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Chemotherapy in Head and Neck Cancer
Chemotherapy in Head and Neck Cancer
CHAPTER 15
Missak Haigentz, Jr.
Since the introduction of the first chemotherapeutic agents during the 1950s, the hope of physicians involved in the care of patients with cancer has been to cure and improve the survival of patients with the use of systemic therapy. Although measures of success for meeting these goals when treating most solid tumors have been modest at best, the evolution of the multidisciplinary treatment of head and neck cancers has challenged traditional surgical oncologic principles and has become the model for organ-preserving and curative-nonsurgical therapies in clinical oncology. Furthermore, increasing knowledge of tumor and molecular biology has led to the rational development of novel and active anticancer drugs with increasingly tolerable toxicity profiles. This chapter will present an overview of chemotherapeutic and biologic therapy for head and neck cancer.
(e.g., surgery, radiation, chemoradiotherapy). Adjuvant therapy is anticancer treatment that is administered after definitive therapy, with the goal of preventing recurrence and improving survival. Evidence of response to therapy is generally defined as complete or partial; however, prolonged disease stability may be another measure of clinical activity in patients with incurable disease. Complete responses, which are often markers of success in clinical oncology, have been observed in laryngeal and other head and neck cancers, particularly among patients with previously untreated disease. However, only in very rare exceptions is chemotherapy alone a curative intervention for previously untreated head and neck cancer. Definitive locoregional therapy with concurrent radiation is needed to control both gross and micrometastatic locoregionally advanced disease.
The role of chemotherapy, which was initially applied only to palliative settings, has evolved into curative management plans for patients with head and neck cancer. The roles of chemotherapy in the management of head and neck cancers are systemic disease cytoreduction, locoregional radiosensitization, or both. Challenges to achieving these end points include preserving the functional status of patients and minimizing toxicities. These conditions are often pronounced in patients with head and neck cancer, who experience considerable morbidity as a result of their disease (e.g., mucositis, dysphagia, cachexia, dyspnea). Considerable improvements in the supportive care of cancer patients have been made to ameliorate the morbidity of cancer therapy, including the use of growth-factor support (e.g., recombinant erythropoietin, granulocyte colonystimulating factor), new antiemetics (e.g., 5-HT3 antagonists, neurokinin antagonists), amifostine to prevent radiation-induced xerostomia, and ongoing research to prevent and treat mucositis. Existing supportive therapies and the development of targeted biologic therapies make increasingly aggressive, curative, nonsurgical regimens possible.
Mechanism of Action and Rationale of Combination Therapy The mechanism of chemotherapeutic activity, although varied, is generally directed toward actively dividing cancer cells. Chemotherapeutic agents are defined as cellcycle specific, which means that they exert specific effects during the different phases of the cell cycle (Figure 15-1), or nonspecific. However, individual classes of chemotherapeutic agents have unique mechanisms of action and are associated with specific toxicity profiles. In the case of solid tumors such as those of head and neck cancer, multiple genetic defects may exist within a heterogeneous tumor population. To maximize anticancer activity and prevent drug resistance, clinical combinations of chemotherapeutic agents are frequently employed in therapeutic regimens. Ideal therapeutic combinations include active agents that have nonoverlapping toxicity profiles when each is administered according to its optimal dose and schedule. The clinical development of targeted biologic therapies in oncology offers the potential for rational combination with either chemotherapy or radiotherapy while minimizing toxicity.
PRINCIPLES OF CHEMOTHERAPY
Radiosensitization
Clinical Settings and End Points
The continued evolution in combinations of curativeintent chemotherapy and radiotherapy has tremendously affected the management of locally advanced head and neck cancer. Aside from the relatively independent, nonoverlapping, and additive activity and toxicity profiles of
Before discussing the various existing therapies, it is important to define several terms used in management plans. Neoadjuvant (induction) therapy is treatment that is administered before a definitive locoregional therapy 181
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Quiescence
G1
Mitosis
M
S
DNA Replication
G2 Figure 15-1. Schematic representation of the cell cycle.
the combination (i.e., local and/or regional for radiotherapy, systemic for chemotherapy), chemotherapeutic and biologic agents have been known to specifically affect tumor response to radiation. Initial studies of combinedmodality therapy involved the use of induction chemotherapy before radiotherapy.1,2 However, several randomized clinical trials involving head and neck cancer have clearly shown that the addition of chemotherapy concurrently with radiation improves locoregional control as compared with radiation alone, often enough to improve survival.3–8 Indeed, recent large, randomized studies have supported the use of concurrent chemoradiotherapy in the postoperative adjuvant setting for patients at high risk of recurrence.9,10 Various mechanisms for chemotherapy-induced radiosensitization (i.e., cell-cycle synchronization, hypoxia sensitization, interference with repair processes) have been proposed, but none have sufficiently explained the observed effects.11 Concurrent chemoradiotherapy is currently a standard treatment for the definitive management of locally advanced head and neck cancer. Although modern chemoradiotherapy regimens have made considerable advances in improving local control, distant failure appears to be increasing.12 To address this need, several investigators are currently exploring an approach known as sequential chemoradiotherapy, which involves the administration of systemic doses of combination chemotherapy followed by concurrent chemoradiotherapy.13–16 This combined approach takes advantage of the benefits of systemic disease chemosensitivity as well as radiosensitization. Common to all such combinations, however, is the concern of additional toxicity to patients as a result not only of the added systemic toxicity of chemotherapy itself but also of the combined effect on locoregional tissues. Indeed, local tissues also appear to be radiosensitized, which results in greater mucositis, weight
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loss, and dysphagia. This is of particular concern in the adjuvant postoperative setting, where certain patients may indeed be overtreated. Furthermore, to accommodate the combination therapy, the toxicity of the concurrent therapy frequently requires less-than-adequate systemic drug dosing. Perhaps this challenge will be best addressed by the sequential approach, as previously described. Optimizing the chemoradiotherapy regimen and the selection of patients for appropriate therapy will be the future challenges for head and neck oncologists.
