernier (2004) et al. Resected: L; HP;
OP; OC
Postop RT CRT
69c 82c
40c 53c Cooper (2004) et al. Resected: L; HP;
OP; OC
Postop RT CRT
72a 82a
NS NS NS not statistically signifi cant, RT radiation, CT chemotherapy, CRT chemoradiation, NP na- sopharynx, L larynx, OP oropharynx, HY hypopharynx, OC oral cavity
aTwo-year data
bThree-year data
cFive-year data
Veterans Affairs Laryngeal Cancer Study Group 1991). This trial was the first randomized H&N trial to use neoadjuvant CT with a primary end point of larynx preservation. Three hundred thirty- two patients with stage-III or stage-IV laryngeal squamous carcinoma were randomized to induction CT (cisplatin and 5-FU) and RT vs laryngectomy fol- lowed by postoperative RT. Patients with no tumor response or with recurrence of their disease went on to salvage laryngectomy. Two-year survival was 68% in both arms. Though more local recurrences were found in the chemoradiation arm, there were fewer distant failures as first site of recurrence. With chemoradiation, the larynx preservation rate was 64% at 5 years (i.e., nearly two-thirds of the surviv- ing patients had their larynx preserved). As a result of this trial, chemoradiation emerged as a standard of care treatment option for many patients with stage-III and stage-IV laryngeal cancer.
In an effort to better examine the optimal timing and necessity for CT, a U.S. Intergroup study was conducted that randomized patients to either induc- tion CT [cisplatin and 5-fluorouracil (5-FU)] then RT vs concurrent chemoradiation (cisplatin) vs RT alone (Forastiere et al. 2003). This study success- fully accrued 547 patients with stage III–IV laryngeal cancer, although patients with advanced T4-stage tumors were specifically excluded. Although there was no difference in overall survival across the three arms, there was improvement in larynx preservation, the primary end point of the trial, with concurrent CT (88%) compared with the induction (75%) and RT (70%) alone arms, respectively. Patients receiving con- current cisplatin also were found to have an improve- ment in local control. With both of the CT arms, an improvement in disease-free survival and distant metastasis rates was realized. As a result of this trial, concurrent cisplatin with RT has become an accepted standard of care in patients undergoing larynx pres- ervation for stage-III and stage-IV disease.
13.2.3 Hypopharynx
Hypopharyngeal tumors include tumors of the pyri- form sinus, postcricoid region, and posterior pha- ryngeal wall. Patients with tumors of the hypophar- ynx tend to have a poor prognosis compared with other subsites within the H&N. Quite commonly, curative therapy requires aggressive surgical resec- tion including at least partial or complete laryngo- pharyngectomy.
In an effort to preserve the larynx, the European Organization for Research and Treatment of Cancer (EORTC) conducted a phase-III trial of 194 patients with stage-II to stage-IV hypopharyngeal tumors and randomized them to receive either definitive laryn- gopharyngectomy with neck dissection followed by RT vs induction CT followed by RT (Lefebvre et al. 1996). Final results showed an improvement in median survival (44 vs 25 months) with chemora- diation, but the 5-year overall survival for the two arms was the same. After 3 years, 28% of patients in the chemoradiation arm were alive with a functional larynx. This study demonstrates that sequential CT/
RT for hypopharyngeal cancer can allow for larynx preservation in some patients, without jeopardizing overall survival.
With regard to definitive chemoradiation vs RT alone, few trials exist that include only primary hypopharyngeal cancers. Multiple trials exist, how- ever, that include hypopharyngeal cancer along with other H&N primaries comparing RT alone vs chemoradiation (Adelstein et al. 2003; Brizel et al. 1998). Several of these trials are summarized in Table 13.1. In addition, the Radiation Therapy Oncol- ogy Group (RTOG) recently published findings from a randomized phase-II study incorporating pacli- taxel into the concurrent chemoradiation treatment of patients with LR advanced oral cavity, oropha- ryngeal, and hypopharyngeal cancers (Garden et al. 2004). Two hundred forty-one patients were randomized to treatment with either cisplatin and 5-FU, hydroxyurea, and 5-FU, or weekly paclitaxel at 30 mg/m2 and weekly cisplatin at 20 mg/m2, along with RT at 70 Gy in 35 fractions. Although statistical comparisons between the arms were not performed, overall grade-3 and grade-4 treatment-related tox- icities appeared slightly greater in the paclitaxel arm; however, the three treatment-related deaths all occurred on the cisplatin and 5-FU arm. Esti- mated 2-year overall survival measured 57.4, 69.4, and 66.6% for the three arms, prompting the inves- tigators to recommend incorporating multi-agent, taxane-containing CT regimens into future com- parative concurrent trials.
