Medical treatment in head and neck cancer

Annals of Oncology 16 (Supplement 2): ii258 –ii264, 2005 doi:10.1093/annonc/mdi735

Medical treatment in head and neck cancer J. B. Vermorken Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium

Introduction

q 2005 European Society for Medical Oncology

Patients with recurrent and/or metastatic disease A large number of conventional single agents have been investigated in the past in patients with recurrent disease [11, 12]. The four most active and most extensively used agents are methotrexate, cisplatin, 5-fluorouracil (5-FU) and bleomycin. These drugs produced a 15 –30% response rate of short duration,  3–5 months, and only rarely complete responses. Several new agents have been introduced more recently and have shown promising results [13– 15]. Of these, in particular the taxoids paclitaxel and docetaxel, the antimetabolite gemcitabine, the vinca alkaloid vinorelbine, the topo-I inhibitor irinotecan and the alkylating agent ifosfamide are worth mentioning. For most of these newer agents no direct comparison has been made with methotrexate. There are two exceptions. The first is a randomized phase II study performed within the EORTC Head and Neck Cancer Group on two infusion schedules of paclitaxel (3 h and 24 h; 175 mg/m2) versus standard-dose methotrexate (40 –60 mg/m2), which showed overlapping 95% confidence intervals (CIs) of the response rates [16]. The second is a randomized phase II trial of weekly docetaxel (40 mg/m2) versus weekly methotrexate (40 mg/m2), showing a significantly higher response rate with docetaxel (27% versus 15%, with non-overlapping 95% CI) [17]. Unless in a phase III study this translates into survival benefit, singleagent methotrexate remains the drug of choice for patients with recurrent disease who are older and/or in less favorable

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Head and neck cancer represents  5% of all cancers and >500 000 new cases are diagnosed worldwide each year. Approximately 60 –65% of patients with head and neck cancer can be cured with surgery and/or radiotherapy. The prognosis of an individual patient depends on the primary tumor site and its extension, the histologic type, nodal involvement and probably grading [1]. The great majority (>90%) of head and neck cancer in the western world is of squamous cell origin. When such patients present with limited disease (stages I and II) they can be effectively treated with single modality treatment. Sixty to 90% will be disease-free after 5 years, the development of second primaries being one the major threats [2]. Most patients with resectable advanced disease (stages III and IV) have in the past been treated with a combined approach (surgery and radiation therapy). Despite such an approach, 60% developed local and/or regional recurrences, 20% distant metastases and others had the risk to develop second primaries. Definitive radiation therapy used as primary therapy for those with unresectable advanced disease resulted in a 5-year survival of <10%, and the majority of such patients recurred or had persistent disease and died within 18 months of therapy [3]. Traditionally, the role of chemotherapy has been mainly for palliation of symptoms in recurrent or metastatic head and neck cancer. Its role has been limited in terms of survival benefit, but symptom relief may be obtained, and in that sense cisplatin-based combination chemotherapy might be superior over single-agent chemotherapy. This clearly should be balanced against the higher toxicities experienced with such more aggressive regimens [4–6]. Because of the poor results obtained with local therapies in patients with locally advanced disease, systemic therapy has been introduced in the primary treatment of such patients. The initial optimism that arose as result of the very high response rates observed with cisplatinbased combination regimens as induction chemotherapy in untreated patients was damped by the lack of its impact on survival [3]. However, after three decades of investigations on radiochemotherapy combinations it has become clear that chemotherapy does have a role to play in head and neck cancer patients and does have a positive impact on their survival. At least four formal meta-analyses have been published investigating the role of chemotherapy when added to locoregional treatment for squamous cell carcinoma of the head and neck

(SCCHN) [7 –10]. The individual patient-based meta-analysis in particular is worth mentioning [9]. Only trials that took place after 1980 were considered in the analysis. Of these trials, 48% involved chemotherapy in the neo-adjuvant setting, 17% were adjuvant trials and another 35% involved concomitant chemotherapy– radiotherapy trials. The study as a whole showed a small but significant reduction in the risk of death of 10%, which translated into an absolute survival benefit of 4% both at 2 years (from 50% to 54%) and at 5 years (from 32% to 36%) for those receiving chemotherapy (P <0.0001). However, the greatest benefit was derived from concomitant chemotherapy and radiation therapy (19% risk reduction; 8% absolute benefit at 5 years; P <0.0001). This review will briefly summarize the status of chemotherapy in patients with head and neck cancer.

