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MINI SYMPOSIUM: HEAD NECK CANCER
Year : 2013  |  Volume : 50  |  Issue : 1  |  Page : 25-30
 

Neo-adjuvant chemotherapy in advanced hypopharyngeal carcinoma


1 Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication20-May-2013

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.112286

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 » Abstract 

Objective: The aim of this retrospective study was to find out the role of neo-adjuvant chemotherapy (NACT) in changing the management and outcome of advanced hypopharyngeal cancer patients. Materials and Methods: This is a retrospective analysis of 59 treatment naïve, advanced hypopharyngeal cancer patients presenting to our tertiary care center from April 2010 to October 2011. NACT was given as two (platinum with taxane) or three drug with (platinum, taxane with 5-flurouracil [5 FU]) as 3 weekly regimen with cisplatin and docetaxel as 75 mg/m 2 each, 5-FU as 1000 mg/m 2 . NACT was either given with the intent of achieving: (1) surgical resection (extensive soft tissue disease, oropharyngeal involvement, extensive disease with cartilage erosion) or (2) organ preservation (Bulky disease with inner cartilage erosion, exolaryngeal disease without cartilage erosion, large N3 nodes). Results: The mean age of this population was 55 years. Most (83%) of the patients had pyriform sinus (PFS) involvement. 69% patients had Stage IVa disease, 21% Stage IVb and 10% Stage III. The overall response rate was 66%, including 06% complete responses and 60% partial responses. Following NACT, resectability was achieved in 30% (10/33) and organ preservation protocol was planned after NACT in 73% (19/26) patients. The main toxicities were neutropenia (grade 3, 4, 04%; febrile neutropenia, 4%), mucositis 5%, diarrhea 5%. The median progression free survival was 20 months. Conclusions: NACT can be useful in patients with oropharyngeal involvement to achieve surgical resection and larynx preservation in patients with bulky T3 disease.


Keywords: Bulky disease, hypopharyngeal cancers, N3 node, neo-adjuvant chemotherapy, organ preservation, resectability


How to cite this article:
Joshi P, Patil V, Joshi A, Norohna V, Chaturvedi P, Chaukar D, Pai P, Nair D, Juvekar S, Agarwal J P, D'Cruz A K, Prabhash K. Neo-adjuvant chemotherapy in advanced hypopharyngeal carcinoma. Indian J Cancer 2013;50:25-30

How to cite this URL:
Joshi P, Patil V, Joshi A, Norohna V, Chaturvedi P, Chaukar D, Pai P, Nair D, Juvekar S, Agarwal J P, D'Cruz A K, Prabhash K. Neo-adjuvant chemotherapy in advanced hypopharyngeal carcinoma. Indian J Cancer [serial online] 2013 [cited 2019 Nov 14];50:25-30. Available from: http://www.indianjcancer.com/text.asp?2013/50/1/25/112286



 » Introduction Top


Hypopharyngeal cancers are notorious for poor prognosis. Majority of them present in advanced stages with extensive submucosal disease, large bulky neck nodes and distant metastasis. The treatment is usually multimodal requiring surgery followed by adjuvant treatment or organ preservation in the form of chemoradiotherapy. Neo-adjuvant chemotherapy (NACT) is recommended as one of the modality of treatment for small primary tumor with positive neck nodes like T1N + stage of hypopharyngeal cancer by National comprehensive cancer network (NCCN). Despite chemoradiotherapy being the treatment of choice for advanced hypopharyngeal cancers, there is no level 1 evidence for this or uniform consensus for the same. [1],[2] Treatment outcomes for bulky and high volume T3 disease are not satisfactory with chemoradiotherapy.

Extensive T4 lesions which are either unresectable or their resection amounts to positive margin, proper treatment is not yet defined. T4 disease includes a spectrum of situations like exolaryngeal spread through a membrane without cartilage erosion or through cricothyroid space or with extension to oropharynx like tonsil or with involvement of prevertebral fascia, parapharyngeal space. In these situations, it is difficult to achieve free margin of resection if surgery is contemplated. The morbidity associated with extensive resections is also very high.

The standard of care for large N3 nodes is concurrent chemoradiation but the response rates vary and a large number of patients have residual disease or stable disease (SD). With the increasing nodal size, the chance of regional control decreases with the use of concurrent chemoradiation. Hanna et al., [3] reported a complete cervical remission rate of 69% (all stages) following chemoradiation which was 93% for patients with N1 disease, 62% for N2 disease, and 47% for N3 disease.

Despite multimodality treatment, locoregional control and survival rates are poor. Hence, in this group of patients, NACT may help in selecting patients for organ preservation or make unresectable disease resectable. Hence, in this retrospective analysis we evaluated the impact of NACT to select subsequent definitive therapy and outcome of these patients.


