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Recurrent squamous-cell carcinoma of the head and neck: Overview of current therapy and future prospects
Annals of Oncology 11: 11-16, 2000. €> 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Review Recurrent squamous-cell carcinoma of the head and neck: Overview of current therapy and future prospects I. Ganly^&S. B. Kaye2 'Department of Ololaryngology. Victoria Infirmary, Glasgow, 2CRC Department of Medical Oncology, Garscube Estate, Glasgow, UK
Summary
Locoregional recurrence is the most common cause of failure after head and neck cancer surgery. It is a disease which causes significant morbidity especially on speech and swallowing. There are many different treatments available including surgery, reirradiation and chemotherapy. However, none of these have produced any significant survival benefit. Because of this, there has been considerable interest in the development of new
biological therapies such as gene therapy and immunotherapy for this disease. The objectives of this article are to provide an overview of the currently available therapies for recurrent head and neck cancer including gene therapy and immunotherapy. Prevention of recurrent disease by the detection and treatment of minimal residual disease is also discussed. Key words: chemotherapy, gene therapy, head and neck cancer, immunotherapy, radiotherapy, recurrent, surgery
vival [5]. Brachman et al. [6] have shown that patients with mutations in the tumour suppressor gene p53 have Locoregional recurrence is the most common cause of a shorter time to recurrence. Overexpression ofp53 has failure after head and neck cancer surgery and results in been shown to correlate with an increased incidence of significant morbidity including effects on speech and recurrence and the development of second primaries swallowing. Recurrence may occur at the site of the and hence reduced survival [7]. Antibodies to p53 have primary tumour often as a diffuse mass, at the site of also been shown to be of prognostic significance [8]. In a the draining lymph nodes or may be multifocal in the prospective study of primary head and neck squamousform of multiple cutaneous tumour seedings. There are cell cancer (HNSCC), patients with positive serum antimany factors which predispose to the development of bodies to p53 had an increased incidence of tumour locoregional recurrence. However, the single most im- recurrence, second primaries and tumour related deaths portant factor is incomplete surgical resection margins (44.7% in antibody positive group compared to 21.1% [1, 2]. This is determined not only by the experience of in antibody negative group). the surgeon but also by the site of the primary tumour which may limit the extent of surgical excision. For example, in larger tumours of the oropharynx and oral Current therapies cavity it may be difficult to obtain adequate surgical resection margins and still preserve organ function. Improvements in surgical reconstruction due to the Recurrence in the neck is more likely if there are multi- development of microvascular free tissue transfer, better ple nodes present and if there is extranodal spread of radiotherapy protocols such as hyperfractionation and disease. As well as site and extent of surgical resection, chemoradiation [9-12] have led to improvements in recurrence is also determined by the dose and timing of locoregional control of head and neck cancer. As a adjuvent radiotherapy. Delays in radiotherapy treatment result, more patients present with distant metastatic beyond six weeks post surgery and radiation doses less disease than before and therefore purely recurrent disthan 54 Gy have been shown to result in poorer survival ease is less frequent. As a consequence, many clinical and disease-free intervals [3]. Other factors which pre- trials describing new treatments for recurrent head and dispose to recurrence include poor differentiation of the neck cancer often include patients not only with locoprimary tumour and evidence of neurogenic and vessel regional recurrence but also with distant metastatic invasion. Woolley et al. [4] also showed an increased risk disease and locally advanced primary disease. The of recurrence if blood transfusion was carried out at the objectives of this review are to describe the current time of primary surgery. Molecular markers are also therapies available for recurrent disease. However it important. Amplification of the oncogene Cyclin Dl should be noted that many clinical trials include this has been associated with recurrence and shortened sur- mixed group of patients and this should be considered Introduction
12 when interpreting any conclusions drawn from these clinical trials. Surgery Surgery plays a role in the treatment of both local and regional recurrence but only where curative surgery is possible or surgery results in significant palliation of symptoms. Recurrence in the neck can be treated surgically if the neck has not been previously treated either with surgery or radiotherapy. If a selective neck dissection has been carried out and recurrence has occurred outside the neck dissection field a complete radical neck dissection can be done in this case. However, usually the neck has already been treated with radiotherapy. In this case it is technically demanding to resect the tumour due to fixation of the tumour to local structures such as the carotid artery or vertebrae and it is also likely to be unsuccessful because of extranodal spread of disease. Surgical treatment of local recurrence is dependent on the site and previous treatment of the primary tumour. Ti and T2 tumours of the glottic larynx are treated with radiotherapy and recurrence in this situation can be treated with curative intent with either a partial laryngectomy [13, 14] or total laryngectomy. Surgical salvage can also be carried out for supraglottic tumours though the chance for cure is less than for glottic tumours [15]. Recurrence in the oral cavity (oral vestibule, buccal mucosa, gums, floor of mouth, oral tongue, hard palate, retromolar trigone) of small Ti and T2 tumours is difficult to detect early if the patient has had radiation treatment. However with close follow-up these patients can be successfully salvaged surgically [16]. With larger T3 and T4 oral cavity tumours, primary surgery and radiotherapy often fail and further surgery is rarely possible nor curative. In the oropharynx (base of tongue, faucial arch, tonsillar pillars and fossa and posterior pharyngeal wall) recurrence can be treated surgically if it involves the tonsillar pillars or fossa. However, recurrence of the base of tongue is rarely curative since these tumours are hard to detect and therefore present late. Radical surgery in the form of a total glossectomy and laryngectomy is often required but even with such surgery further recurrence often occurs within one year and long-term survival is very poor.
