Induction chemotherapy followed by transoral laser microsurgery with or without adjuvant therapy for advanced hypopharyngeal cancer patients: A preliminary result

Abstract

Background:

Hypopharyngeal squamous cell carcinoma (HPSCC) has the poorest prognosis among head and neck cancers. Its treatment may significantly affect breathing, speaking, and swallowing. Induction chemotherapy (ICT) followed by transoral laser microsurgery (TLM) could reduce these adverse effects and achieve good outcomes.

Methods:

This was a retrospective study of 11 patients with advanced HPSCC. All patients underwent ICT and TLM alongside tailor-made adjuvant therapy based on the pathological features.

Results:

Adjuvant therapy was done in seven of 11 patients (64%). The 3-year disease-free survival and laryngeal preservation rates were 78% and 91%, respectively. At the last follow-up, 10 of 11 patients (91%) had no tracheostomy or feeding tube.

Conclusion:

ICT followed by TLM is an appropriate treatment for good tumor control in select patients with advanced HPSCC while preserving laryngeal function.

1. INTRODUCTION

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most common head and neck cancers worldwide. In 2020, there were more than 84 000 new cases worldwide, with 70% diagnosed in Asia.¹ In Taiwan, it is the fourth most common head and neck cancer, and more than 1100 new patients are diagnosed annually. The tumors are male predominate, and most of the patients have habits of tobacco smoking, alcohol drinking, and betel nut chewing.² HPSCC has an aggressive behavior and is characterized by diffuse mucosal and submucosal local spread, early neck lymph node metastasis, a high rate of distant metastasis, and a high incidence of synchronous or metachronous second primary malignancies in the upper aerodigestive tract.^3–6 Because the symptoms of HPSCC are less obvious and not specific, more than 75% of patients present with advanced stages upon the initial diagnosis.^6–9 As a result, HPSCC has the poorest prognosis in all head and neck cancers.^8,10,11

Treatment strategies for advanced HPSCC have changed over the past few decades. Radical surgery plus postoperative radiotherapy (RT) was previously the gold standard treatment^12,13; however, these procedures can severely impair quality of life by compromising respiration, speech, and swallowing.¹⁴ In the early 1980s, a prospective, randomized phase III trial conducted by the Veterans Affairs (VA) Laryngeal Cancer Study Group aimed to compare patients receiving induction chemotherapy (ICT) followed by RT with those undergoing radical surgery followed by postoperative RT for advanced laryngeal cancer. The 2-year overall survival (OS) rate was comparable (68%), but 64% of patients in the ICT group had a preserved larynx.¹⁵ In the 1990s, a similar study was also conducted by the European Organization for Research and Treatment of Cancer (EORTC) for advanced HPSCC. The median survival was 25 months in the immediate surgery arm and 44 months in the ICT arm (p = 0.006). The 3-year retention of a functional larynx was 42% in the ICT arm. The 10-year OS rate was comparable between the two arms (13.8% vs 13.1%).^16,17 ICT has been practical for laryngeal preservation without jeopardizing survival and is one of the standard treatment options for advanced HPSCC patients.^16–18 This treatment aims to shrink the primary tumor and metastatic cervical lymph nodes, lower the clinical stage, preserve the larynx, and decrease the rate of distant metastasis.^16,19,20 However, the late toxicity of chemoradiotherapy (CRT) might impair the function of the larynx or pharynx, causing a need for tracheostomy or feeding tubes after treatment.^21–23

Transoral laser microsurgery (TLM) is an option for larynx-conservation surgery for HPSCC. It can precisely excise the primary tumor with minimal peripheral tissue damage. It has been proven to be an oncological safe method with satisfactory pharyngeal and laryngeal functional outcomes for early and selective advanced HPSCC.²⁴ Even though the larynx preservation rate ranged from 89% to 100% in all stages, the post-treatment quality of life, voice, and swallowing function in patients after TLM plus adjuvant therapy were slightly poorer than that in patients after TLM alone.^24–26 Therefore, we tried to use ICT in the locally advanced HPSCC to shrink the primary tumor first, and then performed TLM to excise the tumor according to the shrinkage tumor. The adjuvant therapy was administrated depending on the pathological results. This study presented the preliminary results of ICT followed by TLM for advanced HPSCC, with an analysis of oncologic results and functional outcomes.

