Advances in multimodality therapy for laryngeal cancer
Authors: J. F. Carew, J. P. Shah
Journal: CA A Cancer Journal for Clinicians (1998)

Head and neck cancer is the sixth most common form of cancer worldwide.1 More than 90% of head and neck cancers are squamous cell carcinomas. The oral cavity is the most common site within the head and neck, and the larynx is the second most common. The American Cancer Society projects 11,100 new cases of laryngeal cancer and 4,300 deaths from laryngeal cancer in the United States in 1998 (Figure).2 In the last two decades, the 5-year survival of patients with laryngeal cancer has not changed dramatically.2 In a recent study of 16,213 patients with laryngeal cancer, overall 5-year disease-specific survival was 75%.3 Of these patients, less than 40% presented with advanced disease (stage III or IV).3 In most patients with early stage disease (stage I or II), local control and survival are achieved with single-modality therapy consisting of either external beam radiation therapy or surgery.3, 4 Advanced-stage squamous cell carcinoma of the larynx, in contrast, requires multimodality therapy. Despite the use of multimodality treatment, survival for patients with advanced-stage disease ranges from 42% to 77%.3, 5-11 Until the early 1980s, multimodality therapy for advanced-stage laryngeal cancer consisted of surgery and external beam radiation therapy. In the early 1980s, however, several trials showed a high rate of tumor response to induction chemotherapy in patients with squamous cell carcinoma of the head and neck. Based on these trials, treatment paradigms evolved using induction chemotherapy followed by radiation therapy.12, 13 The goal of these strategies was to develop a treatment program for laryngeal cancer that preserved laryngeal function but did not adversely affect survival. In the early 1990s, a prospective, randomized trial was conducted of patients with stage III or IV squamous cell carcinoma of the larynx treated at Veterans Affairs Hospitals.5 Patients received either conventional treatment with surgery and postoperative radiation therapy or induction chemotherapy followed by radiation therapy. Patients in the chemotherapy-radiation therapy arm who did not have at least a 50% response to induction chemotherapy or who showed persistent or recurrent disease after radiation therapy were salvaged with surgery. In this landmark study, differences in survival in the two treatment arms were not statistically significant (68% in each arm), and physicians were able to preserve the larynx in 64% of patients in the chemotherapy-radiation therapy arm.5 A new option now existed for patients with advanced-stage laryngeal cancer. In this review, we discuss the advances in multimodality therapy of squamous cell carcinoma of the larynx that have evolved in the last 20 years. American Cancer Society's estimates of new cases of laryngeal cancer and deaths from laryngeal cancer in 1998 (data from Landis et al2). The larynx can be subdivided into glottic, supraglottic, and subglottic anatomic regions. Squamous cell carcinomas of the larynx occur most often in the glottic larynx (56%), next most often in the supra-glottic larynx (31%), and rarely in the subglottis (1%).3 Tumors in these subsites have different clinical behaviors and risks of regional lymph node metastasis. Supraglottic tumors, for example, have a much higher rate of occult and bilateral regional lymph node metastases than do glottic primaries.14, 15 Rates of regional failure for patients with supraglottic primaries, as a result, are higher than those for patients with similarly staged glottic primary tumors.3 Because of the high risk of regional dissemination, patients with supraglottic primaries have worse 5-year disease-free survival rates than do patients with glottic primaries.3 The stage of the disease also affects survival of patients with laryngeal cancer. Patients with stage I or II disease have 5-year disease-specific survival rates ranging from 78% to 91 %, whereas those with stage III or IV have rates ranging from 42% to 67%.3 Presently, the American Joint Committee on Cancer (AJCC) staging system for laryngeal cancer depends on the local extent of the tumor (T stage) and the status of regional lymph nodes (N stage).16 Although survival has been related to both T and N, it is most profoundly affected by the nodal status of the patient.3, 14, 17 Patients with either early localized tumors (T1,2 N0) or advanced localized tumors (T3,4 N0) have 5-year disease-specific survival rates of 87.5% and 72.1%, respectively.3 In contrast, patients with regional lymph node metastasis, have a 5-year disease-specific survival of 46.2% for all T stages (T1–4 N >0).3 Regional lymph node involvement is known to decrease survival by approximately half.14, 17 The present