CLASSES OF CYTOTOXIC CHEMOTHERAPY The cytotoxic chemotherapeutic agents described in this section have been commonly used for the treatment of head and neck cancers.
Platinum Analogues The observation in 1961 that the exposure of bacteria to electromagnetic fields on platinum electrodes resulted in a profound change in their morphology led to the development of platinum complexes as anticancer therapies.17 The platinum analogues are platinum-based compounds that work by inducing platinum-DNA adducts, which results in interstrand and intrastrand DNA cross-links; these then exert effects throughout the cell cycle. Cisplatin (i.e., cis-diamminedichloroplatinum), carboplatin (i.e., cis-diammine-cyclobutanedicarboxylatoplatinum), and oxaliplatin are members of this class of chemotherapeutic agents. The toxicities of cisplatin are primarily myelosuppression, nausea, vomiting, peripheral neuropathy, sensorineural ototoxicity, hypokalemia, hypomagnesemia, and, renal failure, which is the most feared. The potential for severe and protracted nausea and vomiting, which occurs in almost every patient treated with cisplatin and lasts for several days after administration, has been considerably ameliorated by modern antiemetic therapies (e.g., serotonin [5-HT3] receptor antagonists, neurokinin receptor antagonists, dexamethasone); approximately 70% of individuals treated with cisplatin-based chemotherapy regimens today experience no nausea or vomiting.18,19 Aggressive hydration should be administered to prevent renal insufficiency or failure, which may become irreversible. As a result of hydration and electrolyte-replacement concerns for patients with head and neck cancer, who are already prone to dehydration as a result of disease or mucosal toxicity resulting from radiotherapy, the outpatient administration of cisplatin is challenging. Nevertheless, cisplatin is among the most active agents for the treatment of solid tumors, including those of head and neck cancer. It has systemic anticancer effects, and it also induces the potent radiosensitization of cancer cells.
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CHEMOTHERAPY IN HEAD AND NECK CANCER Unlike cisplatin, carboplatin, which is generally associated with less nausea, vomiting, nephrotoxicity, and neurotoxicity, is easily administered in outpatient settings. Myelosuppression, nausea, and vomiting are potential toxicities. Although cisplatin is generally considered to be a more active systemic agent than carboplatin, there is no clinical evidence to support any difference in radiosensitization properties between the two drugs.
Alkylating Agents Alkylating agents were the earliest class of chemotherapeutic agents discovered, and they remain in clinical use. Both cyclophosphamide and its isomer, ifosfamide, exert anticancer effects by alkylating DNA. In addition to causing myelosuppression, nausea, and vomiting, the urinary metabolites of these agents can induce bladder-wall irritation and cause hemorrhagic cystitis. The prevention of hemorrhagic cystitis requires adequate intravenous hydration and the administration of mesna (i.e., sodium 2-mercaptoethane sulfonate), an agent that binds and detoxifies these metabolites. Ifosfamide has been employed in aggressive combination chemotherapy regimens for head and neck cancer.
Peptides Bleomycin is a small peptide that intercalates within DNA strands and results in single- and double-strand DNA breaks. Although bleomycin is an active agent in head and neck cancer, both the feared potential toxicity of pulmonary fibrosis and the development of other active agents for the treatment of head and neck cancer have not increased its use in modern chemotherapy regimens.
Antimetabolites Antimetabolites interfere with the key metabolic pathways of tumor cells. These agents are thought to exert effects specific to the S-phase (i.e., the DNA synthesis phase) of the cell cycle. 5-Fluorouracil (5-FU) is a fluorinated nucleoside analogue of uracil that inhibits the thymidylate synthase enzyme, which interferes with thymine incorporation into replicating DNA. Methotrexate is an antifolate compound that inhibits the dihydrofolate reductase enzyme. Although both agents have low emetogenic potential, toxicities of these agents include myelosuppression, mucositis, and diarrhea. Because 5-FU is commonly administered as a 24-hour continuous infusion, outpatient administration requires the placement of central venous access devices (e.g., peripherally inserted central catheter lines, port-a-caths).
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Combination regimens of 5-FU with cisplatin have demonstrated high rates of clinical response in both previously untreated and recurrent disease.20–26 The most commonly used combination regimen involves the administration of 80 mg/m2 to 120 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1000 mg/m2/day. Methotrexate as a single agent has considerable activity against head and neck cancer. The standard dose and schedule for palliative treatment (40–50 mg/m2/ week) is tolerable, and it is as active as cisplatin used as a single agent.27–29 Much more aggressive doses in combination with the leucovorin rescue of myelosuppression have not been found to be more effective in randomized studies.30 Hydroxyurea, which is an inhibitor of ribonucleotide reductase, is an orally bioavailable agent. Although hydroxyurea has no proven systemic activity for the treatment of head and neck cancer, it is a potent radiosensitizer.31 Gemcitabine, which is a difluorinated analogue of deoxycytidine that is active in non–small-cell lung cancer, bladder cancer, and other malignancies, has not shown encouraging results in phase II studies of patients with head and neck cancer with recurrent disease.32,33 Despite apparent poor systemic activity, however, it is considered a very potent radiosensitizing agent in head and neck cancer.34
Topoisomerase Inhibitors Topoisomerase inhibitors inhibit DNA replication. Members of the camptothecin family, topotecan and irinotecan, are inhibitors of the topoisomerase I enzyme. Etoposide (i.e., VP-16) is an inhibitor of the topoisomerase II enzyme. Doxorubicin (Adriamycin) has antitopoisomerase II activity.
Taxanes The taxanes are a relatively new class of anticancer agents that interfere with microtubule function. Microtubules, which are complexes of tubulin proteins, assemble (i.e., polymerize) and disassemble (i.e., depolymerize) throughout the cell cycle; these functions are critical to cell division and migration. Paclitaxel (Taxol), the first member of this class, binds to polymerized tubulin and inhibits microtubule depolymerization, resulting in cell-cycle arrest during the G2/M phase of the cell cycle (i.e., the metaphase–anaphase boundary). Docetaxel (Taxotere) has a greater affinity for tubulin than paclitaxel, and it also promotes microtubule stabilization. The taxanes are considered to be among the most active chemotherapeutic agents against head and
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neck cancers, with both systemic and radiosensitizing properties.35–38 Although both agents cause minimal nausea and vomiting, they are myelosuppressive, and they can be associated with hypersensitivity reactions. Additionally, paclitaxel can induce peripheral neuropathy, which can be severe and irreversible.