2. METHODS

2.1. Study design and population

This retrospective study was conducted following the principles stated in the Declaration of Helsinki (1964), and the institutional review board of Taipei Veterans General Hospital approved its design. Between January 2016 and October 2022, 11 HPSCC patients were diagnosed and treated at the Department of Otorhinolaryngology, Head and Neck Surgery of Taipei Veterans General Hospital in Taipei, Taiwan. Each patient was reviewed by the multidisciplinary head and neck oncology team, consisting of a radiologist, surgical oncologist, radiation oncologist, and medical oncologist. The American Joint Committee on Cancer 8th TNM classification was used for staging.²⁷ All patients underwent ICT followed by TLM. The inclusion criteria were as follows: (1) biopsy-proven HPSCC; (2) clinical stage III, IVA, or IVB; and (3) Karnofsky performance status scale ≥80. The exclusion criteria were as follows: (1) synchronous second primary cancer at initial diagnosis and (2) history of surgery, RT, or chemotherapy for head and neck cancer.

2.1.1. ICT protocol

Two regimens, docetaxel, cisplatin, 5-fluorouracil (TPF) and cisplatin, 5-fluorouracil (PF), were chosen for ICT. The TPF regimen included intravenous docetaxel (60 mg/m²), cisplatin (75 mg/m²) on day 1, and 5-fluorouracil (750 mg/m²) on days 1 to 4. The PF regimen included intravenous cisplatin (50 mg/m²) on day 1 and 5-fluorouracil (750 mg/m²) on days 1 to 4. The second course of ICT was given at an interval of 21 days from the start of the first course of ICT. The grading system of adverse effects was based on standard terminology criteria for adverse events v5.0.²⁸ After two cycles of ICT, the response was evaluated by flexible nasopharyngoscopy and/or imaging based on the response evaluation criteria in solid tumors.²⁹ TLM was done on patients exhibiting at least a partial response.

2.2. Surgical procedures

All surgeries were performed by the senior author (P.-Y.C.). The larynx was suspended and exposed with a bivalve laryngopharyngoscope, and endoscopes (at 0°, 30°, and 70°) were used to examine the tumor extension. The procedure was performed using a CO₂ laser (Compact 30; Lumenis, Ltd., Yokneam, Israel) coupled with a micromanipulator (Acuspot 712; Sharplan, Tel Aviv, Israel), and the power was set between 2 and 5 W, using the superpulse and continuous modes. The resection margins assumed 1 cm of tumor shrinkage based on blue-dye marks. The tumor was excised with en bloc resection, if possible, after ICT. Otherwise, the piecemeal method was considered if en bloc resection was impossible. A frozen section was sent if there was any suspicion of tumor invasion. Simultaneous ipsilateral or bilateral neck dissection was performed according to the tumor location. Tracheotomy or nasogastric tube insertion was not performed routinely.

An illustrative case involved a 54-year-old man diagnosed with right pyriform sinus cancer, clinical stage T4N2bM0. The tumor penetrated the thyrohyoid membrane and invaded the strap muscle. Following two cycles of ICT with the TPF regimen, the primary tumor and neck lymph nodes showed a partial response. The remaining tumor and neck lymph nodes were excised using TLM and ipsilateral neck dissection. Pathological examination indicated a close deep margin and one positive lymph node (3 mm) without extranodal extension (ENE). The patient underwent adjuvant CRT and remained disease-free for over 4 years (Fig. 1).

Fig. 1.

A 53-y-old male patient with cT4N2bM0 right pyriform sinus cancer (A). The CT scan revealed that the tumor penetrated the thyrohyoid membrane and invaded the strap muscle (B). Following two cycles of ICT, significant tumor shrinkage was observed, nearly achieving complete response (C). The residual tumor was excised using TLM (D). The specimen was sent for pathological examination via en bloc resection (E). The patient underwent adjuvant CRT and remained free of disease for over 4 y (F). CT, computed tomography; ICT = induction chemotherapy; TLM = transoral laser microsurgery.

2.3. Adjuvant therapy

Adjuvant therapy, including RT or CRT, was administered after TLM, based on pathological reports, in the presence of positive margins, perineural invasion, vascular infiltration, multiple lymph node metastasis, or ENE. The RT or CRT was given 4 to 6 weeks after surgery. The total dose of adjuvant RT was between 5400 and 6600 cGy according to the pathological risk features; for those patients with adjuvant CRT, weekly cisplatin (40 mg/m²) was administered.