AJCC staging system groups together into stage III both patients with locally advanced tumors (T3 NO) and patients with regional lymph node metastasis (T1–3 N1).16 This may arbitrarily group together two subsets of patients who have widely different prognoses. Both the stage and the nodal status must be considered in the interpretation of results from the treatment of advanced-stage laryngeal cancer. A critical element in the consideration of any trial involving patients with laryngeal cancers is the proportion of patients with supraglottic primaries, advanced-stage disease, or regional lymph node metastasis. In nonrandomized studies, a selection bias exists that affects which treatment is used for specific patient populations. Even in prospective randomized trials, clinical setting, referral patterns, and inclusion criteria bias the study with regard to which patients constitute the study population. The treatment protocols proposed in these trials, therefore, must be applied with caution. Individual patient factors such as laryngeal subsite, stage, regional lymph node metastasis, comorbidities, and patient compliance, as well as the clinical environment in which the patient is treated, must be considered. Treatment of cancer of the larynx was initially limited by the inability of physicians to examine the larynx adequately. In the mid-1800s, a singing teacher named Manuel Garcia used a mirror to indirectly visualize his own vocal folds.18 Later in the 1800s Kirstein performed the first direct visualization of the endolarynx by direct laryngoscopy.18 Tools used to visualize the interior of the larynx have evolved substantially over the past hundred years. Recently, the widespread use of the fiberoptic laryngoscope has allowed unparalleled visualization of the larynx in the outpatient setting. In the operating room, the use of 0°, 30°, and 70° telescopes has improved visualization of areas that previously had been difficult to examine, such as the subglottis. Early attempts at curative treatment of laryngeal cancer, in the middle and late 1800s, were directed primarily at surgical approaches. The first surgical approach, performed in 1851, was a laryngofissure, in which the thyroid cartilage was split in the midline to gain access to the tumor.18 In 1876, Billroth performed the first total laryngectomy; several years later he performed the first vertical partial laryngectomy.19 Late in the nineteenth century, Solis-Cohen described diverting the tracheal remnant to the skin, and Sorensen reported a single-stage pharyngeal closure.18 Over the ensuing decades, the morbidity and mortality from these procedures decreased as experience increased. In the early twentieth century, Gluck reported 160 total laryngectomies, with no mortalities in the last 63 consecutive cases.20 Surgery remained the mainstay of treatment of laryngeal cancer until the 1920s, when Coutard advocated fractionated external beam radiation therapy as a definitive treatment modality.21 The use of megavoltage radiation further improved results, and this modality was widely applied in the 1950s. From this time onward, external beam radiation therapy has remained an effective form of definitive treatment of early-stage laryngeal cancer and an option for definitive or adjuvant treatment of advanced-stage laryngeal cancer. During most of the mid-twentieth century, external beam radiation therapy was the primary treatment modality for laryngeal cancer. Surgical approaches, however, re-surged in the second half of the twentieth century. Much of this could be attributed to an improved understanding of the predictability of local growth and spread of laryngeal tumors as described by Kirchner in his whole-organ laryngeal sectioning studies.22 This knowledge was applied in further refinements in partial laryngeal surgery as popularized by Alonso and Ogura.23-25 In the latter half of the twentieth century, conservation laryngeal surgery reached its limits with the description of the near-total laryngectomy by Pearson26 and the supracricoid subtotal laryngectomy by Laccourreye et al.27 Another approach to conservation surgery of the larynx evolved from Jako's popularization of the laser as a tool for laryngeal surgery.28 The laser has allowed surgeons to resect lesions through the laryngoscope while maintaining hemostasis. Surgeons are now able to resect T2 and T3 laryngeal tumors through an endoscopic approach using the laser, as reported by Steiner and Zeitels et al.29, 30 Over the last century, attempts to improve the ability to speak after treatment of laryngeal cancer have proceeded on two fronts. First, as mentioned earlier, surgical techniques have evolved that spare as much of the larynx as oncologically possible. Second, improved methods of voice rehabilitation after total laryngectomy have evolved. In