or by combining external beam radiotherapy with chemotherapy (chemoradiation). Low-dose radiotherapy in the form of brachytherapy has been shown to be effective in the treatment of primary head and neck cancer, especially in base of tongue tumours. However it also has a role in recurrent disease. Because the dose of radiation is lower (20-40 Gy) and the depth of radiation penetration small, toxicity in previously irradiated tissue is limited. Nag et al. [19] have reported local control of 17% in patients using I192 implanted wires. The dose of external beam radiotherapy can also be reduced by combining with systemic chemotherapy (chemoradiation). Haraf et al. [20] reported a five-year survival of 22% and progression-free survival of 26% using a combination of cisplatin-5-FUhydroxyurea with radiotherapy (median dose 50 Gy). Interstitial radiotherapy can also be combined with local tumour interstitial hyperthermia since hyperthermia kills hypoxic and S phase cells, neither of which are killed by radiation. Petrovic et al. [21] reported a complete response of 68% and partial response rate of 32% in sites treated by this technique. Recently it was reported that gemcitabine (an analogue of deoxycytidine) was a potent radiosensitizer [22]. Using a low dose of gemcitabine two hours pre-radiotherapy, a phase I trial by Eisbruch et al. [23] in eight patients gave a complete response in seven patients. However, there was excessive mucosal and pharyngeal toxicity at the dose used and therefore studies using lower doses are planned. Chemotherapy
Chemotherapy may be given systemically, intratumourally or intraarterially. Systemic chemotherapy may be given either as a single agent, e.g., methotrexate or in combination, e.g., cisplatin-5-FU. Treatment with combination chemotherapy increases overall response rates to 30%-40% [24] compared with single agents where the response rate is only 10%—20% [25], but there is no improvement in survival (median survival is six months in both cases) [26]. In a randomised trial carried out by the EORTC (European Organisation for Research and Treatment of Cancer), 382 chemotherapy-naive patients with recurrent or metastatic head and neck cancer were randomly assigned to either a combination of CABO (cisplatin, methotrexate, bleomycin, and vincristine), Reirradiation cisplatin and infusional 5-fluorouracil (5-FU), or cisplaSurgery and adjuvent radiotherapy or radiotherapy tin alone [27]. Major responses were similar for CABO alone are the main therapies for primary head and neck (34%) and cisplatin-5-FU (31%) but better than cisplacancer. For recurrent disease, the main concern with tin alone (15%). However, there was no difference in reirradiation is damage to previously irradiated tissues progression free survival and overall survival between such as the spinal cord, skin and salivary gland. Exter- the three arms. Intratumoural chemotherapy has been reported using nal beam radiotherapy can be carried out but is best when the time interval from primary radiotherapy is a cisplatin-epinephrine gel suspension. In a study by greater than 12 months to reduce any potential toxicities. Burris et al. [28], 45 patients had weekly intratumoural Local control of 50% can be achieved if the radiation injection for 4 weeks. The response rate of treated dose is greater than 60 Gy. Alternatively, lower doses of tumours was good with 50% of tumours responding radiation can be given either with brachytherapy [17, 18] to therapy of which 40% were complete responses. How-
13 ever 50% of patients developed local toxicity with pain on injection, swelling, ulceration and reports of carotid artery blowouts and this has limited its use. However intratumoural electrochemotherapy (ECT) may provide improved responses with less local tissue toxicity. Electrochemotherapy involves the intratumoural injection of low dose cytotoxic (cisplatin, bleomycin) and then the application of an electric current via electrodes which penetrate the tumour (electroporation). Electroporation causes a transient increase in cell membrane permeability and allows larger molecules to penetrate the cell. In vivo studies have been encouraging for a wide range of tumour types including head and neck [29, 30]. Studies have also been carried out in head and neck cancer patients. Panje et al. [31] reported 5 complete responses and 3 partial responses in 10 patients treated by electrochemotherapy using a low dose of bleomycin. Intraarterial chemotherapy has also been reported. In a phase I trial carried out by Robbins et al. [32], major responses were 86% (41% CR) in 22 untreated advanced stage patients and 62% (25% CR) in 16 recurrent disease patients. Chemotherapy combined with biological agents such as interferon has been reported but with no major beneficial effects [33-35]. Benasso et al. [33] treated 14 patients with cisplatin-5-FU and recombinant interferon-oc-2b with a major response rate of 54% (31% CR). However, Cascinu et al. [34] treated 34 