Abstract

PATIENTS AND METHODS

RESULTS

Prior therapy

A total of 47 patients were enrolled in the extended access programme from March 2003 to June 2004. Their characteristics and prior therapy are shown in Table 1. Gefitinib was administered orally in 46 cases (98%) and via a gastrostomy tube in one patient (2%). In all, 18 (38%) patients had received prior platinum-based chemotherapy in the context of radical chemoradiotherapy at some point in their treatment. Seven (15%) of these had also received further palliative systemic therapy (including platins, 5-fluorouracil, taxanes and triapine (a novel ribonucleotide reductase inhibitor)) prior to commencing gefitinib. Nine (19%) patients had received prior systemic therapy in a palliative context only, using the same agents, prior to commencing gefitinib. Only four (9%) patients received gefitinib as first-line therapy, the majority (35, 74%) receiving it as second- or third-line therapy, with eight (17%) receiving it as their fourth to seventh line of treatment. Follow-up continued after disease progression until death. Only three patients (6%) received subsequent systemic therapy, two with platinum-based chemotherapy and one within a phase I trial of systemic administration of an oncolytic virus.

Table 1

Patient characteristics

	Patients
Characteristic	No.	%
Total	47	100
Male	35	74
Female	12	26
Age (years)
Median	62
Range	18–93
Disease at time of commencing IRESSA
Locally recurrent	29	62
Metastatica	18	38
Histology
Squamous cell carcinoma	45	96
UCNTb	1	2
Carcinosarcoma	1	2
ECOG performance status
0	0	0
1	26	55
2	19	40
3	2	4
Prior therapy (n=43)
Surgery	22	51
Radiotherapy	40	93
With chemotherapy	18	42
Alone (radical or palliative)	22	51
Chemotherapy	27	63
Radical chemoradiation only	11	26
Radical chemoradiation and then for recurrence or metastases	7	16
Only for recurrent disease or metastases	9	21

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^aThese patients may also have had local recurrence simultaneously with metastatic disease.

^bUndifferentiated carcinoma of nasopharyngeal type.

Response assessment

Treatment responses are summarised in Table 2. In terms of objective clinical response, four (8%) patients achieved a PR, and 13 (28%) had SD as their best response, such that the disease control rate was 36%. Response to treatment was not related to prior therapy. Those who responded all had locally recurrent disease at the time of commencing gefitinib (one in the nasopharynx, two in the region of the pinna and one in the floor of mouth). All four patients subsequently progressed locally with no evidence of systemic metastatic disease. Radiological assessment was performed in only 22 (47%) of patients, largely due to the rapidly progressive nature of the disease in the majority of the remaining patients. A total of 17 patients (36%) progressed and died prior to the 8-week assessment with a further three (6%) having been too unwell to attend their follow-up and imaging appointments. One patient had mucosal disease that was not assessable by imaging, and four patients did not undergo imaging despite having radiologically assessable disease. These results reflect the reality of treating a group of patients with end-stage head and neck cancer in whom performance status and disease activity can change rapidly. One PR was observed (2%), and 12 patients (26%) had SD, giving a radiological disease control rate of 28%. Of the patients with SD, seven had local recurrence at presentation, of whom five subsequently progressed locally with no evidence of metastatic disease and two have not yet progressed. Five patients had metastatic disease at the time of commencing gefitinib and all have since progressed. There was a reported improvement in symptoms in 16 (34%) patients and there was no change in a further five (11%) patients. There was symptomatic deterioration in 26 (55%) of patients.

Table 2

Response

	N	%
Clinical response (objective)
CR	0	0
Partial response	4	8
Stable disease	13	28
Progressive disease	30	64
Radiological response (RECIST)
CR	0	0
PR	1	2
SD	12	26
PD	9	19
nd	25	53
Symptom response (best)
(d) Resolved	0	0
(c) Improved	16	34
(b) Unchanged	5	11
(a) Worse	26	55

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Survival data

In total, 44 of the 47 patients have developed PD. Three patients remain on gefitinib with SD. The median TTP was 2.6 months (range 0–9 months). The median survival was 4.3 months (range 0–13months). The median follow-up time was 5 months (range 2–9 months). Of the 47 patients, eight were still alive at the time of analysis. Figures 1 and ​and22 show the Kaplan–Meier curves for progression-free and overall survival. Univariate analysis showed that stage of disease was the only significant factor affecting progression-free survival (see Table 3).

