Second-line chemotherapy in head and neck cancer: what should we expect?

Head and neck cancer is a primary localized disease and is, thus, most accessible for local treatment options, such as surgery or radiotherapy, with these treatments achieving the best tumor control and cure rates. Nevertheless, for more than 30 years, doctors have been attempting to integrate systemic treatment options into the multimodal curative or palliative therapy of head and neck cancer patients.

Changing role of systemic anticancer therapy

In the 1970s and 1980s, the first reports about cytotoxic drugs for patients with squamous cell carcinoma of the head and neck region were published [1]. Despite initial enthusiasm, systemic treatments with methotrexate, bleomycin, 5-fluorouracil (5-FU) and, some years later, cisplatinum showed only disappointing results. Thus, chemotherapy became a salvage treatment option in recurrent or metastatic disease with poor prognosis. The observed response rates were lower than 10% in monotherapy and nearly 20% in combination regimen [2].

In the early 1990s, the concept of simultaneous chemoirradiation was established for patients with locally advanced disease. This primary chemoirradiation was known as ‘definitive’ chemoirradiation and response rates of 80% in patients suffering from an inoperable locally confined disease were observed. The concomitant administration of cisplatin, 5-FU and radiotherapy became the standard option in primary radiotherapy of the head and neck region in patients who could withstand a more aggressive treatment [3,4].

The increased toxicity of therapy was accompanied by an increasing toxicity of the multimodal treatment regimen. New substances (carboplatin [5] and mitomycin [6]) were integrated into chemoirradiation schedules and demonstrated fewer adverse events. Nevertheless, many patients are not able to endure an intensive chemoradiation schedule, due to the reduced performance status and frequent comorbidity [7]. Even the introduction of radical scavengers, such as amifostine [8] or selenium [9], could not improve the therapeutic ratio.

Also in the 1990s, new substance classes were discovered for anticancer therapy. Taxanes were launched and were shown to be effective in head and neck cancer patients. Paclitaxel was the first drug to achieve remission rates of higher than 20% in monoschedules [10]; however, combinations with cisplatin were only successful in nearly 30% of individuals [11]. The toxicity profile of this combination was more acceptable than the traditional combination of cisplatin and 5-FU.

In the last 10 years, data relating to encapsulated liposomal cytostatics, which are able to accumulate in tumor tissue, have been published. This phenomenon helps to reduce the effective dosage and, hence, the toxicity of the drug in cancer treatment. Our group reported experiences with liposomal doxorubicin (25 mg/m² every 3 weeks) [12]. In total, 32 patients were treated. The response rate was 43.7% and the overall median survival reached 10 months. The toxicity was very moderate and easy to manage: anemia 1/2 in seven patients, hand–food syndrome in two patients, nausea in two patients and ECG changes in three patients. Other liposomal formulations (cisplatin [13] and taxanes [14]) have not shown similar tendencies. Today this approach may be reserved as a treatment option for selected patients, such as those with reduced general appearance, drug resistance or allergies.

In the last few years, new data have been published from basic studies regarding docetaxel. This second taxane has also been shown to be effective, both alone and in combination [15]. It has now been approved for induction chemotherapy, as well as for recurrent or metastatic squamous cell carcinoma of the head and neck region. However, this approach may be not so promising after all, as retrospective data reported in 2003 by Leon et al. showed a chemotherapy-induced benefit of only 3.5 months of overall survival.

Currently, we have the situation where chemotherapy is established as one part of multimodal treatment for head and neck cancer patients. First, we see patients who require primary chemoirradiation because of locally advanced disease [16]. Second, there are a growing number of induction chemotherapy concepts focussing on organ preservation [17]. All of these patients are already receiving adjuvant second-line chemotherapy in case of recurrence or metastasis. Treating these patients with second-line regimens does not necessarily imply that the primary treatment aim in the majority of these patients is palliative. On the contrary, in most cases, the treatment attempt is expected to be curative in this situation too.