recurrent or metastatic disease patients with a similar protocol with a major response rate of only 23%. New chemotherapeutic agents are currently being evaluated. Docetaxel (a taxane) produced a response rate of 32% of median duration of 6.5 months when given to 37 patients with recurrent or metastatic disease [36]. Paclitaxel has produced an overall response rate of 40% in a phase II trial reported by Forastiere et al. [37]. Interestingly response rates were increased to 67%—77% when paclitaxel was combined with cisplatin [38, 39]. However when paclitaxel was combined with carboplatin [40] a response rate of only 23% was observed. These differences are presumably due to the differences in patients studied in respect to site of tumour and previous treatment. However, it is clear that paclitaxel has biological activity in head and neck cancer and has a role in the treatment of recurrent disease either as a single agent or in combination [41]. Other new chemotherapeutic agents include the antimetabolite gemcitabine, an analogue of deoxycytidine. This has shown only 7 partial responses (13% response rate) in 54 patients with recurrent or metastatic disease [42]. However, when combined with paclitaxel a response rate of 41% (11% CR and 30% PR) has recently been reported [43]. Although this response rate is greater than combination therapy with cisplatin-5-FU, the median time to progression of four months and median survival of nine months are not significantly better than cisplatin5-FU therapy. Other new agents include the antimetabolite thymetaq [44], the Topoisomerase I inhibitor topotecan [45] and
Topoisomerase II inhibitor amonafide [46]. Response rates from these agents have been poor at 14%, 14% and 3%, respectively, and it is unlikely that they will have any role in the treatment of recurrent disease. Therefore, overall it is generally agreed that results of chemotherapy show only moderate response rates and these are of short duration producing little or no increase in survival. New chemotherapeutic agents have failed to show any significant improvement in response with the possible exception of the taxanes. In addition, although different delivery systems in the form of intraarterial or intratumoural injection of chemotherapeutics have shown better responses, they are limited by their local tissue toxicity and also by the technical difficulty particularly in intraarterial administration.
Biological therapies Because of the poor results from chemotherapy and radiotherapy, new biological therapies including immunotherapy and gene therapy have recently caused much interest. Such treatment has the potential to selectively target the tumour while leaving normal tissue relatively unaffected. In immunotherapy, the aim is to either increase the immunogenicity of the tumour [47] or increase the effectiveness of tumour infiltrating lymphocytes [48]. Non-specific immunostimulants [such as BCG, levamisole (an antihelminthic imidazole) and OK-432 (an inactivated low virulence strain of Streptococcus pyogenes)] can stimulate cytotoxic T lymphocytes against tumour cells but both BCG [49] and levamisole [50] have failed to show any tumour response and OK-432 has only had limited effect on tumour reduction [51]. The immunogenicity of the tumour can be increased by transfecting into tumour cells MHC class I and II genes to increase antigen presentation [52]. Although this has been reported in melanoma patients [53], no study has been reported in head and neck cancer patients. Another alternative is to transfect in costimulatory molecules B7.1 or B7.2 to tumour cells to increase antigen presentation. Lang et al. [54] have shown that there is impairment of T-cell activation in head and neck cancer patients and this is partly due to lack of B7.1 expression. They also showed that transduction of the B7.1 gene into head and neck cell lines resulted in T-cell activation. Thus gene therapy using the B7.1 gene as the transgene may be a potentially useful method for immunogenic therapy in head and neck cancer patients. Gleich et al. [55] recently reported a phase I study using Allovectin-7 (i.e., B7 gene complexed to a cationic lipid) by direct intratumoural injection in patients with advanced head and neck cancer who did not express HLA-B7. This study showed no toxicity and a partial response to therapy in four out of nine patients treated. HLA-B7 expression was detected in two of the nine patients and their was extensive apoptosis in both these patients. The effectiveness of tumour infiltrating lymphocytes
