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Table of Contents
ORIGINAL ARTICLE
Year : 1998  |  Volume : 1  |  Issue : 1  |  Page : 41-47

Induction chemotherapy (Neoadjuvant) in the management of locally advanced untreated squamous cell carcinoma of the head and neck, a preliminary study


1 Radiotherapy and Oncology Unit, Al Hada Military Hospital, Taif, Saudi Arabia
2 Head and Neck Unit, Al Hada Military Hospital, Taif, Saudi Arabia
3 Anatomical and Clinical Pathology Unit, Al Hada Military Hospital, Taif, Saudi Arabia

Date of Web Publication16-Jun-2020

Correspondence Address:
MD Mostafa Abdel Rahaman
Radiotherpay and Oncology Unit Al Hada Military Hospital, Taif
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-8491.286856

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  Abstract 


This preliminary study was done at Al Hada Hospital Taif, Saudi Arabia, It was planned to assess the role of induction chemotherapy and radical radiotherapy in the treatment of locally advanced untreated squamous cell carcinoma of the head and neck. Eighteen patients were included in this study. Initially all patients received 2courses of chemotherapy using Cisplatinum and 5Fluorouracil infusions. Those with a response >50% were given, another one or two courses before radical irradiation.However, those with a response <50% were commenced on radical external irradiation. The overall response rate after 2 cycles of chemotherapy was 77.7%, all responded partially to treatment. However, a complete response rate of 28.5% was elicited after 3-4 cycles of treatment. Using this protocol larynx conservation was possible in the 3 cases included in this study. Treatment was well tolerated in the majority of cases. Furthermore, no treatment related mortalities were reported in this study. The disease free survival results at a specific time in the study were 66.7%, 63.6% and 33.3% at 1, 2 and 3 years respectivelyHowever when it was correlated with the study group as a whole the corresponding figures were as follows 66.7%,38%, & 11% respectively.

Keywords: induction chemotherapy, neoadjuvant chemotherapy, Cisplatinum, 5Flurouracil, squamous cell carcinoma, radical irradiation


How to cite this article:
Rahaman MA, El-Kholy A, Abou-Azama AM. Induction chemotherapy (Neoadjuvant) in the management of locally advanced untreated squamous cell carcinoma of the head and neck, a preliminary study. Saudi J Otorhinolaryngol Head Neck Surg 1998;1:41-7

How to cite this URL:
Rahaman MA, El-Kholy A, Abou-Azama AM. Induction chemotherapy (Neoadjuvant) in the management of locally advanced untreated squamous cell carcinoma of the head and neck, a preliminary study. Saudi J Otorhinolaryngol Head Neck Surg [serial online] 1998 [cited 2022 Nov 28];1:41-7. Available from: https://www.sjohns.org/text.asp?1998/1/1/41/286856




  Introduction Top


For many years chemotherapy in head and neck cancer was relegated to treating patients with extensive disease or with tumour recurrence following surgery and or radiation therapy. [1]

However, recently interest in administering chemotherapy prior to surgery or radiation therapy in patients with advanced untreated head and neck cancer has surged. [2] This has been variously referred to as induction or neoadjuvant chemotherapy. [3] Induction chemotherapy was started in the mid-1970’sas an adjunct to surgery and radiotherapy in order to optimise the overall management of advanced local disease. [4]

The main reasons behind this approach are to improve the effect of radiation therapy by reducing tumour bulk prior to irradiation, also this bulk reduction may encourage surgeons to operate. Furthermore, induction chemotherapy may eliminate micro-metastases with a possible impact on survival outcome. [5],[6],[7]

The aim of this preliminary study was to evaluate the impact of the use of induction chemotherapy in locally advanced untreated squamous cell carcinoma of the head and neck with special emphasis on the following domains:

  1. Local control.
  2. Treatment related morbidities.
  3. Early survival results.
  4. Organ preservation.



  Materials and Methods: Top


From October 1994 to February 1997, 18 patients with locally advanced [8], untreated squamous cell carcinoma of the head and neck were treated with induction chemotherapy and radical irradiation.[9] Kamofsky index was used for assessment of the patient’s performance status. [10] The following protocol of induction chemotherapy was used [9]: Cisplatinum (CDDP) 20mg/m2 iv infusion dl-5, 5Fiurouracil (5Fu) 1 gm/m2 iv infusion dl-5, cycles were repeated every 21 days.

