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TMPDAPV IN PPArTirc Drugs2on. 71 (12): 1551-1559<br />

InCKAri IrM rKA^II\.>E 0012-0607/11/0012-1561/S55.55/0<br />

© 2011 Adls Data Information BV. Ali rights reserved.<br />

<strong>Management</strong> <strong>of</strong> <strong>Recurrent</strong> <strong>Head</strong> <strong>and</strong><br />

<strong>Neck</strong> <strong>Cancer</strong><br />

Recent Progress <strong>and</strong> Future Directions<br />

Bruce E. Brockstein<br />

Hematology/Oncology, NorthShore University HealthSystem, Evanston, IL, USA<br />

Contents<br />

Abstract 1551<br />

1. <strong>Recurrent</strong> Squamous Carcinoma <strong>of</strong> the <strong>Head</strong> <strong>and</strong> <strong>Neck</strong> 1552<br />

2. Specific Agents 1555<br />

3. Single-Agent versus Combination Ttierapy 1555<br />

4. Biologically Targeted Therapies against Epidermal Growth Factor Receptor 1555<br />

5. Other Molecularly Targeted Therapies 1556<br />

6. Palliative Care Strategies 1557<br />

7. Conclusions 1558<br />

Abstract The incidence <strong>of</strong> squamous cell carcinoma <strong>of</strong> the head <strong>and</strong> neck (SCCHN)<br />

is on the rise in the US despite a drop in cigarette smoking rates. Much <strong>of</strong> this<br />

rise is due to the increasing incidence <strong>of</strong> SCCHN attributable to human papillomavirus<br />

(HPV). HPV-related SCCHN has a high cure rate, which contributes<br />

to the stable death rates despite the increased incidence. Up to half <strong>of</strong><br />

patients with SCCHN will develop recurrence. For these patients, the first<br />

clinical decision is whether the recurrence is potentially treatable for cure, or<br />

is incurable. For those deemed potentially curable, surgical or radiationbased<br />

therapies, or both, are undertaken. For those who have incurable recurrences,<br />

the goals are palliation <strong>and</strong> possibly prolongation <strong>of</strong> life - average<br />

survivals are in the range <strong>of</strong> 6-12 months depending on the type <strong>of</strong> recurrence<br />

<strong>and</strong> other factors.<br />

Several chemotherapy drugs are active in SCCHN, most notably the platinum<br />

compounds, taxanes, fluorouracil (5-FU), methotrexate <strong>and</strong> cetuximab.<br />

Approximately 10-25% <strong>of</strong> patients will respond to treatment with one<br />

<strong>of</strong> these drugs. The response rate is higher for combinations such as a platinum<br />

plus a taxane, a platinum plus 5-FU, a combination <strong>of</strong> the three, or one<br />

<strong>of</strong> more <strong>of</strong> these drugs plus cetuximab. Combination chemotherapy has not<br />

been shown to prolong survival over single-agent therapy, with the exception<br />

<strong>of</strong> the addition <strong>of</strong> cetuximab to a platinum <strong>and</strong> 5-FU combination. A number<br />

<strong>of</strong> orally bioavailable tyrosine kinase inhibitors have been tested or are undergoing<br />

trials in SCCHN. None <strong>of</strong> these has as yet been shown to be more<br />

effective than the currently available drugs. For patients with recurrences<br />

who are undergoing active therapy, <strong>and</strong> especially for those for whom further


1552 Brockstein<br />

American <strong>Cancer</strong> Society figures indicated an<br />

expected 49 260 cases <strong>of</strong> squamous cell carcinoma<br />

<strong>of</strong> the head <strong>and</strong> neck (SCCHN) involving the oral<br />

cavity pharynx, <strong>and</strong> larynx in the US in 2010.''^<br />

This represents an increase over the past 10 years<br />

<strong>of</strong> approximately 9000 cases;'^^ much <strong>of</strong> this increase<br />

is attributable to an increase in the incidence<br />

<strong>of</strong> human papillomavirus (HPV)-related<br />

squamous cell carcinomas <strong>of</strong> the tonsil <strong>and</strong> base<br />