14 can be improved by cytokines interleukins 2 and 4 [56], tumour necrosis factor, interferon-a and -y, and granulocyte-macrophage colony stimulating factor. These cytokines can stimulate the production of both tumour infiltrating lymphocytes and lymphokine activated killer cells in vitro and these expanded cells are then used in adoptive immunotherapy [57-59]. Alternatively interleukin-2 can be injected directly into the patient either peritumourally [60] or perilymphatically [61]. However, although immune activation is seen, responses have been very poor. Other gene therapy approaches include tumour suppressor gene replacement therapy with either retroviral or adenoviral vectors, and gene directed enzyme prodrug therapy (GDEPT). Local intratumoural injection with an adenoviral vector containing the wild type p53 tumour suppressor gene in patients with recurrent/?5J(-) tumours has recently been reported in a phase I trial [62]. This treatment was well tolerated with no serious toxicity, some patients showed evidence of tumour regression and phase II trials are now underway. GDEPT involves the introduction of a gene coding for an enzyme capable of activating an inactive prodrug into an active cytotoxic drug. The most common system used is the herpes simplex virus thymidine kinase/ganciclovir system. The thymidine kinase (tk) enzyme can convert the prodrug ganciclovir into an active cytotoxic agent by phosphorylation. By linking this gene to a tissue or tumour specific promoter, selective targeting of tumours can be achieved. In vitro and in vivo work using this system in head and neck cancer cell lines is encouraging [63] and a phase I trial in recurrent head and neck cancer is underway at Johns Hopkins hospital in the USA. Another potential method of achieving selective cytotoxicity could be the use of selectively replicating viruses. The results of experiments with one example, the selectively replicating adenovirus Onyx-015, which targets cells with mutant p53, have recently been reported [64, 65]. Results of a phase I study in patients with recurrent head and neck cancer using this virus appear to be promising [66]. Phase II trials with this virus alone and in combination with chemotherapy are underway.
Follow up recurrences
no recurrences No recurrence
Recurrence location = at site of +ve tumour margin
Figure 1. Molecular analysis of surgical resection margins in patients with head and neck cancer using a molecular probe to mutant p53.
Brennan et al. [68] used a molecular probe against the patients mutant p53 to detect tumour cells at resection margins. A schematic diagram of this method is shown in Figure 1. Using this technique, 25 patients with negative margins on light microscopy were evaluated. Thirteen were positive by molecular probing and twelve were negative. All patients with negative margins had no recurrence at follow up. Of the 13 patients with positive margins, 5 developed recurrence and 8 did not at 12 months follow-up. Moreover, the site of recurrence was at the site of positive tumour margin. The detection of minimal residual disease at resection margins is clearly important as it will determine further treatment. Those with positive margins can be treated more aggressively by reoperation and adjuvent radiotherapy and closer follow-up, whereas those negative by molecular probing may not need adjuvent therapy thus reducing morbidity. At present these techniques are limited by cost and time but with advancing technology these will be overcome. It may be possible to treat minimal residual disease at the time of primary surgery by injecting the tumour bed and resection margins with agents such as Onyx-015, GDEPT or tumour suppressor gene replacement therapy. Studies involving the use of these agents in minimal residual disease are due to commence in the USA in the near future. Overall, results of current therapy for recurrent head and neck cancer are disappointing. For major improvements to be made better drug therapy in the form of Prevention of recurrence - detection and treatment of tumour directed biological therapy or new cytotoxic minimal residual disease agents will be required. Even so, these may still not lead The single most important factor which predisposes to to curative responses. Therefore it may be that the most recurrence is incomplete surgical resection margins [1, effective approach will be one of prevention of recur2]. The best treatment for incomplete surgical margins is rence by the detection of minimal residual disease to reoperation or radiotherapy if the morbidity from fur- select patients for more aggressive therapy or by treating ther surgery is too great [67]. The detection of tumour patients at the time of primary surgery by direct tissue cells at resection margins is very difficult by light micro- injection with agents to destroy residual disease in the scopy. It is estimated that light microscopy only detects 1 tumour bed or resection margins. In addition, new cancer cell in 20 normal cells (5%) yet less than 1% of imaging techniques such as PET scanning may also prove tumour cells in the total cell population is associated useful in detecting recurrent disease before it is clinically with recurrence. Consequently, more sensitive methods apparent. This would allow curative salvage surgery to are required to detect minimal residual disease. Recently be carried out at an earlier stage [69].