ACTIVITY OF CHEMOTHERAPEUTIC AGENTS IN HEAD AND NECK CANCER Table 15-1 presents the systemic-disease response rates of cytotoxic chemotherapies in clinical trials of individuals with recurrent or metastatic squamous cell carcinoma of the head and neck. It is important to note that the variability in response rates is associated with the extent of prior patient therapy. Of special note is that previously untreated head and neck cancer is a remarkably chemosensitive disease. However, the response rates of recurrent or metastatic head and neck cancer in
TABLE 15-1 Response Rates of Chemotherapeutic Agents in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Response Rate (%) Single Agents Methotrexate27–30
10–30
Cisplatin23,24,27,39
10–30
Carboplatin40
24
5-FU23
13
Paclitaxel37,41
Although combinations of chemotherapeutics are associated with greater response rates as compared with single agents, their toxicity is greater.23 Unfortunately, no survival improvement for patients with recurrent or metastatic head and neck cancer has been demonstrated with more aggressive combinations. The role of chemotherapy in this setting is only palliative. The largest strides in this field have been in curative combinations of chemotherapy with radiotherapy.
Biologic Therapies A growing understanding of tumor and molecular biology has led to the rational development of novel and active anticancer drugs with increasingly tolerable toxicity profiles, and several agents have shown activity in patients with head and neck cancer. Among the most studied biologic anticancer targets has been the epidermal growth factor receptor (EGFR), a cell-surface receptor with tyrosine kinase activity involved in signal transduction pathways that relate to cell proliferation, survival, and angiogenesis. It is overexpressed in approximately 90% of head and neck cancers. This overexpression is associated with the progression of the carcinogenesis of head and neck cancer, and it is associated with a worsened prognosis, thereby making it an attractive target for the development of anticancer therapy.52
13–40
Docetaxel38
32
Gemcitabine32,33
0–13
Vinorelbine42,43
7–14
Combinations Cisplatin ⫹ 5-FU20–26
27–72
Cisplatin ⫹ Paclitaxel
26–44
26–36
Paclitaxel ⫹ Carbo45,46
20–30
Docetaxel ⫹ Cisplatin
40
47
Triplets Pac ⫹ Ifos ⫹ Carbo48
59
Pac ⫹ Ifos ⫹ Cis49
58
Docetaxel ⫹ Cis ⫹ 5-FU50,51
40–44
5-FU, 5-Fluorouracil; Carbo, carboplatin; Cis, Cisplatin; Ifos, ifosfamide; Pac, paclitaxel.
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patients with either distant metastases or unresectable local disease after the failure of primary radiotherapy/ chemoradiotherapy are generally dismal. A critical review of the published literature for patient populations tested in clinical trials is therefore necessary.
Although several agents targeting the EGFR are under active clinical investigation, the most studied agents have been gefitinib (i.e., ZD 1839, IRESSA), erlotinib (i.e., OSI-774, Tarceva), and cetuximab (i.e., C225, Erbitux). Both gefitinib and erlotinib are small-molecule, orally bioavailable inhibitors of the EGFR tyrosine kinase. Cetuximab is a chimeric human and mouse monoclonal antibody that tightly binds to the EGFR, thereby preventing the binding of its ligand (i.e., epidermal growth factor) and resulting in the internalization and downregulation of the receptor. The toxicity profiles of these cytostatic agents are strikingly different from those of the cytotoxic chemotherapies. The most common toxicities of these agents are the development of an acneiform skin rash and diarrhea, which are usually tolerable but can be severe. For as-yet-unknown reasons, the severity of the skin rash appears to be associated with disease response and survival for both erlotinib and gefitinib but not for cetuximab.53–55 Cetuximab administration has rarely been associated with severe, sometimes life-threatening hypersensitivity reactions.
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TABLE 15-2 Single-Agent Activity of Biologic Agents Targeting the Epidermal Growth Factor Receptor in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Single Agents
No. of Patients
Response Rate
Disease Control
Median Survival
Gefitinib (ZD 1839, Iressa)53
52
10.6%
53%
8.1 months
Erlotinib (OSI-774, Tarceva)54
115
4.5%
38%
6 months
Cetuximab (C225, Erbitux)55
103
53%
5.9 months
12%
Table 15-2 presents the single-agent activity of these therapies for patients with recurrent or metastatic head and neck cancer. Although clinical response rates are modest, it is important to note that they are not dissimilar to the activity of the previously mentioned cytotoxic agents in this patient population. However, the rates of disease stabilization and disease control are much higher, and they may be clinically meaningful for this incurable patient population. Furthermore, the tolerable toxicity profiles of these agents allow them to be combined safely with other chemotherapies; several such combinations are being investigated in clinical trials. Recently presented results of one randomized combination therapy have demonstrated, for the first time, a significant survival benefit associated with adding cetuximab to first-line platinum-based chemotherapy for patients with recurrent and metastatic disease.56 There is considerable hope for integrating these relatively less toxic agents with radiotherapy regimens for the treatment of primary disease. The first and most thoroughly studied biologic therapy combined with radiation (i.e., bioradiotherapy) to date is cetuximab, a monoclonal antibody that has high affinity for the EGFR; this combination prevents the binding of ligand to the EGFR and induces receptor downregulation. Preclinical evidence suggested the cetuximabinduced enhancement of the cytotoxic effects of radiotherapy in squamous cell carcinomas, and early clinical feasibility studies suggested that the regimen was well tolerated and active.57 These encouraging results led to the first randomized study of bioradiotherapy in head and neck cancer, which was published in 2006.58 A total of 424 patients with untreated, locoregionally advanced, stage III and IV head and neck cancer were randomly assigned to treatment with definitive radiotherapy or to radiotherapy with cetuximab. Cetuximab was administered 1 week before radiotherapy as a 400 mg/m2 intravenous loading dose, followed by weekly infusions at 250 mg/m2 for the duration of radiotherapy. The median duration of locoregional disease control and progression-free survival was significantly greater in the cetuximab arm, and the median
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survival of patients was nearly doubled (i.e., 49 months vs. 29.3 months; hazard ratio (HR) ⫽ 0.74 [95% confidence interval, 0.57–0.97]; P ⫽ .03). The regimen was well tolerated; more frequently observed toxicities in the cetuximab plus radiotherapy arm included generally tolerable acneiform rash and potentially serious but uncommon infusion-related hypersensitivity reactions. The incidence of other serious (i.e., ⱖgrade 3) toxic events, including mucositis, did not differ significantly between the treatment arms. Although the study has been criticized for not including a chemoradiotherapy arm and for allowing sites to select a radiotherapy regimen (i.e., once-daily fractions, twice-daily fractions, or concomitant boost), it represents the first effort to clearly demonstrate the radiosensitization of head and neck cancers induced by biologic therapies; this observation is likely to be demonstrated with other future therapies. Randomized studies comparing chemoradiotherapy with cetuximab plus radiation are warranted, and several clinical trials are investigating the incorporation of cetuximab in combination with chemoradiotherapy regimens.59 The future of bioradiotherapy, therefore, appears to be very bright.