ii259

Table 1. Taxoid combinations in recurrent/metastatic squamous cell carcinoma of the head and neck Response rates (complete response rates) (%) with

Two drugs

Three drugs

Paclitaxel

Docetaxel

Cisplatin

32–39 (0)

33–52 (9–11)

Carboplatin

33–33 (4–8)

–

5-FU

34 (9)

Vinorelbine

44 (11)

Cisplatin/5-FU

38 (NR)

44 (12)

Cisplatin/ifosfamide

58 (17)

–

Carboplatin/ifosfamide

59 (17)

–

Based on references [14, 18, 19] 5-FU, 5-fluorouracil; NR, not reported.

report quality of life analysis does not favor either treatment. However, final results are eagerly awaited. The data from this trial (E1395) were combined with that of another ECOG trial (E1393, which compared cisplatin plus paclitaxel at two dose levels) and analyzed for prognostic factors for response and survival [21]. The median follow-up of the patients was 4.7 years. The 1-year overall survival rate for all patients was 32% and the median overall survival was 7.8 months. The objective response rate was 32%. On multivariate analysis, the following were found to be independent unfavorable predictors of objective response: weight loss of >5%, an ECOG performance status of 1 (versus 0), residual disease at the primary tumor site, a primary tumor site other than the oropharynx, prior radiation therapy (P = 0.056), and well/moderate tumor cell differentiation (P = 0.067). Independent unfavorable prognostic factors for overall survival were weight loss, an ECOG performance status of 1 (versus 0), well/moderately differentiated tumor cell, a primary tumor in the oral cavity or hypopharynx and prior radiotherapy. Patients with two or fewer adverse prognostic factors were found to have a median overall survival of 1 year, whereas patients with three to five adverse prognostic factors were found to have a median overall survival of 0.5 years (P <0.0001). The authors indicated from this very important analysis that clinical parameters and tumor cell differentiation seemed to be strong pretreatment predictors of outcome and should be considered in the design of future randomized trials in patients with recurrent or metastatic head and neck cancer. Several biological therapies have shown promise in head and neck cancer patients because of their different mechanism of action, greater selectivity and different (less) toxicity. These include drugs that target growth factor receptors, signal transduction, cell cycle control, prostaglandin synthesis, protein degradation, hypoxia and angiogenesis [22]. The epidermal growth factor receptor (EGFR) inhibitors are of particular interest, because EGFR is overexpressed in 90% of patients with SCCHN. Several approaches to block the EGFR in human diseases have been explored, including small molecules and monoclonal antibodies [23]. Gefitinib (Iressa) is one of these small molecules that inhibit EGFR-tyrosine kinase through competitive binding to the ATP-binding site. It produces supra-additive and enhanced antitumor effects of cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, etoposide, topotecan, ralitrexed and doxorubicin in several tumor types, resulting in complete regression in some xenograft tumors [23]. In a phase II study in which gefitinib was given at a dose of 500 mg/day, a response rate of 10.6% was reported and a disease control rate (complete response + partial response + no change) of 53%, with diarrhea as the only important side-effect [24]. An interesting observation in this study was that the development of skin toxicity emerged as a statistically significant predictor of response and improved outcome. In a later study, reported at ASCO 2004, a lower dose of gefitinib (250 mg/day) resulted in only 3.5% responses in 56 patients [24, 25]. A large (still ongoing) randomized trial comparing these two dose levels of gefitinib

