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Therapeutic Options for Laryngeal Cancer

Everett E. Vokes, M.D., and Kerstin M. Stenson, M.D. Every year in the United States, approximately 9500 new cases of laryngeal cancer are diagnosed, and 3800 patients die of this tumor. Persistent hoarseness is a warning sign that can lead to the detection of the tumor at an early stage. Such small tumors (stage T1 or T2, N0, and M0, according to the tumornodemetastasis staging system) are treatable with radiotherapy alone or with modern surgical techniques, both of which can eradicate the tumor as well as preserve vocal quality. More advanced laryngeal cancers (stage III or IV) extend beyond the vocal cords into supraglottic structures, the thyroid cartilage, or the regional lymph nodes (see Figure). Distant metastases at the time of diagnosis are infrequent. For many years, the standard therapy for these advanced cancers was total laryngectomy and postoperative radiotherapy. This treatment cured the disease in some patients, but in most cases it recurred. Moreover, the sequelae of the disease, of the surgical treatment, or of both included loss of the natural voice and the social and functional stigmata of an open stoma. During the 1980s, it was discovered that the administration of chemotherapy before surgery (induction chemotherapy) could dramatically shrink head and neck cancers in up to 80 percent of patients. This observation led to the concepts that induction chemotherapy might improve survival rates if added to standard therapy and that chemotherapy-responsive tumors could subsequently be treated with radiotherapy alone, allowing preservation of the larynx. Increased rates of survival and of laryngeal preservation became the goals of randomized clinical trials designed to test these ideas. In the Department of Veterans Affairs (VA) Laryngeal Cancer Study, a landmark trial reported in the Journal in 1991, patients were randomly assigned to either laryngectomy and postoperative radiotherapy, the standard treatment at that time, or to induction chemotherapy with cisplatin and fluorouracil, followed by radiotherapy (and no surgery) for patients who had a response to induction chemotherapy. Patients who did not have a response to chemotherapy
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or who had residual disease after radiotherapy were offered salvage laryngectomy. The two-year survival rate in both groups was 68 percent. Overall, laryngeal preservation was possible in 64 percent of the patients who had received induction chemotherapy, and at two years, 41 percent were alive and had a functional larynx. Thus, the efficacy of chemotherapy followed by radiotherapy (with surgical salvage) was similar to that of surgery followed by radiotherapy and offered the added benefit of laryngeal preservation in two thirds of the patients treated by this approach. It was quickly pointed out that the trial had left unanswered the questions of whether radiotherapy alone could achieve rates of survival and laryngeal preservation similar to those achieved in the VA study and whether concurrent chemotherapy and radiotherapy (with the added benefit of sensitization to radiation by chemotherapy) might be a superior strategy. In this issue of the Journal, Forastiere et al. (pages 20912098) report a randomized trial (Radiation Therapy Oncology Group and Head and Neck Intergroup study 91-11, initiated in 1991) in which a control regimen treatment with induction chemotherapy followed by radiotherapy was compared with two other regimens: concurrent chemotherapy and radiotherapy in a second group and, in a third, radiotherapy alone. Of note, initial laryngeal preservation was provided to the patients in all three groups. A difference between this study and the VA study is that patients with large, T4 lesions (tumors extending through the thyroid cartilage or into the base of the tongue) were excluded. The two-year and five-year survival rates were similar among the three groups. However, the patients treated with concurrent chemotherapy and radiotherapy had a higher rate of survival with a functioning larynx than the patients in the two other groups as well as higher rates of laryngeal preservation and local control. The rates of acute toxic effects were higher in both chemotherapy groups than in the group that received only radiotherapy, but the rate of late toxic effects, including swallowing dysfunction, was similar in all three groups.
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A
Laryngeal-cancer stages Stage I Stage II Stage III Stage IV Epiglottis

Therapeutic Options for Laryngeal Cancer

B
Invasion of paraglottic space

Vocal cord

Adjacent adenopathy

III Thyroid cartilage IV I II

Thyroid cartilage erosion

Cricoid cartilage

Trachea

Figure. Stage III and IV Tumors of the Larynx. Panel A shows a sagittal section of the larynx, depicting the tumor (T) stages of glottic cancer. Laryngeal cancers can also arise from supraglottic or subglottic areas. Panel B shows a computed tomographic (CT) scan of a stage T3 tumor, which invades the paraglottic space and is accompanied by adjacent adenopathy. Panel C shows a CT scan of a stage T4 tumor, which is eroding the thyroid cartilage.

These data confirm that initial treatment aimed at laryngeal preservation is a realistic and feasible option for most patients with intermediate- or latestage laryngeal cancer. The outcome in patients able to tolerate chemotherapy will be best with concurrent chemotherapy and radiotherapy. The use of induction chemotherapy followed by radiotherapy is not supported by the results of this trial, and patients unable to tolerate concomitant chemotherapy and radiotherapy should receive radiotherapy alone. As is true of patients with many other types of solid tumor, patients with laryngeal cancer must be evaluated by an experienced multispecialty team before therapy is initiated. The role of surgeons has expanded in this regard: surgeons now must carry out initial diagnostic and staging procedures and careful follow-up observation to decide whether and when salvage laryngectomy is required for recurrence or chronic aspiration.