SUPPORTIVE CARE The curative potential of existing therapies in head and neck cancer is limited by the morbidity that is associated with therapy. The administration of modern combination chemotherapy regimens and combinations with radiotherapy have been made possible with advances in supportive care. Although erythropoietic agents and granulocyte-colony stimulating factor use can prevent the myelosuppression associated with chemotherapy, their use in combination with radiotherapy is controversial.60 Antiemetic therapy has additionally improved with the development of long-acting 5-HT3 antagonists (e.g., palanosetron) and neurokinin antagonists (e.g., aprepitant). The prevention of radiotherapy-induced xerostomia has improved with newer radiation technologies (e.g., intensity-modulated radiation therapy) and with the use of amifostine.61 However, mucositis and
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dysphagia remain common results of chemoradiotherapy, and the prevention of these toxicities has not been addressed. The use of recombinant keratinocyte growth factor to prevent mucositis is under clinical investigation, but concerns exist regarding its potential for promoting tumor growth. Improvements in supportive care for patients with this disease cannot come at a cost of sacrificing outcomes.
HOPE OF CHEMOPREVENTION The term chemoprevention, which was coined by Dr. Michael Sporn in 1976, applies to therapeutic agents that are able to reverse, suppress, or prevent the development of disease.62 Although great success in cancer chemoprevention has been documented in the adjuvant treatment of early-stage breast cancer with hormonal therapies in patients with appropriate receptor status, no such therapeutic agent has yet been found for head and neck cancer prevention. Of considerable concern is the high incidence of tumor recurrence and the development of second primary tumors, which are the leading causes of mortality among head and neck cancer patients. Although several natural and synthetic agents (e.g., ␣-tocopherol, beta-carotene, 13-cis-retinoic acid) have been studied, none have proven to consistently demonstrate effectiveness and tolerability, which are the characteristics of an ideal chemopreventive agent.63–65 Although it is beyond the scope of this chapter to critically review these studies, the future of chemoprevention in head and neck cancer will depend on the selection of appropriate biomarkers of disease that can be targeted with specific therapies. It is hoped that ongoing studies of maintenance biologic therapies (after curative-intent treatment of primary disease) will lead to the next generation of chemoprevention research in head and neck cancer.
CONCLUSION The development of potentially organ-preserving nonsurgical therapies in head and neck cancer has revolutionized the treatment of this disease and been a model for the nonsurgical management of other cancers. Although significant advances in care have been made, the future of head and neck cancer treatment will ultimately depend on agents and treatment plans that maximize cure while minimizing morbidity. The clinical development of biologic radiosensitizing agents and advances in supportive care are consistent with that goal. To that end, careful attention to organ functionality and quality-of-life issues is needed for all future studies of this disease. Treatment decisions and supportive care for individual patients will continue to be multidisciplinary challenges.
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36. Gan Y, Wientjes MG, Schuller DE, et al: Pharmacodynamics of Taxol in human head and neck tumors. Cancer Res 1996;56: 2086–2093. 37. Forastiere AA, Shank D, Neuberg D, et al: Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinomas of the head and neck: An Eastern Cooperative Group trial (PA390). Cancer 1998;82:2270–2274. 38. Catimel G, Verweij J, Mattijssen V, et al: Docetaxel (Taxotere): An active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck: EORTC Early Clinical Trials Group. Ann Oncol 1994;5:533–537. 39. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646–8654. 40. Al-Sarraf M, Metch B, Kish J, et al: Platinum analogs in recurrent and advanced head and neck cancer: A Southwest Oncology Group and Wayne State University Study. Cancer Treat Rep 1987;71:723–726. 41. Langer CJ, Li Y, Jennings T, et al: Phase II evaluation of 96-hour paclitaxel infusion in advanced (recurrent or metastatic) squamous cell carcinoma of the head and neck (E3395): A trial of the Eastern Cooperative Oncology Group. Cancer Invest 2004;22:823–831. 42. Saxman S, Mann B, Canfield V, et al: A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol 1998;21:398–400. 43. Degardin M, Oliveira J, Geoffrois L, et al: An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 1998;9:1103–1107. 44. Forastiere AA, Leong T, Rowinsky E, et al: Phase III comparison of high dose paclitaxel ⫹ cisplatin ⫹ granulocyte colony stimulating factor versus low dose paclitaxel ⫹ cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001;19:1088–1095. 45. Clark JI, Hofmeister C, Choudhury A, et al: Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer 2001;92:2334–2340. 46. Pivot X, Cais L, Cupissol D, et al: Phase II trial of a paclitaxelcarboplatin combination in recurrent squamous cell carcinoma of the head and neck. Oncology 2001;60:66–71. 47. Glisson BS, Murphy BA, Frenette G, et al: Phase II trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol 2002;20:1593–1599. 48. Shin DM, Khuri FR, Glisson BS, et al: Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer 2001;91:1316–1323. 49. Shin DM, Glisson BS, Khuri FR, et al: Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 1998;16:1325–1330. 50. Janinis J, Papadakou M, Xidakis E, et al: Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: A phase II feasibility study. Am J Clin Oncol 2000;23:128–131. 51. Baghi M, Hambek M, Wagenblast J, et al: A phase II trial of docetaxel, cisplatin, and 5-fluorouracil in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). Anticancer Res 2006;26:585–590. 52. Kalyankrishna S, Grandis JR: Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006;24:2666–2672. 53. Cohen EEW, Rosen F, Stadler WM, et al: Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–1987. 54. Soulieres D, Senzer NN, Vokes EE, et al: Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2004;22:77–85.