2.4. Statistical analysis

Data were analyzed using the IBM Statistical Product and Service Solutions 20 package (SPSS Inc., Chicago, IL). Patient characteristics were subject to descriptive statistical analyses. The follow-up interval was calculated in months from the date of the first course of ICT until death or last follow-up. OS was defined as the time interval from the start of the first ICT to any cause of death or last follow-up. Disease-specific survival (DSS) was defined as the time interval from the start of the first ICT to cancer-related death. Laryngectomy-free survival (LFS) was defined as the time interval from the starting date of the first ICT to laryngectomy or death from any cause. Recurrence-free survival (RFS) was defined as the time interval from the starting date of the first ICT to cancer-related death or tumor recurrence. The Kaplan–Meier method was used to calculate OS, DSS, LFS, and RFS. In all analyses, a p value <0.05 indicated statistical significance.

3. RESULTS

Table 1 illustrates the demographic data of the 11 patients. There were nine males and two females. The median age was 64 years old. The primary tumor subsites included nine pyriform sinuses and two posterior pharyngeal walls. There were 2 T2, 5 T3, and 3 T4. Nine patients had cervical lymph node metastasis, and two did not. There were four stage III and seven stage IV disease. Table 2 shows ICT regimens, courses, tumor response, and toxicity of ICT. All patients received ICT as initial treatment, including 10 patients who received a TPF regimen and one who had only a PF regimen due to a medical condition. Ten patients underwent two cycles of ICT, and one patient underwent one cycle due to intolerance of toxicity. During ICT, five patients (45%) had grade 4 neutropenia, and three patients (27%) had grade 3 toxicity. After ICT, three patients (27%) had a clinical complete response, and eight (73%) had a partial response, respectively.

Table 1.

Patient characteristics

Variables	Number of patients	%
Gender
Male	9	82
Female	2	18
Median age, y (range)	64 (51-77)
Median follow-up, mo (range)	52 (25-99)
Primary subsite
Pyriform sinus	9	82
Posterior pharyngeal wall	2	18
Clinical T stage
2	3	27
3	5	45
4a	3	27
Clinical N stage
0	2	18
1	2	18
2b	3	27
2c	2	18
3	2	18
Clinical stage
III	4	36
IVA	7	64

N = neck; T = tumor.

Table 2.

Regimen, courses, tumor response, and toxicity of induction chemotherapy

Patient	Gender	Age	Primary tumor	cT	cN	Clinical stage	ICT regimen	ICT courses	T-RR	N-RR	AE-neutropenia
1	Male	51	PPW	T2	N2c	IVA	TPF	2	PR	PR	Grade 2
2	Male	54	PS	T4a	N3b	IVB	TPF	2	PR	PR	Grade 4
3	Female	52	PPW	T3	N0	III	TPF	2	PR	-	Grade 3
4	Male	73	PS	T2	N1	III	TPF	1	PR	PR	Grade 4
5	Male	77	PS	T3	N1	III	TPF	2	PR	SD	Grade 3
6	Male	54	PS	T4a	N2b	IVA	TPF	2	PR	PR	Grade 4
7	Male	52	PS	T3	N3b	IVB	TPF	2	CR	PR	Grade 3
8	Male	73	PS	T4a	N2b	IVA	TPF	2	CR	PR	Grade 2
9	Female	72	PS	T2	N2b	IVA	PF	2	PR	PR	Grade 4
10	Male	76	PS	T3	N2c	IVA	TPF	2	CR	PR	Grade 2
11	Male	64	PS	T3	N0	III	TPF	2	PR	-	Grade 4

AE = adverse effect; CR = complete response; cN = clinical neck; cT = clinical tumor; ICT = induction chemotherapy; N-RR = neck lymph node response rate; PPW = posterior pharyngeal wall; PR = partial response; PS = pyriform sinus; SD = stable disease; T-RR = primary tumor response rate.

All of the 11 patients underwent TLM. Simultaneous ipsilateral or bilateral neck dissection was also performed, except in one patient with clinical N0 at the initial diagnosis. Only one patient (9%) had tracheotomy before ICT due to airway obstruction. The tracheotomy tube was removed 1 week after surgery. A nasogastric tube was inserted in seven patients (64%) during TLM, and all were removed with a median time of 5 days (4-37 days). At the last follow-up, all patients could eat by mouth without a feeding tube, except one patient with a local tumor recurrence.

After surgery, the pathology showed two patients had positive margins, three had close margins, and six had free margins. Table 3 shows tumor stage shift, adjuvant therapy, and treatment outcomes after surgery. In a comparison of the clinical and pathological stages before and after surgery, eight patients (73%) had a downstage of the primary tumor, and five patients (45%) had a downstage of the cervical lymph node. Overall, seven patients (64%) had a downstage of TNM classification, while two patients (18%) had upstaged due to ENE at pathology. Of the 11 patients, four (36%) underwent surgery alone, six (55%) had adjuvant CRT, and one (9%) had adjuvant RT. Total radiation dose ranged from 5940 to 6600 cGy, with a median dose of 6200 cGy.