 » Materials and Methods Top


This is a retrospective analysis of patients with hypopharyngeal cancers who presented to our Tertiary Health Center from April 2010 to October 2011. The medical records of patients with proven squamous cell carcinoma of the hypopharynx were screened for the study. Cases were selected based on the following eligibility criteria: (1) biopsy confirmed squamous cell carcinoma of the hypopharynx, (2) Patients with extensive and bulky T3 disease or with inner cartilage erosion/T4 disease (3) All patients with N3 nodes or nodes with restricted mobility. Of the total 69 patients who were treated, 59 patients were eligible for analysis. Ten patients did not come for follow up after completion of treatment.

A complete medical history was obtained and tumor assessment was performed at baseline. Complete pre-operative evaluation was done in all patients including a direct laryngoscopy, imaging with contrast enhanced computed tomography (CT) scans and barium swallows.

The primary objectives of the study were resectability and organ preservation and secondary objectives were response rate of the tumor to NACT, side effects, progression free survival, overall survival. Resectability was defined as tumors which surgeon considered as resectable with adequate margins post two cycles NACT and which were considered un-resectable at baseline. Similarly, organ preservation was defined as treatment with chemoradiotherapy with preservation of larynx for patients who were not fit for organ preservation at baseline. NACT was either given with the intent of achieving

Resectability (surgical resection) - extensive soft tissue disease, oro-pharyngeal involvement, extensive disease with cartilage erosion or

Organ preservation - Bulky disease with doubtful inner cartilage erosion, exolaryngeal disease without cartilage erosion, large N3 nodes or nodes with restricted mobility.

NACT was given as two (platinum with taxane) or three drug (platinum, taxane and 5-fluorouracil [5-FU]) as 3 weekly regimen with cisplatin and docetaxel as 75 mg/m 2 each on day 1 and 5-FU as 750 mg/m 2 as 24 h iv infusion for 5 days for three cycles. Patients receiving 3 drug regimen were given granulocyte-colony stimulating factor prophylactically from day 6 to day 12. Tablet levofloxacin 500 mg once daily was given for the same duration as primary prophylaxis for bacterial infections. Carboplatin as area under curve 6 was given to older individuals or those with compromised glomerulo-filtration rate of less than 60 ml/min. Only those patients who at least completed 2 cycles of NACT were included in the study.

Response to NACT was assessed with response evaluation criteria in solid tumors (RECIST) criteria 1.1. All CT scans were evaluated by a senior radiologist pre and post NACT. Side effects were assessed with common toxicity criteria version 4. Dose reduction was done for any grade 3 or grade 4 toxicity. Dose response was assessed after two cycles of chemotherapy. Those with stable disease (SD) were treated with radical radiotherapy/chemoradiotherapy or surgery. Those with partial response (PR) or complete response (CR) were given III cycle and then were either operated or treated with chemoradiation/radiation. Patients with progressive disease (PD) or extensive disease received palliative radiotherapy. One patient developed hemiplegia while taking second cycle of docetaxel + cisplatin + 5-FU; hence the chemotherapy was stopped immediately.

Tumor responses were assessed by clinical evaluation and imaging studies like positron emission tomography CT scan done 12 weeks after the completion of chemoradiotherapy. Patients were monitored every 3 monthly for recurrence for first 2 years by clinical examination or imaging. In our study, the follow-up varied from 2 months to 21 months.

Statistical analysis was done using the software SPSS 20.0 (IBM, NY, USA). P values were calculated using Chi-square or t-tests. A P value of less than 0.05 was considered significant. Survival was calculated with Kaplan-Meier analysis.


 » Results Top


The mean age of the population was 55 years ranging from 22 years to 80 years. Majority of these lesions (49/59) involved the PFS. Extension to larynx was noticed in 95% of the patients (55/59). While the majority of the tumors were T4a (54%), only 5% were T4b. The tumor, nodal status and stage of the disease and European cooperative oncology group (ECOG) scale are described in [Table 1]. The median hemoglobin of the population was 12.35 g/dl (8.9-17.2 g/dl) and median albumin was 4 mg/dl (2.7-4.7 mg/dl).
Table 1: Demographic details

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Twelve (20%) of our patients received three drug regimen while 47 (80%) received two drug regimen. Fifty patients (85%) received two cycles and 9 (15%) patients received three cycles of NACT. In all the patients, docetaxel was used. According to RECIST criteria 1.1, the overall response rate was 66% with 06% CR and 60% PR rate. Thirty percent patients had SD and 4% had PD. The response assessment when done separately for primary and nodes was 76% and 65% respectively.

