Annals of Oncology Advance Access published online on May 7, 2008
Annals of Oncology, doi:10.1093/annonc/mdn173
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Functional organ preservation with definitive chemoradiotherapy for T4 laryngeal squamous cell carcinoma
1 Department of Radiation and Cellular Oncology, Chicago
2 Cancer Research Center
3 Pritzker School of Medicine, University of Chicago, Chicago
4 Section of Otolaryngology/Head and Neck Surgery, University of Chicago, Chicago
5 Section of Hematology/Oncology, University of Chicago, Chicago, USA
* Correspondence to: Dr J. K. Salama, Department of Radiation and Cellular Oncology, University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA. Tel: +1-773-702-6870; Fax: +1-773-834-7340; E-mail: jsalama{at}radonc.uchicago.edu
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Abstract |
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Background: Randomized trials established chemoradiotherapy as standard treatment for advanced laryngeal cancer. Patients with large-volume T4 disease (LVT4) were excluded from these trials. The purpose of this study was to report T4 laryngeal cancer patient outcome, including those with LVT4 disease, treated with chemoradiotherapy.
Patients and methods: This study is a retrospective subset analysis of 32 patients with T4 laryngeal carcinoma including LVT4 tumors treated on three consecutive protocols investigating paclitaxel (Taxol), 5-fluorouracil, hydroxyurea, and 1.5-Gy twice daily (BID) radiotherapy (TFHX).
Results: Median follow-up is 43 months. Four-year locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and laryngectomy-free survival (LFS) was 71%, 67%, 53%, and 86%, respectively. Four patients required laryngectomy for recurrent or persistent disease. Of disease-free patients with 
1 year follow-up, 90% demonstrated normal or understandable speech. None required laryngectomy for complications. Among LVT4 patients, 4-year LRC, DFS, OS, and LFS was 71%, 65%, 56%, and 81%, respectively. Induction chemotherapy improved 4-year LRC (90% versus 46%, P = 0.03) and DFS (84% versus 42%, P = 0.03).
Conclusions: Promising control and functional outcomes are achieved with TFHX for T4 laryngeal patients. LVT4 disease had outcomes similar to patients with less advanced disease treated on Radiation Therapy Oncology Group 91-11. Induction chemotherapy improved outcomes, warranting further investigation.
chemoradiotherapy, head and neck cancer, induction chemotherapy, larynx therapy, organ preservation, T4 laryngeal cancer
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introduction |
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In the United States there are
10 000 cases of laryngeal cancer each year, with 40% of these patients presenting with locoregionally advanced disease [1]. Landmark trials conducted by the U.S. Department of Veterans Affairs (VA) Laryngeal Study Group and the Radiation Therapy Oncology Group (RTOG) 91-11 have shown that a primary organ preservation approach with chemotherapy and radiation yields survival similar to laryngectomy followed by adjuvant radiotherapy with high rates of larynx preserving and excellent functional outcome [2, 3]. The favorable outcomes reported in these trials have led both the American Society of Clinical Oncology [4] and the National Comprehensive Cancer Network expert panels to recommend a larynx preserving approach for most patients with T3 and low-volume T4 tumors. Although 9% of patients in the VA Larynx trial had cartilage invasion, RTOG 91-11 excluded patients with large-volume T4 (LVT4) tumors defined as extension of tumor through thyroid cartilage or tumor extension >1 cm into the base of tongue [3]. These patients were considered poor organ preservation candidates, as many clinicians argue that functional outcome following organ preservation treatment is unacceptably poor [5]. We hypothesized that with modern combined-modality hyperfractionated chemoradiotherapy, it would be possible to control large-volume head and neck cancers, including T4 laryngeal tumors with an organ preservation approach. The aims of the current analysis were to determine whether patients with T4 tumors and specifically those patients with LVT4 could be treated with concurrent chemoradiotherapy (CRT) with good functional outcome.