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Received 30 July 1999; accepted 28 October 1999. Correspondence to: I. Ganly, Md, PhD, FRCS CRC Beatson Laboratories Garscube Estate Switchback Road Glasgow. G6I 1BD UK E-mail: ig8j(a:udcf.gla.ac.uk
Review Recurrent squamous-cell carcinoma of the head and neck: Overview of current therapy and future prospects I. Ganly^&S. B. Kaye2 'Department of Ololaryngology. Victoria Infirmary, Glasgow, 2CRC Department of Medical Oncology, Garscube Estate, Glasgow, UK
Summary
Locoregional recurrence is the most common cause of failure after head and neck cancer surgery. It is a disease which causes significant morbidity especially on speech and swallowing. There are many different treatments available including surgery, reirradiation and chemotherapy. However, none of these have produced any significant survival benefit. Because of this, there has been considerable interest in the development of new
biological therapies such as gene therapy and immunotherapy for this disease. The objectives of this article are to provide an overview of the currently available therapies for recurrent head and neck cancer including gene therapy and immunotherapy. Prevention of recurrent disease by the detection and treatment of minimal residual disease is also discussed. Key words: chemotherapy, gene therapy, head and neck cancer, immunotherapy, radiotherapy, recurrent, surgery
vival [5]. Brachman et al. [6] have shown that patients with mutations in the tumour suppressor gene p53 have Locoregional recurrence is the most common cause of a shorter time to recurrence. Overexpression ofp53 has failure after head and neck cancer surgery and results in been shown to correlate with an increased incidence of significant morbidity including effects on speech and recurrence and the development of second primaries swallowing. Recurrence may occur at the site of the and hence reduced survival [7]. Antibodies to p53 have primary tumour often as a diffuse mass, at the site of also been shown to be of prognostic significance [8]. In a the draining lymph nodes or may be multifocal in the prospective study of primary head and neck squamousform of multiple cutaneous tumour seedings. There are cell cancer (HNSCC), patients with positive serum antimany factors which predispose to the development of bodies to p53 had an increased incidence of tumour locoregional recurrence. However, the single most im- recurrence, second primaries and tumour related deaths portant factor is incomplete surgical resection margins (44.7% in antibody positive group compared to 21.1% [1, 2]. This is determined not only by the experience of in antibody negative group). the surgeon but also by the site of the primary tumour which may limit the extent of surgical excision. For example, in larger tumours of the oropharynx and oral Current therapies cavity it may be difficult to obtain adequate surgical resection margins and still preserve organ function. Improvements in surgical reconstruction due to the Recurrence in the neck is more likely if there are multi- development of microvascular free tissue transfer, better ple nodes present and if there is extranodal spread of radiotherapy protocols such as hyperfractionation and disease. As well as site and extent of surgical resection, chemoradiation [9-12] have led to improvements in recurrence is also determined by the dose and timing of locoregional control of head and neck cancer. As a adjuvent radiotherapy. Delays in radiotherapy treatment result, more patients present with distant metastatic beyond six weeks post surgery and radiation doses less disease than before and therefore purely recurrent disthan 54 Gy have been shown to result in poorer survival ease is less frequent. As a consequence, many clinical and disease-free intervals [3]. Other factors which pre- trials describing new treatments for recurrent head and dispose to recurrence include poor differentiation of the neck cancer often include patients not only with locoprimary tumour and evidence of neurogenic and vessel regional recurrence but also with distant metastatic invasion. Woolley et al. [4] also showed an increased risk disease and locally advanced primary disease. The of recurrence if blood transfusion was carried out at the objectives of this review are to describe the current time of primary surgery. Molecular markers are also therapies available for recurrent disease. However it important. Amplification of the oncogene Cyclin Dl should be noted that many clinical trials include this has been associated with recurrence and shortened sur- mixed group of patients and this should be considered Introduction
12 when interpreting any conclusions drawn from these clinical trials. Surgery Surgery plays a role in the treatment of both local and regional recurrence but only where curative surgery is possible or surgery results in significant palliation of symptoms. Recurrence in the neck can be treated surgically if the neck has not been previously treated either with surgery or radiotherapy. If a selective neck dissection has been carried out and recurrence has occurred outside the neck dissection field a complete radical neck dissection can be done in this case. However, usually the neck has already been treated with radiotherapy. In this case it is technically demanding to resect the tumour due to fixation of the tumour to local structures such as the carotid artery or vertebrae and it is also likely to be unsuccessful because of extranodal spread of disease. Surgical treatment of local recurrence is dependent on the site and previous treatment of the primary tumour. Ti and T2 tumours of the glottic larynx are treated with radiotherapy and recurrence in this situation can be treated with curative intent with either a partial laryngectomy [13, 14] or total laryngectomy. Surgical salvage can also be carried out for supraglottic tumours though the chance for cure is less than for glottic tumours [15]. Recurrence in the oral cavity (oral vestibule, buccal mucosa, gums, floor of mouth, oral tongue, hard palate, retromolar trigone) of small Ti and T2 tumours is difficult to detect early if the patient has had radiation treatment. However with close follow-up these patients can be successfully salvaged surgically [16]. With larger T3 and T4 oral cavity tumours, primary surgery and radiotherapy often fail and further surgery is rarely possible nor curative. In the oropharynx (base of tongue, faucial arch, tonsillar pillars and fossa and posterior pharyngeal wall) recurrence can be treated surgically if it involves the tonsillar pillars or fossa. However, recurrence of the base of tongue is rarely curative since these tumours are hard to detect and therefore present late. Radical surgery in the form of a total glossectomy and laryngectomy is often required but even with such surgery further recurrence often occurs within one year and long-term survival is very poor.