the most significant of these, popularized by Blom and Singer,31 a fistula is created between the trachea and the esophagus and a small duck-billed prosthesis is placed in the fistula. This procedure allows the patient to produce lung-powered speech that is often quite satisfactory. Despite the many advances made in the treatment of laryngeal cancer over the last century, survival in patients with advanced cancer of the larynx has improved little in the last 25 years.2 Improving survival continues to be the ultimate goal in treating patients with advanced-stage laryngeal cancer. Recently, however, because of the lack of improvement in survival, significant efforts have been made to improve the quality of life in these patients. Paramount to this is preservation of a functional larynx. Treatment options have been formulated with the hope of increasing laryngeal preservation without sacrificing survival. A small cohort of patients given the choice opt for treatments that may improve laryngeal preservation even if survival rates are not as good as those achieved with other techniques.18 Multimodality therapy in the form of neoadjuvant chemotherapy, radiation therapy, and surgical salvage has emerged as a viable treatment option that allows anatomic preservation of the larynx without sacrificing survival.5 Now that a method of laryngeal preservation has been established, future goals in treatment are to increase the rates of both laryngeal preservation and survival. In the past, conventional treatment of advanced-stage laryngeal cancer consisted of surgery and postoperative external beam radiation therapy. Surgical resection of most advanced-stage laryngeal lesions consisted of total laryngectomy with the resultant deleterious effects on deglutition and phonation and the creation of a permanent tracheostoma. The psychosocial consequences of total laryngectomy have been well studied.32-35 Not surprisingly, quality-of-life measurements and pyschosocial indicators are significantly affected by total laryngectomy. Although techniques for voice rehabilitation have improved, studies have shown that the psychosocial effects of laryngectomy are related as much to loss of voice as they are to other factors, such as the need for a permanent tracheostoma.32-35 Appreciation of the psychosocial consequences of total laryngectomy has spurred the development of treatment options that could preserve the larynx of patients with advanced-stage laryngeal cancer. Initially, study of the anatomic barriers to and routes of tumor spread led to conservation surgical procedures in which tumors are resected en bloc while the function of the larynx is preserved. In selected patients, conservation surgical procedures can be used for advanced-stage tumors, often in combination with adjuvant radiation therapy to improve locoregional control. Conservation surgical procedures continue to evolve and in combination with postoperative radiation therapy remain an effective form of multimodality treatment for selected patients with advanced-stage laryngeal cancer. Many patients, however, are not suitable candidates for conservation laryngeal procedures because of either oncologic concerns or patient factors such as inadequate pulmonary reserve. Other modalities have evolved for treatment of patients with laryngeal cancer who are not candidates for conservation surgical procedures. With the results of the Veterans Affairs Laryngeal Cancer Study Group (VALCSG) trial, the combination of induction chemotherapy and radiation therapy has emerged as a treatment option that preserves the larynx in nearly two-thirds of patients.5 Despite the convincing results of this prospective randomized trial, many controversies exist about it and its application to all patients with advanced-stage laryngeal cancer. Table 1 summarizes results of several studies evaluating multimodality therapy in the treatment of patients with advanced-stage laryngeal cancer with the goal of preserving the larynx.5-11, 36 In all but one study, more than 90% of patients evaluated had stage III or IV disease. Most studies included only patients who would have required a total laryngectomy if treated by conventional means (i.e., surgery and postoperative radiation therapy). The incidence of regional lymph node involvement in the studies varied widely, from 28% to 83%. Treatment results for patients treated with chemotherapy and radiation therapy in the various studies are consistent, with 2-year survival rates ranging from 50% to 77%, larynx preservation rates ranging from 64% to 79%, locoregional failure rates ranging from 20% to 33%, and distant failure rates ranging from 8% to 21%.5-10, 36 Only one of these studies, however, was limited only to patients with laryngeal primaries.5 The other studies all included patients with the