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Figure 1

Progression-free survival.

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Figure 2

Overall survival.

Table 3

Univariate analysis of (a) progession-free survival and (b) overall survival

	n	Hazard ratio (95% CI)	P-value
(a)
Gender
Female	12	1	0.7
Male	35	1.15 (0.5–2.29)	—
Age
Per year	47	1 (0.99–1.02)	0.75
Line of therapy
First	21	1	0.35
Second+	26	0.75 (0.4–1.38)	—
Stage
Local disease	11	1	0.03
Nodal±distant mets	36	2.52 (1.09–5.77)
PS
1	18	1	0.13
2 or above	29	1.6 (0.86–2.97)	—
(b)
Gender
Female	12	1	0.81
Male	35	1.1 (0.49–2.45)	—
Age
Per year	47	1.01 (0.99–1.03)	0.41
Line
First	21	1	0.06
Second+	26	0.51 (0.25–1.02)	—
Stage	11	1	0.27
Local disease	36	1.61 (0.69–3.73)	—
Nodal±distant mets
PS
1	18	1	0.1
2 or above	29	1.84 (0.89–3.82)	—

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Toxicity

Toxicity data and dose reductions are summarised in Table 4. In all, 34 patients were assessable for toxicity. Of the 13 (28%) patients in whom toxicities were not documented, nine died before their scheduled outpatient visit, one deteriorated and missed the scheduled visit, two were admitted to other hospitals and no toxicity was documented, and one patient was lost to follow-up.

Table 4

Toxicity grades and dose reductions

			Grade (no of patients affected)
Toxicity	No.	%	0	1	2	3	4	n.s.
No toxicities documented	13	30	—	—	—	—	—	—
Of remaining 34 patients
Skin	26	76	8	9	11	4	0	2
Diarrhoea	16	47	18	12	4	0	0	—
Fatigue	5	15	29	2	3	0	0	—
Anorexia	2	6	32	2	0	0	0	—
Lung toxicity	0	0	0	0	0	0	0	—
Dose reduction
Patients requiring dose reduction: n=14 (30%)
Reasons:
Folliculitis alone	11
Folliculitis and diarrhoea	2
Fatigue	1
Timing of dose reduction:
Eight patients at 2–6 weeks
Five patients at 9–13 weeks
One patient at 17 weeks
Of 14 patients requiring dose reduction, four had had a partial response
10 had had stable disease
Of patients receiving dose reduction, patients who had to discontinue therapy: n=4
Temporary cessation (2–3 weeks) due to folliculitis	3
Permananent cessation following supraventricular tachycardia	1

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n.s., not significant.

Skin toxicity in the form of an acneiform folliculitis usually affecting the face (65% of those affected) and trunk (42% of those affected) was the most frequently observed side effect. Of the 26 patients affected, 20 experienced grade 1–2 skin reactions with only four patients experiencing a grade 3 reaction. Folliculitis was the commonest reason for dose reduction. Diarrhoea (grade 1–2) affected 16 (47%) of the patients in whom toxicities were recorded. Fatigue and anorexia were reported in a few cases, and one patient experienced plantar-palmar erythema. No patient experienced treatment-related lung toxicity and no grade 4 toxicity of any type was observed.

A dose reduction from 500 to 250mg per day was made in 14 (30%) of the patients. In all but two of these patients (both with grade 2 folliculitis), the side effects improved. Gefitinib was stopped temporarily in three patients with folliculitis and after resolution of symptoms was restarted at a dose of 250mg. One patient was admitted to another centre with an episode of supraventricular tachycardia of uncertain aetiology. In this patient, gefitinib was stopped and not restarted due to simultaneous demonstration of PD on imaging investigations.

DISCUSSION

This is the second report on the use of gefitinib in locally advanced, recurrent or metastatic head and neck cancer and, despite the fact that it represents a single institutional study of relative small numbers of patients, we believe that it provides important further clinical information in this area. Owing to the nature of the extended access programme under which the drug was made available, there was no scope for inclusion of a control arm (placebo, best supportive care or alternative systemic therapy). This issue is currently being addressed in a randomised trial of gefitinib vs methotrexate.