<strong>of</strong> tongue.'^l Thus, despite fewer smokers <strong>and</strong><br />

a decrease in the number <strong>of</strong> tobacco-related<br />

oropharyngeal cases,^'*' the number <strong>of</strong> cases is<br />

actually increasing. Whereas this represents the<br />

eighth or ninth most common malignancy in the<br />

US, in other parts <strong>of</strong> the world, SCCHN is an<br />

even bigger problem. Worldwide, these exact<br />

numbers are harder to ascertain. In that same<br />

10-year period from 2000 to 2010, death rates in<br />

the US are steady at an expected 11 500, representing<br />

about a 75% 'cure' rate. Death rates may<br />

be even higher though, as we know that cure rates<br />

for the two-thirds <strong>of</strong> patients presenting with<br />

locoregionally advanced disease are only in the<br />

range <strong>of</strong> 30-60%. Some <strong>of</strong> these patients with<br />

recurrences may be recorded as having died <strong>of</strong><br />

noncancer-related causes, although some may be<br />

direct or indirect: complications <strong>of</strong> the cancer or<br />

its therapy. In addition, many patients without<br />

recurrences die in a period <strong>of</strong> 5-10 years from<br />

co-morbidities that correlate with head <strong>and</strong> neck<br />

cancer.t'f These include cardiovascular disease<br />

from smoking, pulmonary disease from smoking,<br />

alcohol-related liver problems, <strong>and</strong> other tobacco<strong>and</strong><br />

alcohol-related malignancies, which result in<br />

the death <strong>of</strong> many <strong>of</strong> these patients in a 5-10 year<br />

period while, they are free <strong>of</strong> cancer. Therefore,<br />

although the numbers are hard to ascertain exactly,<br />

<strong>of</strong> the 49 000 patients with head <strong>and</strong> neck<br />

cancer in the US, up to half may at some point<br />

develop a recurrence <strong>of</strong> their SCCHN in a 5-year<br />

period, or die <strong>of</strong> late cancer or treatment-related<br />

complications.<br />

therapy is no longer appropriate or is declined, strict attention is necessary to<br />

palliation <strong>of</strong> pain, oral <strong>and</strong> airway issues, <strong>and</strong> to nutrition, speech, <strong>and</strong> social<br />

<strong>and</strong> psychological issues.<br />

The 'st<strong>and</strong>ard' treatment for SCCHN is dependent<br />

upon numerous factors. Early stage<br />

(I-II) SCCHN is typically treated by surgery or<br />

radiation with approximately equivalent cure<br />

rates. The choice <strong>of</strong> modality depends upon the<br />

expected morbidities <strong>of</strong> each treatment, patient<br />

co-morbidities, available expertise <strong>and</strong> patient<br />

preferences. Patients with locoregionally advanced<br />

(stage III <strong>and</strong> IV) disease are generally<br />

treated with multi-modality therapy. Resectable<br />

oral cavity cancers are generally treated surgically<br />

with postoperative radiation with or without<br />

chemotherapy. In the pharynx <strong>and</strong> larynx,<br />

most locoregionally advanced head <strong>and</strong> neck<br />

cancers are treated with organ preservation intent<br />

with concomitant chemotherapy <strong>and</strong> radiation,<br />

with surgery used for residual disease in the neck<br />

or primary site, or for salvage.<br />

The challenges <strong>of</strong> treating these patients with<br />

recurrent disease, representing up to 50% <strong>of</strong> those<br />

initially diagnosed, are outlined in this review.<br />

PubMed was searched using the terms 'head <strong>and</strong><br />

neck cancer' linked with 'chemotherapy', 'tyrosine<br />

kinase inhibitors', 'reirradiation', 'chemotherapy'<br />

<strong>and</strong> 'r<strong>and</strong>omized trials'; in addition, all<br />

published abstracts from Proceedings <strong>of</strong> the<br />

American Society <strong>of</strong> Clinical Oncology (ASCO)<br />

from 2006-10 were searched.<br />

1. <strong>Recurrent</strong> Squamous Carcinoma <strong>of</strong> the<br />

<strong>Head</strong> <strong>and</strong> <strong>Neck</strong><br />

<strong>Recurrent</strong> SCCHN is <strong>of</strong>ten incurable; however,<br />

recurrent <strong>and</strong> incurable are not synonymous <strong>and</strong><br />

should not be confused. The first clinical question<br />

with any recurrence is to categorize the recurrence<br />

as one that is potentially salvageable for a<br />

cure, or one for which the goals are palliation <strong>and</strong><br />

prolongation <strong>of</strong> life.<br />

Isolated recurrences in the neck or primary site<br />

may be curable. This is most commonly encountered<br />

with isolated neck recurrences in ipsilateral or<br />

© 2011 Adis Data Information BV. All righfs reserved. Drugs 2011:71 (12)


