Therapeutic results of laryngeal preservation: a retrospective study
Summary. Aim: The objective of this study is to report the therapeutic results of the preservation strategy in locally advanced laryngeal cancers. Patients and Methods: Between January 2008 and December 2015, 24 patients with locoregional advanced non-metastatic laryngeal cancer (T2–4/N0–2) were collected retrospectively. Different therapeutic sequences were used: either induction chemotherapy followed by concurrent chemoradiotherapy or induction chemotherapy followed by radiotherapy or concurrent chemoradiotherapy or radiotherapy alone. Results: The objective response rate was 85.7%. Overall survival rates at 1 year, 3 years and 5 years were 91.3%, 80.2% and 53.5%, respectively. Administration of induction chemotherapy did not improve overall survival. The 1-year overall survival was 83.3% in the induction chemotherapy group vs 94.1% for those who did not received induction chemotherapy (p = 0.7). Conclusion: Our study showed the feasibility of this preservation strategy in clinical practice, with acceptable term toxicity.
Submitted: October 22, 2019.
*Correspondence: E-mail: firstname.lastname@example.org
Abbreviations used: CCR — concomitant chemoradiotherapy; CT — chemotherapy; ICT — induction chemotherapy; OS — overall survival; PF — cisplatin + 5-fluorouracil; RT — radiotherapy; TL — total laryngectomy; TPF — docetaxel + cisplatin + 5-fluorouracil.
The treatment of advanced laryngeal cancers consisted of radical total laryngectomy (TL). The first TL was made in 1873 by Theodor Billroth . In order to preserve the voice of the patients and to limit the functional sequelae, the partial surgeries were proposed starting from 1960. Exclusive external radiotherapy (RT) was introduced in 1950 for the treatment of early-stage cancers. Thus, surgery and locoregional RT were the only therapeutic means until the late eighties. The combination of RT and chemotherapy (CT) has proved its value by several randomized trials. It became the standard treatment in the United States for advanced cancers (T3T4-N0N1), after the first “veteran” study in 1994 . In this study, the overall survival (OS) with induction chemotherapy (ICT) followed by RT (68% at 2 years) was similar to that obtained with TL followed by RT (64% at 2 years) [2, 3]. In 2003, the concept of ICT followed by RT after a satisfactory tumor response was introduced. Several randomized trials have demonstrated the superiority of concomitant chemoradiotherapy (CCR) compared to RT alone in terms of local control and survival with preservation of the larynx [4, 5, 6]. The objective of this study is to report the therapeutic results of the preservation strategy in locally advanced laryngeal cancers.
PATIENTS AND METHODS
Eligibility criteria. Between January 2008 and December 2015, 24 patients with locoregional advanced non-metastatic laryngeal cancer (T2-4/N0-2) were collected retrospectively. The study was approved by the Ethical Committee of Habib Bourguiba Hospital. The ethical standards relevant to the retrospective studies have been followed. The T2 tumors included in the study were ineligible for partial surgery. From 2010, the tumors were classified according to the TNM 2010 classification and previous cases were reclassified according to the same TNM 2010 classification. We exclude from our study laryngeal cancers that were unresectable by TL, recurrent cancers and those with metastases. The epidemiological, anatomo-clinical data, as well as the therapeutic results were identified. The initial assessment included clinical examination with indirect laryngoscopy, and panendoscopy with laryngeal biopsies, laryngeal, cervical, and thoracic computed tomography and abdominal ultrasound. Histological diagnosis was made according to the WHO classification.
Treatment. Different therapeutic sequences were used: either ICT followed by CCR or ICT followed by RT or CCR or RT alone. ICT was based on TPF regimen (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, 5-fluorouracil 750 mg/m2/day × 5 days) (every 21 days) or PF regimen (cisplatin 75 mg/m2 day 1, 5-fluorouracil 750 mg/m2/day × 5 days (every 21 days). Concomitant CT with RT was based on cisplatin (100 mg/m2 day 1–22–43). Patients not eligible for CT with сisplatin received weekly carboplatin (AUC2) with RT. Patients who had received RT alone had T2N0M0 tumors and had a contraindication to partial laryngectomy. RT at a dose of 70 Gy was delivered to the tumor and involved lymph nodes. From 2008 to 2011, the RT was conventional in 2D delivered by a 60Co (in 12 patients) using 2 lateral beams middle cervical together with an anterior cervical field nodes. Since 2011, a conformational technique was used (in 11 patients) with a linear accelerator.