Initially 2 cycles were given. Tumour response was assessed at the end of 2 cycles. Patients with response >50% were given another one to 2 cycles before radical irradiation. On the other hand those with response <50% were irradiated. Irradiation was given to the primary site and regional lymph nodes. Shrinking field and CAT Scanning planning techniques were used. The tumour dose to the primary and immediate draining lymph nodes ranged from 60-66Gy. All patients were later monitored for response to treatment, time to failure, overall survival and treatment related morbidities. [12]


  Results: Top


Patients Characteristics.

Males accounted for 66.7% of cases. In this study the age ranged from 16 to 62 years with a median of 53 years Performance status > 90% was noted in 66.7% of patients. Nasopharyngeal carcinoma was reported in 55.6% of patients in this group.Seventy seven point seven per cent of cases received 3-4 cycles of induction chemotherapy. In 3/14 (21.4%) of cases four cycles of chemotherapy were given. [Table 1] Stage III cases were seen in 44 4% of cases. [Table 2].
Table 1: Base Line Characteristics Of Treated Patients

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Table 2: stage grouping & primary site

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Response to Induction Chemotherapy.

After 2 cycles partial response (PR) (>50%) was noted in 14/18 (77.7%), [Table 3]. After 3-4 cycles complete response (CR) was noted in 42.8% of stage III and in 14.2% of stage IV with an overall CR rate of 4/14 (28.5%). [Table 4].
Table 3: Stage Grouping, Primary Site &Response After 2 Cycles Of Chemotheraphy

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Table 4: Stage Grouping, Primary Site &Response After 3-4 Cycle

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Morbidities of Induction Chemotherapy,

Nausea and vomiting was noted in 72.2% and 61.1% respectively. Mild degree of leukopenia was observed in 44.4% of cases. However, none of the patients inthis group developed febrile neutropenia, [Table 5]. Skin hyperpigmentation was noted in 78.5% of cases. It was of mild degree and it resolved spontaneously. Mild degree of anaemia was observed in 57% of cases after 3-4 cycles. [Table 6].
Table 5: Treatment Related Toxicities After Two Cycles

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Table 6: Treatment Related Toxicities After 3-4 cycles

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Local Control, Organ Preservation and Survival Results.

Analysis of survival has shown that cases with no active disease (NAD) were reported in 66.6%, 63.6% and 33.3% of cases after I year, 2 years and 3 years respectively. However if the whole group is taken into consideration lower figures are noted at the second and third year of follow up, 38% & 11% respectively. Cases living with residual disease were noted in 22.2% 9.0% after I year and 2 years respectively. Local recurrence rate was very low. It was noted in 6.6%and 9.0%after 1.5 years and 2 years respectively [Table 7].
Table 7: Survival Results

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Survival was higher in patient >40 years. Furthermore it was higher in males than in females. Results were encouraging in the group of the nasopharyngeal carcinoma. In all cases with laryngeal carcinoma the larynx was preserved with chemotherapy and irradiation Stage III cases exhibited higher survival rate than stage IV patients. Good performance status was associated with better results. Response continues after 2 cycles and those who received >2 cycles have better survival outcome than those patients who received 2 cycles only. However statistical analysis of the results was not possible because of the smaller number of patients and the diversity of the clinical groups in addition to the limited period of follow up [Table 8].
Table 8: Correlation Of Survivors & Some Prognostic Factors