hypopharynx, oropharynx, oral cavity, and even paranasal sinuses as sites of primaries.6-11 Most of the studies including nonlaryngeal sites did so because surgical treatment of the primary would have required total laryngectomy. The data in Table 1 refer to the subset of patients with laryngeal primaries whenever possible, although this information was not always available. In two of the studies summarized in Table 1 comparisons were made between conventional treatment (surgery and postoperative radiation therapy) and treatment with induction chemotherapy and radiation therapy.5, 11 The VALCSG study was a randomized prospective trial, whereas the M.D. Anderson study was a matched-pair analysis. Neither showed a statistically significant difference in survival in the chemotherapy-radiation therapy arm compared with the conventional treatment arm. Two interesting observations were made, however, that did have statistical significance. First, in both studies, locoregional control was improved in patients who received conventional therapy.5, 11 Second, a decrease in the rate of distant metastasis was seen in the chemotherapy-radiation therapy arm in the VALCSG study. The latter may represent a delay in the presentation of the distant metastasis. Some investigators claim that this difference in rate of distant metastasis is not durable and equilibrates with time.37, 38 Although the significance of these differences in locoregional failure and distant failure have been debated, neither has translated into a survival advantage in either group. These trials provide convincing evidence that induction chemotherapy followed by radiation therapy is an acceptable treatment option in patients with advanced laryngeal cancers that otherwise would have required a total laryngectomy. Critical analysis of these data, however, requires consideration of the results of conventional treatment with surgery and radiation therapy. The results of the largest and most recent studies of conventional treatment are listed in Table 2.14, 17, 39-43 In several of these studies, single-modality therapy in the form of definitive radiation therapy yielded disease-specific survival rates similar to those seen with the combination of induction chemotherapy and radiation therapy. Although these studies include fewer stage IV and node-positive patients than do the studies of chemotherapy and radiation therapy, the contribution of chemotherapy to these laryngeal preservation protocols remains undetermined. Previous randomized prospective trials did not include a radiation therapy-only arm; however, an ongoing intergroup trial has included a radiation therapy-only arm to address this question. Two recently published studies compare radiation therapy alone with concurrent chemotherapy (cisplatin and 5-fluorouracil [5-FU]) and radiation therapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck.44, 45 In these studies, between 36% and 56% of patients had either laryngeal or hypopharyngeal primaries. In both studies, a statistically significant increase in 3-year relapse-free survival was seen in the concurrent chemotherapy-radiation therapy arm compared with the radiation therapy-alone arm (P < 0.00444 and P < 0.0345). Currently, cisplatin with 5-FU is the most common chemotherapeutic combination used in these protocols.5-7, 9-11, 36 Cisplatin is used in combination with bleomycin less often.8, 9, 36 The pulmonary toxicity associated with bleomycin makes it a difficult agent to use in patients with squamous cell carcinoma of the larynx, who have a significant incidence of tobacco-related lung disease. The VALCSG trial had several exclusion criteria as a result of the toxicity of the chemotherapy. These included performance status less than 50 on the Karnofsky scale; creatinine clearance less than 1 ml/second; white blood cell count less than 4,000/ml; platelet count less than 100,000/ml; and inadequate auditory, nutritional, pulmonary, or cardiac status. Because head and neck cancer patients have a high incidence of comorbidities, these criteria can exclude a significant number of patients. Toxicity from induction chemotherapy also has prevented 7% to 18% of patients from receiving a full course of chemotherapy.5, 6, 8, 10 Even mortality as a direct result of induction chemotherapy toxicity has been reported to range from 0.6% to 6%.5, 7-11, 36 In addition to toxicity, the use of induction chemotherapy in combination with radiation therapy results in a complicated protocol with which it is difficult for patients to comply. The association of tobacco and alcohol use with squamous cell carcinoma of the larynx contributes to the poor compliance in these patients. In one study, protocol violations occurred in 12 of 40 patients because of toxicity or patient noncompliance.8 Finally, a small percentage of patients