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patients and methods |
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From December 1996 to May 2002, 376 patients with locoregionally advanced nonmetastatic squamous cell and poorly differentiated head and neck carcinoma were enrolled on three sequential phase II CRT trials (Protocols 7929, 8626, and 9502). Details of these protocols have been published previously [6–8]. To be eligible for protocol treatment, patients had to have pathologically proven squamous cell or poorly differentiated carcinoma; had to have performance status of zero to two; and had to be evaluated before enrollment by medical, radiation, and surgical oncologists. Before any therapy, patients were evaluated with a complete history and physical; radiographic assessment of the primary tumor, neck, and chest; bone scan; panendoscopy; dental evaluation; speech and swallowing evaluation; and quality-of-life evaluation. Patients were staged with T4 supraglottic or glottic laryngeal cancer, based on American Joint Committe on Cancer 2002 criteria, at a multidisciplinary conference and were designated as having LVT4 disease if the primary tumor penetrated through thyroid or cricoid cartilage and/or had invasion
1 cm into the base of tongue (the same criteria as RTOG 91-11).
treatment regimen
concurrent chemoradiotherapy
Chemoradiotherapy was administered on days 1–5 (d1–5) of each cycle followed by a 9-day break without chemotherapy or radiotherapy. Cycles were repeated every 14 days until the completion of chemoradiotherapy. CRT consisted of paclitaxel (Taxol, Bristol-Myers Squibb, New York City, USA), oral hydroxyurea, continuous-infusion 5-fluorouracil (5-FU), and 1.5-Gy BID radiation (TFHX), administered as previously described [6–8]. As shown in Figure 1, 500 mg hydroxyurea was administered p.o. every 12 h on d1–5 of each cycle, given 2 h before each fraction of radiotherapy. Additionally, 600 mg/m2/day 5-FU, continuous infusion, was administered on d1–5. From 1996 to 2000, patients received continuous-infusion paclitaxel (20 mg/m2/day, d1–5), and on subsequent protocols, patients received a 1-h infusion of paclitaxel (100 mg/m2) on d1 of each cycle after the first fraction of radiotherapy.
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Patients treated on Protocol 9502 received induction chemotherapy before CRT, while patients on Protocols 8626 and 7929 did not. Initially, the induction regimen consisted of six-weekly cycles of paclitaxel (135 mg/m2 over 3 h) and carboplatin [area under the curve (AUC) = 2 over 30 min]. Later, while the induction agents remained unchanged, paclitaxel (100 mg/m2 d1, 8, 15) and carboplatin (AUC = 6 d1) were administered every 4 weeks for two cycles.
radiotherapy
All patients underwent computed tomography (CT)-based treatment planning and risk-defined volumes were contoured by a single radiotherapist (DJH). Patients receiving chemotherapy before CRT underwent two CT simulations both before and after administration of induction chemotherapy. The gross tumor volume (GTV) included all known areas of gross disease detected on physical or radiographic examination before the administration of chemotherapy. The highest risk volume, planning target volume 1 (PTV1), included the GTV expanded 1.5 cm. PTV2 included PTV1 plus the first echelon of uninvolved lymph nodes, and PTV3 included PTV2 plus the second echelon of uninvolved lymph nodes. Volumes were modified to avoid spinal cord overlap or extension beyond the skin.
Radiotherapy was delivered via 6-MV photons using twice-daily 1.5-Gy fractions with a minimum 6-h interfraction interval. Occasionally, patients received a single 2-Gy fraction for mechanical failure or holiday. In general, PTV1 received 72–75 Gy, PTV2 received 51–60 Gy, and PTV3 received 36–45 Gy. Most patients on Protocols 7929 and 8626 were treated with conventional two- or three-dimensional conformal radiotherapy. As intensity-modulated radiotherapy became available, it was increasingly used, particularly on Protocol 9502.