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condition (either as result of the tumor itself or due to comorbidity) [18]. Combination chemotherapy is very often considered in patients who are young and in a good condition, in particular when other favorable prognostic factors for response to chemotherapy are available [12]. Cisplatin/infusional 5-FU (PF) is the combination most frequently used. In a number of randomized trials performed in the 1990s, this PF combination induced overall response rates of 31 –32%, being superior than the response rates observed with single-agent cisplatin, 5-FU or methotrexate (response rates 10 –17%) [4 –6]. However, these trials failed to show a meaningful survival advantage over single-agent regimens. Of the newer agents, the taxanes have been studied most extensively in combination chemotherapy regimens [14, 18, 19]. The response rates of two- or three-drug combinations with paclitaxel or docetaxel in non-randomized studies are summarized in Table 1. There are no data from randomized trials available in this setting to suggest that such three-drug combinations are in any way superior to a two-drug taxane–cisplatin combination. Having said this, it should still be mentioned that the TIP and TIC combinations studied at the M. D. Anderson Hospital in Houston showed the highest response rates, but were also the most toxic ( 30% febrile neutropenia). Balance against observed toxicity is therefore warranted, and quality of life needs to be questioned and assessed, in particular because in this subset of patients chemotherapy is merely given for palliation. In that sense, the early data from the Eastern Cooperative Oncology Group (ECOG) trial (E1395) comparing the standard PF regimen with paclitaxel plus cisplatin (TP) seemed quite promising [20]. So far, efficacy data were reported as being comparable (response rates 22% versus 28%, median survival 8 versus 9 months, 1-year survival 41% versus 30%), but both grade 3–4 hematological (in particular anemia and thrombocytopenia) and grade 3–4 non-hematological toxicity (in particular diarrhea, stomatitis and infection) were less frequent with the TP regimen. This may have some important consequences for patients in the recurrent disease settings in terms of treatment tolerance. So far, the initial

ii260 Table 2. Cetuximab: clinical program in squamous cell carcinoma of the head and neck: efficacy data in platinum-pretreated patients Reference

Type of study

Treatment

Outcome

Baselga (2002) [27]

Phase II

96 (PD)

Pt + C225

RR 11%, NC 36%, MS 152 days

Kies (2002) [28]

Phase II

51 (NC)

Pt + C225

RR 24%, NC 61%

78 (PD)

Pt + C225

RR 12%, NC 17%

C225

RR 12%, NC 33%, TTP 2.3 months, MS 5.9 months

Trigo (2004) [29]

Phase II

No. of patients

103 (PD)

Pt, platinum; C225, cetuximab; RR, response rate; NC, no change; PD, progressive disease; MS, median survival; TTP, time to progression.

rence of distant metastases and finally to improve the diseasefree and overall survival. Unfortunately, the outcome of most randomized trials has been disappointing in all these aspects apart from a favorable influence on the development of distant metastases [32–35]. The results of these large randomized trials and the data from the meta-analyses have changed the attitude of many physicians in that concurrent chemotherapy and radiation therapy now gets more attention as treatment for patients with locally advanced head and neck cancer [36]. This is true for both patients with resectable disease and those with non-resectable disease. In spite of that, with the introduction of the newer cytotoxic agents the role of induction chemotherapy is being revisited. Very high overall response rates (up to 93%) and impressive complete response rates (40–63%) have been reported both with the triple combinations of docetaxel with cisplatin and 5-FU (TPF) and of paclitaxel with cisplatin and 5-FU (PPF) [37–39]. Preliminary results of a Spanish randomized phase III study of PPF versus the standard 5-day infusional PF regimen in patients with locally advanced disease (followed by cisplatin-based chemoradiation) showed superiority of the triple regimen (median progression-free survival 21.7 versus 17.7 months, P = 0.024; median overall survival not reached versus 37.7 months, P = 0.038) and less grade 3 –4 mucositis (16% versus 52%; P <0.0000001) [40]. Similarly, TPF-like regimens are under study in randomized trials versus the standard PF regimen as induction chemotherapy both in the USA and Europe

Integration of chemotherapy in the primary treatment of head and neck cancer Neo-adjuvant chemotherapy Neo-adjuvant chemotherapy in the early days was employed to increase the locoregional control rate, to reduce the occur-

Table 3. Cetuximab: clinical program in squamous cell carcinoma of the head and neck: efficacy data in chemo-naı¨ve patients Reference

Type of study

No. of patients

Treatment arms

RR (CR) (%)

Burtness (2002) [30]a

Phase III

60

Pt + C225

26 (2)

63

Pt + placebo

10

8.0

Humblet (2004) [31]

Phase I/II

27

PF + C225

33 (4)

10.6

26

CF + C225

38 (4)

8.5

a

Median survival (months) 9.3

Updated by Forastiere during ASCO 2004 (poster discussion session). Pt, platinum; C225, cetuximab; RR, response rate; CR, complete response; PF, cisplatin/infusional 5-fluorouracil; CF, carboplatin/5-fluorouracil.

