TITLE: Chemotherapy for Head and Neck Cancer
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds Presentation
DATE: November 25, 1998
RESIDENT: Herve' J. LeBoeuf, M.D.
FACULTY: Anna M. Pou, M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.
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"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."
Many malignancies are seen in the head and neck. However, the term head and neck cancer usually refers to those cancers arising from the surface epithelium of the upper aerodigestive tract. Approximately 42,000 new cases were diagnosed in the United States last year, comprising 3% of all invasive malignancies. Squamous cell carcinoma was the histologic type in over 90% of these tumors. Tobacco and alcohol abuse seem to be the most important risk factors, which has given rise to a second primary rate of 4-7%/year.
Historically, in early stage cancers, surgery with or without radiation therapy has been the primary treatment modality to achieve a cure. In advanced stage SqCCa treated with XRT and/or surgery, recurrence rates have remained at about 65% for the past forty years. Approximately 2/3 of these recurrences represent locoregional disease and the rest are distant metastases. Treatment with chemotherapy has yielded impressive responses in certain patients, but alone it is not yet curative. Therefore, historically it has been used to treat advanced unresectable cancers in the palliative setting. In the past decade multiple clinical studies have examined various ways to integrate systemic therapy with standard loco-regional treatment in the hope of improving outcomes. Three main objectives have been pursued: (1) to improve the chances of a cure; (2) to improve functional and/or cosmetic outcome by avoiding surgical procedures (i.e. organ preservation); (3) to decrease the incidence of distant metastases and second primary cancers. Achievement of these objectives has not been demonstrated to date, however, the future of chemotherapy remains promising. It should be noted that nearly all studies have been conducted on late stage (T3,4), recurrent, or metastatic disease only. The following is a review of the advances made to date.
Antimetabolites were the earliest of the agents to be used effectively against squamous cell carcinoma of the head and neck (SCCHN). They are similar to natural occurring substances and are incorporated into DNA or RNA as faulty purines, pyrimidines and nucleic acids, and thus interfere with nucleic acid synthesis and enzyme action. Cytotoxicity depends on dose and duration of exposure, in that prolonged time of exposure enhances antitumor activity. Methotrexate was the original agent used for palliation. It has largely been replaced with combination chemotherapy, but remains an alternative due to its relatively low toxicity. 5-Fluorouracil is commonly used as a combination agent but has some anti-tumor effects as a single agent as well. Hydroxyurea is mainly used in conjunction with XRT as a radiation sensitizer. It synchronizes cells in the G1 phase which is the phase of cell division that radiation has its greatest cytotoxic effect in. Side effects of these agents include mucositis, myelosuppression, nausea, vomiting, and diarrhea.
The use of platinum derivatives began in the early seventies with the introduction of cisplatin. Since then they have become the most potent agents for use in lung, ovarian, testicular and SCCHN. They bind directly to DNA, causing single stranded and double stranded breaks. Cisplatin has been reported as having a single agent response rate of 27-30%, nearly double that of the antimetabolites. Carboplatin has a lower response rate as a single agent, but also has lower toxicity. Side effects include myelosuppression, complete alopecia, ototoxicity, peripheral neuropathies, renal failure and severe emesis.
Of the anthracyclines, doxorubicin is the most commonly used agent. It’s antitumor activity is from free radical formation and topoisomerase-I DNA damage. Doxorubicin is very active against non Hodgkins lymphoma, nasopharyngeal carcinoma, adenoid cystic carcinoma and adenocarcinoma of the salivary glands. Toxicities include extravasation necrosis, myelosuppression, alopecia, CHF, pericarditis and arrhythmias.
Of the plant alkaloids, vincristine, vinblastine and more recently vinorelbine have been used. These agents bind tubulin, thereby preventing spindle formation and disrupting mitosis. Toxicities include peripheral neuropathy, nausea, extravasation necrosis and myelosuppression. Vinorelbine shows the greatest activity against SCCHN amony the alkaloids.
The taxoids (paclitaxel and docetaxel) are the newest group of agents with very encouraging activity against SCCHN. They interfere with the mitotic spindle by stabilizing microtubules against depolymerization. Primary toxicities are myelosuppression and nonreversible neurotoxicity. As single agents these drugs have efficacies comparable with the platinum compounds.