or by combining external beam radiotherapy with chemotherapy (chemoradiation). Low-dose radiotherapy in the form of brachytherapy has been shown to be effective in the treatment of primary head and neck cancer, especially in base of tongue tumours. However it also has a role in recurrent disease. Because the dose of radiation is lower (20-40 Gy) and the depth of radiation penetration small, toxicity in previously irradiated tissue is limited. Nag et al. [19] have reported local control of 17% in patients using I192 implanted wires. The dose of external beam radiotherapy can also be reduced by combining with systemic chemotherapy (chemoradiation). Haraf et al. [20] reported a five-year survival of 22% and progression-free survival of 26% using a combination of cisplatin-5-FUhydroxyurea with radiotherapy (median dose 50 Gy). Interstitial radiotherapy can also be combined with local tumour interstitial hyperthermia since hyperthermia kills hypoxic and S phase cells, neither of which are killed by radiation. Petrovic et al. [21] reported a complete response of 68% and partial response rate of 32% in sites treated by this technique. Recently it was reported that gemcitabine (an analogue of deoxycytidine) was a potent radiosensitizer [22]. Using a low dose of gemcitabine two hours pre-radiotherapy, a phase I trial by Eisbruch et al. [23] in eight patients gave a complete response in seven patients. However, there was excessive mucosal and pharyngeal toxicity at the dose used and therefore studies using lower doses are planned. Chemotherapy
Chemotherapy may be given systemically, intratumourally or intraarterially. Systemic chemotherapy may be given either as a single agent, e.g., methotrexate or in combination, e.g., cisplatin-5-FU. Treatment with combination chemotherapy increases overall response rates to 30%-40% [24] compared with single agents where the response rate is only 10%—20% [25], but there is no improvement in survival (median survival is six months in both cases) [26]. In a randomised trial carried out by the EORTC (European Organisation for Research and Treatment of Cancer), 382 chemotherapy-naive patients with recurrent or metastatic head and neck cancer were randomly assigned to either a combination of CABO (cisplatin, methotrexate, bleomycin, and vincristine), Reirradiation cisplatin and infusional 5-fluorouracil (5-FU), or cisplaSurgery and adjuvent radiotherapy or radiotherapy tin alone [27]. Major responses were similar for CABO alone are the main therapies for primary head and neck (34%) and cisplatin-5-FU (31%) but better than cisplacancer. For recurrent disease, the main concern with tin alone (15%). However, there was no difference in reirradiation is damage to previously irradiated tissues progression free survival and overall survival between such as the spinal cord, skin and salivary gland. Exter- the three arms. Intratumoural chemotherapy has been reported using nal beam radiotherapy can be carried out but is best when the time interval from primary radiotherapy is a cisplatin-epinephrine gel suspension. In a study by greater than 12 months to reduce any potential toxicities. Burris et al. [28], 45 patients had weekly intratumoural Local control of 50% can be achieved if the radiation injection for 4 weeks. The response rate of treated dose is greater than 60 Gy. Alternatively, lower doses of tumours was good with 50% of tumours responding radiation can be given either with brachytherapy [17, 18] to therapy of which 40% were complete responses. How-
13 ever 50% of patients developed local toxicity with pain on injection, swelling, ulceration and reports of carotid artery blowouts and this has limited its use. However intratumoural electrochemotherapy (ECT) may provide improved responses with less local tissue toxicity. Electrochemotherapy involves the intratumoural injection of low dose cytotoxic (cisplatin, bleomycin) and then the application of an electric current via electrodes which penetrate the tumour (electroporation). Electroporation causes a transient increase in cell membrane permeability and allows larger molecules to penetrate the cell. In vivo studies have been encouraging for a wide range of tumour types including head and neck [29, 30]. Studies have also been carried out in head and neck cancer patients. Panje et al. [31] reported 5 complete responses and 3 partial responses in 10 patients treated by electrochemotherapy using a low dose of bleomycin. Intraarterial chemotherapy has also been reported. In a phase I trial carried out by Robbins et al. [32], major responses were 86% (41% CR) in 22 untreated advanced stage patients and 62% (25% CR) in 16 recurrent disease patients. Chemotherapy combined with biological agents such as interferon has been reported but with no major beneficial effects [33-35]. Benasso et al. [33] treated 14 patients with cisplatin-5-FU and recombinant interferon-oc-2b with a major response rate of 54% (31% CR). However, Cascinu et al. [34] treated 34 recurrent or metastatic disease patients with a similar protocol with a major response