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  Discussion: Top


The experience with induction chemotherapy for patients with squamous cell carcinoma of the head and neck started long time ago, when several trials evaluated sequential single agent chemotherapy and irradiation.[5],[6],[7],[13] The earliest trials were uncontrolled and used Methotrexate in a variety of doses before local treatment. However, none of these trials has shown any improvement in the disease free survival or overall survival rates. [14],[15],[16] Since the late 1970’s numerous uncontrolled trials have been performed. The results of these studies are encouraging with a response rate ranging from 50-90%. Such trials suggest a role for induction chemotherapy. [7],[17],[18] However, recently several prospective randomised controlled trial have been published. Stell and co-workers [19] ,utilised one cycle of induction chemotherapy with a complete response of 15%. Holoye and et al[20] administered either one or two cycles of Cisplatinum (CDDP)based regimen with a complete response rate of 10%.Hass and co workers [21] used 3 cycles of Cisplatinum (CDDP) and 5Fu infusion with a complete response rate of 17%. Schuller et. al [22], evaluated a 9 weeks, 3 course regimen of neoadjuvant chemotherapy with a total and complete response of 65% and 20% respectively, with no survival improvement. In our study similar findings were obtained. In this series 61.1% of cases received 3 cycles of chemotherapy, while 16.7 % of patients received 4cycles. Analysis of the results has shown no difference between the two groups.

However the overall number of patients is still small and the period of follow up is still limited. In a randomised trial, Richard et. Al[23] studied neoadjuvant chemotherapy and surgery while Merlano et. al. [24],tried induction chemotherapy and irradiation and both trials reported a survival benefit in complete rcsponders. In all the trials, induction chemotherapy was well tolerated by most of the patients with no significant side effects. [19],[20],[21],[22],[23],[24],[25] Such findings were also confirmed in our series.

Neoadjuvant chemotherapy is now considered an effective strategy for organ preservation; such procedure will improve the quality of life, without compromising the overall survival. This was proved by the large study done by MDA & Tumour Institute. [26] In their study the larynx was preserved in 64% of cases with induction chemotherapy and radiation therapy. Furthermore a low rate of recurrence was noted compared to those cases treated by surgery and post operative radiation therapy. In this study the larynx was preserved in all the cases included with a minimum follow up of 2 years. Although optimising initial approaches to local control is essential, use of adjuvant chemotherapy after adequate local control is warranted for further reduction of local recurrences and distant metastases.


  Conclusion Top


Induction chemotherapy is accompanied with a high overall response and complete response rates prior to locoregional treatment. Tumour regression continues and response rates increase through at least 3 cycles of induction treatment. Complete response to induction chemotherapy is associated with an optimal locoregional control of tumour. Those patients who respond to chemotherapy continue to respond to radiation therapy. However, those with minimal or no response to initial chemotherapy usually fail to respond to irradiation. Induction chemotherapy is tolerable with no significant side effects. Furthermore, the toxicity of local treatment is not significantly increased by initial neoadjuvant treatment. Organ preservation is possible with induction chemotherapy. Furthermore such treatment protocol is associated with a positive impact on the quality of life. However a larger number of patient and a longer period of follow are needed for definite conclusions.



 
  References Top

1.
Al-Sarraf M, Drelichman A, Jacobs J et al: Adjuvant chemotherapy with cisplatinum, oncovin, bleomycin followed by surgery and/or radiotherapy in patient with advanced previously untreated head and neck cancer: Final report, in Salmon S, Jones S (eds): Adjuvant Therapy of Cancer 111. New York, Grune and Stratton, 1981.  Back to cited text no. 1
    
2.
Dreyfuss Al, Clark JR, Wright JC et al; Continuous infusion high dose leucovorin with 5-Fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Am Int Med 1990; 112:167.  Back to cited text no. 2
    
3.
Forastierre AA: Chemotherapy of head and neck cancer. A Oncol(suppl3) 1992;I1.  Back to cited text no. 3
    
4.
Hong WX, Bhutani R, Shapskay SM, Strong MS: Induction chemotherapy in advanced previously untreated squamous cell head and neck cancer with cisplatin and bleomycin, infusion.Cancer 1979;44:19-25.  Back to cited text no. 4
    
5.
Kirkwood JM, Miller D, Weichselbaum R, Pitman S: Predefinitive and post definite chemotherapy for locally advanced squamous cell carcinoma of the head and neck. Laryngoscope 1979;89:573.  Back to cited text no. 5
    
6.
Demard F, Chauvel P, Santini J et al: Response to chemotherapy as justification of the therapeutic strategy for pharyngo- laryngeal carcinoma. Hand & Neck 1990; 12:225.  Back to cited text no. 6
    
7.
Vokes EE: Chemotherapy and integrated approaches in head and neck cancer. Curr Opin Oncol 1991;529.  Back to cited text no. 7
    