surgery
No patient had surgical resection of the primary tumor before the initiation of chemoradiotherapy. Allowed surgical procedures before the initiation of treatment included tracheostomy placement for airway-compromising tumors, neck dissection, or gastrostomy tube placement. Patients were recommended to undergo planned post-treatment biopsy of the primary. Patients with N2 disease were recommended to undergo posttherapy selective neck dissection. Salvage surgery at the primary site was reserved for patients with biopsy-proven recurrent or residual disease on post-treatment biopsy.
functional outcome measurements
All patients were followed by an experienced multidisciplinary head and neck team, consisting of a single radiotherapist, dedicated medical oncologists, head and neck surgeons, and speech pathologists for assessment of functional outcome. Functional outcomes were collected on patients who remained disease free with a minimum 12-month follow-up after completing CRT. Patients who underwent salvage laryngectomy or developed recurrent disease were not included in the functional outcome analysis. Patients were scored for the presence of a gastrostomy tube and/or tracheostomy both before treatment and at last follow-up. Voice quality was scored by a single radiation oncologist (DJH) and otolaryngologist (KMS) and translated into a four-point scale. Patients deemed to have normal voice production by their treating physicians were given a score of 1. Patients with hoarseness or breathiness were given a score of 2. Those patients who could only produce a whisper were given a score of 3, and patients who were aphonic were given a score of 4. In cases where the scoring of voice quality differed between the assessing physicians, the poorest score was recorded.
statistical analysis
Evaluation of response was carried out following induction chemotherapy (if administered) and at the completion of all therapy. Response was assessed clinically by a multidisciplinary team and included physical examination as well as radiographic evaluation. A complete response was defined as the complete disappearance of all clinically detectable disease, a partial response was defined as an average reduction of all measurable disease by at least 50% and no appearance of new lesions. Patients suspected of progressive or residual disease at the primary site were required to undergo biopsy confirmation.
Actuarial survival and disease control parameters were calculated via the method of Kaplan and Meier. Overall survival (OS) was defined as time from the first day of treatment until death from any cause or last date of contact. Time to progression was measured as the time from the first day of treatment until the date of local, regional, distant failure and/or treatment-related death. Patients with residual disease at the primary site and patients dying within 30 days after completing treatment were counted as treatment failures. Patients who developed a secondary primary cancer were not counted as treatment failures.
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results |
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Patient and tumor characteristics are summarized in Table 1. Median follow-up is 43 months (3–114.2). The median patient age was 58 years, and 66% of patients were male. Of the 376 patients treated on the three protocols, 32 patients with T4 laryngeal tumors were identified. Supraglottic primary tumors were more common (91%) than glottic primary tumors (9%). About 56% of superglottic primaries involved one or both true vocal cords. In all, 23 patients (72%) had LVT4 tumors, with 20 (87%) having extension through the thyroid cartilage, three having >1 cm extension into the base of tongue; one had both base of tongue and cartilage involvement. In all, 28 patients (88%) were resectable (T4a) and the remaining four were unresectable. In all, 19 patients (59%) received induction chemotherapy.
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Acute toxic effects fell within the expected range for this CRT platform. About 66% of patients experienced acute grade 3–4 mucositis, and 57% experienced acute grade 3–4 dermatitis. Grade 3–4 neutropenia was less common (25%), and 16% experienced grade 3 fever/infection. One patient died 30 days after completing treatment of unknown causes; autopsy was offered, but refused.
locoregional and distant control
The 4-year actuarial local control, locoregional control (LRC), and distant metastasis-free survival (DMFS) were 83%, 71%, and 71%, respectively. There were no differences in LRC (71% versus 70%) or disease-free survival (DFS) (65% versus 70%) between patients with large-volume disease and those without, as shown in Table 2. The 4-year actuarial DFS and OS for all patients was 67% and 53%, respectively. DFS (70% versus 65%) and OS (44% versus 56%) were similar between large-volume and nonlarge-volume T4 tumors, respectively. Interestingly, patients receiving induction chemotherapy had significantly improved LRC (90% versus 46%, P = 0.03) and DFS (84% versus 42%, P = 0.03). Patients receiving induction chemotherapy trended towards improved DMFS (84% versus 51%, P = 0.14) and improved laryngeal preservation following induction chemotherapy (95% versus 72%, P = 0.11), as shown in Table 2. No survival benefit was seen with administration of induction chemotherapy.