The objective clinical response rate was only 8.4%, less than the radiologically confirmed 10.6% response rate reported in the only other published study of this agent in patients with head and neck cancer (Cohen et al, 2003a, 2003b) This study also reports a reduced median TTP (2.6 vs 3.4 months) and median survival (4.3 vs 8.1 months) compared to the previous report. The survival rate at 12 months was 29% in Cohen's series, compared to 0% in this study. The reasons for these differences may be explained in terms of the characteristics of the patients in the two studies. In general, the patients reported here represented a group with a very poor prognosis in whom palliative chemotherapy was not an option. The patients in our study were more likely to have locally recurrent disease (62 vs 44%) and have a poorer performance status (PS 0: 0 vs 21%, PS 1: 55 vs 62%, PS 2: 40 vs 17% and PS 3: 4 vs 0%). Many of our patients had rapidly progressing disease at the time of commencing gefitinib, as demonstrated by the number of patients who progressed before the first scheduled radiological assessment. More patients in Cohen's study had been fit to receive prior therapy, especially surgery (89 vs 51%) and chemotherapy (85 vs 63%), underscoring the fact that more of the patients recruited to our programme had never been fit enough to receive radical treatment.

The obvious attraction of using gefitinib in this group of patients (in the absence of other available therapeutic manoeuvres) was the ease of oral administration and the predicted lack of significant toxicity. In this study, the toxicity of palliative gefitinib was mild, although the folliculitis previously reported with gefitinib was more prevalent and florid than has been previously reported. Facial rash was a frequent cause of patients feeling self-conscious about their appearance and a rash affecting the trunk or limbs was frequently pruritic. The impact of the cutaneous rash on the QoL of patients has not been formally assessed in this study but it is noteworthy that the only reason for dose reduction in 11 patients was folliculitis, and that it was a contributory factor in another two patients. It has previously been suggested that the folliculitis associated with gefitinib may be a marker of treatment outcome (Perez-Soler, 2003). Our data provide some support for this conclusion in that four of the 14 patients who required a dose reduction had a PR and the other 10 had SD. However, in this group of patients, it is also possible that the association of response with skin rash is a reflection of the fact that patients who responded or who had SD were likely to have been taking the drug long enough to develop the side effect, whereas the nonresponders tended to stop taking gefitinib early. Diarrhoea and fatigue were mild and infrequent and generally managed by simple antidiarrhoeal medication. There was no evidence of pulmonary toxicity in this group of patients. Despite the apparent lack of activity of this agent, 21 (45%) patients reported stabilisation or improvement of disease-related symptoms on treatment. It is worth bearing this figure in mind when considering the use of gefitinib as a palliative therapy in patients with head and neck cancer. However, given that the objective response rate is inferior to that reported for platinum-based chemotherapy in this context, the latter should remain the standard of care in this setting for those patients who are fit enough to tolerate such therapy.

In the last 2 years a number of studies have begun to shed light on factors that predict the probability of response to gefitinib in patients with lung cancer. In particular, it appears that patients with mutations in exons 18–21 of the EGFR gene (corresponding to the ATP binding site) are more likely to respond to treatment (Paez et al, 2004). These mutations have been identified predominantly in patients with adenocarcinoma but similar mutations have been identified in two patients with squamous cell lung cancers (Kim et al, 2005). Recently, deletions in exon 19 have been reported in three of 41 Korean patients with squamous cell cancer of the head and neck (Lee et al, 2005). These discoveries have given renewed impetus to the prospect of using gefitinib (and related drugs) in patients with head and neck cancer. However, as with other targeted therapies, it is likely that if gefitinib does find a role it will be in combination with established therapies, such as chemotherapy and radiotherapy in patients with newly diagnosed disease. In addition to other agents that target the EGFR pathway (erlotinib, cetuximab), gefitinib will have to be considered alongside a plethora of novel agents directed against a variety of cellular targets. In particular, agents that target different growth factor receptors, the angiogenic switch and the apoptotic pathway appear to hold great promise in the treatment of head and neck cancer.

References