No response rate for any single agent has been higher than 30-35%. When interpreting reported response rates, it is important to know that complete and partial (only 50% tumor regression) responses are included. The response only has to last 4 weeks to be included in these reports. Therefore, it is difficult to compare many of the study results reported in the past. More appropriate end points to use for comparison of therapies may be survival and quality of life. Current clinical trials are defining these measures at present.
Combination chemotherapy now seems to be the ideal way to administer these agents. The goal is to find agents that act synergistically and that do not have the same primary toxicity profile. Cisplatin and 5-FU have been the most extensively studied, and have resulted in response rates as high as 90%. However, no single agent or combination regimen has yet proved to extend survival in recurrent and metastatic disease.
Neoadjuvant chemotherapy, also known as induction chemotherapy, is the use of chemotherapy as the primary treatment before definitive surgery or radiation therapy. Advantages of this include an intact vascular bed for better drug delivery, reduced tumor bulk, and early eradication of regional and distant micrometastases. Disadvantages include delay of surgery, morbidity of "overtherapy", and patient noncompliance after chemotherapy. In previously untreated patients response rates as high as 90% have been achieved with combination chemotherapy with 5-FU and cisplatin. However, none of the studies conducted have shown an overall survival benefit with induction chemotherapy.
Probably the most frequently cited study in the literature today regarding induction chemotherapy is from the VA Laryngeal Cancer Study Group38. They compared traditional surgery and XRT with neoadjuvant chemotherapy and XRT utilizing surgical salvage for treatment failures. Although they failed to show a difference in survival between the two arms, total laryngectomy was avoided in 64% of patients with primary chemotherapy. This has been the single greatest argument utilized for organ preservation with laryngeal cancer and induction chemotherapy to date.
Another recent landmark study was a trial reported by Paccagnella and colleagues39. Patients had induction chemo, followed by surgery and XRT for operable patients or XRT only for inoperable patients. The control groups had similar treatment without chemotherapy. They reported a statistically significant 3 year survival benefit (24% v. 10%) for inoperable patients with induction chemotherapy.
All of the recent studies suggest a trend toward a lower incidence of distant metastases as a site of first failure with neoadjuvant chemotherapy. However, poor loco-regional control still led to the same survival rates in most trials. The VA trial suggests that induction chemo and XRT may be given as an alternative to extensive surgery in advanced SCCHN cases without altering survival rates. This may lead to better quality of life, although this has yet to be proven. Prolonged survival has been shown for inoperable patients with N2 disease. Otherwise, there is currently no role for induction chemotherapy outside clinical trials.
This is the simultaneous use of chemotherapy and radiation which has been primarily utilized to increase locoregional control. Chemotherapy should increase the efficacy of XRT for local control and also provides a measure of systemic control of micrometastases. It is believed that chemotherapy may have some benefit against radioresistant hypoxic tumor cells. However, the simultaneous use of chemotherapy and XRT often increases toxicities to intolerable levels. If both are to be administered at appropriate doses, then the XRT must be occasionally interrupted. It is well documented that any interruption in XRT for single modality treatment reduces efficacy. Today’s research focuses on using split course and alternating chemoradiotherapy to decrease toxicity.
Most single agents have proved to have some radiosensitizing effect. The most efficacious are cisplatin, 5-FU and more recently paclitaxel. Several studies have shown prolonged overall survival and benefit in locoregional control over XRT alone for unresectable disease. Most studies suggest improvement in local control and survival rates with concomitant chemoradiotherapy over sequential chemoradiotherapy. However, the routine use of chemoradiotherapy awaits further data.
Few studies have examined the use of adjuvant chemotherapy. Most patients will not tolerate the toxicity of chemotherapy after surgical and radiation therapies. In addition, the few studies that have been done fail to show any benefit except for a slight trend in decreasing distant metastases.
Intra-arterial chemotherapy has drawn much attention in the literature over the past several years. The practicality of using this technique for a given tumor is based on several principles. First, the tumor must be in a region that would be totally infused by regional artery cannulation and the artery must be accessible to cannulation. Second, the agents to be used must be tumoricidal in their infused state (i.e. not require hepatic processing to be effective). Finally, the higher doses achieved locally must provide adequate tumoricidal activity to justify administration.