Table 3.

Tumor stage shift, adjuvant therapy, and treatment outcomes after surgery

Patient	cT	cN	Clinical stage	ND	N+ max. size (mm)	ENE	pT	pN	Pathological stage	Down stage	PORT/POCCRT	RT dose	Recurrence	Laryngeal preservation
1	T2	N2c	IVA	Yes	25	Yes	T2	N3b	IVB	No	Yes	6600	No	Yes
2	T4a	N3b	IVB	Yes	42	Yes	T3	N3b	IVB	No	Yes	5940	No	Yes
3	T3	N0	III	No	-	-	T1	-	I	Yes	No	-	Local	Yes
4	T2	N1	III	Yes	10	No	T2	N0	II	Yes	Yes	6400	No	Yes
5	T3	N1	III	Yes	28	Yes	T3	N2a	IVA	No	Yes	6600	Local	No
6	T4a	N2b	IVA	Yes	3	No	T1	N1	III	Yes	Yes	6600	No	Yes
7	T3	N3b	IVB	Yes	5	No	T0	N1	III	Yes	Yes	5400	No	Yes
8	T4a	N2b	IVA	Yes	12	No	Tis	N1	III	Yes	No	-	Distant	Yes
9	T2	N2b	IVA	Yes	8	No	T1	N1	III	Yes	No	-	No	Yes
10	T3	N2c	IVA	Yes	2	No	T0	N2c	IVA	No	Yes	6000	No	Yes
11	T3	N0	III	Yes	-	No	T1	N0	I	Yes	No	-	No	Yes

cT = clinical tumor; cN = clinical neck; ENE = extranodal extension; max. = maximal; N+ = neck metastasis; ND = neck dissection; pN = pathological neck; POCCRT = postoperative concurrent chemoradiotherapy; PORT = postoperative radiotherapy; pT = pathological tumor; RT = radiotherapy; “-“ = not applicable.

With a median follow-up time of 52 months, three patients (36%) had tumor recurrence, including two local recurrences and one distant metastasis. One patient with local recurrence did not receive adjuvant therapy at initial treatment. The patient had repeated TLM and postoperative CRT with no evidence of disease 91 months after initial treatment. The other patient had only tracheotomy and palliative chemotherapy. The patient died of the disease 24 months after initial treatment. One patient had multiple lung metastases without locoregional recurrence. The patient undergoing palliative chemotherapy was alive with stable disease 35 months after initial treatment. The 3-year OS, DSS, RFS, and LFS were 89%, 78%, 73%, and 91%. The oncologic outcomes are presented in Table 3.

4. DISCUSSION

ICT for advanced laryngeal and hypopharyngeal cancers has been a treatment strategy for organ preservation since the early 1980s.^15,16 Both the VA study and EORTC trial, using an ICT regimen of PF compared with surgery plus adjuvant therapy, had demonstrated practicality in preserving the larynx without compromising survival and is established as a standard treatment approach for patients with advanced laryngeal and hypopharyngeal cancers. Since then, PF regimen is considered a standard combination of ICT. In recent years, two significant randomized clinical trials^30,31 have provided evidence favoring the use of ICT with TPF regimen over the traditional PF combination. These findings indicate superior survival rates with TPF. Additionally, patients with tumors situated in the oropharynx, hypopharynx, or larynx had shown more favorable responses to this treatment approach compared with those with oral cancers.

ICT followed by TLM with or without adjuvant therapy can be applied to select advanced HPSCC patients with good tumor control. In our study, most patients (10/11) received ICT with the TPF regimen, while only one received the PF regimen due to medical reasons. Following ICT, all patients showed shrinkage in their primary tumors, with 27% achieving a complete response and 73% showing a partial response. One patient with a PF regimen achieved a nearly complete response after two cycles of ICT. The favorable tumor response observed with TPF ICT was consistent with previous findings.^20,32 Additionally, after ICT, 64% (7/11) experienced a downstaging in TNM classification, and 73% (8/11) had a downstaging of the primary tumor after surgery. This downstaging facilitated easier TLM excision, with approximately two-thirds of tumors resected en bloc. Consequently, this made it more precise for pathologists to assess surgical margins compared with piecemeal resection of the primary tumor.