<strong>Management</strong> <strong>of</strong> <strong>Recurrent</strong> <strong>Head</strong> <strong>and</strong> <strong>Neck</strong> <strong>Cancer</strong> 1553<br />

contralateral previously non-dissected necks.<br />

Recurrence in an un-irradiated neck may be<br />

treated for a cure with a first course <strong>of</strong> radiation<br />

or surgery plus radiation in some cases. Likewise,<br />

some primary site recurrences may be salvageable<br />

for cure. Perhaps most notable would be larynx<br />

recurrences in patients previously treated with<br />

organ preservation attempt by radiation with or<br />

without chemotherapy. Salvage laryngectomy in<br />

the setting <strong>of</strong> larynx-only recurrence results in<br />

cure rates <strong>of</strong> up to 50%.'^' Other subsites within<br />

the head <strong>and</strong> neck may be treated for cure<br />

with salvage surgery but with lower cure rates.<br />

Given the high recurrence rates, postoperative<br />

re-irradiation following salvage surgery has been<br />

used. However, one r<strong>and</strong>omized clinical trial has<br />

compared re-irradiation plus chemotherapy postsalvage<br />

surgery with no further therapy. In this<br />

study, there was a disease-free survival benefit for<br />

re-irradiation but no benefit for overall survival.t^'<br />

As with locoregional recurrence in the head<br />

<strong>and</strong> neck, identification <strong>of</strong> distant disease should<br />

first prompt the question on goal <strong>of</strong> therapy. For<br />

example, an isolated lesion in the lung may represent<br />

a second primary lung cancer, which if<br />

diagnosed as a small peripheral lesion may be<br />

treated with surgery with cure rates <strong>of</strong> up to 80%.<br />

There are additional data suggesting that resection<br />

<strong>of</strong> true isolated métastases in the lung, adrenal<br />

gl<strong>and</strong> or other organs may yield 5-year survival<br />

rates <strong>of</strong> 20%,'^ <strong>and</strong> therefore the goal <strong>of</strong> treatment<br />

may be cure, once other distant metastatic disease is<br />

excluded by proper radiological workup.<br />

Locoregional recurrent disease in an inoperable,<br />

previously irradiated field is generally incurable.<br />

An exception to this may be lower volume disease<br />

amenable to treatment with chemotherapy <strong>and</strong><br />

re-irradiation. Several clinical trials have demonstrated<br />

3- to 5-year disease-free rates <strong>of</strong> up to<br />

20% or 30%.t^"'°i Prognostic factors identified<br />

that correlate with increased locoregional control,<br />

progression-free survival or overall survival include<br />

lower tumour bulk at re-irradiation, higher<br />

re-irradiation treatment dose, tumour subsite<br />

(nasopharynx), lack <strong>of</strong> co-morbidities <strong>and</strong> organ<br />

dysfunction, longer interval since prior irradiation,<br />

use <strong>of</strong> intensity-modulated radiation therapy,<br />

<strong>and</strong> specific chemotherapy regimens.'^;'°1 In<br />

general, re-irradiation should only be undertaken<br />

in healthy patients without major co-morbidities<br />

<strong>and</strong> without major sequelae following their first<br />

course <strong>of</strong> radiotherapy.<br />

The remainder <strong>of</strong> this article focuses on those<br />

patients for whom curative therapy is not an available<br />

option. For those patients without an available<br />

curative attempt option, the goals <strong>of</strong> therapy<br />

should be clearly defined to the patient <strong>and</strong> those<br />

helping him or her to make decisions. Some patients<br />

may opt against potentially life-prolonging<br />

therapies given their interpretation <strong>of</strong> the risk <strong>and</strong><br />

benefit issues, <strong>and</strong> may opt for palliative or comfort<br />

care alone. This, too, poses many therapeutic<br />

challenges for these patients, as they are not being<br />

actively treated for their cancer but require significant<br />

multidisciplinary care <strong>and</strong> therapy for<br />

proper palliation <strong>of</strong> tumours that may cause pain<br />

<strong>and</strong> interfere significantly with eating, breathing,<br />

speaking <strong>and</strong> social functioning.<br />

It remains somewhat unproven as to whether<br />

systemic therapy for recurrent SCCHN provides<br />

an advantage in terms <strong>of</strong> duration <strong>of</strong> survival. Only<br />

one study, performed many years ago, compared<br />

chemotherapy with best supportive care, <strong>and</strong><br />

showed a small survival advantage,t"l Multiple<br />

r<strong>and</strong>omized clinical trials <strong>of</strong> single-agent chemotherapy<br />

versus combination chemotherapy (without<br />

a control arm <strong>of</strong> best supportive care) demonstrated<br />

no survival benefit (table I),t'^"'^l with overall<br />

survival durations <strong>of</strong> 6-8 months. In a study assessing<br />

two commonly used two-drug regimens,<br />

no survival difference was seen in a comparison<br />

<strong>of</strong> cisplatin <strong>and</strong> infusional fluorouracil (5-FU)<br />

versus the combination <strong>of</strong> cisplatin <strong>and</strong> taxol,''^'<br />