Many locations of SCCHN seem well suited for regional infusion chemotherapy. The carotid artery is accessed and the predominant artery perfusing the tumor is identified. Cytotoxic agents are then infused at supranormal concentrations. This provides high local concentrations of the agent, but hematologic dilution at peripheral sites in the body which results in decreased systemic toxicity. To date there is no evidence that this prolongs survival or increases response rates for SCCHN, but trials are under way.
Nasopharyngeal carcinoma is endemic in Southeast Asia and China with increased incidences in the Mediterranean countries. It is relatively rare in the United States and Continental Europe. It differs markedly from other head and neck cancers based on its distinct histology, its association with EBV, its marked responsiveness to chemotherapy, and its rapid growth with early dissemination. Young women and men without the usual tobacco and alcohol risk factors are the norm. Presentation is commonly a locally advanced stage with nodal involvement or metastases. Bones are the predominant metastatic site and most patients die from metastasic disease.
A combined modality approach with chemotherapy and radiation has become standard treatment for nasopharyngeal carcinoma. The most notable prospective trial to date examined induction with 5-FU and cisplatin followed by radiation. The overall initial response rate was 93% and the 6 year survival was 67%. Future studies will examine adjuvant and concomitant chemotherapy.
Immunotherapy is based on theory of immunosurveillance, which postulates that specific effector molecules and cells of the immune system recognize and eradicate neoplastic cells, thereby preventing tumor formation. By extension, the theory predicts that immunomodulation can be an effective means of anticancer therapy. Two main avenues of research have been followed. One is the "boosting" of the patient’s own immune system in an attempt to increase the patients own tumoricidal response. The other is the identification of tumor specific antigens so that monoclonal antibodies may be created and directed at these antigens.
A natural corollary to the theory of immunosurveillance is that tumors acquire phenotypic properties that enable them to escape immune recognition or destruction during the process of tumor progression. The observation that SCCHNs are infiltrated by granulocytes and lymphocytes, the latter known as tumor-infiltrating lymphocytes (TILs), at the tumor margins, within the stroma, or in nests of tumor cells has been well documented by several groups of investigators.
Analysis of these TILs in situ, revealed that they have decreased proliferative and cytolytic activity relative to peripheral lymphocytes. TILs also exhibit decreased cytokine production and decreased Natural Killer cell activity. It is assumed that the tumor is somehow able to suppress these cells locally, but the nature of this suppression is not yet known. A number of SCCHN cell lines have been shown to spontaneously produce prostaglandin PGE2, a potent immunosuppressant. One study has shown that tumor cell suppression of lymphocytes locally can be inhibited by the anti-prostaglandin indomethacin. Patients with SCCHN have been found to have higher serum levels of PGE2 than normal controls, and these levels were seen to decrease after tumor treatment and increase with tumor recurrence. Consequently, immunomodulation by specific inhibitors of prostaglandin synthesis may be of potential benefit in the treatment of head and neck cancer.
Some tumor cell lines have also been shown to exhibit IL-2 receptors on their surface. Several studies have shown direct growth inhibitory effects of IL-2 against SCCHN in nude mice, with total tumor regression. Therapy aimed at increasing human production of IL-2 is under investigation. Recombinant IL-2 has been administered using several different regimen but with only partial responses to date. Similarly gamma-interferon has been administered in several studies with minimal tumoricidal effect. Because the preclinical trials with these agents strongly support their antitumor effects, further studies examining alternate dosing regimens are warranted.
The technology for producing monoclonal antibodies to specific antigens is well documented. The utility of this technology in SCCHN has been limited by the absence of known specific antigens expressed by the tumor cells. Recently, two promising monoclonal antibodies have been developed. The E48 and U36 antibodies have been coupled to various radiotracers and shown to bind to a number of SCCHN cell lines, as well as to some normal squamous epithelium. Technetium labeled E48 IgG was shown to adequately localize cervical lymph node metastases in a recent clinical trial. Re-labeled E48 has been shown to have a dose dependent effect on tumor regression in nude mice, suggesting that radioimmunotherapy may become a useful approach. Further promising research has shown effective anti-tumor activity utilizing human purified IL-2 activated NK cells with antiSCCHN monoclonal antibodies.