responding favorably to chemotherapy refuse further treatment, not understanding the lack of durability of their response. In addition to the difficulties with patient compliance, the complexities of the chemotherapy-radiation therapy protocols make them difficult to transfer from the tertiary referral centers where they were developed to the community. Extensive cooperation among the head and neck surgeon, the radiation oncologist, and the medical oncologist is essential to maintaining the current rates of larynx preservation and survival. Detecting patients who fail to respond to induction chemotherapy or who display persistent or recurrent disease after radiation therapy is critical to successful early surgical salvage. Often the posttreatment changes seen in the mucosa of the upper aerodigestive tract hamper the detection of persistent or recurrent disease. Once persistent or recurrent disease has been identified, early surgical salvage is the only curative option. The mucosa and tissues of the neck undergo changes after chemotherapy-radiation therapy. These not only make detection of recurrence difficult but also can make clinical assessment of the extent of locoregional disease challenging. Many factors have been evaluated for their ability to predict local failure and the need for salvage laryngectomy. The VALCSG study found two patient groups with a statistically significant increased risk for local persistence or recurrence—those with T4 primary lesions and those with stage IV disease.5 Survival was not affected by failure to respond to induction chemotherapy in this study.5 Salvage laryngectomy may be required for patients who fail to respond to induction chemotherapy and for those with persistent or recurrent disease after completing chemotherapy-radiation therapy. Approximately equal numbers of patients were found in these two groups in a recent study.46 Most patients who require salvage laryngectomy because of persistent or recurrent disease after chemotherapy-radiation therapy manifest the disease within 1 to 2 years of completion of radiation therapy.5, 46 Reports of 2-year disease-specific survival after salvage laryngectomy range from 56% to 80%.5, 11, 46 Major complications after salvage laryngectomy, however, occur in nearly 50% of patients.46, 47 The most common complication is pharyngocutaneous fistula, which occurs at a rate of 27% to 50% in this cohort.46-48 Wound complications and pharyngocutaneous fistula remain significant problems in salvage laryngectomy. Survival after salvage neck dissection is worse than that after salvage laryngectomy. In the VALCSG study, of 24 patients who underwent salvage neck dissection, only 9 survived.49 Treatment of the neck in the context of multimodality treatment of the larynx thus remains controversial.49, 50 In the VALCSG trial, patients were evaluated after the second cycle of chemotherapy. If a major response of the primary tumor occurred and no evidence of disease progression in the neck was present, patients went on to receive definitive radiation therapy. After completion of radiation therapy, persistent or recurrent disease in the neck was salvaged with neck dissection. Of the 46 patients with N2 or N3 neck disease, 39% achieved a complete response in the neck with induction chemotherapy. Of the patients experiencing a complete response in the neck, 28% subsequently required salvage neck dissection.49 In the study by Armstrong and colleagues,50 the response of the primary tumor and the spread of disease in the neck also were evaluated after induction chemotherapy. Patients who had a major response in the neck were treated either with neck dissection followed by radiation therapy or with radiation therapy alone. Most patients with advanced N2c or N3 neck disease underwent neck dissection, and all patients with N1 neck disease were treated solely with radiation therapy. Of the patients experiencing a major response to induction chemotherapy, only 23% failed in the neck and required salvage neck dissection.50 The optimal treatment of the neck and the possible identification of patients who do not require neck dissection await further study. A recent report encompassing 9,334 patients with laryngeal cancer treated in the United States between 1990 and 1992 noted that only 8.2% of patients with stage III laryngeal cancer and 11% of those with stage IV were treated with the combination of chemotherapy and radiation therapy.3 Although, these patients were treated during the time that the VALCSG report was published, it illustrates the point that as recently as 5 years ago, only approximately 10% of patients with advanced-stage laryngeal cancer were treated with chemotherapy-radiation therapy. At our institution, most patients with advanced-stage laryngeal cancer who would require total laryngectomy