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versus methotrexate (40 –60 mg/m2/week) will perhaps give an answer to this suggested dose –effect relationship. Cetuximab is a human-chimeric monoclonal antibody, which competitively binds to the extracellular receptor site to prevent binding by natural EGFR ligands (EGF and tumor growth factor-a). Standard treatment entails a loading dose or 400 mg/m2 at week 1, followed by a maintenance dose of 250 mg/m2 weekly [26]. Tables 2 and 3 summarize the efficacy data with cetuximab in platinum-pretreated and in chemotherapy-naı¨ve patients, respectively. The data illustrate that cetuximab is able to overcome resistance to platinum compounds. In both the European study [27] and the US study [28], 11 –12% of the patients who had progressed on platinum responded again when, afterwards, the same platinum compound was given in combination with cetuximab. Moreover, an additional 17 –36% of patients showed stabilization of disease. In a large phase II study, cetuximab alone induced 12% objective responses and 33% stabilization of disease [29]. This and a surprising 5.9-month median survival in patients who had progressed on platinum suggest that cetuximab might be an important addition to our armamentarium of drugs for head and neck cancer patients. The data on platinum plus cetuximab in chemotherapy-naı¨ve patients showed that (i) full doses of cytotoxic chemotherapy can be combined with this compound, and (ii) an increased response rate is observed with the combination (in the randomized study). The usual toxicity of the cytotoxic chemotherapy, in particular myelosuppression, did not seem to be enhanced, but skin rash does occur frequently (80%; 3% severe). Allergic reactions can be seen, but only in a minority of cases (3%) [27]. At present, a large randomized trial is ongoing in patients with recurrent/ metastatic SCCHN, comparing platinum/infusional 5-FU alone with platinum/infusional 5-FU plus cetuximab (protocol 62 202-002, the Extreme study), with overall survival as the primary end point.

ii261

Concurrent chemotherapy and radiation therapy (chemoradiation)

Trial (type of disease)

As mentioned earlier, chemoradiation has come forward as the most promising approach towards patients with locally advanced head and neck cancer [9]. Since the late 1960s, efforts have been undertaken to improve the results that can be obtained with radiation therapy by either the simultaneous use of active single agents or a combination of such agents [3]. In the 1980s and 1990s, the drugs of choice in chemoradiation were mitomycin C, cisplatin and 5-FU, and these were selected based on both in vitro and in vivo experiments. Cisplatin has come forward as an attractive agent not only because of its activity in this disease as a single agent, but also because it does not produce mucositis. Various dose schedules of cisplatin have been applied when combined with radiation therapy, the high dose (80–100 mg/m2) given once every 3 weeks showing the most promising results with acceptable toxicity. Combinations with 5-FU have also been used. However, very often the dose of cisplatin, 5-FU or both had to be reduced [3]. There is no proof that results with cisplatincontaining multiagent chemoradiation are superior to singleagent cisplatin-based chemoradiation. No randomized trial has been performed to show this and the most recent update of Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) database focusing on concomitant chemotherapy and radiation therapy did not suggest this either [48]. Overall, the following conclusions have been made when comparing chemoradiation with radiation therapy alone: (i) chemoradiation is more efficacious than radiation therapy alone; (ii) there is no consensus regarding the optimal radiation dose fractionation in chemoradiation trials; (iii) chemoradiation may be more efficacious than maximally intensive radiation therapy alone; and (iv) acute toxicity is increased with the use of chemoradiation in comparison with standard radiation therapy alone [49]. In the postoperative management of high-risk patients the optimal schedule remains to be clarified. No experience with multi-agent chemoradiation is available from randomized trials in this setting, most likely because of the expected reduce tolerance of patients after surgery. Three randomized trials have shown beneficial effects of chemoradiation with single-agent cisplatin over radiation therapy alone (Table 5). The initial study by Bachaud et al. [50] using 50 mg of cisplatin weekly total dose was positive, but in a limited number of patients. Both the EORTC [51] and the RTOG [52] studies, with their intention to confirm these data, employed higher doses of cisplatin, i.e. 100 mg/m2 on days 1, 22 and 43 of the treatment program. There are some discrepancies between the EORTC trial and the RTOG trial that might be responsible for the difference in outcomes observed. Nevertheless, taking into account that also in the RTOG trial there was a significant difference in 2-year disease-free survival in favor of the chemoradiation arm, the bulk of evidence suggests that postoperative chemoradiation with cisplatin is superior over conventional radiation therapy alone.