There have been several meta-analyses of ran- domized trials performed suggesting a survival benefit with use of concurrent CT with external beam RT in H&N cancer (Munro 1995; El-Sayed and Nelson 1996; Pignon et al. 2000; Bourhis et al.
2004). Among these meta-analyses, one was based on the collection of updated individual patient data.
This meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) previously confirmed a
survival benefit for concurrent chemoradiation and was recently updated to include 24 new trials utiliz- ing chemoradiation completed between 1994 and 2000 (Pignon et al. 2000; Bourhis et al. 2004). This update reconfirmed the benefit of concurrent RT/CT for patients with LR advanced disease, yielding an HR of 0.81 (p<0.001), with an absolute survival ben- efit of 8% at 5 years (Table 13.2). The investigators found no significant difference between mono- and poly-chemotherapy regimens used concurrently.
The benefit was found to be more pronounced for platinum-based combinations with or without 5-FU.
In addition, the benefit of adding chemotherapy was more significant in younger patients and progres- sively decreased to become non-detectable beyond the age of 70 years. Together, these data support the use of concurrent chemoradiation as a standard of care treatment option for stage-III and stage-IV H&N cancer patients who can tolerate systemic che- motherapy.
no further treatment or a combination of vincris- tine, cyclophosphamide, and adriamycin for six monthly cycles (Rossi et al. 1988). At 4 years, how- ever, there was no difference in overall survival or disease-free survival. Distant failure was the pri- mary mode of failure in about 50% of the patients on this trial, so additional studies with CT were encouraged.
Chan and colleagues (1995) explored the use of neoadjuvant and adjuvant chemoradiotherapy vs RT alone as a means of intensifying CT. In that study, patients in the combined modality arm received two cycles of induction cisplatin followed by radical RT and then four cycles of adjuvant cis- platin. Again, there was no difference in overall survival, disease-free survival, local control, or distant metastasis. It was not until the completion of Intergroup Study 0099 that combined modality treatment became a broadly accepted standard of care for patients with advanced nasopharyngeal cancer. In this study, patients were randomized to concurrent and adjuvant chemoradiation vs RT alone. Patients on the experimental arm received cisplatin (100 mg/m2) on days 1, 22, and 43 during RT. Adjuvantly, cisplatin (80 mg/m2) and 5-FU (1000 mg/m2) every 4 weeks for three cycles were administered. The RT regimen delivered 70 Gy in 2-Gy-daily fractions in both arms (Al-Sarraf et al. 1998). At 3 years, survival was dramatically higher in the combined arm (76%) vs the RT alone arm (46%). Although this intergroup study enrolled small patient numbers (only 69 and 78 evaluable patients in the RT arm combined modality arm, respectively), achieved exceptionally poor results in the RT alone arm, had a notably different propor- tion of WHO-type histologies than the Asian trials where nasopharynx cancer is endemic, and could not isolate the actual benefit of the adjuvant che- motherapy, the results, nonetheless, were striking enough to promote combined RT/CT as a standard of care in the treatment of patients with advanced nasopharynx cancer.
More recently, several additional trials have examined chemoradiation vs RT alone for naso- pharyngeal cancer deriving from major center experiences in Southeast Asia. Wee et al. (2004) recently reported the results of SQNPO1, a phase- III randomized trial of 220 patients receiving cis- platin and RT vs RT alone. In this trial, there was an 8% overall survival advantage at 2 years (85 vs 77%) in favor of the combined modality treatment arm. This result lends support to the findings of the U.S. Intergroup trial, although with much improved
Table 13.2. Meta-analysis summary results of chemoradiation vs radiation alone. (Adapted from Pignon et al. 2000) Trial category
(chemotherapy)
Hazard ratio Five-year absolute survival benefi t (%) Adjuvant 0.98 (0.851.19) 1
Neoadjuvant 0.95 (0.881.01) 2 Concurrent 0.81 (0.760.88) 8
Overall, there was a 4% absolute benefi t after 5 years
13.2.4 Nasopharynx
Tumors of the nasopharynx are generally consid- ered distinct from other H&N tumors, because of their unique histological, epidemiological, and clin- ical features. On the order of 90% of patients with nasopharyngeal cancer present with cervical lym- phatic involvement with up to 50% presenting with bilateral neck disease. For patients with advanced neck disease, there is a relatively high rate of dis- tant metastasis. As a result, nasopharyngeal cancers were among the first tumors of the H&N to routinely incorporate radiochemotherapy strategies in their management.