if treated surgically are currently being treated with a larynx-preservation protocol of chemotherapy and radiation therapy. Current studies in the multimodality treatment of laryngeal cancer include evaluations of the benefit and role of chemotherapy in chemotherapy-radiation therapy protocols, patient selection, and biological markers predicting survival. Efforts to improve survival via innovative regimens, delivery systems, and novel therapeutic modalities are ongoing. The most significant recent advances in the multimodality treatment of advanced-stage laryngeal cancer are seen in trials that investigate optimizing the delivery of radiation therapy and chemotherapy. Results of these studies are summarized in Table 3. Higher rates of locoregional failure with chemotherapy-radiation therapy strategies have led to alterations in the timing and scheduling of radiation therapy. Protocols with accelerated fractionation of radiation therapy and plans using concomitant chemotherapy and radiation therapy have been investigated. Researchers theorize that the increased locoregional failures seen with chemotherapy-radiation therapy protocols result in part from an accelerated tumor cell repopulation during the prolonged course of treatment.51, 52 Clinical and experimental evidence suggests that tumor cell populations, after a lag period of several weeks, decrease their doubling time and increase their rate of regrowth after cytotoxic treatment begins, no matter whether it is chemotherapy or radiation therapy.51, 52 A longer treatment time therefore results in high rates of failure.53 To combat these problems in chemotherapy-radiation therapy regimens, investigators have evaluated accelerated radiation therapy regimens and concomitant chemotherapy-radiation therapy protocols. In the past, accelerated (twice a day) courses of radiation therapy have improved 3-year local control of advanced laryngeal tumors (T3–4) from 26% to 59% (P < 0.0001).54 These gains in local control are not without a cost in terms of treatment-related morbidity, however. In a study by Eisbruch et al,55 grade 2 or 3 mucositis was seen in all patients, and 60% experienced late complications of radiation therapy. Of the 20 patients treated with chemotherapy and accelerated-fraction radiation therapy in this study, two required long-term tracheostomy and two required a long-term percutaneous gastrostomy tube. Although the larynx was anatomically preserved, its function was profoundly impaired in a subset of patients. Significant long-term treatment-related morbidity was seen in 25% of patients, which is more than the 5% to 11% rates seen in nonaccelerated protocols.5, 8 Additionally, all patients in this series undergoing salvage surgery after radiation therapy had major wound complications.55 Ultimately, a benefit in local or regional control or survival was not seen in this study, although the study size was relatively small.55 Another method of shortening treatment time, decreasing the effects of accelerated tumor cell repopulation, and improving results involves the use of concomitant chemotherapy and radiation therapy. Previous studies using concomitant chemotherapy and radiation therapy in advanced-stage head and neck cancer have shown promising results with regard to locoregional control, organ preservation, and survival.56, 57 Prospective randomized trials assessing the benefit of concomitant chemotherapy and radiation therapy for advanced-stage laryngeal cancer have not been done, however. In a study by Pfister et al58 evaluating cisplatin-based chemotherapy with concomitant radiation therapy, less than 50% of patients enrolled were able to receive the planned treatment. Significant chemotherapy-related toxicity combined with a 37% nonresponse rate limited this study's ability to detect an advantage to concomitant therapy. At this time, neither accelerated-fraction radiation therapy nor concomitant chemotherapy-radiation therapy has conclusively proved more beneficial than induction chemotherapy followed by conventional-fraction radiation therapy in treating advanced-stage laryngeal cancer. For this reason, along with the potential for treatment-related morbidity, accelerated-fraction radiation therapy remains investigational. The Radiation Therapy Oncology Group is conducting a phase III trial comparing the following three treatment arms: (1) radiation therapy alone, (2) induction chemotherapy and radiation therapy, and (3) concomitant chemotherapy and radiation therapy. This trial may help to define the role of concomitant therapy and the efficacy of radiation therapy without induction chemotherapy in advanced-stage laryngeal cancer. The chemotherapy regimen most commonly used to treat advanced-stage laryngeal cancer is the combination of cisplatin and 5-FU. Several studies have evaluated