Arms

Outcome

CA 139-322 PF versus PPF CCRa (TTP, OS) Improved with PPF (resectable/non-resectable) ! CRT (CDDP) EORTC 24 971/TAX 323 (non-resectable)

PF versus TPF ! RT

US trial PF versus TPF (resectable/non-resectable) ! CRT (Cb)

PFSa (RR, OS) Improved with TPF No data yet

a

Primary end points. PF, cisplatin/infusional 5-FU; PPF, PF + paclitaxel; CRT, chemoradiation; CDDP, cisplatin; CCR, clinical complete response; TTP, time to progression; OS, overall survival; PFS, progression-free survival; TPF, PF + docetaxel; RT, radiation therapy; Cb, carboplatin.

(see Table 4). The preliminary report of the European study, comparing TPF with PF followed by conventional radiation therapy (EORTC 24 971/TAX 323), demonstrated that after a median follow-up of 32 months, the TPF arm was superior in terms of progression-free survival [hazard ratio (HR) 0.72; 95% CI 0.56 –0.91; P = 0.006], overall survival (HR 0.73; 95% CI 0.57 –0.94; P = 0.016) and response rate (67.8% versus 53.6%; P = 0.007), while the PF arm showed greater grade 3–4 nausea (7.3% versus 0.6%), vomiting (5.0% versus 0.6%) and stomatitis (11.2% versus 4.6%), and more toxic deaths (5.5% versus 2.3%) [41]. The data from the US study are not available yet. However, both the Spanish and the US trials are using the concept of neo-adjuvant chemotherapy followed by chemoradiation. This latter approach now gets major attention and seems to be the line of research for the coming years, not only for squamous cell carcinoma but also for nasopharyngeal carcinoma [42, 43]. These induction regimens are followed by standard radiation therapy or chemoradiation. At present, the most important application of neo-adjuvant chemotherapy is its contribution in organ preservation programs in patients with advanced resectable disease of the larynx and hypopharynx [34, 44]. Because survival benefit has not been observed in these trials, this type of approach has not been accepted by all as the reference [45]. Indeed, trials are ongoing or have been just completed to investigate whether neo-adjuvant chemotherapy followed by radiation is the most optimal approach for organ preservation (Intergroup trial R9111 and EORTC trial 24 954). The final results of the Intergroup trial for patients with locally advanced laryngeal cancer showed that radiotherapy with concurrent administration of cisplatin was superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control [46]. The EORTC protocol 24 954 is comparing the neo-adjuvant chemotherapy followed by radiation therapy with an alternating radiochemotherapy schedule, as described by Merlano et al. [47]. This study as planned has recently been closed for patient accrual in 2004.

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Table 4. Randomized trials of neo-adjuvant chemotherapy in locally advanced head and neck cancer

ii262 Table 5. Randomized trials of postoperative cisplatin-based chemoradiation Reference

Treatment arms

Bachaud 1996 [50]

RT/RT + CDDP

No. patients 88

Median follow-up

LC-CTR rate

Survival benefit

5 years

59% vs 77%

13% vs 36%

Bernier 2004 [51]

RT/RT + CDDP

(P = 0.08)

(P <0.05)

334

60 months

31% vs 18%a

40% vs 53%b

Cooper 2004 [52]

RT/RT + CDDP

(P = 0.007)