Head and neck carcinogenesis is a multistage process driven by genetic alteration which proceeds to dysregulation of cell growth, proliferation and differentiation. Chemoprevention refers to the use of specific agents to suppress carcinogenesis and therefore prevent the development of invasive primary and secondary cancer. In 1953, Slaughter found extensive premalignant lesions (hyperplasia, dysplasia, CIS) adjacent to tumor sites in SCCHN. This led to the concept of "field cancerization". The development of recurrent tumors in the upper aerodigestive tract may be due to diffuse mucosal insult by oral carcinogens (tobacco, alcohol).
Oral leukoplakia is considered a premalignant lesion, with a rate of malignant transformation to SCCHN of 17.5 percent over eight years23. Retinoids have been shown to have significant activity in reversing epithelial preneoplasia. Vitamin A is essential for the development and maintenance of normal epithelium. Deficiency of vitamin A causes a change in the differentiation pathway resulting in epithelial hyperplasia and squamous metaplasia in laboratory animals. Epidemiologic surveys suggest that the risk of head and neck tumorigenesis is increased in vitamin A deficiency. Retinoids retarded the development of premalignant and malignant lesions in hamster oral carcinogenesis models24. Retinoids also suppress epidermal growth factor receptor (EGF-R) mRNA expression, tyrosine kinase activity and ligand binding in association with an antiproliferative effect on human oral squamous cell carcinoma cell lines.
Multiple recent studies have shown that retinoids can reverse oral leukoplakia in vivo. Data to date indicates that retinoids must be given systemically at low doses on a 9-12 month maintenance program25. Progression free maintenance rates have been as high as 92% over three years. Other agents being examined include B-carotene, vitamin E, selenium and N-acetyl-cysteine.
Two studies showed regression of laryngeal papillomatosis with either 13-cis-retinoic acid or etretinate26,27. The overall response rate to each agent was 67 per cent. It is known that laryngeal papilloma is associated with human papilloma virus (HPV). The transforming proteins of HPV are E6 and E7 proteins which bind to p53 and retinoblastoma tumor suppressor gene proteins, respectively. The wild type p53 and retinoblastoma protein are involved in cell cycle control. The binding of the viral transforming proteins to these tumors suppressor gene products will dysregulate cell cycle control and result in growth aberation. Retinoic acid can suppress the production of these viral transforming proteins which may be one of the mechanisms of tumor suppression. Recent in vitro and in vivo work in human laryngeal papilloma cells supports this hypothesis. Current work is using retinoic acid plus interferon in the treatment of laryngeal papillomatosis based on recent in vitro in vivo and clinical results in many systems including HPV-related neoplasias.
The multicentric neoplasia is a consequence of multistage field cancerization in aerodigestive tract cancer, high incidence of second primary tumors, and activity of 13-cis-retinoic acid in reversal of oral carcinogenesis to the development of an adjuvant trial of 13 cRA in squamous cell carcinoma of head and neck28. Eligible patients including biopsy-proven stage I-II (MO) disease were rendered disease-free after surgery and/or radiation. Salivary gland and nasopharyngeal carcinoma were excluded from this study since they are outside the field at risk to tobacco-related carcino-genesis.
Patients were stratified by site (oral cavity, oropharynx, hypopharynx, or larynx) and treatment (radiation, surgery, or both) to receive 13 cRA (50 to 100 mg/kg/day) or placebo for 12 months. The treatment was initiated no later than 10 weeks after surgery or 16 weeks after radiation. The endpoint of this adjuvant study was disease failure as primary disease recurrence (local, regional or distant) and second primary tumor (SPT).
At 42 months of follow-up, on 3 of 49 patients (6%) in the 13 cRA arm developed SPTs, whereas, 14 of 51 patients (28%) in the placebo arm failed with SPTs (p<0.005). The incidence of SPTs in the placebo arm in the prospective study (roughly 10% per year) was higher than the 2 to 6 per cent per year reported in retrospective studies and tumor registries. No patient developed SPT during the 12 months of 13 cRA therapy. Only two patients in the 13 cRA arm (4%) developed SPTs in the aerodigestive tract, whereas, twelve (24%) in the placebo arm failed with SPTs in this region, P<0.005. Median time to the development of SPTs was 18 months. The rate of primary disease recurrence was not significantly different in the 2 study arms. Overall disease-failure rate was significantly lower in the 13 cRA group (37% vs. 61%%, p<0.05). Survival differences have not yet reached statistical significance12.
