Salvage radiotherapy for recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) after first-line treatment with surgery alone: a 10-year single-centre experience

Seventy-five patients with laryngeal or hypopharyngeal SCC treated for recurrence after prior surgery at the Department of Radiation Oncology of the University Hospital Heidelberg between 2007 and 2017 were identified retrospectively and patient′s records were analysed regarding local progression-free survival (LPFS), overall survival (OS) and distant progression-free survival (DPFS). Additionally, potential prognostic factors were assessed and calculated for local control (LC), OS and DPFS.

Follow-up was performed with magnetic resonance imaging (MRI) or computed tomography (CT) 6 weeks after completion of therapy, at three-month intervals during the first 2 years after treatment, every 6 months during the third year after treatment and then, once a year. Yearly CT scans of the chest and abdominal ultrasound were performed to identify distant relapse.

Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) and tumor response to the current Response Evaluation Criteria in Solid Tumors (RECIST) [8, 9]. TNM (tumor, nodal, metastasis) stage was assessed and adjusted to the eight edition of the TNM classification system [10].

All patients received RT in a secondary setting for recurrence after first-line treatment with surgery alone (median number of operations 1, range 1–4). Patients who received a prior radiation treatment were excluded from the study. Initially, postoperative RT (n = 13, 17%) for UICC stage III/IV or CRT (n = 22, 29%) for incomplete resection margin (n = 11, 15%), lymph node metastases with extracapsular spread (ECS; n = 9, 12%) or both (n = 2, 3%) was obligatory in overall 47% of the patients but was declined from the patient. Therefore, two treatment groups were differed within the study population; early stage patients without an initial indication for postoperative RT (n = 40, 53%) and patients with advanced tumors who declined postoperative RT after first-line surgery (n = 35, 47%). Prior total laryngectomy was performed in 24% of the patients (n = 18), prior unilateral neck dissection (ND) in 9% of the patients (n = 7) and bilateral ND in 35% of the patients (n = 26). In 79%, lymph node metastases could be identified (n = 26), in 11/26 patients with ECS (for detailed treatment characteristics please see Table 2).

The majority of the patients were male (n = 64, 85%) and older than 60 years (n = 45, 60%) at RT initiation (median age of 64 years, range 46–83 years). The most common initial tumor sites were the glottic larynx with 61% (n = 46), the hypopharynx with 19% (n = 14) and the supraglottic larynx with 16% (n = 12). Regarding the recurrent tumor sites after prior surgery, the glottic larynx (n = 31, 41%), the neopharynx (n = 12, 16%) and the hypopharynx (n = 14, 19%) dominated. At first diagnosis, 56% of the tumors were at UICC stage I-II (n = 44). At recurrence, higher UICC stages could be identified with 28% for UICC stage III (n = 21), 25% for UICC stage IVA (n = 19), 13% for UICC stage IVB (n = 10) and 1% for UICC stage IVC (n = 1). Patient characteristics are shown in Table 1.

For treatment planning, CT and MRI were performed and patients were immobilized with custom-made thermoplastic masks with shoulder fixation. Clinical target volume 1 (CTV1) including the macroscopic tumor and the potential microscopic spread and CTV2 including the CTV1 and the lymphatic drainage were outlined. Planning target volumes (PTVs) were generated with a margin of 5 mm around the CTVs and received at least 90% of the prescription dose. All patients received intensity modulated radiotherapy (IMRT) via tomotherapy with (n = 70, 93%) or without simultaneous integrated boost (SIB, n = 5, 7%) at a median time of 7 months after the first operation (range 1–333 months). Single doses and prescription doses differed, thus we calculated the equivalent dose in 2 Gy per fraction with the following formula for better dose comparibility: EQD2 = D x ((d + α/β)/(2 + α/β)) (D = total dose in Gy, d = single dose in Gy, α/β = 2).

The median prescribed total dose was 54 Gy (range 52.2–66 Gy) with a median single dose fraction of 1.8 Gy (range: 1.8–2.0 Gy) to the bilateral cervical lymph drainage and 66 Gy (range 58–72 Gy) with a median single dose fraction of 2.2 Gy (range 1.8–2.2 Gy) to the macroscopic tumor. The median equivalent dose to a 2 Gy single dose fraction (EQD2) prescribed on the macroscopic tumor was 67 Gy (range 60–73 Gy). In 5 cases, treatment could not be finished (7%). Thus, these patients received smaller cumulative doses. The median PTV1 was 101 cc (range 21–222 cc) and the median PTV2 was 740 cc (range 51–1301 cc). Overall, 77% of the patients were treated with concomitant systemic therapy (n = 58) of whom 64% received concomitant chemotherapy (n = 48) with carboplatin/5-fluoruracil in week 1 and 5 (n = 4) or cisplatin weekly (n = 44) and 13% concomitant immunotherapy with cetuximab weekly (n = 10). Treatment characteristics are depicted in Table 2.