The first randomized trial comparing RT with or without CT involved 60–70 Gy of RT via split course over 10 weeks. Patients that achieved a complete response to RT were randomized to receive either
RT alone results and a smaller magnitude of differ- ence between the treatment arms. In a similar trial design from Lee and colleagues (2004) in Hong Kong that enrolled 348 nasopharynx patients, no overall survival advantage was realized with the addition of CT (84% in both arms), though the local control (95 vs 84%) and progression-free survival (76% vs. 68%) favored the combined treatment arm;
therefore, even in geographic regions where naso- pharyngeal cancer (particularly WHO type III) is endemic, there remains some disparate clinical data regarding the absolute impact of CT, though the collective results support general favoring for concomitant chemoradiation in those patients with advanced-stage disease.
The role of adjuvant CT in patients with naso- pharynx cancer remains ill-defined. In general, the use of adjuvant chemotherapy has not proven to be of benefit for H&N cancer patients overall, and the delivery of adjuvant regimens has not been well tol- erated; however, adjuvant chemotherapy was a com- ponent of the U.S. Intergroup nasopharynx trial, and it is not inconceivable that this contributed to the improved outcome for these patients. Kwong et al.
(2003) recently reported on a four-arm randomized trial in Hong Kong comparing concurrent uracil- tegafur with RT vs RT followed by cisplatin and 5-FU alternating with vincristine, bleomycin, and methotrexate for six cycles vs concurrent chemora- diation with adjuvant chemotherapy (per the first two arms) vs RT alone. The study was closed early due to poor accrual. In comparing arms using con- current CT vs those that did not, concurrent RT was found to reduce distant metastases; however, there was only a borderline difference in 3-year overall survival (86.5 vs 76.8%; p=0.06). In reviewing the above nasopharynx trial results, a much smaller difference is observed between the chemoradia- tion vs RT arms compared with that seen in the U.S.
Intergroup trial. In the Hong Kong and Singapore trials, RT alone patients achieved overall survival results that were very similar to the U.S. combined modality arm. There may well be biological differ- ences in the natural history of nasopharynx cancer in the North American vs Asian populations. In the endemic regions, the majority of tumors are WHO grade-III histology as opposed to less than half in the U.S. Intergroup series. These histologi- cal variants carry important distinctions relating to association with EBV (WHO type III), smoking history, propensity for distant metastases, age at presentation, and other features. Based purely on the relative infrequency of nasopharynx cancer in
the U.S., many centers have limited experience in the complex RT treatment design required for these patients.
13.3
Induction Chemotherapy
Several rationales support the concept of induction CT in the multimodality treatment of LR advanced H&N cancer; these include optimal drug distribu- tion in the untreated fully vascularized tumor, tumor shrinkage to enhance local control, treatment of dis- tant metastases, organ preservation, and improved treatment tolerance prior to definitive radiation and/or surgery. Investigators at Wayne State Univer- sity developed induction regimens using cisplatin and 5-FU (PF). Such regimens yielded overall tumor response rates of 70–90%, with complete response rates of 20–50% (Kish et al. 1985; Vokes et al. 1991);
however, with few exceptions, a broad series of ran- domized clinical trials and meta-analyses over the past 2 decades strongly suggest that the induction CT approach does not ultimately enhance local con- trol, disease-free survival, or overall survival.
More recently, organ preservation, rather then overall survival, has served as the primary end point of several studies of induction CT, most nota- bly the Veterans Affairs Laryngeal Cancer Study and the RTOG 9111, discussed previously. These trials established organ preservation as a tangible goal in the non-surgical treatment of LR advanced laryngeal carcinoma. Additionally, the RTOG 9111 trial shed further light on the use of induction CT followed by single agent definitive local treatment (radiotherapy in this case; Forastiere et al. 2003).