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laryngeal preservation
At last follow-up, 86% of all patients and 81% of LVT4 tumors had an intact larynx following definitive chemoradiotherapy. No laryngectomies were required for patients with nonbulky T4 tumors. Additionally, no patient underwent laryngectomy for treatment complications.
patterns of failure
Nine patients had documented progression of their disease. The first site of progression was locoregional (within the irradiated volume) in five patients and distant in three patients. No patient progressed regionally as the first site of treatment failure. One patient was discovered to have simultaneous locoregional and distant failure. Of the five patients who first progressed locoregionally, four later developed distant metastatic disease (see Table 2). Cumulatively, eight patients developed locoregional recurrences. Six of these recurrences occurred in LVT4 patients, with five initially presenting with tumor extension through cartilage and one with base of tongue involvement. Four patients with locally recurrent disease underwent salvage laryngectomy. Only one significant surgical complication was encountered, a pharyngeal-cutaneous fistula which healed without intervention. All patients undergoing salvage laryngectomy died of metastatic disease. One with a positive margin died 4 months later from metastatic disease to the chest with a malignant pleural effusion, and the other three patients with negative surgical margins died from distant metastatic disease at 12, 23, and 44 months after undergoing laryngectomy.
At last follow-up, 14 patients were alive and well. Nine patients had progressive disease, with all who progressed eventually dying of disease (29%). Five patients died of intercurrent disease (16%), one patient died from a second malignancy, and one patient died 30 days after completing chemoradiotherapy. This patient was scored as a DFS failure. Two patients are alive with second primary cancers.
functional outcome
Vocal and swallowing function was assessed in all 20 patients who remained disease free with a minimum 12-month follow-up (Table 3). About 30% of patients had normal speech (score of 1), 60% had hoarseness (score of 2), and 10% could only whisper (score of 3). No patients had complete loss of voice (score of 4). Patients with large-volume disease were less likely to have normal speech (27% versus 40%) and more likely to speak with a whisper (13% versus 0%), than those without large-volume disease.
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While 60% (12/20) of patients required a gastrostomy tube before or during CRT, at last follow-up only three (15%) were gastrostomy tube dependent. This included two patients with large-volume disease and one patient with nonlarge-volume disease. Furthermore, 65% of patients (13/20) had a tracheostomy placed before or during CRT, but only five had a tracheostomy at last follow-up. All long-term tracheostomies were for persistent glottic and/or pharyngeal edema. Only one patient without a tracheostomy before or during treatment required tracheostomy placement following TFHX (Table 3).
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conclusions |
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During the past two decades, the treatment paradigm for locoregionally advanced head and neck malignancies has rapidly evolved with CRT, a current standard as definitive or adjuvant treatment [9–15]. The VA Laryngeal Cancer Study Group provided early evidence that locally advanced laryngeal tumors could be successfully controlled with a multimodality organ preservation approach without compromising OS [2]. Recently, RTOG 91-11 demonstrated that CRT was superior to induction chemotherapy followed by radiotherapy in terms of laryngeal preservation [16]. Historically, however, patients with LVT4 laryngeal tumors have been considered poor candidates for organ preservation. In a previously reported series of patients with T4 laryngeal tumors treated with radiation alone, suboptimal rates of local control and disease-specific survival were reported [17].
Several trials from our institution have reported high rates of LRC and OS utilizing an organ preservation approach in patients with locally advanced head and neck malignancies [8, 18–20]. In the current analysis, we specifically addressed those issues for patients with locally advanced laryngeal cancer including LVT4.
