The Role of Chemotherapy in Larynx Organ Preservation

The trials evaluating induction chemotherapy, while disappointing with regard to improving survival as an endpoint, did provide the backdrop for current organ preservation strategies. Investigators observed that some patients refused surgery after initial chemotherapy and proceeded with radiation alone.87 Some of these patients were controlled over the long term without surgery, and there appeared to be a positive correlation between initial response at the primary site to induction chemotherapy and the likelihood of disease control with radiation alone. Pilot organ preservation studies demonstrated that induction chemotherapy followed by definitive dose radiation, with surgery to the primary site reserved for non-response or relapse, was a feasible approach.88,89 Reported survival results in selected patients were comparable to those anticipated with standard surgery and radiotherapy, but surgery to the primary site was avoided in a significant proportion of patients (Figure 22-1). Avoiding total laryngectomy was the focus of many of these studies, as the procedure is widely acknowledged to be among those most feared by

Laryngeal Cancer Treatment
Figure 22-1. Photographs of a larynx cancer treated with chemotherapy/radiotherapy with larynx preservation intent. A, Pre-treatment; B, Post-treatment.

patients. The potential negative impact on the quality of life of patients who undergo it are well described in the literature,90,91 and include loss of functional voice, impairment of deglutition, permanent tracheotomy, and adverse effect on cosmetic appearance. Larynx preservation studies serve as a paradigm for the application of organ preservation to other primary sites and will be discussed in more detail.

In patients with locally advanced but resectable tumors of the larynx and surrounding structures, standard surgical management will jeopardize the larynx in the majority of patients. Unfortunately, an organ-preserving surgical procedure will be applica ble to only selected patients with locally advanced disease. Radiation alone may cure some patients, but anticipated local control rates when radiation alone is used as a single modality are disappointing.92,93 Accordingly, combined modality treatment strategies that decrease surgical morbidity without compromising locoregional control rates and overall survival have generated considerable interest. The best studied approach to date uses induction chemotherapy followed by definitive-dose radiation therapy, with surgery reserved for non-response to chemotherapy, persistent disease after radiation, or relapse. Three randomized studies have compared variations on this approach to standard surgical treatment (Table 22-7).

The Veterans Affairs Laryngeal Cancer Study Group (VALCSG) evaluated 332 patients with resectable stage III or IV laryngeal cancer. The chemotherapy regimen included standard cisplatin and infusional 5-fluorouracil given for three cycles. The radiation treatment after the chemotherapy for responding patients included daily fractions of 180 to 200 cGy to a total dose of 6,600 to 7,600 cGy. If necessary, neck dissection was done after radiation therapy. Patients who presented with progression of disease during any chemotherapy cycle, or a lack of major objective response at the primary site after the second chemotherapy cycle, underwent salvage surgery. Larynx preservation was achieved in 31 percent of patients randomized to the induction chemotherapy arm (62% of survivors).7 With a median follow-up of 98 months, the overall and median survival rates were comparable between both arms. Patients who received salvage laryngectomy after initial chemotherapy had similar survival outcome, compared with patients randomized directly to surgical treatment, suggesting that the delay in the surgery caused by the administration of chemotherapy did not adversely affect survival.7,95 Follow-up data suggests that quality of life outcomes were superior on the chemotherapy/radiotherapy arm.96

The European Organization for Research and Treatment of Cancer (EORTC) study, reported by Lefebvre and colleagues, included 202 patients with squamous cell carcinoma of the pyriform sinus or of the hypopharyngeal aspect of the aryepiglottic fold. Patients with stage T2 to T4 disease were eligible.

Table 22-7.

RESULTS OF RANDOMIZED LARYNX PRESERVATION TRIALS

Group

No of Patients

Tumor Site

Control Organ Regimen Schedule Arm Preservation

Survival Comparison

VALCSG7 332 Larynx CDDP + 5-FU Sequential S ^ RT 31% at 3 years Comparable to up to 3 cycles surgery plus RT

EORTC8 202 Hypopharynx CDDP + 5-FU Sequential S ^ RT 42% at 3 years Comparable to up to 3 cycles surgery plus RT

GETTEC94 68 Larynx CDDP + 5-FU Sequential S ^ RT 20% at 3 years Inferior to up to 3 cycles surgery plus RT