Modern, multi-agent aggressive chemotherapy<br />

regimens result in median survival durations <strong>of</strong><br />

10-12 months,''^'^^! Lead time bias, associated with<br />

more intensive <strong>and</strong> sensitive radiological monitoring,<br />

however, may artificially inflate survival<br />

numbers now, as recurrent disease is <strong>of</strong>ten discovered<br />

at an earlier time in the natural history <strong>of</strong><br />

the recurrent disease process. Only one.study, the<br />

recent EXTREME (Erbitux in First-Line Treatment<br />

<strong>of</strong> <strong>Recurrent</strong> or Metastatic <strong>Head</strong> <strong>and</strong> <strong>Neck</strong><br />

<strong>Cancer</strong>) trial,P^l has shown an advantage for one<br />

chemotherapy regimen over another. In this trial,<br />

442 patients were r<strong>and</strong>omly assigned to receive<br />

© 2011 Adis Data informotion BV. Aii rights reserved. Drugs 2011; 71 (12)


1554 Brockstein<br />

Table I. R<strong>and</strong>omized trials comparing drug combinations with single agents or comparing drug combinations<br />

study Regimen<br />

SWOGI'21 Cis/5-FU<br />

Carbo/5-FU<br />

MTX<br />

Jacobs et al.'^^' Cis/5-FU<br />

Cis<br />

5-FU<br />

LHNOGl^"! Cis/5-FU<br />

Cis/MTX<br />

Cis<br />

MTX<br />

EORTC'^^1 Cis/5-FU<br />

Cis/MTX/Bleo/V<br />

Cis<br />

SECSG'^^i Cis/Vinbl/Bleo<br />

MTX<br />

ECOG'^'l Cis/MTX/Bleo<br />

MTX<br />

ECOGI'^I Cis/5-FU<br />

No. <strong>of</strong> patients<br />

87<br />

86<br />

88<br />

79<br />

83<br />

83<br />

50<br />

50<br />

50<br />

50<br />

116<br />

127<br />

122<br />

92<br />

98<br />

80<br />

83<br />

98<br />

Response rate (%)<br />

Cis/Taxol<br />

96<br />

28<br />

9<br />

5-FU=fluorouracil; Bleo=bleomycin; Carbo=carboplatin; Ci9=cisplatin; ECOG = Eastem Cooperative Oncology Group; EORTC=European<br />

Organization for the Research <strong>and</strong> Treatment <strong>of</strong> <strong>Cancer</strong>; LHNOG = Liverpool <strong>Head</strong> <strong>and</strong> <strong>Neck</strong> Oncology Group; MTX=methotrexate;<br />

SECSG = Southeastern <strong>Cancer</strong> Study Group; SWOG = Southwest Oncology Group; Taxol = paclitaxel; V=vincristine; Vlnbl = vinblastin8.<br />

infusional 5-FU plus cisplatin or carboplatin <strong>and</strong><br />

weekly cetuximab, or the same chemotherapy<br />

without cetuximab. Chemotherapy was limited to<br />

six cycles, but cetuximab could be continued. The<br />

median survival significantly favoured the cetuximab<br />

arm, 10.1 versus 7.4 months (ha¿ard<br />

ratio [HR] 0.80; 95% CI 0.64, 0.99). However,<br />

there was no crossover to allow cetuximab administration<br />

for those not initially receiving cetuximab.<br />

This may well have artificially turned<br />

what would have been only a progression-free<br />

survival benefit into an overall survival benefit.<br />

No other properly conducted phase III study <strong>of</strong><br />

one regimen versus another has demonstrated a<br />

survival benefit. Thus, the optimal approach<br />

when undertaking systemic therapy remains unclear.<br />

Issues <strong>of</strong> toxicity <strong>and</strong> need for rapidity <strong>of</strong><br />

response should factor into the decision as to the<br />

treatment approach. For example, a patient with<br />

asymptomatic metastatic disease might be optimally<br />

treated with single-agent chemotherapy in<br />

a sequetitial fashion, with change <strong>of</strong> therapy at<br />

32<br />

21<br />

10<br />

32<br />

17<br />

13<br />

24<br />

22<br />

28<br />

12<br />

34<br />

37<br />

16<br />

24<br />

16<br />

48<br />

35<br />

22<br />

Survival rate (%)<br />

time <strong>of</strong> progression. On the other h<strong>and</strong>, a patient<br />