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55. Trigo J, Hitt R, Koralewski P, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/ metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a Phase II study. Proc Am Soc Clin Oncol 2004;22:5502a. 56. Vermorken J, Mesia R, Vega V, et al: Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy—results of a randomized phase III (Extreme) study. Proc Am Soc Clin Oncol 2007;25:abstr 6091. 57. Huang SM, Harari PM: Anti-EGF receptor monoclonal antibody (C225) inhibits proliferation and enhances radiation sensitivity in human squamous cell carcinoma of the head and neck. Head Neck 1998;20:457. 58. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578. 59. Pfister DG, Su YB, Kraus DH, et al: Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006;24: 1072–1078.
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60. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255–1260. 61. Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18:3339–3345. 62. Sporn MB: Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976;36:2699–2702. 63. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323:795–801. 64. Benner SE, Pajak TF, Lippman SM, et al: Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: Long term follow up. J Natl Cancer Inst 1994;86:140–141. 65. Bairati I, Meyer F, Gelinas M, et al: A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J Natl Cancer Inst 2005;97:481–488.
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CHAPTER 15
Missak Haigentz, Jr.
Since the introduction of the first chemotherapeutic agents during the 1950s, the hope of physicians involved in the care of patients with cancer has been to cure and improve the survival of patients with the use of systemic therapy. Although measures of success for meeting these goals when treating most solid tumors have been modest at best, the evolution of the multidisciplinary treatment of head and neck cancers has challenged traditional surgical oncologic principles and has become the model for organ-preserving and curative-nonsurgical therapies in clinical oncology. Furthermore, increasing knowledge of tumor and molecular biology has led to the rational development of novel and active anticancer drugs with increasingly tolerable toxicity profiles. This chapter will present an overview of chemotherapeutic and biologic therapy for head and neck cancer.
(e.g., surgery, radiation, chemoradiotherapy). Adjuvant therapy is anticancer treatment that is administered after definitive therapy, with the goal of preventing recurrence and improving survival. Evidence of response to therapy is generally defined as complete or partial; however, prolonged disease stability may be another measure of clinical activity in patients with incurable disease. Complete responses, which are often markers of success in clinical oncology, have been observed in laryngeal and other head and neck cancers, particularly among patients with previously untreated disease. However, only in very rare exceptions is chemotherapy alone a curative intervention for previously untreated head and neck cancer. Definitive locoregional therapy with concurrent radiation is needed to control both gross and micrometastatic locoregionally advanced disease.
The role of chemotherapy, which was initially applied only to palliative settings, has evolved into curative management plans for patients with head and neck cancer. The roles of chemotherapy in the management of head and neck cancers are systemic disease cytoreduction, locoregional radiosensitization, or both. Challenges to achieving these end points include preserving the functional status of patients and minimizing toxicities. These conditions are often pronounced in patients with head and neck cancer, who experience considerable morbidity as a result of their disease (e.g., mucositis, dysphagia, cachexia, dyspnea). Considerable improvements in the supportive care of cancer patients have been made to ameliorate the morbidity of cancer therapy, including the use of growth-factor support (e.g., recombinant erythropoietin, granulocyte colonystimulating factor), new antiemetics (e.g., 5-HT3 antagonists, neurokinin antagonists), amifostine to prevent radiation-induced xerostomia, and ongoing research to prevent and treat mucositis. Existing supportive therapies and the development of targeted biologic therapies make increasingly aggressive, curative, nonsurgical regimens possible.
Mechanism of Action and Rationale of Combination Therapy The mechanism of chemotherapeutic activity, although varied, is generally directed toward actively dividing cancer cells. Chemotherapeutic agents are defined as cellcycle specific, which means that they exert specific effects during the different phases of the cell cycle (Figure 15-1), or nonspecific. However, individual classes of chemotherapeutic agents have unique mechanisms of action and are associated with specific toxicity profiles. In the case of solid tumors such as those of head and neck cancer, multiple genetic defects may exist within a heterogeneous tumor population. To maximize anticancer activity and prevent drug resistance, clinical combinations of chemotherapeutic agents are frequently employed in therapeutic regimens. Ideal therapeutic combinations include active agents that have nonoverlapping toxicity profiles when each is administered according to its optimal dose and schedule. The clinical development of targeted biologic therapies in oncology offers the potential for rational combination with either chemotherapy or radiotherapy while minimizing toxicity.