8.
American joint committee on cancer: Manual of staging of cancer; 2 nd ed, pp25- 54. Philadelphia, JB Lippincott, 1983.  Back to cited text no. 8
    
9.
Weaver A, Flemming S; Kish J. et al: Cisplatinum and 5-Fluorouracil as induction therapy for advanced head and neck cancer. Am J Surg 1982;144:445-448  Back to cited text no. 9
    
10.
Kamofsky D-A: An assessment of patient’s performance status. Cancer 1948; 1,634.   Back to cited text no. 10
    
11.
Miler A.B: Definition of objective responce in solid tumours. Cancer 1981; 47,207.  Back to cited text no. 11
    
12.
Miller A.B. Grading of acute & subacute toxicities post chemotherapy.Cancer 1981; 47 207  Back to cited text no. 12
    
13.
Bertino JR, BostonB, Capissi RL: The role of chemotherapy in the management of cancer of the head and neck: A review. Cancer 1976; 36, 752.  Back to cited text no. 13
    
14.
Lane M,MOoore JE111,Levin H,Smith FE Methotrexate therapy for squamous cell carcinoma of the head and neck.JAMA 1968; 204:561.  Back to cited text no. 14
    
15.
Leone LA Albala MM, Rege CVB Treatment of carcinoma of the head and neck with intravenous methotrexate. Cancer 1968; 21, 828.  Back to cited text no. 15
    
16.
Fazekas JT,Sommer C,Krammer S Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, larynx or hypopharynx. IntJ Radiat Oncol Biol Phys 1980, 6: 533.  Back to cited text no. 16
    
17.
Elias EG,Chretien PB,Monnard E. Chemotherapy prior to local therapy in advanced squamous cell carcinoma of the head and neck. Cancer 1979; 43,1025-1031.  Back to cited text no. 17
    
18.
Martin M, Mazeron Jj, BrunB. Neoadjuvant polychemotherapy of head and neck cancer. Proc Am Soc Clin One (Abstr) 1988; 152:7.  Back to cited text no. 18
    
19.
Stell OM, Dalby JE, Strickmand P. et al: Sequential chemotherapy and radiotherapy in advanced head and neck cancer. Clin Radiol 1983;34:463-467.  Back to cited text no. 19
    
20.
Holoye PY, Grossman TW, Toohill RJ, et al: Randomized study of adjuvant chemotherapy for head and neck cancer. Otolaryngol Head and Neck Surg 1985; 93: 712-717.  Back to cited text no. 20
    
21.
Haas C,Anderson T, Byhardt R, et al: Randomized neo-adjuvant study of 5- fluorouracil (FU) and cisplatinum (DDP) for patients (PTS) with advanced resectable head and neck squamous carcinoma (ARHNSC) (abstract 735). Proc Am Assoc Cancer Res 1986; 27: 185  Back to cited text no. 21
    
22.
Schuller DE. Wilson H, Hodgson S, et al: Preoperative reductive chemotherapy for stage III or IV operative epidermoid carcinoma of the oral cavity, oropharynx, or larynx, phase 111: A Southwest Oncology Group study (abstract 185). Presented at the International Conference on Head and Neck Cancer, Baltimore, 1984.  Back to cited text no. 22
    
23.
Richard JM.Sancho-Gamier H.Kramar A. Randomised EORTC Head and Neck Cooperative Group Trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma. Eur J Cancer 1991;27:821-827.  Back to cited text no. 23
    
24.
Merlano M, Rosso R, Benasso M. Alternating chemotherapy and radiotherapy versus radiotherapy in advanced inoperable SCC-HN: a cooperative randomized trial. Proc Am Soc,clin Oncol 1991; 10:198.  Back to cited text no. 24
    
25.
Vokes EE, Schilsky RL,Weichselbaun RR. Induction chemotherapy with Cisplatin, 5FU, and high-dose Leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis. J Clin Oncol 1990; 8: 241-247.  Back to cited text no. 25
    
26.
Department of Veterans Affairs laryngeal Cancer Study Group Induction chemotherapy plus radiation in patients with advanced laryngeal cancer. N Eng J Med 1991; 324: 168, 5-1690.  Back to cited text no. 26
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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