In addition to facilitating easier resection of the primary tumor during TLM, this method also offers the benefits of rapid functional recovery. In our study, the majority of patients undergoing TLM did not require tracheotomy, except for one patient who needed it before ICT due to a large tumor causing airway obstruction. The tracheotomy tube was removed within a week after surgery. During TLM, seven patients (64%) required nasogastric tube insertion, all of which were removed within a median time of 5 days. Overall, none of the patients became dependent on either tracheotomy or nasogastric tube postoperatively. Comparatively, a study by Sampieri et al³³ involving two cycles of neoadjuvant chemotherapy (NACT) with cisplatin and TS-1 (an oral combination of gimeracil, oteracil, and tegafur) regimen followed by transoral robotic surgery (TORS) for 100 patients with stage III and IV laryngeal and hypopharyngeal cancers reported a higher rate of prophylactic tracheotomy, with 85% of patients undergoing the procedure. Tracheotomy tubes were removed after an average of 12.59 days, with 26% of patients still requiring them at discharge. Additionally, all patients required nasogastric tube feeding, removed after an average of 12.7 days, and 9% had gastrostomy tubes at discharge.

One advantage of ICT followed by TLM is that it allows for pathologic analysis of the treatment outcome, enabling personalized adjuvant therapy, as observed in seven of 11 patients in this study. This approach also potentially reduces radiation dosage to 6200 cGy (ranging from 5400 to 6600 cGy), which may help mitigate adverse effects. Our findings align with those of Park et al,³⁴ who reported that 26% of patients underwent surgery alone, with most receiving postoperative RT doses between 6000 and 6600 cGy. In our study, using ICT with the TPF regimen followed by TLM demonstrated satisfactory oncologic outcomes. The 3-year OS, DSS, RFS, and LPR were 89%, 78%, 73%, and 91%, respectively. Although two patients experienced local recurrence, salvage TLM followed by adjuvant CRT effectively controlled the tumor and preserved the larynx. The final laryngeal preservation rate reached 91% (10/11). Our results were comparable to Park et al.³⁴ The 3-year DSS rate was 82%, and the RFS rate was 69%.

A combination of docetaxel, cisplatin, and fluorouracil is considered the best regimen for ICT in head and neck cancer, but this is associated with a high rate of grade 3 or 4 acute toxicity.^20,22,31,35 In our patients, the acute adverse effects of ICT were prominent, but all were reversible. The median duration from the first course of ICT to TLM was 42 days. Our protocol was the same as in previous studies, and most of our patients with acute toxicity could recover from the last cycle.^31,35 Only one patient had a treatment-associated delay due to febrile neutropenia, resulting in a 66-day interval from the start of the first ICT to TLM. None of the patients died due to the acute toxic effect of ICT.

The surgical margin is one of the most important prognostic factors for head and neck cancers. How much margin should be excised during surgery has always been controversial. In the report by Park et al³⁴ on NACT followed by TORS for advanced laryngopharyngeal cancer, resection margins were determined according to the initial tumor extent and location to account for potential nonconcentric tumor shrinkage.³⁴ However, according to our previous report on tongue preservation treatment for patients with cT2-4 oral tongue cancer,³⁶ ICT was administered first when initial evaluations estimated a surgical defect of over 4 cm. Subsequently, the extent of surgical resection was determined based on the size of the remaining lesion. Among the 16 responders who underwent surgery after ICT, only one patient experienced local recurrence. Similar approaches have been used in breast cancer patients receiving NACT, resulting in optimal oncological and cosmetic outcomes.³⁷

This study has several limitations. First, it was a retrospective case study with a small sample size and a relatively short follow-up period. A prospective randomized controlled study with a larger sample size should be conducted to mitigate selection bias. Additionally, longer-term follow-up is needed to validate the oncologic outcomes. Second, functional outcomes were solely assessed based on the placement of feeding tubes or tracheotomies. Improvement could be achieved by incorporating validated questionnaires for assessing quality of life, along with imaging studies of swallowing function, to evaluate functional changes both subjectively and objectively comprehensively.

ICT, followed by TLM, is suitable for selective patients with advanced HPSCC. Those showing a favorable response to ICT can proceed to TLM, simultaneous neck dissection, and subsequent pathological examination. Based on the pathological findings, tailor-made adjuvant therapy can be devised. The satisfactory oncological outcomes and well-preserved laryngeal function are promising. However, further prospective studies with large-scale designs and long-term follow-up are necessary to compare its efficacy with other treatment modalities.

ACKNOWLEDGMENTS

This study was fund by grants from the Taipei Veterans General Hospital (V112C-043), the research program of the Ministry of Science and Technology (112-2314-B-075-007-MY3), and kind financial support from Dr. Morris Chang and Sophie Chang, who had no involvement or conflict of interests in this study.