In particular, induction PF for two to three cycles followed by RT did not improve larynx preservation rates, overall survival, rates of distant metastases, or local tumor control, and was more toxic compared with RT alone. As previously discussed, concurrent chemoradiation appears the preferred regimen to maximize the possibility of larynx preservation, with RT alone reserved for those patients unable to receive CT.
In an effort to build upon the success of concur- rent chemoradiation in H&N cancer, a renewed inter- est in the concept of induction CT has re-emerged.
Several new cytotoxic agents have been studied as a component of induction CT. Multiple groups have investigated adding taxanes or replacing 5-FU with taxanes (Posner 2001; Posner et al. 2001; Shin et
al. 2002; Fonseca et al. 2005). Shin (et al. 2002) demonstrated an 81% response rate in the induction setting with TIC (paclitaxel, ifosfamide, and carbo- platin); however, the role of carboplatin is unclear as studies have suggested inferior efficacy results when compared head to head with cisplatin (Shin et al. 2002; De Andres et al. 1995). Fonseca et al.
(2005) randomized 83 patients to induction CT with either PF or cisplatin and docetaxel in the phase-II setting. Antitumor response rates were comparable between the two arms, with 70% for the docetaxel group and 69% for the 5-FU patients. Toxicities were likewise fairly similar between the two treatments.
The Dana Farber center has investigated the use of docetaxel added to PF, first with and then without leucovorin (Posner et al. 2001; Colevas et al. 1999).
Forty-three patients with unrestricted primary dis- ease sites received docetaxel at 75 mg/m2, infusional 5-FU at 1000 mg/m2 daily times 4 days, or cisplatin at either 75 or 100 mg/m2 (TPF) for three cycles prior to definitive local therapy. All patients received pro- phylactic antibiotics. While toxicity was consider- able, efficacy outcomes showed a 94% response rate and a pathologically complete response in 18 of the 25 patients sampled (Posner et al. 2001). Prelimi- nary results from Katori et al. (2005) parallel the findings of RTOG 9111, in that induction CT with TPF followed by definitive RT yielded inferior 3-year survival (64%) compared with concurrent chemo- radiation, using slightly dose-reduced TPF (83%).
Finally, the EORTC has reported preliminary results from a phase-III trial randomizing 358 patients to four cycles of induction treatment with either PF vs cisplatin (75 mg/m2), 5-FU (infusional 750 mg/m2 daily times 5 days), and docetaxel (75 mg/m2; TPF), followed by definitive radiotherapy (Vermorken et al. 2004). The investigational arm was less toxic with diminished nausea, vomiting, stomatitis, and fewer toxic deaths (2.3% for the TPF arm and 5.5% for PF). With a median follow-up of 32 months, tumor response (68% for TPF vs 54% for PF; p=0.007), pro- gression-free survival and overall survival all favored patients receiving TPF. While these early data sug- gest that TPF may be superior to PF as an induction CT regimen, the ultimate clinical significance of induction CT preceding definitive local treatment has yet to demonstrate consistent clinical benefit.
With the recent success of concurrent chemoradia- tion, induction CT followed by concurrent chemora- diation should be compared with definitive concur- rent chemoradiation alone, before concluding that induction CT will benefit the overall population of patients with LR advanced H&N cancer.
13.4
Induction Chemotherapy Followed by Concurrent Chemoradiation
Induction chemotherapy followed by concurrent chemoradiation may provide advantages for both phases of treatment: systemic therapy to reduce distant metastases and bimodality for locoregional control. Several groups are studying this treatment scheme in controlled clinical trials. In one study, 42 H&N patients received two cycles of induction CT with cisplatin, 5-FU, and leucovorin, followed by chemoradiation with two cycles of cisplatin at 100 mg/m2 and 70 Gy of external beam RT (Psyrri et al. 2004). Two- and 5-year overall survival rates were 67 and 52%, respectively. Toxicities to both induction and concurrent CT were considered manageable.