Follow-up and response evaluation. Before each cycle of CT, clinical conditions, regional lymph node status, blood count, renal function, toxicities (according to WHO criteria) and patient complaints were evaluated. After the end of treatment, the follow-up was every 3 months for the first 2 years, every 6 months for the next 3 years and then every year. Treatment response was assessed after the third cycle of CT (according to RECIST criteria) and 3 months after the end of radiotherapy by laryngeal examination and cervical computed tomography.
Statistical analysis. Data were entered and analyzed using SPSS software version 20. We conducted a statistical study with 2 stages: a descriptive study of various data and an analytical study. OS curve was obtained using the Kaplan — Meier method. The survival data were calculated as follows: OS from the date of the positive diagnosis (date of laryngeal biopsy) to the date of death of any cause or the date of the latest follow-up. The date of the latest news was set for February 2020.
Patients’ characteristics. The median age was 42.2 years (18–71) (Table 1). Histological examination showed a well-differentiated squamous cell carcinoma in 18 cases (75%), moderately differentiated in 4 cases (16.67%), and poorly differentiated in 2 cases (8.33%). Tables 1 and 2 describe tumors distribution and extension according to the TNM 2010 classification. Two patients had received CT followed by RT, 4 patients received CT followed by CCR, 14 patients treated by CCR and 4 patients underwent RT alone (see Table 1).
Table 1. Patient’s characteristics
Table 2. T and N classification according to locoregional lymph node and tumor extension
Twenty-three patients completed the laryngeal preservation protocol. One patient died after ICT. Two patients were lost to follow-up, and did not consult again for the evaluation. We analyzed the evaluation data of 21 patients.
Treatment response. The objective response rate was 85.7%. Indirect and direct laryngoscopy after the end of the treatment showed tumor thickening with a positive biopsy in 3 cases (14.3%). Mean OS was 72.5 months (Figure). OS rates at 1 year, 3 years and 5 years were 91.3%, 80.2% and 53.5%, respectively. Administration of ICT did not improve OS. The 1-year OS was 83.3% in the ICT group vs 94.1% for those who did not received ICT (p = 0.7). The 3-year OS was 66.7% for the ICT group and 85.6% in those with no ICT. Locoregional relapse occurred in four patients treated by TL; and distant metastatic disease in three patients (2 cases of pulmonary metastases treated with palliative CT by PF regimen, and 1 case of cerebral metastasis treated with cerebral RT and supportive care).
Figure. Overall survival
Treatment toxicities. ICT was complicated by toxic death in one case following grade 4 febrile aplasia, grade 4 vomiting and acute renal failure in a 63-year-old man after the second TPF course. One patient had grade 3 non-febrile neutropenia requiring delay of the next 15-day course (Table 3). The 21-day interval period was respected in 4 cases. Toxicities observed most frequently after RT were mucositis and radiodermatitis and they were worse in the group receiving CCR (Table 4).
Table 3. Toxicities during ICC
Table 4. Toxicities secondary to CCR and RT
All tumors in our series were strictly laryngeal and predominantly T3 (66.6%). Only three patients had lymph node involvement (12.5%). The characteristics of our population were similar to those of the pivotal study of the “veterans” , which also included patients with laryngeal cancer only and limited lymph node involvement (at 66%) and similar proportion of patients with fixation of the vocal cords (55%). Table 5 summarizes the characteristics of the population of our series and those reported in the literature [8–15].
Table 5. Stage of patients included in our study compared to series of the literature
Different therapeutic sequences have been used in our patients: ICT followed by either exclusive RT or CRC, RT alone, or CRC. The induction CT was TPF or PF. Concomitant CT was cisplatin-based CT, and carboplatin-based CT for patients unable to receive cisplatin. A RT of 70 Gy was delivered at the tumor and the invaded lymph nodes, and of 50 Gy on the rest of the ganglionic areas. The induction CT, when indicated, was 2 or 3 courses of TPF or PF. In the two large randomized trials, that of “veterans” and that of EORTC, the induction CT was based on 2 courses PF and then, if there was a partial or complete response on the evaluation after the 2nd course, a 3rd cure was added [7, 16]. The toxicities secondary to CT did not require interruption of treatment. Adherence to this CT was good and interval between courses were respected in all cases. Only one patient died of chemo-induced toxicity, that is 4%. Toxic death rates reported in the literature were 1–2% . During the RT, we noted a slight increase in mucosal and cutaneous toxicity with CRC compared to RT alone. Long-term toxicities have not been studied due to the lack of information in the files.