presenting with reasonably good performance<br />

status <strong>and</strong> disease-related symptoms requiring<br />

rapid attention might be best treated with multiagent<br />

chemotherapy, which may lead to a more<br />

reliable response <strong>and</strong> improvement <strong>of</strong> diseaserelated<br />

symptoms. The addition <strong>of</strong> cetuximab<br />

increases progression-free survival, <strong>and</strong> may<br />

improve overall survival, although this remains<br />

unclear.<br />

If available, patients should be <strong>of</strong>fered participation<br />

in clinical trials. In most cases, clinical<br />

trials <strong>of</strong> new drugs not yet demonstrated to be <strong>of</strong><br />

benefit are ethically justifiable based on the lack<br />

<strong>of</strong> survival advantage demonstrated for early<br />

versus delayed therapy <strong>of</strong> incurable SCCHN. Many<br />

<strong>of</strong> the drugs currently used as st<strong>and</strong>ard management<br />

<strong>of</strong> SCCHN (e.g. paclitaxel, docetaxel, cetuximab)<br />

have been identified through clinical trials in the last<br />

10-20 years, <strong>and</strong> those patients participating in<br />

these trials had the first opportunity to benefit from<br />

these most active drugs.<br />

© 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (12)<br />

7<br />

5<br />

6<br />

6<br />

5<br />

6<br />

5<br />

5<br />

7<br />

.4<br />

6<br />

8<br />

5<br />

6<br />

6<br />

6<br />

6<br />

8


<strong>Management</strong> <strong>of</strong> <strong>Recurrent</strong> <strong>Head</strong> <strong>and</strong> <strong>Neck</strong> <strong>Cancer</strong> 1555<br />

2. Specific Agents<br />

There are multiple drugs with single-agent<br />

activity in SCCHN (table II). Drugs such as<br />

methotrexate were evaluated with older response<br />

criteria, in some cases overstating the response<br />

rate,'^'*' now seen to be lower in studies using<br />

modern radiological response evaluation.''^! Direct<br />

comparative studies have not established the<br />

superiority <strong>of</strong> one drug over another; however,<br />

the most active agents, or at least those most commonly<br />

currently used include docetaxel, paclitaxel,<br />

cisplatin, carboplatin, 5-FU, cetuximab <strong>and</strong> methotrexate.<br />

When choosing single-agent therapy,<br />

considerations include expected toxicities, comorbidities<br />

<strong>and</strong> prior therapy. The latter is an<br />

increasingly important consideration, as many patients<br />

who develop recurrent or metastatic disease<br />

have been treated with chemotherapy as part <strong>of</strong> a<br />

multi-modality curative intent chemoradiation<br />

regimen. For example, a patient developing metastatic<br />

disease 3 months after induction chemotherapy<br />

with a platinum <strong>and</strong> taxane-containing<br />

induction chemotherapy regimen would be unlikely<br />

to benefit from re-treatment with these<br />

agents. On the other h<strong>and</strong>, a patient who received<br />

low-dose radio-sensitizing cisplatin along with<br />

radiation, <strong>and</strong> then develops a distant relapse<br />

2 years later, may derive some benefit from a platin<br />

agent by itself or in combination with a taxane or<br />

other drug. As with other cancers, the likelihood<br />

Table II. Single-agent activity <strong>of</strong> chemotherapy drugs<br />

Drug° Response rate (%)<br />

Docetaxel<br />

Paclitaxel<br />

Cisplatin<br />

Carboplatin<br />

Fiuorouracil<br />

Ifosfamide<br />

Methotrexate<br />

Bleomycin<br />

Cetuximab<br />

35<br />

30<br />

20-25<br />

20-25<br />

13<br />

25<br />

20-25<br />

30<br />

10-13<br />

a Gefitinib, eriotinob, bydroxyurea, doxorubicin, cyclophospbamide,<br />

gemcitabine, vinorelbine, irinotecan are also used.<br />

b Response rate variation at least partly accounted for based on era<br />

<strong>of</strong> determination.<br />

<strong>of</strong> responding to additional lines <strong>of</strong> therapy decreases<br />

with each additional line <strong>of</strong> therapy.<br />

3. Single-Agent versus Combination<br />

Therapy<br />

Numerous studies have addressed the question<br />

<strong>of</strong> benefit <strong>of</strong> combination chemotherapy over<br />