Regarding the incorporation of taxanes into induction or concurrent H&N cancer treatment, Hitt et al. (2003) completed a large phase-III study (n=387) that randomized patients to three cycles of induction CT with either PF or cisplatin, 5-FU, and paclitaxel, followed by concurrent chemoradiation using three cycles of full-dose cisplatin and 70 Gy of RT. The primary study end point was the com- plete response rate to induction CT, which may be at odds with historical experience that high rates of antitumor response with induction treatment fail to consistently improve survival. Patients with a variety of H&N disease sites were eligible; muco- sitis was less in the paclitaxel-containing arm. The primary end point of the study was met, in that the complete response rate to the paclitaxel-containing induction regimen was statistically superior (33%) than that seen with PF (14%); survival data are not yet available. This group has also published prelim- inary findings comparing two induction regimens (PF vs TPF), followed by cisplatin-based concur- rent chemoradiation, vs concurrent chemoradia- tion alone (Hitt et al. 2005). Although early rates of complete response are encouraging (>80% fol- lowing all treatment in both induction arms vs 47%
in the concurrent arm), rates of treatment-related mortality appear quite high, exceeding 5% in all arms. The Eastern Cooperative Oncology Group (ECOG) evaluated two cycles of induction carbo- platin and paclitaxel (Cmelak et al. 2005), followed by RT with weekly paclitaxel for patients with unre- sectable laryngeal or oropharyngeal cancer, while Haddad et al. (2005) incorporated TPF induction CT, followed by concurrent chemoradiation with concurrent weekly carboplatin plus either paclitaxel or docetaxel for LR advanced patients. While this
latter study reported an 89% pathological complete response rate to induction treatment in early find- ings, data maturation is needed to better evaluate the impact of induction CT followed by concur- rent chemoradiation as an effective and tolerable treatment regimen. Comparative trials using this approach vs concurrent chemoradiation alone, with comprehensive efficacy, toxicity, and quality-of-life analyses, are necessary to best gauge the potential merits of induction CT in the treatment of patients with LR advanced H&N cancer.
13.5
Adjuvant Chemoradiation after Primary Surgery
In parallel to the success of concurrent chemo- radiation in the definitive H&N treatment setting, efforts have also focused on optimizing adjuvant treatment following surgery in advanced H&N cancer. Two significant trials recently performed by the EORTC and RTOG showed clinical out- come improvements with postoperative concurrent chemoradiation vs RT alone. In the EORTC study, 334 patients with stage-III or stage-IV H&N squa- mous cell cancer were randomized to receive either 66 Gy of RT alone or 66 Gy with 100 mg/m2 cisplatin given every 3 weeks for three cycles. With a median follow-up of 5 years, local control and overall sur- vival were significantly improved in the chemora- diation arm (Bernier et al. 2004). In the RTOG trial, 459 patients were randomized to receive RT alone (60–66 Gy) vs same dose RT with 100 mg/m2 cispla- tin delivered every 3 weeks (Cooper et al. 2004). At 2 years, local control was modestly improved from 72 to 82% with chemoradiotherapy but there was no difference in overall survival.
In an effort to better characterize those patients most likely to benefit from postoperative chemora- diation vs radiation alone, a combined analysis of the pooled data from the RTOG and EORTC trials was conducted (Bernier et al. 2005). Patients with extra- capsular nodal extension and positive margins on the primary resection derived the most benefit from addi- tion of chemotherapy. There was a trend for improved outcome in patients with stage-III to stage-IV dis- ease, perineural invasion, vascular embolisms, or clinically involved level-IV to level-V nodes. Patients with greater than one positive lymph node without ECE did not appear to derive this same benefit. Over- all, the findings of these two trials are consistent
with a previous randomized trial by Bachaud and colleagues (1996). In that trial, stage-III and stage-IV patients with extracapsular nodal spread were ran- domized to weekly cisplatin concurrently with RT vs RT alone. There was an improvement in survival and local control with chemoradiation. None of these trials identified a change in the incidence of distant metastases. For H&N cancer patients with high-risk pathological features following surgery, consider- ation of combined chemoradiation is warranted, although at the cost of increased toxicity.
The potential value and role of CT in the manage- ment of advanced HNSCC has become much better understood in recent years. As discussed, the use of platinum-based CT in conjunction with RT has improved LR disease control, and in some instances, overall survival, however at the expense of increased toxicity in both the definitive and adjuvant settings.
The most common cisplatin schedule validated in randomized trials is 100 mg/m2 on days 1, 22, and 43 during the course of RT. The role of induction CT remains in evolution. This approach has yet to estab- lish clear survival improvement, and the results of RTOG 9111 call into question the precise contribu- tion of induction CT to larynx preservation. Never- theless, the potential role of more effective induction CT regimens preceding concurrent chemoradiation remains under active investigation.