All patients were assigned to receive chemoradiotherapy beginning 3-6 weeks after the start of the third cycle of induction chemotherapy (second cycle when received two cycles only). Weekly cisplatin at a dose of 30 mg/m 2 was given as an intravenous infusion for the 1-hour period for 6-7 weekly doses during the course of radiotherapy. The definitive curative radiation dose administered to the primary tumor was between 66 Gy and 70 Gy, administered as fractions of 2 Gy per day 5 days/week. The dose administered to uninvolved lymph nodes was at least 50 Gy. Involved lymph nodes were to receive 60-70 Gy. Surgery was done for those patients who had resectable residual disease at the primary site or in the neck post neoadjuvant treatment.

Following NACT, patients were assessed by the joint clinic and final decision of resection was taken by the surgeon. Ten patients underwent total laryngectomy and thus, following NACT, resectability was achieved in 30% (10/33) patients when the intent of giving NACT was resectability. Of the operated 10 patients, three patients had no residual tumor post NACT and two patients had close margins of resection. However, Organ preservation protocol was planned after NACT in 73% (19/26) patients where intent was to select patient for organ preservation.

All 10 patients who underwent surgery received adjuvant chemoradiotherapy or radiotherapy. Six patients who had PD with NACT received palliative radiotherapy. Two patients denied further treatment as they had relief of symptoms with NACT and did not consent for radical treatment. One patient died of disease and other was alive with disease at follow up of 3 months. This patient had PR to NACT. Rest of the 41 patients either received definitive radiotherapy or chemoradiotherapy. One patient underwent total laryngectomy and one patient radical neck dissection post chemoradiotherapy. Both were disease free at follow-up of 12 and 8 months respectively.

Twenty seven percent (9/33) patients were disease free in surgery followed by chemoradiotherapy group when the intent of giving NACT was resectability and 62% (15/24) were disease free at a median follow up of 12 months in patients where the intent of receiving NACT was organ preservation. The mean overall survival for the whole population was 22 months and median duration was not reached. The mean and median progression free survival was 18 and 20 months respectively. Two patients who did not take treatment post NACT were excluded from survival analysis.

The pattern of failure was mostly regional followed by locoregional and distant metastasis. Patients who did not receive definitive treatment post NACT were excluded from this analysis. The pattern of failures is described in detail in [Table 2].
Table 2: Failures by treatment given*

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The main toxicities of NACT were neutropenia (grade 3, 4) 04%, febrile neutropenia 4%, mucositis 5% and diarrhea 5%. Other side effects included nausea, anorexia, renal dysfunction and failure, hypokalemia, hyponatremia as described in [Table 3].
Table 3: Side effects of chemotherapy

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 » Discussion Top


Hypopharyngeal cancers present in advanced stages due to late and non-specific symptoms and thus have poor overall survival. Recently, chemotherapy has widened its application in the treatment of head and neck cancer. NACT combined with subsequent radiation therapy has emerged as one of the possible treatment options for advanced, but resectable head and neck cancer. [4] Several multi-institutional studies have shown that use of NACT can be helpful in avoiding extensive surgeries and achieving organ preservation with survival rates comparable to standard surgery and post-operative radiation. [5] This is particularly important in hypopharyngeal cancers, which undergo extensive laryngeal and pharyngeal resection with significant morbidity. A significant number of these patients retain their larynx, which otherwise would have been removed without the use of organ preservation treatment.

The indications for NACT are not well defined yet. NACT is used as it helps in control of micrometastasis and might downstage the tumor and hence making the lesions operable. [6],[7] In a study by Paccagnella, [8] the 5 and 10 year survival data of operable and inoperable patients showed benefit in terms of reduction in distant metastasis in those who received induction chemotherapy followed by radiotherapy when compared with radiotherapy alone. However, none of the randomized trial has shown any benefit in the overall survival. This might be attributed to the sample size of each trial, which could be too underpowered to demonstrate any positive results.

The Head And Neck Tumors Italian Study Group clinical trial [8] showed that NACT given in patients who were inoperable and hence went for radical RT were benefitted in term of disease free survival and overall survival. This benefit was observed 10 years after the treatment also.

The 10 year update of European organization for research and treatment of cancer 24891 [9] trial has shown the induction followed by radiotherapy arm to be similar to surgery followed by radiotherapy arm in terms of overall and disease free survival. The 10-year overall survival rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year progression-free survival rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year survival with a functional larynx rate was 8.7%. These results are especially important as all these patients had hypopharyngeal cancers only. Though the group of patients were not entirely similar to those of our study; however, they still included advanced tumor and nodal stage as in our study; thus, giving a good evidence for the role of induction chemotherapy as useful as surgical management in terms of overall and disease free survival.

Volume of the disease is a strong predictor of outcome for hypopharyngeal cancers when radiotherapy is used for treatment. Those patients with tumor volume less than 40 ml on CT scan should be considered for organ preservation. [10] Thus, in our study also, those patients who had bulky or high volume disease were given NACT followed by radical chemoradiation. Though, the volume of disease was not calculated objectively, it was based on joint decision by a radiologist, and treating medical oncologist, surgical oncologist and radiation oncologist.

