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 » Results
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 629-631
 

Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Division of Clinical Research and Biostatistics, Malabar Cancer Centre, Kannur, Kerala, India

Date of Web Publication10-Mar-2016

Correspondence Address:
V Noronha
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.178374

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 » Abstract 

BACKGROUND: Oral tyrosine kinase inhibitor (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success. In this report, we aim to quantify the symptomatic benefit, progression-free survival (PFS) and overall survival (OS) when erlotinib is given as second-line treatment in Head and neck cancers. METHODS: This was a post-hoc retrospective analysis of a randomized study comparing metronomic chemotherapy with cisplatin. A patient who progressed on chemotherapy and had a PS0-2 were offered second-line chemotherapy. Patients who had received erlotinib (150 mg PO OD) as second line treatment were selected for this analysis. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCAE version 4.02 (NCI,USA) and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death. RESULTS: Twenty-three patients were identified. The median age of these patients at the start of the second line was 47 years (interquartile range 40.5–51.75 years). The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%).The best radiological response documented were a partial response in 04 patients (19.2%). The median estimated PFS and OS were 110 days (95% confidence interval [CI]: 61–175 days) and 156 days (95% CI: 126–185 days) respectively. CONCLUSION: Erlotinib single agent has promising activity in the second line and needs to be explored in future studies.


Keywords: Erlotinib, head and neck cancers, palliative chemotherapy, platinum failure, second-line


How to cite this article:
Patil V, Karpe A, Noronha V, Joshi A, Muddu V, Bhattacharjee A, Dhumal S, Prabhash K. Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers. Indian J Cancer 2015;52:629-31

How to cite this URL:
Patil V, Karpe A, Noronha V, Joshi A, Muddu V, Bhattacharjee A, Dhumal S, Prabhash K. Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers. Indian J Cancer [serial online] 2015 [cited 2019 Dec 16];52:629-31. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/629/178374





 » Introduction Top


Palliative chemotherapy in head and neck cancers is still in infancy. Development of cisplatin, 5 FU, and cetuximab regimen has been one of the first major steps towards progress.[1],[2] However, median survival is still dismal, with very few patients been long-term survivors.[3] Post progression on first line chemotherapy at present, there is no standard recommended regimen.[4] Unfortunately, in developing world the access to targeted therapy is poor. A study from Africa highlighted this, only 1% of patients had access to cetuximab.[5] Similar condition prevails in India. Recently we reported a randomized study done in economically deprived population, not affording cetuximab. We had compared metronomic chemotherapy (methotrexate and celecoxib) with cisplatin chemotherapy.[6] Metronomic chemotherapy improved both progression-free survival (PFS) and overall survival (OS). In this study post progression on chemotherapy, a few patients were fit for second line treatment. On the compassionate ground, most of these patients were offered erlotinib.

Erlotinib has shown activity in Head and neck cancer cell lines.[7] Oral tyrosine kinase inhibitor (TKI) (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success.[1] In this report, we aim to quantify the symptomatic benefit, PFS and OS when erlotinib is given as second-line treatment in head and neck cancers.


 » Methods Top


This was a post-hoc retrospective analysis of phase 2 randomized study whose results have been reported. In short this study was a phase 2 study, designed to compare the efficacy of oral metronomic chemotherapy regimen of methotrexate and celecoxib against single agent intravenous cisplatin in recurrent or metastatic or very locally advanced head and neck cancers. A Patient who progressed on chemotherapy were offered second-line chemotherapy subjected to their performance status. Patients with ECOG PS0-2 on progression were offered second-line chemotherapy. If PS was 3–4 then they were offered best supportive care only. Twenty-three patients were selected for this study subjected to below-mentioned selection criteria

Selection criteria

  1. Radiological or clinically progressive disease
  2. Received second line treatment with erlotinib.


These patients had received tablet erlotinib at a dose of 150 mg OD daily. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCA version 4.02 and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death.

Statistical analysis

R studio version 3.1.2 was used for analysis (R: A Language and Environment for Statistical Computing, R Core Team, Vienna, Austria). Descriptive statistics was performed for baseline characteristics. Frequencies are mentioned categorical variables while median with interquartile range (IQR) is provided for continuous variables. PFS was calculated from the date of start of second-line erlotinib till the date of progression. For patients who had not progressed in them the date of last follow-up was used for calculations these patients were censored during the estimation of PFS by Kaplan–Meier methods. OS was calculated from the date of start of second-line erlotinib till the date of death. For patients who had not died in them the date of last follow-up was used for calculations, these patients were censored during the estimation of OS by Kaplan Meier method. COX regression analysis was done to identify factors affecting OS. The factors considered were age (continuous variable), gender (categorical variable), immediate previous chemorx received (categorical variable, metronomic versus cisplatin), PFS to immediate previous chemotherapy (continuous variable) and development of rash any time on erlotinib (categorical variable, Yes or No). P = 0.05 was taken as significant. Proportional odds (PO) of OS was also calculated to study the impact of previous immediate treatment on OS with erlotinib.