Finally, the optimal use of concurrent CT with altered radiation fractionation regimens requires further validation in controlled clinical trials.
13.6 Toxicity
The intensified H&N chemoradiation treatment regimens are associated with significantly increased acute toxicity profiles. Efforts to reduce the side effects of treatment are actively under investigation.
In the acute setting predominant treatment toxici- ties include mucositis, esophagitis, skin reactions, increased mucous production, and fatigue. Chronic toxicities include xerostomia, soft tissue fibrosis, and several less common adverse effects such as cervical plexopathy, soft tissue, or bone necrosis. Efforts to diminish the negative impact of xerostomia with pilocarpine have shown mixed success (Johnson et al. 1993; Warde et al. 2002; Gosselin et al. 2005).
The use of amifostine has been actively studied in H&N cancer as a normal tissue protector. Trials have been conducted that show promising results with
this agent; however, issues regarding toxicity, cost, patient tolerance, and ultimate efficacy have hin- dered widespread implementation (Buntzel et al.
1998; Brizel et al. 2000; Wasserman et al. 2000;
Wasserman and Brizel 2001a,b; Antonadou et al.
2002; Buntzel et al. 2002; Wasserman et al. 2005).
Rapid advances in high-precision radiation delivery, such as intensity-modulated radiotherapy (IMRT) and tomotherapy, now afford additional opportuni- ties for parotid gland sparing that notably reduce the severity of late xerostomia (see Fig. 13.1).
Two trials conducted through the RTOG are inves- tigating the use of IMRT for H&N cancer patients in an effort to reduce toxicity (RTOG 0022 and RTOG 0225 which recently completed accrual). Recombinant keratinocyte growth factor (KGF) is also under eval- uation in an effort to reduce the acute mucosal toxici- ties of RT or RT/CT. Preclinical results suggest that when given prior and subsequent to RT exposure, oral mucositis may be reduced (Dorr et al. 2005).
13.7 Conclusion
The H&N region is anatomically complex and densely populated with a variety of normal tissue structures and organs that are vital for daily func- tion and life quality. The H&N cancer patients are frequently burdened with substantial cosmetic and functional morbidities from their tumors and from our current treatment regimens. As we gradually increase the percentage of patients who are cured, we may face increasing numbers of patients with chronic H&N dysfunction with regard to swallow
and speech capacity, cervical fibrosis, and other tox- icities. Although the recent outcome improvement with concurrent chemoradiation for advanced H&N cancer patients appears quite real, the magnitude of the overall impact on the broad H&N cancer popula- tion is modest, and the approaches are certainly toxic, complex, and expensive to achieve. The H&N cancer patients commonly carry a variety of comorbidities in light of chronic alcohol and tobacco use, and they are prone to the development of synchronous or meta- chronous upper aerodigestive tract malignancies.
Many patients do not meet basic eligibility criteria for intensive chemoradiation approaches. Nevertheless, improved precision and conformality of radiation dose delivery (e.g., 3D, IMRT, tomotherapy) offers high promise to diminish radiation toxicity in H&N normal tissue structures (salivary gland, auditory apparatus, mandible, spinal cord). New molecular agents that target growth factor receptors central to the growth of many H&N cancers (i.e., cetuximab reviewed in Chap. 8) similarly offer promise to pro- vide less toxic and more discriminate approaches for the future. The hypoxic cell cytotoxin tirapaza- mine is now in final evaluation in two large phase-III H&N chemoradiation trials that will help define the potential role of this agent in improving outcome for advanced H&N cancer patients (Rischin et al. 2005).
New salivary and mucosal protectants continue to emerge that may bring improved efficacy and ease of administration to diminish the adverse impact of RT and CT in H&N cancer patients. For each new treatment strategy, as with the current generation of chemoradiation studies, a rigorous, thorough, and dispassionate evaluation regarding the impact of treatment on the overall welfare of the H&N cancer patient population will be required.
Fig. 13.1. Representative head and neck intensity-modulated radiation therapy (IMRT) plan. Representative IMRT plan for a patient with oropharyngeal cancer. The delineated isodose distribution illustrates sparing of the left parotid gland for reduc- tion in xerostomia
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