We found that patients with T4 laryngeal cancer and even those with large-volume disease were able to retain functional larynges following a course of TFHX. Four-year LRC, DFS, and OS were comparable between patients with large-volume disease and those with nonlarge-volume disease. Furthermore, all nonlarge-volume T4 patients and 81% of LVT4 tumors were able to maintain their larynges.
Not only was organ preservation possible but also in many patients larynges remained functional. While all patients with nonlarge-volume T4 disease maintained normal or at least hoarse speech, so did 87% of LVT4 patients. Furthermore, only 20% of patients who were disease free and followed for >1 year required tracheostomy and 13% depended on gastrostomy tubes for nutrition. No patient without a gastrostomy tube at the completion of CRT required placement for late complications.
Although many of our patients had more advanced disease than the patients included in RTOG 91-11, our 4-year rate of larynx preservation for all patients (86%) and those with LVT4 tumors (81%) was remarkably similar to the 5-year RTOG 91-11 rates (83.6%) [16], as shown in Table 4. The VA Larynx trial-reported salvage laryngectomy was required more often for T4 and stage IV patients, with a trend for more frequent salvage in patients with cartilage invasion and fixed vocal cords [2]. Our analysis indicates that with modern combined-modality therapy even these patients can retain their larynges. Furthermore, almost all patients with large-volume disease in this analysis had a functional voice following treatment, with only two patients able to speak with a whisper only.
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Although some have voiced concerns about the ability to carry out salvage surgery following definitive chemoradiotherapy for patients with large-volume tumors [21], we did not find this to be true. Of the four patients undergoing salvage laryngectomy, only one significant complication was encountered either during or after surgery, a pharyngeal-cutaneous fistula which spontaneously resolved with conservative management.
The role of induction chemotherapy in patients with advanced laryngeal cancer is presently unclear. In our analysis we found that patients receiving induction chemotherapy had significantly improved LRC (90% versus 46%) and DFS, while trending towards improvements in DMFS (84% versus 51%) and laryngeal preservation (95% versus 72%). Theoretically, the improvement in DMFS was due to the eradication of distant micrometastases, while improved LRC was due to cytoreduction at the primary site. While others have reported induction chemotherapy and CRT regimens for patients with locoregionally advanced laryngeal cancer, they have included patients with both T3 and T4 disease [22]. Even these reports, however, demonstrated that laryngeal preservation was possible, albeit not as well as this regimen.
Additionally, some have advocated that response to a single cycle of induction chemotherapy be used to select patients for CRT while those not responding undergo surgical resection [22]. This approach is based on the principle that patients not responding to induction chemotherapy will not respond to CRT. This paradigm may, however, unnecessarily commit some patients with a slow response to the first cycle of chemotherapy to laryngectomy. Furthermore, 70% of patients with stable disease (< 50% reduction and < 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) following induction chemotherapy can be controlled locoregionally and maintain their larynges (Salama 9502). In fact, laryngeal preservation rates in the University of Michigan experience were lower than the rates reported in RTOG 91-11 (84% versus 70%) [16, 22].
In conclusion, definitive chemoradiotherapy results in high rates of disease control and larynx preservation in patients with T4 laryngeal carcinoma. Patients with LVT4 disease had similar rates of disease control compared with less advanced T4 tumors. Our outcome compares favorably with the results obtained in RTOG 91-11, which excluded patients with large-volume tumors. Most importantly, patients cured of their disease had good functional outcomes following definitive chemoradiotherapy. The results of this study challenge the convention that patients with T4 laryngeal cancer should be treated with upfront laryngectomy. In the modern era of multiagent chemotherapy, altered fractionation, and improved radiotherapy techniques, patients with locally advanced disease should be considered for organ preservation therapy on clinical trials. Furthermore, patients receiving induction chemotherapy before CRT exhibited higher rates of disease control, warranting further investigation.
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Acknowledgements |
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The author acknowledges the help provided by Maureen Crowley, RN, and Allison Dekker, RN.
Received for publication November 17, 2007. Revision received January 29, 2008. Accepted for publication March 25, 2008.
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