the chemotherapeutic agents used in larynx-preservation protocols. Pfister et al performed a matched-pair analysis comparing cisplatin/5-FU, cisplatin/vinblastine, and cisplatin/bleomycin (Table 3).59 Survival and locoregional control were statistically equivalent among the groups. Another study investigated the benefit of adding leucovorin to cisplatin and 5-FU and found a 59% major response rate, but significant toxic effects were noted.60 Two other studies evaluating the combination of cisplatin, 5-FU, and leucovorin showed overall response rates of 81% in patients with stage III and stage IV squamous cell carcinoma of the head and neck.61, 62 Finally, new chemotherapeutic agents continue to be developed. One such agent, paclitaxel, has yielded overall response rates of 58% when used in combination with cisplatin and ifosfamide in patients with recurrent head and neck squamous cell carcinoma.63 Future studies should help to define the optimal chemotherapeutic regimen for larynx-preserving protocols. Robbins et al64 proposed a unique strategy using high-dose intraarterial cisplatin with a systemic neutralizing agent along with conventional radiation therapy. Results are promising (Table 3). Although most patients in this study had stage IV disease (86%) and clinically involved regional lymph nodes (79%), a major response rate was seen in 95% of patients. Nine of ten patients retained their larynx; 2-year disease-specific survival was 76%, and locoregional disease control was achieved in 86% of patients. Three of the 42 patients, however, had central nervous system complications as a result of catheterization of the carotid system. Nevertheless, this remains a promising option and a novel approach in the treatment of advanced laryngeal cancer. Other advances in the treatment of laryngeal cancer have involved the use of molecular biological techniques to characterize biological markers that may predict which patients will be resistant to treatment. If a marker that would identify nonresponders could be defined, more aggressive treatment approaches or earlier surgical salvage could be instituted to improve survival in this cohort. Factors evaluated as potential biological markers predicting tumor response include adjusted DNA index, S-phase fraction labeling, potential doubling time, p53 overexpression, and pl05 labeling.65-71 An increase in the adjusted DNA index has been correlated with an increase in complete response to induction chemotherapy.69 In one study, all patients with a complete response to chemotherapy had an adjusted DNA index greater than 0.024, whereas 37% of patients having either a partial response or no response had an index lower than 0.024. Another study showed a higher rate of larynx preservation in patients with tumors overexpressing p53.68 Finally, patients with aneuploid tumors have shown higher rates of complete response to induction chemotherapy than have those with diploid tumors.70 Studies by Robbins and colleagues72 have shown a correlation between in vitro sensitivities to chemotherapeutic agents as determined by histoculture drug sensitivity assay and patient response to chemotherapy. This assay may provide a model for predicting which patients may respond favorably to chemotherapy. Further study is needed to assess the reliability of all the tests mentioned earlier in identifying patients who will be nonresponders and the ability to translate this information into improved survival.65-68 Pretreatment measurements of potential doubling time have been used to determine which patients will benefit from accelerated-fraction radiation therapy.67 In patients with a potential doubling time of 5 days or less, conventional radiation therapy yielded local control rates of 8% and accelerated-fraction radiation therapy resulted in control rates of 41% (P < .02).67 Other studies have shown trends toward a decrease in local control with longer treatment regimens in patients whose tumors display rapid cell division.73 Patients with advanced-stage laryngeal cancer who have short potential doubling times may benefit from shorter treatment plans in the form of either accelerated-fraction radiation therapy or concomitant chemotherapy-radiation therapy. Whether this pretreatment selection would affect locoregional control and, more importantly, survival awaits further evaluation. An interesting analysis of the relative costs of the various treatment options for advanced-stage laryngeal cancer was presented at the Fourth International Conference on Head and Neck Cancer. A model was created in which 100 hypothetical patients with T3N0 laryngeal tumors were treated by various protocols. Historical control rates were used to calculate the percentage of patients who required surgical salvage after treatment failed.74 The treatment options included (1) primary radiation therapy with surgical salvage, (2) conventional surgery and postoperative radiation therapy, and (3) induction chemotherapy, radiation therapy, and surgical salvage. The cost for the group that received primary radiation therapy with surgical salvage was $4.2 million; for the group treated with conventional surgery and postoperative radiation therapy, it was $6.2 million; and for the group that received induction chemotherapy, radiation therapy, and surgical salvage it was $6.4 million.74 This analysis focused on direct costs and did not consider indirect costs related to morbidity, mortality, and lost income. In previous analysis, indirect costs have usually accounted for two-thirds of the total cost.74 Factors other than cost, which are difficult to factor into this equation, such as quality of life, also must be considered. Although the cost of treatment options is an interesting consideration, the optimal treatment of patients with laryngeal cancer remains the primary concern. With the encouraging results from the various trials using the combination of induction chemotherapy and radiation therapy for advanced laryngeal cancer, similar trials have been applied to other sites that would require total laryngectomy if treated conventionally. The most commonly studied site is the hypopharynx. Results of these studies are summarized in Table 4.75-79 Hypopharyngeal tumors (most often involving the pyriform sinus) have shown lower rates of larynx preservation (29% to 52%), locoregional control (39% to 69%), and survival (19% to 42%) compared with laryngeal primaries.75-79 In the largest randomized prospective trial, Lefebvre et al75 reported equal survivals in the conventional surgery-radiation therapy arm and the induction chemotherapy-radiation therapy arm. These results have been corroborated by results from retrospective studies.77, 79 A recent study by Beauvillain et al,76 however, showed an improved 5-year survival in patients receiving induction chemotherapy, surgical resection, and postoperative radiation therapy (37%) compared with patients receiving induction chemotherapy and radiation therapy (19%). However, the patients who did not respond to induction chemotherapy went on to definitive radiation therapy rather than opting for early surgical salvage as in the VALCSG trial.76 Controversy continues regarding the optimal treatment of hypopharyngeal cancer, and improvements in locoregional control and survival are needed. Although chemotherapy-radiation therapy protocols have defined their role in the treatment of advanced-stage laryngeal cancer, conservation surgery that preserves the function of the larynx remains an excellent treatment option in selected patients. Recently, supracricoid partial laryngectomy with either cricohyoidopexy or cricohyoidoepiglottopexy has extended surgeons' ability to resect advanced laryngeal lesions with acceptable functional outcome and survival.27 Overall, treatment protocols using chemotherapy-radiation therapy to preserve organ function have successfully shown their ability to preserve the larynx anatomically without compromising survival. One aspect of these protocols that is often underappreciated, however, is the functional capacity of the retained organs. Few investigators have clearly documented the functional sequelae of chemotherapy and radiation therapy. In a retrospective study of patients being treated with chemotherapy and radiation therapy Lazarus et al80 found that 40% had swallowing difficulties. Clinical evidence of disorders in the pharyngeal phase of swallowing has been shown in patients who have undergone chemotherapy and radiation therapy for tumors of the upper aerodigestive tract. Reduced laryngeal closure, reduced laryngeal elevation, and reduced posterior tongue base movement relative to age-matched controls have been documented.80 Certainly, patients who successfully undergo chemotherapy-radiation therapy treatments to preserve the larynx have a much improved quality of life compared with patients requiring total laryngectomy. Nevertheless, it should be realized that anatomic preservation does not always result in functional preservation. The combination of induction chemotherapy with external beam radiation therapy has been established as an effective means of treating selected patients with advanced-stage laryngeal cancer. The cooperation of the head and neck surgeon, radiation oncologist, and medical oncologist is paramount to the successful use of this treatment. Investigations continue to evaluate the ideal treatment regimen, the delivery of chemotherapy, patient selection, biological markers predicting response, functional outcome, and the effectiveness of this treatment at other sites. The goal, however, remains to improve survival in patients with advanced-stage disease.