single-agent chemotherapy. Virtually all have resulted<br />

in the same conclusion - there is a higher<br />

response rate with two-drug chemotherapy combinations<br />

over single agents in general, with response<br />

rates <strong>of</strong> 30% versus 15%.''^"'^^ However,<br />

there is no associated survival benefit (table I),<br />

but the higher rate <strong>of</strong> response may be important<br />

when a more rapid radiological response (symptomatic<br />

response) is needed. The optimal regimen<br />

will depend on prior chemotherapy. If no prior<br />

chemotherapy has been given, for example in the<br />

setting <strong>of</strong> a patient presenting with recently diagnosed<br />

metastatic disease, then a combination<br />

<strong>of</strong> cisplatin or carboplatin with either 5-FU or a<br />

taxane (paclitaxel or docetaxel) is optimal. A study<br />

comparing cisplatin <strong>and</strong> infusional 5-FU (CF) versus<br />

cisplatin <strong>and</strong> paclitaxel (CP) was undertaken<br />

by the Eastern Cooperative Oncology Group<br />

(ECOG).''^1 This demonstrated equivalent response<br />

<strong>and</strong> survival duration with a different spectrum<br />

<strong>of</strong> toxicity, with increased haematological <strong>and</strong><br />

gastrointestinal toxicity in the CF group, <strong>and</strong><br />

equivalent neurotoxicity in both. The combination<br />

<strong>of</strong> carboplatin <strong>and</strong> a taxane has not been directly<br />

compared with the CF or CP combinations. Modern<br />

three-drug regimens include a combination <strong>of</strong><br />

a taxane, a platinum <strong>and</strong> 5-FU.'^''^^! This has<br />

been most notably tested in the induction chemotherapy<br />

setting where objective response rates<br />

are high (70% in multi-institutional studies), <strong>and</strong><br />

is associated with a survival benefit when compared<br />

with the two-drug CF regimen.'•^^••^^1<br />

4. Biologicaiiy Targeted Therapies<br />

against Epidermai Growth Factor<br />

Receptor<br />

Cetuximab (a monoclonal antibody directed<br />

against epidermal growth factor receptor [EGFR])<br />

was initially approved in 2006 by the US FDA for<br />

© 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (12)


1556 Brockstein<br />

use in combination with radiation therapy for<br />

the treatment <strong>of</strong> locally or regionally advanced<br />

SCCHN or as a single agent for the treatment <strong>of</strong><br />

patients with recurrent or metastatic SCCHN for<br />

whom prior platinum-based therapy has failed. It<br />

remains the only biologically targeted therapy approved<br />

for use in SCCHN, <strong>and</strong> the only drug other<br />

than methotrexate specifically indicated for SCCHN<br />

(docetaxel is indicated for induction chemotherapy<br />

in combination with cisplatin <strong>and</strong> 5-FU).<br />

Initial studies <strong>of</strong> cetuximab in recurrent <strong>and</strong><br />

metastatic SCCHN focused on the use <strong>of</strong> this<br />

drug as a single agent or in combination with<br />

cisplatin (table UTfP''-^^^ Although initial enthusiasm<br />

supported the ability <strong>of</strong> cetuximab to<br />

restore cisplatin sensitivity, with response rates <strong>of</strong><br />

10-13% seen,[^^-^^l single-agent cetuximab in the<br />

same setting resulted in similar response rates.[^"^<br />

Therefore, the concept <strong>of</strong> restoration <strong>of</strong> cisplatin<br />

sensitivity was ab<strong>and</strong>oned, <strong>and</strong> cetuximab is used<br />

without a platinum in the setting <strong>of</strong> refractoriness<br />

to platinum compounds. However, a study in the<br />

first-line setting compared cisplatin alone with<br />

the combination <strong>of</strong> cisplatin plus cetuximab, <strong>and</strong><br />

response rates were significantly different. Specifically,<br />

the combination resulted in a 26% response<br />

rate versus 10% for the single agent (p = 0.03).<br />

Although a trend towards improved overall survival<br />

was seen with the combination, this was not<br />

statistically significant.<br />

Several useful observations regarding chnical<br />

<strong>and</strong> molecular predictive factors for response<br />

to cetuximab came out <strong>of</strong> these studies. For example,<br />

in one study by ECOG,'^''! a survival advantage<br />

was seen by severity <strong>of</strong> skin toxicity<br />

(HR = 0.42, favouring cetuximab for more severe<br />

toxicity). However, the response rate was greater<br />

Table III. Studies <strong>of</strong> cetuximab as single agent or with cisplatin<br />