Photodynamic therapy (PDT) is a local therapy for treatment of superficially located tumors. In this approach a photosensitive dye (photosensitizer) is injected intravenously, whereafter it accumulated more or less selectively in the tumor. After exposure to laser light in the near-infra-red region, the sensitizer is excited and is able to produce singlet oxygen, a cytotoxic form of oxygen. Direct cell killings as well as occlusion of tumor blood vessels can occur, both processes resulting in tumor necrosis. PDT has been used in Europe for the non-invasive treatment of many types of cancer, including colon, bladder, lung, and head and neck cancer.
In the past PDT was mostly used for palliation in inoperable patients with advanced stage HNSCC. The objective in these studies was to induce tumor shrinkage, by which impaired physiological functions like swallowing and breathing could be improved. Nowadays, PDT is more often used with a curative intent for the treatment of small localized primary, second primary and recurrent tumors as well as pre-malignant lesions. At this stage of development of PDT, only lesions for which treatment with radiotherapy or surgery is not an option are treated. Moreover, these lesions must be localized in an area where homogenous illumination is possible.
Cancer should be considered as a genetic disease. During the last decade enormous progress has been made in the identification of the genetic factors that underlie HNSCC. Somatic gene therapy aims to treat this disease by introduction of therapeutic genes into somatic cells. One of the possible ways of obtaining a therapeutic effect is by correction of the faulty gene. Mutated tumor-suppressor genes (e.g. p53 gene) can be neutralized by replacement or overexpression of oncogenes (e.g. K-ras) can be blocked. Another possibility is by in vivo transduction of tumor cells with genes encoding for toxins like diphtheria A toxin and staphylococcal enterotoxin. In this latter approach, selective transduction of tumor cells would be required due to the toxic potential of the toxins. Cytotoxicity can also be obtained with gene-dependent enzyme prodrug therapy. In this approach, the gene of choice encodes for an enzyme (e.g. herpes simplex virus thymidine kinase) which is not expressed in normal cells and which is able to convert a non-toxic prodrug into a toxic drug at the tumor site.
For effective somatic gene therapy the gene of choice should be efficiently brought to the target tissue and into the cells of that tissue. For introduction into the target cell, nascent DNA can be transduced in vitro using common techniques like direct injection, calcium phosphate, and electroporation. One disadvantage if these methods is that the DNA usually remains non-integrated, resulting in rapid degradation of the DNA. Therefore, the gene of choice will be expressed only transiently, and for effective therapy the procedure may have to be repeated several times.
Introduction of viruses as vectors for gene transfer has solved many of the aforementioned problems. Since viruses are infectious in nature, efficient introduction and stable and high expression of the gene of interest has become possible. Retroviruses, adenovirus, herpes virus, adeno-associated virus, vaccinia virus and polio virus, which have been made incapable of replication and non-pathogenic, are the most commonly explored.
O’Malley et al22 used adenovirus-mediated transfer of the HSV-tk gene followed by ganciclovir administration for the treatment of established human HNSCC tumors growing in the floor of the mouth of nude mice. The recombinant adenovirus was injected directly into tumors of 21-75 mm. The survival studies showed that 50% of all treated mice were free of tumor at 160 days after virus injection, while all control mice died or required sacrifice within 43 days. Furthermore, the best responses were found with the smallest tumors. No evidence for local or systemic toxicity was found. Wilson et al21 explored a similar model. They used mice with HNSCC xenografts on both flanks. Remarkably, while only the tumors in the left flank were treated with the HSV-tk gene, the tumors in the contralateral flank also regressed after administration of ganciclovir.
A third strategy comprises the introduction of wild-type p53 in HNSCC tumors containing mutations or deletions in their p53 tumor suppressor gene. It is believed that the wild-type p53 is capable of antagonizing the growth-stimulating activity of oncogenes and of restoring the possibility for programmed cell death (apoptosis).
It can be expected that the efficiency and safety of methods for transfer and expression of therapeutic genes into somatic cells will continue to improve during the coming years. An aspect of special consideration will be the specificity of therapeutic gene expression. As a large proportion of cancer patients suffer from systemic disease, the question with some of the aforementioned approaches is: how to make the therapeutic gene expressed selectively in all tumor cells? The currently used gene transfer systems are not able to target HNSCC cells selectively. Among the possible solutions to the problem are the use of targeting vehicles, e.g. monoclonal antibodies, and the exploration of tissue-specific promoters.
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