Biological modifiers in the treatment of head & neck cancer

In the 1960s, several authors reported on the use of different retinoids in the therapy of oral leukoplakia [18]. This idea came to the fore again in the 1990s when Hong et al. were able to demonstrate that secondary malignancies could be avoided by subsequent interferon and retinoic acid therapy in head and neck cancer patients [19]. A worldwide program was started to investigate the molecular mechanism of this therapy and to integrate retinoids into the primary systemic therapy of head and neck cancer patients. Today, we know that the expression of retinoic acid receptors declines as the cancer progresses to more advanced stages of disease [20]. Therefore, retinoids will not have an important place in the treatment of recurrent or metastatic disease.

Interferons and IL-2 were also seen as potential elements of anticancer protocols in the 1990s. IFN-β in nasopharyngeal cancer is the only indication that was established successfully [21]. Local administrations of interferons to the tumor were only casually reported over the years [22].

Some years ago, we looked forward to the increasing expression of p53 mutations and Ki67 as a therapeutic goal in improving the systemic therapy of head and neck cancer [23]. The more advanced the disease, the more that both the oncogenes are expressed. p53 has been used as a target for tumor treatment in various studies, but the clinical results have remained disappointing. Despite this fact, p53 research was not futile. The frequent changes occurring in the p53 pathway in head and neck cancer patients imply that molecular and immunocytochemical analysis of this critical tumor-suppressor network may be of diagnostic and prognostic utility in clinical management. Furthermore, it has opened the eyes of clinicians to the surface of the cell and the genetic setting of cancer cells as a new target for cancer therapy.

Today, we know that there is a high expression rate of EGF receptors (EGFRs) in the majority of head and neck cancers. This antigen is expressed in squamous cell carcinomas, carcinomas of the salivary glands, nasopharyngeal carcinomas and thyroid carcinomas. The expression rate correlates with the stage in individual carcinogenesis.

Inhibiting the EGFR resulted in clinical benefit. Thereby, a novel strategy was born for the systemic therapy of advanced head and neck cancer patients [24].

Finally, we will discuss the use of small molecules in the treatment of advanced head and neck cancer. In particular, tyrosine kinase inhibitors have shown remission rates of nearly 20%. Examples are gefitinib [25], erlotinib [26] or lapatinib [27].

Reliable clinical long-term data in combination therapy are still awaited. The inhibition of the enzymes is normally a reversible effect.

Chemotherapy with palliative intention?

The basic idea of each palliative therapy is a benefit in quality of life and survival related to an acceptable toxicity profile of the treatment. This therapeutic ratio will obviously decrease if survival time is very short or toxicity too high. The real therapeutic benefit is the sole difference between overall survival time and the expected survival in cases where the patients received only best supportive care. Leon et al. in their analysis observed a difference of only 15 days [28].

We shall discuss this topic in more detail, classifying the treatments by how they are administered. Oral administration is the easiest method of application. We have experience with three substances that are effective against head and neck cancer and are available as oral formulations: methotrexate [29], capecitabine [30] and trofosfamid [31].

However, problems appear when using oral formulations to treat patients with marked dysphagia. Subcutaneous (or intramuscular) application is an alternative method of drug delivery, with a comparably high rate of compliant patients. Such treatments can be performed at home. Methotrexate has been extensively used in this setting. Accordingly, there must be strict inclusion criteria for the delivery of intravenous chemotherapy.

Anticancer drugs are often combined because of the low response rates of the single substances [32]. It is necessary to bear in mind the main toxicities of the substances in order to select a low toxicity profile with adequate response chances.

The classic combination regimen consists of platinum derivates and 5-FU. Cisplatinum is particularly well known for its oto- and nephrotoxicity, whereas carboplatin is more hematotoxic [33]. 5-FU produces stomatitis in higher dosages. A third of patients suffer from side effects on this regimen [34].

A modern regimen is the combination of taxanes with platinum derivates. Taxanes often cause moderate but reversible neurotoxicity. Randomized studies have shown that the combination of taxanes and platinum is no more effective than platinum and 5-FU, but is less toxic [35]. The shortened application time (4 h vs 5 days) is also important for the patients and their relatives.