VALCSG7 332 Larynx CDDP + 5-FU Sequential S ^ RT 31% at 3 years Comparable to up to 3 cycles surgery plus RT

EORTC8 202 Hypopharynx CDDP + 5-FU Sequential S ^ RT 42% at 3 years Comparable to up to 3 cycles surgery plus RT

GETTEC94 68 Larynx CDDP + 5-FU Sequential S ^ RT 20% at 3 years Inferior to up to 3 cycles surgery plus RT

CDDP = cisplatin; EORTC = European Organization for Research and Treatment of Cancer; GETTEC = Groupe d'Etudes des Tumeurs de la Tête et du Cou; 5-FU = 5-fluorouracil; RT = radiotherapy; S = surgery; VALCSG = Veterans Affairs Laryngeal Cancer Study Group.

As with the VALCSG study, the chemotherapy regimen also consisted of standard cisplatin and infu-sional 5-fluorouracil administered for three cycles followed by radiotherapy. The surgical procedure performed in the standard arm was total laryngec-tomy with partial pharyngectomy and neck dissection followed by postoperative radiation therapy. Patients in the chemotherapy arm had to achieve a complete response, including normalization of vocal cord mobility to proceed to definitive radiation therapy. The time of neck dissection was left to the discretion of the involved surgeon. With a median follow-up of 51 months, there was no statistical difference in terms of 5-year overall and disease-free survival between the arms. Disease control rates at 3 and 5 years without total laryngectomy, need for tra-cheostomy or gastrostomy, and with the larynx preserved were 42 percent and 35 percent, respectively.8 As with the VALCSG study, delay in local therapy caused by non-response to induction chemotherapy did not appear to adversely affect survival outcome.7 The third study was performed by the Groupe d'Études des Tumeurs de la Tête et du Cou (GETTEC) trial, and 68 patients (total planned: 300 patients) with locally advanced and resectable larynx cancer were accrued. More than 90 percent of the patients presented with stage III disease, and glottic tumors predominated. Salvage surgery was performed for those who failed to achieve at least a partial response. The locoregional control rates, as well as 3-year disease-free and overall survival rates, were significantly better on the surgery/radiation arm.94 Limitations of this trial include the poor patient accrual, imbalance between arms (more patients with stage IV disease in the chemother apy/radiation arm), and lack of uniformity in the radiographic tests required for disease staging.94

A meta-analysis including the above described three studies showed a 5-year overall survival of 39 percent and 45 percent for patients randomized to chemotherapy/radiotherapy and surgery/radiotherapy, respectively (95% confidence interval = 0.97 to 1.47, p = 0.1). The 5-year disease-free survival was 34 percent and 40 percent, respectively (95% confidence interval = 0.97 to 1.44, p = 0.1). The locore-gional failure rates were greater in the chemotherapy/radiotherapy arm (35% vs. 20%), although the incidence of distant metastasis was higher in the surgery/radiotherapy arm.97 When taken collectively, these data suggest that sequential chemotherapy and radiation, with surgery reserved for salvage, yield survival rates comparable to, but certainly no better than, that observed with "up-front" total laryngectomy and postoperative radiotherapy. Such an approach is appropriately offered to patients with advanced squamous cell carcinomas of the larynx or hypopharynx seeking to avoid the morbidities of total laryngectomy. Close interdisciplinary communication and cooperation is fundamental to the success of such an approach.

Randomized trials in progress are currently addressing important questions. The United States Intergroup Trial 91-11 will include 546 patients with resectable stage III or IV laryngeal cancer (excluding T1 and unfavorable T4 lesions) for a comparison in a three-arm trial of the following treatment strategies: sequential chemotherapy (cis-platin/5-fluorouracil) followed by radiotherapy, versus concurrent chemotherapy (cisplatin) and radiotherapy, versus radiotherapy alone, with all arms including surgery for salvage. This study addresses one of the criticisms of the VALCSG study—the lack of a radiation-alone control arm. The EORTC Trial 24954 is planning accrual of 564 patients with stages T3/T4, N0 to N2 larynx cancer and stages T2 to T4, N0 to N2 hypopharynx cancer for a two-arm randomized trial comparing sequential (like the VALCSG and EORTC studies) versus an alternating chemotherapy and radiation therapy program. Both of these trials should provide insights regarding the optimal chemotherapy/radiotherapy schedule in the larynx preservation setting.

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