rate of only 23%. New chemotherapeutic agents are currently being evaluated. Docetaxel (a taxane) produced a response rate of 32% of median duration of 6.5 months when given to 37 patients with recurrent or metastatic disease [36]. Paclitaxel has produced an overall response rate of 40% in a phase II trial reported by Forastiere et al. [37]. Interestingly response rates were increased to 67%—77% when paclitaxel was combined with cisplatin [38, 39]. However when paclitaxel was combined with carboplatin [40] a response rate of only 23% was observed. These differences are presumably due to the differences in patients studied in respect to site of tumour and previous treatment. However, it is clear that paclitaxel has biological activity in head and neck cancer and has a role in the treatment of recurrent disease either as a single agent or in combination [41]. Other new chemotherapeutic agents include the antimetabolite gemcitabine, an analogue of deoxycytidine. This has shown only 7 partial responses (13% response rate) in 54 patients with recurrent or metastatic disease [42]. However, when combined with paclitaxel a response rate of 41% (11% CR and 30% PR) has recently been reported [43]. Although this response rate is greater than combination therapy with cisplatin-5-FU, the median time to progression of four months and median survival of nine months are not significantly better than cisplatin5-FU therapy. Other new agents include the antimetabolite thymetaq [44], the Topoisomerase I inhibitor topotecan [45] and
Topoisomerase II inhibitor amonafide [46]. Response rates from these agents have been poor at 14%, 14% and 3%, respectively, and it is unlikely that they will have any role in the treatment of recurrent disease. Therefore, overall it is generally agreed that results of chemotherapy show only moderate response rates and these are of short duration producing little or no increase in survival. New chemotherapeutic agents have failed to show any significant improvement in response with the possible exception of the taxanes. In addition, although different delivery systems in the form of intraarterial or intratumoural injection of chemotherapeutics have shown better responses, they are limited by their local tissue toxicity and also by the technical difficulty particularly in intraarterial administration.
Biological therapies Because of the poor results from chemotherapy and radiotherapy, new biological therapies including immunotherapy and gene therapy have recently caused much interest. Such treatment has the potential to selectively target the tumour while leaving normal tissue relatively unaffected. In immunotherapy, the aim is to either increase the immunogenicity of the tumour [47] or increase the effectiveness of tumour infiltrating lymphocytes [48]. Non-specific immunostimulants [such as BCG, levamisole (an antihelminthic imidazole) and OK-432 (an inactivated low virulence strain of Streptococcus pyogenes)] can stimulate cytotoxic T lymphocytes against tumour cells but both BCG [49] and levamisole [50] have failed to show any tumour response and OK-432 has only had limited effect on tumour reduction [51]. The immunogenicity of the tumour can be increased by transfecting into tumour cells MHC class I and II genes to increase antigen presentation [52]. Although this has been reported in melanoma patients [53], no study has been reported in head and neck cancer patients. Another alternative is to transfect in costimulatory molecules B7.1 or B7.2 to tumour cells to increase antigen presentation. Lang et al. [54] have shown that there is impairment of T-cell activation in head and neck cancer patients and this is partly due to lack of B7.1 expression. They also showed that transduction of the B7.1 gene into head and neck cell lines resulted in T-cell activation. Thus gene therapy using the B7.1 gene as the transgene may be a potentially useful method for immunogenic therapy in head and neck cancer patients. Gleich et al. [55] recently reported a phase I study using Allovectin-7 (i.e., B7 gene complexed to a cationic lipid) by direct intratumoural injection in patients with advanced head and neck cancer who did not express HLA-B7. This study showed no toxicity and a partial response to therapy in four out of nine patients treated. HLA-B7 expression was detected in two of the nine patients and their was extensive apoptosis in both these patients. The effectiveness of tumour infiltrating lymphocytes