PO = {(s()÷(1-s())}÷{(s(θ)÷(1-s())}

where gives the survival at time (t) for the treatment for patients who were immediately prior treated with cisplatin and for the treatment for patients who were immediately prior treated with metronomic. Under the null hypothesis, it is assumed that the PO will be 1 between two groups.


 » Results Top


Baseline characteristics

Twenty-three patients were identified. Data for one patient was missing in second line hence analysis of 22 patients is provided. The median age of these patients at the start of the second line was 47 years (IQR 40.5–51.75 years). There were 20 male (90.9%) and 02 (9.1%) female patients. The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Overall 13 patients and 09 patients were exposed to platinum and radiotherapy previously. The median PFS to last administered chemo regimen was 68 days (IQR 63.0–99.8 days).

Symptomatic benefit

Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). Baseline pain, dysphagia, external swelling and the foul smell was present in 17, 06, 18 and 02 patients respectively. The decrement in pain, dysphagia, external swelling and foul smell at 1-month were seen in 16, 02, 17 and 02 patients respectively. The requirement for analgesic (a decrement in WHO ladder) was seen in 08 patients.

Radiological response and duration

The best radiological response documented were a partial response in 04 patients, standard deviation (SD) in 10 patients and PD in 08 patients. The response rate was 19.2% (95% confidence interval [CI]: 6.9–39.3%). The SD for more than 3 months was seen in 06 patients.

Toxicity

The grade 3–4 toxicity were seen in 4 patient. The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%). There was no toxicity related mortality seen. The details of toxicity are provided in [Table 1].
Table 1: The CTCAE adverse events grading during erlotinib treatment

Click here to view


Progression free survival and overall survival

All patients had progressed and except 1 all had died. The median estimated PFS and OS were 110 days (95% CI: 61–175 days) and 156 days (95% CI: 126–185 days) respectively. The [Table 2] provides the details of COX regression analysis. The only factor that affected the OS was the immediate previous treatment received.
Table 2: Factors affecting OS are shown

Click here to view


After initial 140 days follow-up, the calculated PO of survival observed was 0.43 in patients treated with metronomic previously in comparison to cisplatin. Hence, it seems that the performance of patients who were treated with cisplatin previously was better than the patients treated with metronomic previously after 140 days. The PO of survival dramatically reduced from 0.63 to 0.20 in the metronomic group in comparison to cisplatin group from treatment initiation to treatment termination. So it seems that the benefit of erlotinib on OS was more in patients who were treated with cisplatin previously.


 » Discussion Top


Second line chemotherapy options in head and neck cancers are limited. A small retrospective analysis of 21 patients with Xydakis et al. did show that combination of gemcitabine and methotrexate is active in second line with response rate of 21.4% and a median time to progression of 8 months (1–74 months).[8] However, such exciting results have not been confirmed in prospective studies. Numico and Merlano explored the option of docetaxel as a second line agent in head and neck cancers in a phase 2 study.[9] The results were largely disappointing with a response rate of 11%, the median time to progression of 19 weeks and median survival of 26 weeks. However, despite the low response rate almost 50% of patients had symptomatic benefit. Targeted agents have been added to chemotherapy in second line treatment in the bid to improve results. Zalutumumab a fully humanized IgG1 monoclonal antibody against epidermal growth factor receptor has shown promising single-agent activity patients who had failed prior platinum therapy against best supportive care. However, though this study documented an increment in PFS, it did fail to show a statistical significant improvement in OS.[10] Other molecules like small oral TKI Inhibitor (gefitinib) and insulin-like growth factor-1 receptor inhibitor [Figitumumab] results have not met the expectations.[11],[12] Consistently in the prospective studies OS in the second line is around 5–6 months.[9],[10],[13] This suggests that in countries like us where Head and neck cancer is the commonest malignancy a large unmet need for effective second-line agent is present.