In our series, the average survival was 72.5 months; and the 1-year and 3-year OS rates were 91.3% and 80.2%, respectively. These rates are higher than some reported in the literature. In the Veterans trial, the 2-year and 3-year OS rates were 68 and 53%, respectively . In the EORTC trial, the median survival was 44 months, and the OS rate at 3 and 5 years was 53% and 38%, respectively . Also, it was 73% at 2 years and 60% at 3 years in the GORTEC 2000-01 study . The difference between the results could be explained by the less advanced stages of tumors included in our series (mostly T2/T3 in 83.33% of cases) compared to those included in other series of the literature. This is also due to the initial nodal extension and its negative impact on survival . This difference can also be explained by the fact that in our study, the preservation protocol should include laryngeal cancers; while in the other studies, they included hypopharyngeal cancers that would have a worse prognosis. In our series, the administration of the induction CT did not allowed an improvement of the OS contrary to several findings of the literature. In fact, in the literature, the survival rate also depends on the rate of response to this induction CT [20, 21]. In our series, all patients who had induction CT had a complete response, and their 5-year OS was 75%.
Numerous trials have shown the advantage of intensity-modulated RT in terms of improving quality of life of patients with head and neck cancer, particularly in terms of salivary dysfunction and oral discomfort [22–25], without compromising the local control rate or altering survival. Intensity-modulated RT was not used in our study.
In order to determine the optimal treatment that should be adopted after the primary CT in the laryngeal preservation strategy, cetuximab was tested for this indication with the concomitant RT. Mesia et al.  proposed a scheme combining cetuximab with RT after a good response to the induction CT, which improved the survival rate with functional larynx (70% at 3 years). Bonner et al.  demonstrated a higher rate of laryngeal preservation when cetuximab was added to RT in the treatment of locally advanced hypopharynx and larynx cancers; but also the absence of additional toxicities compared to RT alone and an identical quality of life. Subsequently, several studies compared the two molecules in combination with the RT, in order to determine the superiority of one compared to the other. Two studies [27–29] showed the superiority of cisplatin compared with cetuximab in terms of OS, DFS and laryngeal preservation rate. The TREMPLIN phase II study, however, did not demonstrate superiority of modalities over the other . The place of cetuximab in the preservation protocol remains to be determined through phase III studies.
Two preservation protocols are mainly validated: ICT followed by RT or CCR. A direct comparison between these two options would be necessary to determine the best therapeutic strategy. A Phase III study: GORTEC 2014-03 is currently underway, comparing TPF induction CT followed by RT with cisplatin to answer this question.
Despite the retrospective character and the limited sample of our study, our results are promising and even better than some series in the literature. Our study showed the feasibility of this preservation strategy in our clinical practice, with acceptable term toxicity. ICT did not improve OS compared with those who received chemoradiotherapy alone. Before proposing a laryngeal preservation protocol, it is crucial to discuss the benefits and risks of this strategy. Optimal patient selection improves oncologic and functional outcomes. The best laryngeal preservation strategy remains to be defined by numerous studies, comparing various protocols and testing new molecules.
Conflict of interest
ТЕРАПЕВТИЧНІ РЕЗУЛЬТАТИ ОРГАНОЗБЕРІГАЮЧОЇ СТРАТЕГІЇ ПРИ МІСЦЕВО-ПОШИРЕНОМУ РАКУ ГОРТАНІ: РЕТРОСПЕКТИВНЕ ДОСЛІДЖЕННЯ
Резюме. Мета: Проаналізувати результати лікування при застосуванні органозберігаючої стратегії при місцево-поширеному раку гортані. Пацієнти і методи: У період з січня 2008 р. до грудня 2015 р. ретроспективно було зібрано інформацію про 24 хворих з місцевопоширеним неметастатичним раком гортані (T2-4/N0-2). Були використані різні схеми лікування: індукційна хіміотерапія з наступною одночасною хіміопроменевою терапією, індукційна хіміотерапія з наступною променевою терапією, або тільки хіміопроменева або променева терапія. Результати: Частота об’єктивної відповіді становила 85,7%. Показники 1-, 3- та 5-річної загальної виживаності становили 91,3, 80,2 і 53,5%, відповідно. Призначення індукційної хіміотерапії не покращило загальну виживаність. 1-річна загальна виживаність становила 83,3% в групі індукційної хіміотерапії проти 94,1% у тих, хто не отримав індукційну хіміотерапію (p = 0,7). Висновок: Дослідження показало доцільність застосованої органозберігаючої стратегії лікування місцево-поширеного раку гортані в клінічній практиці.
Ключові слова: рак гортані, хіміотерапія, променева терапія, хіміопроменева терапія.
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