Five patients could not finish therapy for deterioration of their general condition (KPS < 60%) and were lost to follow-up after treatment. Therefore, we excluded these patients from the analysis (7%). Median follow-up for all remaining patients was 41 months (range 8–120 months) and for surviving patients 50 months (range 8–120 months). At last follow-up, 56% of the patients were still alive (n = 39) of whom 87% were free of local failure (n = 34). Median OS from first diagnosis up to last follow-up or death was 59 months (range 11–373 months) and from RT up to last follow-up or death 43 months (range 14–121 months). Overall, complete remission was seen in 48 patients (64%) and partial remission in six patients (8%). 20% of the patients developed an in-field recurrence (n = 14) and one patient a locoregional recurrence in cervical lymph nodes (1%) after a median time of 12 months (range 3–19 months) after RT. All local and locoregional recurrences occurred within the first 2 years after RT. Distant metastases (n = 13) were diagnosed in 19% of the patients after a median time of 28 months (range 2–88 months) after the first diagnosis with pulmonary failure in 11 cases (16%) and bone metastases in 2 cases (3%). Corresponding 3-year and estimated 5-year LPFS, OS and DPFS were 75, 76, 85 and 75%, 64, 82% for all patients without significant differences for initially early stage (without an initial indication for adjuvant RT) vs. advanced stage (with an initial indication for adjuvant RT) larynx/hypopharynx tumors in the LPFS (p = 0.431; HR = 1.12; 95%-CI = 0.38–21.30), OS (p = 0.518; HR = 0.89; 95%-CI = 1.24–12.46) and DPFS (p = 0.081; HR = 3.04; 95%-CI = 1.98–8.34), respectively. Patients with local or locoregional recurrence received either palliative systemic therapy (n = 5, 7%), best supportive care (n = 1, 1%), salvage larynx-preserving surgery (n = 2, 3%), salvage ND (n = 1, 1%), salvage total laryngectomy (n = 5, 7%) or re-RT (n = 1, 1%). Thus, preservation of the larynx could be achieved in 90% (n = 47/52) of the patients apart from patients who were initially treated by total laryngectomy.

We analysed the impact of potential prognostic factors at time of first-line treatment with surgery alone (initial T, N, G stage, ECS, tumor site, Karnofsky performance status (KPS), prior laryngectomy vs. larynx-preserving surgery, prior ND yes vs. no, time period between first operation and first recurrence) and at time of second-line treatment with salvage RT (recurrent T, N, G stage, KPS, number of prior operations, EQD2 > 70 Gy vs. ≤70 Gy, PTV1 ≥ 101 cc vs. < 101 cc, cisplatin weekly chemotherapy vs. others, local recurrences yes vs. no after RT and metastases yes vs. no) on OS, LPFS and DPFS. Several potential prognostic factors were identified using the log-rank test for univariate analyses. Independent prognostic factors were assessed by the cox regression model for multivariate analysis. The results of univariate and multivariate analysis are shown in Table 3.

Regarding LPFS, we could identify the use of concomitant chemotherapy with cisplatin weekly (p = 0.006) and an EQD2 > 70Gy prescribed on the macroscopic tumor as positive prognostic factors (p = 0.032). Patients who received concomitant systemic therapy were included into analysis only. The use of concomitant chemotherapy with cisplatin weekly resulted in a 5-year LPFS of 86% vs. 44% compared with patients who received concomitant chemotherapy with carboplatin/5-FU in week 1 and 5 or cetuximab weekly (Fig. 1). With regard to the applied EQD2 on the macroscopic recurrent tumor, patients who received an EQD2 > 70 Gy had a 5-year LPFS of 90% vs. 68% compared with patients who received an EQD2 ≤ 70 Gy (Fig. 2).

Patients with local or locoregional recurrence after salvage RT had a significant worse OS with a 5-year OS of 25% vs. 74% estimated from Kaplan-Meier analysis compared with patients who were free from recurrence at last follow-up (p = 0.041), respectively. Furthermore, recurrent tumor site showed an estimated impact on patients′ OS. Thus, patients with glottic recurrence had a survival benefit with a 5-year OS rate of 89% compared with patients who had recurrences in the area of the supraglottic or subglottic larynx, hypopharynx or neopharynx with a 5-year OS rate of 25% (p = 0.05). Additionally, initial N stage seemed to have a further impact on OS with a survival benefit for patients without initial lymph node metastases, but in the multivariate analysis, the significance level could not be achieved (p = 0.06).