PRINCIPLES OF CHEMOTHERAPY
Radiosensitization
Clinical Settings and End Points
The continued evolution in combinations of curativeintent chemotherapy and radiotherapy has tremendously affected the management of locally advanced head and neck cancer. Aside from the relatively independent, nonoverlapping, and additive activity and toxicity profiles of
Before discussing the various existing therapies, it is important to define several terms used in management plans. Neoadjuvant (induction) therapy is treatment that is administered before a definitive locoregional therapy 181
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Quiescence
G1
Mitosis
M
S
DNA Replication
G2 Figure 15-1. Schematic representation of the cell cycle.
the combination (i.e., local and/or regional for radiotherapy, systemic for chemotherapy), chemotherapeutic and biologic agents have been known to specifically affect tumor response to radiation. Initial studies of combinedmodality therapy involved the use of induction chemotherapy before radiotherapy.1,2 However, several randomized clinical trials involving head and neck cancer have clearly shown that the addition of chemotherapy concurrently with radiation improves locoregional control as compared with radiation alone, often enough to improve survival.3–8 Indeed, recent large, randomized studies have supported the use of concurrent chemoradiotherapy in the postoperative adjuvant setting for patients at high risk of recurrence.9,10 Various mechanisms for chemotherapy-induced radiosensitization (i.e., cell-cycle synchronization, hypoxia sensitization, interference with repair processes) have been proposed, but none have sufficiently explained the observed effects.11 Concurrent chemoradiotherapy is currently a standard treatment for the definitive management of locally advanced head and neck cancer. Although modern chemoradiotherapy regimens have made considerable advances in improving local control, distant failure appears to be increasing.12 To address this need, several investigators are currently exploring an approach known as sequential chemoradiotherapy, which involves the administration of systemic doses of combination chemotherapy followed by concurrent chemoradiotherapy.13–16 This combined approach takes advantage of the benefits of systemic disease chemosensitivity as well as radiosensitization. Common to all such combinations, however, is the concern of additional toxicity to patients as a result not only of the added systemic toxicity of chemotherapy itself but also of the combined effect on locoregional tissues. Indeed, local tissues also appear to be radiosensitized, which results in greater mucositis, weight
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loss, and dysphagia. This is of particular concern in the adjuvant postoperative setting, where certain patients may indeed be overtreated. Furthermore, to accommodate the combination therapy, the toxicity of the concurrent therapy frequently requires less-than-adequate systemic drug dosing. Perhaps this challenge will be best addressed by the sequential approach, as previously described. Optimizing the chemoradiotherapy regimen and the selection of patients for appropriate therapy will be the future challenges for head and neck oncologists.
CLASSES OF CYTOTOXIC CHEMOTHERAPY The cytotoxic chemotherapeutic agents described in this section have been commonly used for the treatment of head and neck cancers.
Platinum Analogues The observation in 1961 that the exposure of bacteria to electromagnetic fields on platinum electrodes resulted in a profound change in their morphology led to the development of platinum complexes as anticancer therapies.17 The platinum analogues are platinum-based compounds that work by inducing platinum-DNA adducts, which results in interstrand and intrastrand DNA cross-links; these then exert effects throughout the cell cycle. Cisplatin (i.e., cis-diamminedichloroplatinum), carboplatin (i.e., cis-diammine-cyclobutanedicarboxylatoplatinum), and oxaliplatin are members of this class of chemotherapeutic agents. The toxicities of cisplatin are primarily myelosuppression, nausea, vomiting, peripheral neuropathy, sensorineural ototoxicity, hypokalemia, hypomagnesemia, and, renal failure, which is the most feared. The potential for severe and protracted nausea and vomiting, which occurs in almost every patient treated with cisplatin and lasts for several days after administration, has been considerably ameliorated by modern antiemetic therapies (e.g., serotonin [5-HT3] receptor antagonists, neurokinin receptor antagonists, dexamethasone); approximately 70% of individuals treated with cisplatin-based chemotherapy regimens today experience no nausea or vomiting.18,19 Aggressive hydration should be administered to prevent renal insufficiency or failure, which may become irreversible. As a result of hydration and electrolyte-replacement concerns for patients with head and neck cancer, who are already prone to dehydration as a result of disease or mucosal toxicity resulting from radiotherapy, the outpatient administration of cisplatin is challenging. Nevertheless, cisplatin is among the most active agents for the treatment of solid tumors, including those of head and neck cancer. It has systemic anticancer effects, and it also induces the potent radiosensitization of cancer cells.
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CHEMOTHERAPY IN HEAD AND NECK CANCER Unlike cisplatin, carboplatin, which is generally associated with less nausea, vomiting, nephrotoxicity, and neurotoxicity, is easily administered in outpatient settings. Myelosuppression, nausea, and vomiting are potential toxicities. Although cisplatin is generally considered to be a more active systemic agent than carboplatin, there is no clinical evidence to support any difference in radiosensitization properties between the two drugs.
Alkylating Agents Alkylating agents were the earliest class of chemotherapeutic agents discovered, and they remain in clinical use. Both cyclophosphamide and its isomer, ifosfamide, exert anticancer effects by alkylating DNA. In addition to causing myelosuppression, nausea, and vomiting, the urinary metabolites of these agents can induce bladder-wall irritation and cause hemorrhagic cystitis. The prevention of hemorrhagic cystitis requires adequate intravenous hydration and the administration of mesna (i.e., sodium 2-mercaptoethane sulfonate), an agent that binds and detoxifies these metabolites. Ifosfamide has been employed in aggressive combination chemotherapy regimens for head and neck cancer.
Peptides Bleomycin is a small peptide that intercalates within DNA strands and results in single- and double-strand DNA breaks. Although bleomycin is an active agent in head and neck cancer, both the feared potential toxicity of pulmonary fibrosis and the development of other active agents for the treatment of head and neck cancer have not increased its use in modern chemotherapy regimens.
Antimetabolites Antimetabolites interfere with the key metabolic pathways of tumor cells. These agents are thought to exert effects specific to the S-phase (i.e., the DNA synthesis phase) of the cell cycle. 5-Fluorouracil (5-FU) is a fluorinated nucleoside analogue of uracil that inhibits the thymidylate synthase enzyme, which interferes with thymine incorporation into replicating DNA. Methotrexate is an antifolate compound that inhibits the dihydrofolate reductase enzyme. Although both agents have low emetogenic potential, toxicities of these agents include myelosuppression, mucositis, and diarrhea. Because 5-FU is commonly administered as a 24-hour continuous infusion, outpatient administration requires the placement of central venous access devices (e.g., peripherally inserted central catheter lines, port-a-caths).