(P = 0.02)

459

46 months

72% vs 82%

57% vs 64%c

(P = 0.01)

(P = 0.19)

a

Relapse rate. Five-year survival. c Two-year survival (disease-free survival at 2 years: 45% versus 54%; P = 0.04). LR-CTR, locoregional control; RT, radiation therapy; CDDP, cisplatin. b

Adjuvant chemotherapy In general the use of adjuvant chemotherapy after local therapies has proved to be difficult in patients with head and neck cancer in terms of compliance. This has been observed in patients who received adjuvant chemotherapy per se after locoregional therapy [54, 55], but even more in patients who had been treated both with induction chemotherapy and adjuvant chemotherapy [32, 56] or with chemoradiation followed by adjuvant chemotherapy [57]. No survival benefit has been observed in these individual studies, being in line with the meta-analyses. The exception to this is the outcome of the Intergroup trial in advanced-stage cancer of the nasopharynx [57] (Table 6). Patients with stages III or IV nasopharyngeal cancer were randomized to receive standard radiotherapy or cisplatin (100 mg/m2 days 1, 22 and 43) during radiation followed by three cycles of adjuvant cisplatin and 5-FU. The trial was closed after an interim analysis showed a significant improvement in 2-year survival (80% versus 55%) with the combined treatment.

Of the 151 patients randomized to the maintenance arm in the Head and Neck Contract Program [32], only 13 (9%) completed all six cycles. At the Dana Farber Institute only 46 of the original 73 patients eligible for randomization accepted this. In the Intergroup study, of the 78 patients randomized to the chemotherapy arm, only 55% proved compliant with all three planned cycles of adjuvant chemotherapy. Overall, for SCCHN this adjuvant approach does not seem to be very promising. Because the tolerance of adjuvant chemotherapy after concurrent chemoradiation is poor, the strategy of neo-adjuvant chemotherapy followed by concurrent chemoradiation may prove to be the optimal way to deliver maximumtolerated therapy [58].

Conclusions There are very clear indications based on well performed randomized trials and several meta-analyses as to which directions need to be followed in the coming years. With the introduction of new agents not only have new possibilities to palliate patients with recurrent and/or metastatic disease been created, but this has also brought a better outlook for patients with locally advanced disease. There is a renewed interest in neo-adjuvant chemotherapy, in particular when it is followed by concurrent chemoradiation programs. This will undoubtedly lead to more toxicity, and methods to reduce or overcome these toxicities should be further explored. At the same time, it should be understood that there will be a limit to what can

Table 6. Randomized trials on adjuvant chemotherapy Reference

Patient groups

No. of patients

Chemotherapy a

Outcome

GETTEC [54]

N+, ECS+

287

PBM 3

DM " , OS #

UFT group [55]

Stages II–IV

424

UFT (1 year)

DM # , OS =

Head and Neck Contracts [32]

Stages II–IV

443

CDDP 6

DM # , OS =

Dana Farber [56]

Stages III–IV

46

PBM 3

OS =

Intergroup [57]

Stages III–IV

147

PF 3

DM # , OS "

a

Followed by 5 BM. N+, involved nodes; ECS+, extracapsular spread; PBM, cisplatin, bleomycin and methotrexate; UFT, tegafur and uracil; CDDP, cisplatin; PF, cisplatin and 5-fluorouracil; DM, distant metastases; OS, overall survival.

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No randomized trials are available of new chemoradiation combinations, including taxoids, topo-I inhibitors and nucleoside analogs (e.g. gemcitabine). In phase I–II trials these combinations score very high in terms of complete response rates (being >60% in most studies). However, toxicities can be tremendous and sometimes unacceptable, in particular with respect to mucositis, skin toxicity and late fibrotic reactions [53].

ii263 be expected from new chemotherapy programs. A better individual patient risk profiling by biological assays, tissue microarrays and DNA microarrays might lead to a better guidance in how to optimally treat patients with head and neck cancer. There is hope that with the new non-cytotoxics, which are more specific in their activity against tumor cells and usually have a somewhat different (less) toxicity profile than the cytotoxic agents, an additional improvement in outcome might be expected.

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