Erlotinib has not been tested as a second line agent in Head and neck cancers. There is an encouraging data of about erlotinib in upfront setting in addition to cisplatin and bevacizumab. In combination with cisplatin in upfront setting reported median OS was 8 months and in combination with bevacuzimab it was 7.1 months.[13],[14] Both regimens were well tolerated. Erlotinib single-agent response rates in neoadjuvant setting have been around 30%.[15] The benefit seen with erlotinib with cisplatin is comparable to benefit observed with cetuximab and cisplatin. In developing countries like ours access to cetuximab is an issue, and hence these patients reported in the study received erlotinib on compassionate grounds. The results of this study revealed that median PFS is around 3.6 months and median os around 5.2 months. These figures are comparatively lower than the figures reported in above studies. However it's imperative to consider that majority of our patients had oral cancer primary and its known from the subgroup analysis of EXTREME study that in upfront setting the median OS with only chemotherapy in oral cancers is 4.0 months.[16] In our setup too the median OS with cisplatin-based chemotherapy in oral cancers in only 4.6 months.[6] In light of these considerations, when reported median OS in the first line setting being around 4 months, median OS of 5.2 months seen in our report seems promising.

This regimen was well tolerated. There was no mortality seen with this regimen. Interestingly in the subgroup analysis it was seen that patients who had immediately received platinum-based regimen had a better survival than patients receiving metronomic chemotherapy. This points towards the fact that may be disease progression on platinum and metronomic are occurring via different pathways. Unfortunately, we had not acquired the tissue samples at progression, and this is one hypothesis we would be addressing in our future studies. Upregulation of VEGF is one of the ways in cell line studies erlotinib resistance is acquired.[17] Hence, it seems logical to administer metronomic with antiangiogenic agents. Cohen et al. has shown that such a strategy may provide sustained response and symptom benefit in some patients. We are planning a similar study to see the effect of erlotinib and metronomic in the palliative care setting in oral cancers.


 » Conclusion Top


Second-line treatment with erlotinib has promising activity, and more studies are warranted to explore its exact role in Head and neck cancers.

 
 » References Top

1.
Pendleton KP, Grandis JR. Cisplatin-based chemotherapy options for recurrent and/or metastatic squamous cell cancer of the head and neck. Clin Med Insights Ther 2013;2013:10.4137/CMT.S10409.  Back to cited text no. 1
    
2.
Vermorken JB, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol 2010;21 Suppl 7:vii252-61.  Back to cited text no. 2
    
3.
Platinum-based Chemotherapy (CT) Plus Cetuximab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Cancer (R/M-SCCHN): 5-year Follow-up Data for the Extreme Trial. | 2014 ASCO Annual Meeting | Abstracts | Meeting Library n.d.  Back to cited text no. 3
    
4.
Grégoire V, Lefebvre JL, Licitra L, Felip E, EHNS-ESMO-ESTRO Guidelines Working Group. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v184-6.  Back to cited text no. 4
    
5.
Ignacio DN, Griffin JJ, Daniel MG, Serlemitsos-Day MT, Lombardo FA, Alleyne TA. An evaluation of treatment strategies for head and neck cancer in an African American population. West Indian Med J 2013;62:504-9.  Back to cited text no. 5
    
6.
Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Bhosale B, et al. A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol 2015;51:279-86.  Back to cited text no. 6
    
7.
Reuter CW, Morgan MA, Eckardt A. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br J Cancer 2007;96:408-16.  Back to cited text no. 7
    
8.
Xydakis E, Repassos E, Poulou M, Papadakou M, Boukis C, Panagos G. Second line chemotherapy with methotrexate and gemcitabine in patients with relapsing head and neck cancer. J BUON 2006;11:419-24.  Back to cited text no. 8
    
9.
Numico G, Merlano M. Second-line treatment with docetaxel after failure of a platinum-based chemotherapy in squamous-cell head and neck cancer. Ann Oncol 2002;13:331-3.  Back to cited text no. 9
[PUBMED]    
10.
Machiels JP, Subramanian S, Ruzsa A, Repassy G, Lifirenko I, Flygare A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: An open-label, randomised phase 3 trial. Lancet Oncol 2011;12:333-43.  Back to cited text no. 10
    
11.
Schmitz S, Kaminsky-Forrett MC, Henry S, Zanetta S, Geoffrois L, Bompas E, et al. Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Clinical activity and molecular response (GORTEC 2008-02). Ann Oncol 2012;23:2153-61.  Back to cited text no. 11
    
12.
Stewart JS, Cohen EE, Licitra L, van Herpen CM, Khorprasert C, Soulieres D, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864-71.  Back to cited text no. 12
    
13.
Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: A phase I/II study. Lancet Oncol 2009;10:247-57.  Back to cited text no. 13
    
14.
Huguenin P, Beer KT, Allal A, Rufibach K, Friedli C, Davis JB, et al. Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol 2004;22:4665-73.  Back to cited text no. 14
    
15.
Thomas F, Rochaix P, Benlyazid A, Sarini J, Rives M, Lefebvre JL, et al. Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92.  Back to cited text no. 15
    
16.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.  Back to cited text no. 16
    
17.
Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res 2001;61:5090-101.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2]

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