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Combination regimens of 5-FU with cisplatin have demonstrated high rates of clinical response in both previously untreated and recurrent disease.20–26 The most commonly used combination regimen involves the administration of 80 mg/m2 to 120 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1000 mg/m2/day. Methotrexate as a single agent has considerable activity against head and neck cancer. The standard dose and schedule for palliative treatment (40–50 mg/m2/ week) is tolerable, and it is as active as cisplatin used as a single agent.27–29 Much more aggressive doses in combination with the leucovorin rescue of myelosuppression have not been found to be more effective in randomized studies.30 Hydroxyurea, which is an inhibitor of ribonucleotide reductase, is an orally bioavailable agent. Although hydroxyurea has no proven systemic activity for the treatment of head and neck cancer, it is a potent radiosensitizer.31 Gemcitabine, which is a difluorinated analogue of deoxycytidine that is active in non–small-cell lung cancer, bladder cancer, and other malignancies, has not shown encouraging results in phase II studies of patients with head and neck cancer with recurrent disease.32,33 Despite apparent poor systemic activity, however, it is considered a very potent radiosensitizing agent in head and neck cancer.34
Topoisomerase Inhibitors Topoisomerase inhibitors inhibit DNA replication. Members of the camptothecin family, topotecan and irinotecan, are inhibitors of the topoisomerase I enzyme. Etoposide (i.e., VP-16) is an inhibitor of the topoisomerase II enzyme. Doxorubicin (Adriamycin) has antitopoisomerase II activity.
Taxanes The taxanes are a relatively new class of anticancer agents that interfere with microtubule function. Microtubules, which are complexes of tubulin proteins, assemble (i.e., polymerize) and disassemble (i.e., depolymerize) throughout the cell cycle; these functions are critical to cell division and migration. Paclitaxel (Taxol), the first member of this class, binds to polymerized tubulin and inhibits microtubule depolymerization, resulting in cell-cycle arrest during the G2/M phase of the cell cycle (i.e., the metaphase–anaphase boundary). Docetaxel (Taxotere) has a greater affinity for tubulin than paclitaxel, and it also promotes microtubule stabilization. The taxanes are considered to be among the most active chemotherapeutic agents against head and
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neck cancers, with both systemic and radiosensitizing properties.35–38 Although both agents cause minimal nausea and vomiting, they are myelosuppressive, and they can be associated with hypersensitivity reactions. Additionally, paclitaxel can induce peripheral neuropathy, which can be severe and irreversible.
ACTIVITY OF CHEMOTHERAPEUTIC AGENTS IN HEAD AND NECK CANCER Table 15-1 presents the systemic-disease response rates of cytotoxic chemotherapies in clinical trials of individuals with recurrent or metastatic squamous cell carcinoma of the head and neck. It is important to note that the variability in response rates is associated with the extent of prior patient therapy. Of special note is that previously untreated head and neck cancer is a remarkably chemosensitive disease. However, the response rates of recurrent or metastatic head and neck cancer in
TABLE 15-1 Response Rates of Chemotherapeutic Agents in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Response Rate (%) Single Agents Methotrexate27–30
10–30
Cisplatin23,24,27,39
10–30
Carboplatin40
24
5-FU23
13
Paclitaxel37,41
Although combinations of chemotherapeutics are associated with greater response rates as compared with single agents, their toxicity is greater.23 Unfortunately, no survival improvement for patients with recurrent or metastatic head and neck cancer has been demonstrated with more aggressive combinations. The role of chemotherapy in this setting is only palliative. The largest strides in this field have been in curative combinations of chemotherapy with radiotherapy.
Biologic Therapies A growing understanding of tumor and molecular biology has led to the rational development of novel and active anticancer drugs with increasingly tolerable toxicity profiles, and several agents have shown activity in patients with head and neck cancer. Among the most studied biologic anticancer targets has been the epidermal growth factor receptor (EGFR), a cell-surface receptor with tyrosine kinase activity involved in signal transduction pathways that relate to cell proliferation, survival, and angiogenesis. It is overexpressed in approximately 90% of head and neck cancers. This overexpression is associated with the progression of the carcinogenesis of head and neck cancer, and it is associated with a worsened prognosis, thereby making it an attractive target for the development of anticancer therapy.52
13–40
Docetaxel38
32
Gemcitabine32,33
0–13
Vinorelbine42,43
7–14
Combinations Cisplatin ⫹ 5-FU20–26
27–72
Cisplatin ⫹ Paclitaxel
26–44
26–36
Paclitaxel ⫹ Carbo45,46
20–30
Docetaxel ⫹ Cisplatin
40
47
Triplets Pac ⫹ Ifos ⫹ Carbo48
59
Pac ⫹ Ifos ⫹ Cis49
58
Docetaxel ⫹ Cis ⫹ 5-FU50,51
40–44
5-FU, 5-Fluorouracil; Carbo, carboplatin; Cis, Cisplatin; Ifos, ifosfamide; Pac, paclitaxel.
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patients with either distant metastases or unresectable local disease after the failure of primary radiotherapy/ chemoradiotherapy are generally dismal. A critical review of the published literature for patient populations tested in clinical trials is therefore necessary.
Although several agents targeting the EGFR are under active clinical investigation, the most studied agents have been gefitinib (i.e., ZD 1839, IRESSA), erlotinib (i.e., OSI-774, Tarceva), and cetuximab (i.e., C225, Erbitux). Both gefitinib and erlotinib are small-molecule, orally bioavailable inhibitors of the EGFR tyrosine kinase. Cetuximab is a chimeric human and mouse monoclonal antibody that tightly binds to the EGFR, thereby preventing the binding of its ligand (i.e., epidermal growth factor) and resulting in the internalization and downregulation of the receptor. The toxicity profiles of these cytostatic agents are strikingly different from those of the cytotoxic chemotherapies. The most common toxicities of these agents are the development of an acneiform skin rash and diarrhea, which are usually tolerable but can be severe. For as-yet-unknown reasons, the severity of the skin rash appears to be associated with disease response and survival for both erlotinib and gefitinib but not for cetuximab.53–55 Cetuximab administration has rarely been associated with severe, sometimes life-threatening hypersensitivity reactions.