In terms of DPFS, recurrent T stage showed the most significant impact on DPFS with a 5-year DPFS of 90% for rT1/2 tumors and 70% for rT3/4 tumors (p = 0.028). Further, PTV1 (≥ median of 101 cc vs. < median of 101 cc) had a worse impact on DPFS with increasing volume (p = 0.038). At least, initial N stage could be diagnosed as further prognostic factor for DPFS with a significant lower occurrence of metastases for iN0 stage compared with iN+ stage (p = 0.042). Increasing N+ stage (N1 vs. N2 vs. N3) had no impact on DPFS (p = 0.140).

Overall, 20% of the patients reported acute grade 3 (n = 14) and 19% of the patients chronic grade 3 and grade 4 toxicity (n = 13). During and six weeks after therapy, no acute grade 4 toxicity could be identified. An overview of acute and late side effects is shown in Table 4. Acute grade 3 toxicity consisted of mucositis (n = 2, 3%), dysphagia (6%, n = 4), odynophagia (n = 5, 7%), dermatitis (n = 4, 6%), xerostomia (n = 1, 1%), hoarseness (n = 3, 4%) and lymphedema (n = 1, 1%). Three months after therapy, the majority of the acute grade 3 side effects disappeared. Nevertheless, 3 patients received tracheostomy for acute dyspnea due to grade 4 lymphedema of the larynx (4%) and in one patient a laryngoesophageal fistula could be diagnosed 6 months after therapy (1%). 3 patients claimed about chronic severe dysphagia with high-grade stenosis of the laryngoesophageal junction with the need of regular bougienage up to the last follow-up (4%). Further, one patient developed a laryngocutaneous fistula 12 months after RT (1%) and one patient developed a wound healing disorder in radiation field 24 months after therapy (1%).

Under RT, 43% of the patients needed supportive nutrition for nutritional difficulties due to acute side effects (n = 30). Acute gastric tube dependence counted 34% (n = 24). 3 to 6 months after therapy, only 13% of the patients needed farther a gastric tube for nutrition (n = 9). Only one patient was dependent on a gastric tube for more than 2 years (1%).

Nowadays, CRT is seen as an equivalent therapy option to surgery regarding tumor control in laryngeal and hypoharyngeal tumors [11, 12]. Thus, Mendenhall et al. reported 2001 RT alone for T1/2 N0 larynx tumors as an alternative curative therapy option to surgery with a comparable 5-year LPFS of 72 to 94% depending on T stage, a 5-year OS of 79% and a 5-year DPFS of 98% [13]. Nevertheless, surgery in form of organ-preserving endoscopic resection, laser surgery or open-neck partial laryngectomy is still considered as the gold standard in the treatment of early stage tumors with local control rates of 60 to 95%, declining with increasing T stage [12]. While local relapses are relatively rare after primary treatment of early stage tumors, local control in advanced hypopharyngeal and laryngeal tumors remains a challenge. As organ-preserving treatment strategies are increasingly used as first-line treatment, the use of organ-preserving RT in combination with chemotherapy for advanced stages gained in importance within the last decades [5, 13, 14]. However, 40 to 60% of patients with advanced tumors relapse after primary CRT [5, 15]. Salvage treatment options for these patients are limited, as re-irradiation is mostly limited by the tumor site and the necessary prescription dose to the recurrent tumor. In these cases, salvage surgery is mostly required. The effectiveness of salvage surgery after failure of primary CRT (2-year OS between 27 and 71%) is reported by several studies [16‐18]. Taguchi et al. reported a 5-year OS and disease-specific survival of 61 and 66% for salvage surgery after primary CRT vs. 10 and 10% for patients who failed primary CRT but did not undergo salvage surgery [18]. While poor prognosis with a 5-year OS of 16% is described for recurrent hypopharyngeal tumors after salvage surgery, the same treatment method offers 5-year OS rates ranging from 57 to 70% for recurrent laryngeal tumors [19‐21]. Recurrent hypopharyngeal tumors are mostly considered inoperable and should, therefore, be treated with alternative salvage methods [22]. Salvage CRT is generally reserved for recurrent tumors after primary total laryngectomy, for patients with inoperable recurrent tumors or in cases, where the patient rejects total laryngectomy as the only remaining treatment option in order to further preserve the organ function. Patients who receive salvage CRT mostly appear with initially early stage tumors and represent a non-comparable patient collective to patients who receive salvage surgery after failure of primary CRT. Nevertheless, studies describing a homogeneous patient population after salvage CRT including recurrent hypopharyngeal and laryngeal tumors only are lacking. Lee et al. reported a 2-year OS and progression-free survival of 74 and 68% for patients with recurrent hypopharyngeal and laryngeal tumors who underwent different salvage treatment methods, i.e. salvage surgery with or without RT, RT alone, chemotherapy alone, after different initial treatments, i.e. CRT for advanced tumors or primary surgery for early stage tumors [23]. Li et al. analysed patients who were initially treated with surgery, RT or CRT for recurrent laryngeal tumors. The patients received salvage treatment with surgery for operable recurrent tumors in 54% and radiation in 16% of the cases [24]. Salvage surgery resulted in a 5-year OS rate of 73% vs. 32% for other salvage treatment methods like RT, while the high OS rate for salvage surgery and the decreased OS of salvage RT were discussed via patient selection bias (operable tumors, initial tumor stage). This could be a valuable reason for the excellent survival results in the current analysis as well, as the majority of our patients had initially early stage tumors (56% UICC I/II). Nevertheless, survival analysis showed no significant difference in the LPFS, OS and DPFS for initially early stage and initially advanced tumors.