Study<br />

Burtness et al.'"'<br />

Herbst et al.^«<br />

Baselga et al.^^i<br />

Vermorken et al.P"'<br />

No. <strong>of</strong> pts<br />

117<br />

130<br />

96<br />

103<br />

Combination<br />

Cisplatin -1- cetuximab vs<br />

Cisplatin-1-placebo<br />

Cisplatin-i-cetuximab<br />

Platin+cetuximab<br />

Cetuximab<br />

(cetuximab -i- platinum)<br />

PFS = progression-free survival; pts=patients.<br />

Setting<br />

First line<br />

when EGFR staining was present in


<strong>Management</strong> <strong>of</strong> <strong>Recurrent</strong> <strong>Head</strong> <strong>and</strong> <strong>Neck</strong> <strong>Cancer</strong> 1557<br />

5.5 months. Disease stabilization was seen in 53% in<br />

the 500 mg study. Higher degrees <strong>of</strong> skin toxicity<br />

predicted better response <strong>and</strong> survival for both.<br />

A single-agent phase II trial <strong>of</strong> erlotinib was<br />

conducted in 115 patients.'^^1 Objective responses<br />

were seen in 4.3% <strong>and</strong> disease stabilization in 38%<br />

with a median overall survival <strong>of</strong> 6 months. Disease<br />

control correlated with skin toxicity but not<br />

EGFR expression.<br />

Thus far, pretreatment measures <strong>of</strong> EGFR<br />

have not proven consistently helpful in identifying<br />

those who will respond to EGFR inhibition<br />

by monoclonal antibodies or by TKIs. While skin<br />

toxicity or rash correlates well with response, it<br />

is not a useful pretreatment predictive marker.<br />

Thus, these targeted agents are still given relatively<br />

indiscriminately, based not on molecular predictive<br />

features but rather on clinical features alone.<br />

Both sunitinib <strong>and</strong> sorafenib have been studied<br />

in the setting <strong>of</strong> advanced SCCHN. Sunitinib<br />

has been extensively studied in three clinical trials<br />

as a single agent in advanced SCCHN.'^'*"^^! A<br />

total <strong>of</strong> 77 patients were treated with only two<br />

objective responses, <strong>and</strong> short times to progression<br />

<strong>and</strong> multiple episodes <strong>of</strong> fatal or non-fatal bleeding.<br />

Williamson at al. report a multi-institutional<br />

phase II study from the South Western Oncology<br />

Group (SWOG), utilizing single-agent sorafenib<br />

in patients with no prior chemotherapy for<br />

metastatic disease <strong>and</strong> performance status 0 or<br />

l.'^^l Only one <strong>of</strong> 41 patients responded; however,<br />

median time to progression was 4 months <strong>and</strong><br />

median survival 9 months, better than that seen<br />

with sunitinib or oral EGFR TKIs. However, in a<br />

more advanced population who had been treated<br />

with prior chemotherapy for advanced disease, a<br />

study by Elser et al. demonstrated time to progression<br />

<strong>and</strong> overall survival <strong>of</strong> only 2 <strong>and</strong> 4 months,<br />

respectively, for sorafenib.'^^'<br />

Abidoye et al. treated 42 patients with recurrent<br />

or metastatic SCCHN with lapatanib, an<br />

oral inhibitor <strong>of</strong> EGFR <strong>and</strong> human EGFR 2<br />

(HER2) tyrosine kinases. Of these patients, 27 had<br />

not received prior EGFR therapy <strong>and</strong> 15 had received<br />

prior treatment with an EGFR inhibitor.'^^'<br />

No responses were seen <strong>and</strong> median progressionfree<br />

survival was 1.6 months. Burris et al. treated<br />

seven SCCHN patients with lapatinib in the context<br />

<strong>of</strong> a much larger phase I study; one <strong>of</strong> these seven<br />

patients achieved a partial response.^'**''<br />

Afatinib (BIBW 2992) is an oral irreversible<br />

inhibitor <strong>of</strong> EGFR/HER2 receptor tyrosine kinases.<br />

A study r<strong>and</strong>omizing patients to afatinib<br />

or cetuximab was presented in preliminary form<br />

at ASCO 2010. A total <strong>of</strong> 124 patients were r<strong>and</strong>omized<br />