Newer drugs like platinum, taxanes and 5-FU have very good efficacy and response rates. In our series, the overall response rate was 66%, including 06% CR and 60% PR rate which is comparable with 72% and 64% response rates with Taxane, cisplatin and 5-Fluorouracil and cisplatin and 5-Fluorouracil respectively in TAX 324(Cisplatin and fluorouracil with or without docetaxel as induction treatment for locally advanced SCCHN trial). [11] Toxicity was acceptable with the NACT in our series with grade 3 and 4 neutropenia in 08% patients and with no grade 3 and 4 thrombocytopenia. This is in sharp contrast with TAX 324 where the grade 3 and 4 neutropenia was 83% in TPF and 56% in PF and the grade 3 and 4 thrombocytopenia was 11% and 4% respectively. This could be attributed to reduction of dose of chemotherapy in those patients who had side effects and use of 2 drugs in the majority of patients. This also highlights that two drug combination of taxane with platinum needs to be investigated further to replace three drug combination.

Recently, two new randomized trials, [12],[13] of neoadjuvant followed by chemoradiotherapy versus chemoradiotherapy in advanced head and neck cancers have shown that the overall survival and disease free survival were similar in both arms. However, there results need to be taken with caution as they have certain flaws with the design and interpretation of the results. In both these studies, majority of the patients were oropharynx which otherwise also have a good prognosis and the accrual of patients was not sufficient to detect the statistical significant difference between the two arms. But the incidence of distant metastasis was statistically lower in the NACT group.


 » Conclusion Top


Role of NACT in hypopharyngeal cancer is evolving. With the use of NACT, resection could be achieved in more than one fourth of the patients particularly in those with oropharyngeal involvement. Larynx could be preserved in more than half of patients with bulky and extensive disease, which otherwise would have undergone surgery. Our present study though a retrospective analysis without a control group dictates the important role of NACT in achieving organ preservation and resectability in otherwise unresectable and advanced lesions where it is difficult to aim for cure.

 
 » References Top

1.Corvò R. Evidence-based radiation oncology in head and neck squamous cell carcinoma. Radiother Oncol 2007;85:156-70.  Back to cited text no. 1
    
2.Hall SF, Groome PA, Irish J, O'Sullivan B. Radiotherapy or surgery for head and neck squamous cell cancer: Establishing the baseline for hypopharyngeal carcinoma? Cancer 2009;115:5711-22  Back to cited text no. 2
    
3.Hanna E, Alexiou M, Morgan J, Badley J, Maddox AM, Penagaricano J, et al. Intensive chemoradiotherapy as a primary treatment for organ preservation in patients with advanced cancer of the head and neck: Efficacy, toxic effects, and limitations. Arch Otolaryngol Head Neck Surg 2004;130:861-7.  Back to cited text no. 3
    
4.Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-8.  Back to cited text no. 4
    
5.Wolf GT, Hong WK, Fisher SG, Urba S, Endicott JW, Close L, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685-90.  Back to cited text no. 5
    
6.Bernier J, Bentzen SM. Altered fractionation and combined radio-chemotherapy approaches: Pioneering new opportunities in head and neck oncology. Eur J Cancer 2003;39:560-71.  Back to cited text no. 6
    
7.Specenier PM, Vermorken JB. Neoadjuvant chemotherapy in head and neck cancer: Should it be revisited? Cancer Lett 2007;256:166-77.  Back to cited text no. 7
    
8.Zorat PL, Paccagnella A, Cavaniglia G, Loreggian L, Gava A, Mione CA, et al. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J Natl Cancer Inst 2004;96:1714-7.  Back to cited text no. 8
    
9.Lefebvre JL, Andry G, Chevalier D, Luboinski B, Collette L, Traissac L, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 2012;23:2708-14.  Back to cited text no. 9
    
10.Chen SW, Yang SN, Liang JA, Tsai MH, Shiau AC, Lin FJ. Value of computed tomography-based tumor volume as a predictor of outcomes in hypopharyngeal cancer after treatment with definitive radiotherapy. Laryngoscope 2006;116:2012-7.  Back to cited text no. 10
    
11.Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.  Back to cited text no. 11
    
12.Haddad RI, Rabinowits G, Tishler RB, Adkins D, Khuri FR, Clark J, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. The Lancet Oncology 2013;14:257-64.  Back to cited text no. 12
    
13.Cohen EW, Karrison T, Kocherginsky M, Huang CH, Agulnik M, Mittal BB, et al. The DeCIDE Study: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 2012;30:(suppl; abstr 5500).  Back to cited text no. 13
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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