14 can be improved by cytokines interleukins 2 and 4 [56], tumour necrosis factor, interferon-a and -y, and granulocyte-macrophage colony stimulating factor. These cytokines can stimulate the production of both tumour infiltrating lymphocytes and lymphokine activated killer cells in vitro and these expanded cells are then used in adoptive immunotherapy [57-59]. Alternatively interleukin-2 can be injected directly into the patient either peritumourally [60] or perilymphatically [61]. However, although immune activation is seen, responses have been very poor. Other gene therapy approaches include tumour suppressor gene replacement therapy with either retroviral or adenoviral vectors, and gene directed enzyme prodrug therapy (GDEPT). Local intratumoural injection with an adenoviral vector containing the wild type p53 tumour suppressor gene in patients with recurrent/?5J(-) tumours has recently been reported in a phase I trial [62]. This treatment was well tolerated with no serious toxicity, some patients showed evidence of tumour regression and phase II trials are now underway. GDEPT involves the introduction of a gene coding for an enzyme capable of activating an inactive prodrug into an active cytotoxic drug. The most common system used is the herpes simplex virus thymidine kinase/ganciclovir system. The thymidine kinase (tk) enzyme can convert the prodrug ganciclovir into an active cytotoxic agent by phosphorylation. By linking this gene to a tissue or tumour specific promoter, selective targeting of tumours can be achieved. In vitro and in vivo work using this system in head and neck cancer cell lines is encouraging [63] and a phase I trial in recurrent head and neck cancer is underway at Johns Hopkins hospital in the USA. Another potential method of achieving selective cytotoxicity could be the use of selectively replicating viruses. The results of experiments with one example, the selectively replicating adenovirus Onyx-015, which targets cells with mutant p53, have recently been reported [64, 65]. Results of a phase I study in patients with recurrent head and neck cancer using this virus appear to be promising [66]. Phase II trials with this virus alone and in combination with chemotherapy are underway.
Follow up recurrences
no recurrences No recurrence
Recurrence location = at site of +ve tumour margin
Figure 1. Molecular analysis of surgical resection margins in patients with head and neck cancer using a molecular probe to mutant p53.
Brennan et al. [68] used a molecular probe against the patients mutant p53 to detect tumour cells at resection margins. A schematic diagram of this method is shown in Figure 1. Using this technique, 25 patients with negative margins on light microscopy were evaluated. Thirteen were positive by molecular probing and twelve were negative. All patients with negative margins had no recurrence at follow up. Of the 13 patients with positive margins, 5 developed recurrence and 8 did not at 12 months follow-up. Moreover, the site of recurrence was at the site of positive tumour margin. The detection of minimal residual disease at resection margins is clearly important as it will determine further treatment. Those with positive margins can be treated more aggressively by reoperation and adjuvent radiotherapy and closer follow-up, whereas those negative by molecular probing may not need adjuvent therapy thus reducing morbidity. At present these techniques are limited by cost and time but with advancing technology these will be overcome. It may be possible to treat minimal residual disease at the time of primary surgery by injecting the tumour bed and resection margins with agents such as Onyx-015, GDEPT or tumour suppressor gene replacement therapy. Studies involving the use of these agents in minimal residual disease are due to commence in the USA in the near future. Overall, results of current therapy for recurrent head and neck cancer are disappointing. For major improvements to be made better drug therapy in the form of Prevention of recurrence - detection and treatment of tumour directed biological therapy or new cytotoxic minimal residual disease agents will be required. Even so, these may still not lead The single most important factor which predisposes to to curative responses. Therefore it may be that the most recurrence is incomplete surgical resection margins [1, effective approach will be one of prevention of recur2]. The best treatment for incomplete surgical margins is rence by the detection of minimal residual disease to reoperation or radiotherapy if the morbidity from fur- select patients for more aggressive therapy or by treating ther surgery is too great [67]. The detection of tumour patients at the time of primary surgery by direct tissue cells at resection margins is very difficult by light micro- injection with agents to destroy residual disease in the scopy. It is estimated that light microscopy only detects 1 tumour bed or resection margins. In addition, new cancer cell in 20 normal cells (5%) yet less than 1% of imaging techniques such as PET scanning may also prove tumour cells in the total cell population is associated useful in detecting recurrent disease before it is clinically with recurrence. Consequently, more sensitive methods apparent. This would allow curative salvage surgery to are required to detect minimal residual disease. Recently be carried out at an earlier stage [69].
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Received 30 July 1999; accepted 28 October 1999. Correspondence to: I. Ganly, Md, PhD, FRCS CRC Beatson Laboratories Garscube Estate Switchback Road Glasgow. G6I 1BD UK E-mail: ig8j(a:udcf.gla.ac.uk