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TABLE 15-2 Single-Agent Activity of Biologic Agents Targeting the Epidermal Growth Factor Receptor in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Single Agents
No. of Patients
Response Rate
Disease Control
Median Survival
Gefitinib (ZD 1839, Iressa)53
52
10.6%
53%
8.1 months
Erlotinib (OSI-774, Tarceva)54
115
4.5%
38%
6 months
Cetuximab (C225, Erbitux)55
103
53%
5.9 months
12%
Table 15-2 presents the single-agent activity of these therapies for patients with recurrent or metastatic head and neck cancer. Although clinical response rates are modest, it is important to note that they are not dissimilar to the activity of the previously mentioned cytotoxic agents in this patient population. However, the rates of disease stabilization and disease control are much higher, and they may be clinically meaningful for this incurable patient population. Furthermore, the tolerable toxicity profiles of these agents allow them to be combined safely with other chemotherapies; several such combinations are being investigated in clinical trials. Recently presented results of one randomized combination therapy have demonstrated, for the first time, a significant survival benefit associated with adding cetuximab to first-line platinum-based chemotherapy for patients with recurrent and metastatic disease.56 There is considerable hope for integrating these relatively less toxic agents with radiotherapy regimens for the treatment of primary disease. The first and most thoroughly studied biologic therapy combined with radiation (i.e., bioradiotherapy) to date is cetuximab, a monoclonal antibody that has high affinity for the EGFR; this combination prevents the binding of ligand to the EGFR and induces receptor downregulation. Preclinical evidence suggested the cetuximabinduced enhancement of the cytotoxic effects of radiotherapy in squamous cell carcinomas, and early clinical feasibility studies suggested that the regimen was well tolerated and active.57 These encouraging results led to the first randomized study of bioradiotherapy in head and neck cancer, which was published in 2006.58 A total of 424 patients with untreated, locoregionally advanced, stage III and IV head and neck cancer were randomly assigned to treatment with definitive radiotherapy or to radiotherapy with cetuximab. Cetuximab was administered 1 week before radiotherapy as a 400 mg/m2 intravenous loading dose, followed by weekly infusions at 250 mg/m2 for the duration of radiotherapy. The median duration of locoregional disease control and progression-free survival was significantly greater in the cetuximab arm, and the median
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survival of patients was nearly doubled (i.e., 49 months vs. 29.3 months; hazard ratio (HR) ⫽ 0.74 [95% confidence interval, 0.57–0.97]; P ⫽ .03). The regimen was well tolerated; more frequently observed toxicities in the cetuximab plus radiotherapy arm included generally tolerable acneiform rash and potentially serious but uncommon infusion-related hypersensitivity reactions. The incidence of other serious (i.e., ⱖgrade 3) toxic events, including mucositis, did not differ significantly between the treatment arms. Although the study has been criticized for not including a chemoradiotherapy arm and for allowing sites to select a radiotherapy regimen (i.e., once-daily fractions, twice-daily fractions, or concomitant boost), it represents the first effort to clearly demonstrate the radiosensitization of head and neck cancers induced by biologic therapies; this observation is likely to be demonstrated with other future therapies. Randomized studies comparing chemoradiotherapy with cetuximab plus radiation are warranted, and several clinical trials are investigating the incorporation of cetuximab in combination with chemoradiotherapy regimens.59 The future of bioradiotherapy, therefore, appears to be very bright.
SUPPORTIVE CARE The curative potential of existing therapies in head and neck cancer is limited by the morbidity that is associated with therapy. The administration of modern combination chemotherapy regimens and combinations with radiotherapy have been made possible with advances in supportive care. Although erythropoietic agents and granulocyte-colony stimulating factor use can prevent the myelosuppression associated with chemotherapy, their use in combination with radiotherapy is controversial.60 Antiemetic therapy has additionally improved with the development of long-acting 5-HT3 antagonists (e.g., palanosetron) and neurokinin antagonists (e.g., aprepitant). The prevention of radiotherapy-induced xerostomia has improved with newer radiation technologies (e.g., intensity-modulated radiation therapy) and with the use of amifostine.61 However, mucositis and
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dysphagia remain common results of chemoradiotherapy, and the prevention of these toxicities has not been addressed. The use of recombinant keratinocyte growth factor to prevent mucositis is under clinical investigation, but concerns exist regarding its potential for promoting tumor growth. Improvements in supportive care for patients with this disease cannot come at a cost of sacrificing outcomes.
HOPE OF CHEMOPREVENTION The term chemoprevention, which was coined by Dr. Michael Sporn in 1976, applies to therapeutic agents that are able to reverse, suppress, or prevent the development of disease.62 Although great success in cancer chemoprevention has been documented in the adjuvant treatment of early-stage breast cancer with hormonal therapies in patients with appropriate receptor status, no such therapeutic agent has yet been found for head and neck cancer prevention. Of considerable concern is the high incidence of tumor recurrence and the development of second primary tumors, which are the leading causes of mortality among head and neck cancer patients. Although several natural and synthetic agents (e.g., ␣-tocopherol, beta-carotene, 13-cis-retinoic acid) have been studied, none have proven to consistently demonstrate effectiveness and tolerability, which are the characteristics of an ideal chemopreventive agent.63–65 Although it is beyond the scope of this chapter to critically review these studies, the future of chemoprevention in head and neck cancer will depend on the selection of appropriate biomarkers of disease that can be targeted with specific therapies. It is hoped that ongoing studies of maintenance biologic therapies (after curative-intent treatment of primary disease) will lead to the next generation of chemoprevention research in head and neck cancer.
CONCLUSION The development of potentially organ-preserving nonsurgical therapies in head and neck cancer has revolutionized the treatment of this disease and been a model for the nonsurgical management of other cancers. Although significant advances in care have been made, the future of head and neck cancer treatment will ultimately depend on agents and treatment plans that maximize cure while minimizing morbidity. The clinical development of biologic radiosensitizing agents and advances in supportive care are consistent with that goal. To that end, careful attention to organ functionality and quality-of-life issues is needed for all future studies of this disease. Treatment decisions and supportive care for individual patients will continue to be multidisciplinary challenges.
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