to oral afatinib or intravenous cetuximab;<br />

101 patients were both évaluable <strong>and</strong> had<br />

response data available. Afatinib patients had a<br />

complete plus partial response rate <strong>of</strong> 22% versus<br />

13%forcetuximab.t'"'<br />

Fury et al. reported a phase II trial <strong>of</strong> semaxinib,<br />

a vascular endothelial growth factor receptor-2<br />

TKI. One <strong>of</strong> 31 patients had a partial response<br />

<strong>and</strong> overall survival was only 6 months.'''^'<br />

Hanrahan et al. treated 15 patients with oral<br />

lonafarnib, an oral farnesyl transferase inhibitor.<br />

None <strong>of</strong> 15 patients responded <strong>and</strong> time to progression<br />

was only 2 months.'''^'<br />

Combination biologicals are also being tested.<br />

The combination <strong>of</strong> gefitinib <strong>and</strong> bevacizumab<br />

was studied in a phase I/II trial <strong>of</strong> 46 patients. At<br />

the phase II dose <strong>of</strong> erlotinib 150mg daily <strong>and</strong><br />

bevacizumab 15mg/kg every 3 weeks, 15% <strong>of</strong><br />

patients responded, with an overall survival <strong>of</strong><br />

7.1 months. Skin rash was near universal <strong>and</strong><br />

diarrhoea very common.'''"'1<br />

Many other studies <strong>of</strong> single-agent biologicals<br />

or combination single-agent biological <strong>and</strong> chemotherapy<br />

are being studied currently.<br />

6. Pailiative Care Strategies<br />

Virtually all patients with incurable, recurrent or<br />

metastatic SCCHN will require aggressive palliative<br />

care (i) as a primary treatment approach; (ii) as<br />

concomitant care during their palliative or lifeprolonging<br />

chemotherapy approach; or (iii) after<br />

exhaustion <strong>of</strong> other therapeutic measures.<br />

Pain is frequently an issue, in particular as<br />

tumours become erosive, ulcerative or space occupying<br />

in the tight, highly innervated head <strong>and</strong><br />

neck region. Other unique challenges include<br />

difficulties with speech <strong>and</strong> swallowing, breathing<br />

<strong>and</strong> social functioning.<br />

Long-acting analgesia may be accomplished with<br />

long-acting oral narcotics, or by transdermal<br />

© 2011 Adis Dafa Information BV. Ali rigiits reserved. Drugs 2011: 71 (12)


1558 Brockstein<br />

narcotic patches or occasionally continuous patientcontrolled<br />

anaesthesia. Breakthrough pain medicines<br />

<strong>of</strong>ten have to be delivered in a liquid form<br />

due to dysphagia or feeing tube use. Surgeons <strong>and</strong><br />

wound care specialists may need to be involved<br />

with tumours that ulcerate through skin or cause<br />

orocutaneous or pharyngealcutanous fistula.<br />

Oral, laryngeal or trachéal airways may become<br />

compromised late in the course <strong>of</strong> the disease,<br />

Tracheostomy may become necessary as a purely<br />

palhative measure. Disease-related complications<br />

augmented by underlying treatment-related adverse<br />

effects such as xerostomia, may necessitate<br />

placement <strong>of</strong> a feeding tube for nutrition <strong>and</strong>/or<br />

hydration at the end stage <strong>of</strong> the disease. Gastric<br />

feeding tubes are almost always more comfortable<br />

than nasogastric feeding, <strong>and</strong> more practical<br />

than jejunostomy feeding. Hospice care should be<br />

initiated early whenever possible so that patients<br />

<strong>and</strong> their families can receive maximum benefit<br />

from palliative care services.<br />

7. Conclusions<br />

Most patients with recurrent or metastatic<br />

SCCHN cannot be cured. Care must be taken to<br />

determine if a patient does have an isolated, curable<br />

recurrence. Incurable recurrences can be<br />

treated with chemotherapy <strong>and</strong> biological therapy,<br />

which may provide some relief <strong>and</strong> some<br />

prolongation <strong>of</strong> life. Combination chemotherapy<br />

provides little or no survival benefit over singleagent<br />

chemotherapy, with the exception <strong>of</strong> cetuximab<br />

added to cisplatin <strong>and</strong> 5-FU,<br />

Acknowledgements<br />

No funding was received for the preparation <strong>of</strong> this article.<br />

The author has provided consulting for <strong>and</strong> received honoraria<br />

from Novartis, Exelixis <strong>and</strong> Oncolytics.<br />

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Correspondence; Dr Bruce E. Brockstein, MD, Division<br />

<strong>Head</strong>, Hematology/Oncology, NorthShore University<br />

HealthSystem, 2650 Ridge Avenue, Room 4816, Evanston,<br />

IL 60201, USA.<br />

E-mail; BBrockstein@northshore.org<br />

© 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (12)

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