It is interesting that despite higher rates of local and systemic control in the group treated with concurrent chemotherapy and radiotherapy, the duration of survival in this group was no greater than that in the other two groups. The authors did not provide a cause-of-death analysis, but it is known that patients with advanced head and neck cancers are exposed to competing risks. These risks include not only local and systemic recurrence of the laryngeal cancer but also second cancers (due to exposure of the entire airway and upper digestive tract to alcohol and tobacco) and cardiovascular and pulmonary events (also linked to alcohol and tobacco use). Prevention of second cancers and preventive cardiovascular care will be important for improving survival rates among patients with laryngeal cancer or other tobacco-related malignant tumors. How do these findings affect patients with head and neck cancers arising from other mucosal sur-

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faces, such as oral or pharyngeal carcinomas? Here, too, increased rates of organ preservation and survival are achievable goals. Improved survival rates have already been reported in patients with unresectable head and neck cancer who received concurrent chemotherapy and radiotherapy, as compared with those who received radiotherapy alone. Further intensification of concurrent chemotherapy and radiotherapy through the addition of a second chemotherapeutic agent, acceleration of the radiotherapy schedule, or both may be of value. Investigations of the use of agents directed against molecular targets known to be relevant to tumor cells or to the tu-

Therapeutic Options for Laryngeal Cancer

mor environment, such as inhibitors of the epidermal growth factor receptor and antiangiogenic agents, are in progress. It is hoped that these measures will lead to further improvements in the rate of survival and the rate of organ preservation among patients with head and neck cancer and offer future patients easier therapy and a better prognosis.
We are indebted to Drs. Gregory Wolf and Susan Fisher for providing updated information on the VA Laryngeal Cancer Study. From the Department of Medicine, Section of Hematology Oncology (E.E.V.), the Department of Surgery, Section of OtolaryngologyHead and Neck Surgery (K.M.S.), and the Cancer Research Center (E.E.V., K.M.S.), University of Chicago, Chicago.

Lp(a) Lipoprotein Coping with Heterogeneity

Angelo M. Scanu, M.D. In persons who are fasting, lipids circulate in the plasma as constituents of lipoprotein particles that are defined on the basis of their density as very-low-, intermediate-, low-, and high-density lipoproteins. The lipoproteins categorized as very-low, low, and intermediate density, although differing in the content and composition of their lipid core, have in common 1 mol of apolipoprotein B-100 per particle. Subclasses that have special biologic importance have been recognized, such as the small, dense low-density lipoprotein (LDL) particles, which have greater atherogenic potential than their large, buoyant counterparts. In addition to LDL, the plasma contains particles, called Lp(a) lipoprotein, that have as a protein moiety apolipoprotein B-100 linked, on a 1:1 molar basis, by a disulfide bond to apolipoprotein (a). This multikringle structure is similar to that of plasminogen. Kringles contain an average of 80 amino acids organized in three disulfide-linked loops, resembling a looped Danish pastry (kringle), on a twodimensional display. A striking feature of Lp(a) lipoprotein is its heterogeneity with respect to both apolipoprotein (a) and the lipoprotein component, commonly LDL (see Figure). In contrast to apolipoprotein B-100, which remains relatively constant in weight, apolipoprotein (a), under genetic control, ranges between 300 and 800 kD. This apolipoprotein (a)size polymorphism is due to differences in the number of kringle IV type 2 repeats and is a main determinant of the density of Lp(a) lipoprotein, which is also affected by variations in the content and composition of the lipid core. Elevated levels of Lp(a) lipoprotein constitute a recognized risk factor for cardiovascular disease that is influenced by proatherogenic and prothrombotic factors, both genetic and environmental, including age, sex, race, and ethnic background. An example of the effect of sex is provided by the prospective study reported in this issue of the Journal by Ariyo and colleagues (pages 21082115). In this study, the level of plasma Lp(a) lipoprotein was an independent predictor of the risk of cardiovascular events and death from all causes in men but not in women. No explanation for the observed difference is given. Apolipoprotein (a), the specific marker of Lp(a) lipoprotein, is synthesized in the liver and travels in plasma in covalent association with lipoproteins containing apolipoprotein B-100, mainly LDL. The smaller isoforms of apolipoprotein (a) are of interest because of their effect on plasma Lp(a) lipoprotein levels and because of the suggestion that they may represent a higher risk to the cardiovascular system than the larger isoforms. The particles of LDL that are found in Lp(a) lipoprotein also vary in size. The Lp(a) lipoprotein that contains small, dense particles of LDL particularly in the presence of the small isoforms of apolipoprotein (a) would be favored as a mechanism of transfer from

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