Several meta-analyses and randomized studies have proven the beneficial role of concomitant chemotherapy in combination with RT, especially regarding cisplatin chemotherapy, showing superior local control and OS rates in laryngeal/hypopharyngeal tumors as well as in other HNC either in the primary or postoperative setting [5, 15, 25‐27]. Besides an EQD2 > 70 Gy achieved by using fractionation doses >2Gy, we could identify a significant impact of cisplatin chemotherapy on LPFS only [28, 29]. Nevertheless, Pignon et al. could show in the MACH-NC meta-analysis that chemotherapy with carboplatin and 5-fluoruracil is considered to be equivalent to cisplatin chemotherapy. The results of the current study could possibly be explained by patient selection bias between both groups [30]. In the current literature, further factors influencing LPFS, i.e. T stage, N stage, G stage, sex, age, vocal cord invasion, overall treatment time and RT field size are discussed in the first-line treatment [13, 31‐34]. Glottic tumors seem to have a survival benefit compared with other tumor sites, thus in several studies superior OS rates are described [17‐20]. The occurrence of local recurrence after treatment, tumor size and N stage are accepted as further prognostic factors [31‐35]. For second-line treatment, initial tumor in the hypopharynx vs. the larynx, recurrent tumor in the hypopharynx vs. the larynx, advanced primary tumor, advanced recurrent tumor, advanced primary N stage and advanced initial and recurrent G stage were most frequently associated with decreased progression-free survival resulting in a poor prognosis [23, 24, 36]. In multivariate analysis, we could not identify an impact of tumor size and N stage on OS, possibly due to the low patient number but on DPFS. Thus, tumors with initial N+ stage and increased recurrent tumor size (PTV1, rT stage) influenced distant control negatively [34]. Additionally, tumor differentiation (G stage) can be considered as further prognostic factor regarding DPFS [31].

Superior dose conformity and decreased toxicity due to improved preservation of organs at risk compared with 3D-RT is described for IMRT [37‐40]. Nevertheless, toxicity after IMRT remains high [41‐45]. Especially in the hypopharynx and larynx region, significant higher rates of late side effects occur due to the proximity of several organs at risk compared with other regions of the head and neck [45]. For patients treated with concurrent CRT, Forastiere et al. could show in the RTOG trial 91–11 a high rate of severe late grade 3 and 4 toxicity, especially regarding mucositis (43%) [44]. In a RTOG analysis of three RTOG trials (RTOG 91–11, RTOG 97–03, RTOG 99–14), Machtay et al. identified 43% late side effects after CRT for locally advanced squamous cell carcinoma of the head and neck, and described grade 3 and 4 pharyngeal and laryngeal dysfunction in 39%, gastric tube dependence longer than 2 years in 13% and treatment-related death within 3 years in 10% of the patients. Swallowing limitations, aspiration, laryngoesophageal stricture and dysphagia dominated regarding laryngoesophageal dysfunction [45]. Caudell et al. reported a 3-year laryngoesophageal dysfunction-free survival (LEDFS) of 32% for patients who were treated with CRT for advanced SCC of the larynx and hypopharynx [42]. For salvage treatment methods as well, high toxicity rates are reported. Several authors described complication rates between 44 and 59% for salvage surgery after first-line CRT [16, 17, 46]. A systematic review and meta-analysis of the complications of salvage total laryngectomy including 3293 patients by Hasan et al. showed a complication rate of 68% with 29% pharyngocutaneous fistula [47].In the current analysis, in contrast, only 19% of the patients claimed about severe chronic toxicity. Especially laryngoesophageal dysfunction consisting of severe dysphagia (4%), fistula (3%), dyspnea (4%) or wound healing disorder (1%) were observed. Only one patient showed feeding tube dependence over 2 years after RT (1%). We could not identify any treatment-related deaths within the follow-up time. Despite first-line surgery and second-line dose-escalated RT, we identified moderate toxicity rates making salvage CRT after failed surgery a safe therapy alternative.