The launching of cetuximab may be a milestone in the systemic anticancer therapy for patients with tumors of the head and neck region. This EGFR inhibitor is showing improved response rates with less toxicity.

The recently published EXTREME study compared the combination of platinum derivates with 5-FU and cetuximab with chemotherapy alone (cisplatin or carboplatin and 5-FU) [36]. In total, 442 patients with good performance status were included (see also the critical letter by Guntinas-Lichius et al.[37]). The study was performed at 80 sites in 17 European countries. Vermorken et al. demonstrated a longer overall survival (10.1 vs 7.5 months) as well as a longer disease-free survival (5.6 vs 3.3 months). The response rate increased from 20 to 36%. The main toxicities were neutropenia due to platinum derivates and skin reactions due to EGFR inhibitors.

In patients with platinum-resistant recurrent head and neck cancer, the EGFR antibody cetuximab may be an attractive treatment option. Little is known about results of this therapeutic option. The objective of our own ASCO 2007 study was to evaluate therapeutic benefit of this indication [38]. In total, 23 patients with histologically confirmed recurrent head and neck cancer (18 males and three females; median age of 57 years) were included in this exploratory Phase II study. All recurrences had occurred after chemotherapy with platinum derivates. A total of 19 patients received radiation therapy during primary treatment. No surgical or radiotherapeutic option in recurrent disease was possible. Two patients were diagnosed with lung metastasis. The second-line therapy consisted of carboplatinum (200 mg/m²) and paclitaxel (200 mg/m²) every 3 weeks (week 1, 4 and 7) and, additionally, cetuximab, which was administered with a loading dose of 400 mg/m² in week 1 and 250 mg/m² in weeks 2–6. A significant tumor response was observed in 13 out of the 23 patients (56%). Overall, seven partial, five minor and one complete remission were observed. The median survival time was 8 months (range: 3–10 months) and four patients are still alive at the time of writing. Median time to progression was 5 months (range: 2–8 months). Side effects were rash (16 out of 22 individuals), fever (nine out of 22 individuals) and typical chemotherapy induced toxicities, such as neuropathy (seven out of 22 individuals) and cytopenia (four out of 22 individuals). All side effects were moderate and easy to treat. We concluded that the described combined chemoimmunotherapy of cetuximab with paclitaxel and carboplatinum seems to offer new strategies in second- and third-line chemotherapy for patients with platinum-resistant head and neck cancer, potentially overcoming primary platinum resistance.

There are a small number of similar small Phase II studies on cetuximab monotherapy in recurrent or metastatic head and neck cancer [39]. Characteristics are a low-toxicity profile and an overall survival time of between 6 and 7 months. The treatment is still applicable in patients with reduced general appearance and these patients will benefit from the therapy. Further studies are definitely needed in this area.

There are some reports about rare allergic reactions due to cetuximab; the incidence appears to be 3% or less [40]. We observed only two cases during the last 5 years. Allergic reactions are generally limited to the skin, but systemic shock reactions were also registered in individual patients. Further clinical observation is necessary to collect data about such allergic or pseudoallergic toxicities.

New development of other EGFR inhibitors will offer therapeutic alternatives. Zalutumumab or panitumumab are just two clinically successful examples of monoclonal antibodies inhibiting EGFR [41]; they may provide promising new perspectives [24].

Conclusion

Three decades of research have led to the integration of chemotherapy into the curative management of squamous cell carcinoma of the head and neck region. Nearly all patients with locally advanced head and neck cancer receive some kind of chemotherapy as part of their initial or second-line treatment. Nevertheless, the treatment results of systemic therapy alone only gradually improved compared with the first anticancer drugs, such as methotrexate or platinum.

New targeted therapy, including the use of enzyme inhibitors or antibodies, may give a promising perspective. In particular, easy application modi or low-toxicity profiles are important topics. Other focuses of future trials should be on survival improvement, better quality of life and further toxicity reduction.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.