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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 20-24
 

Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers


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

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. 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/ijc.IJC_160_17

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 » Abstract 

BACKGROUND: The present match pair analysis was planned to compare the efficacy of cetuximab-paclitaxel-based chemotherapy versus metronomic therapy. MATERIALS AND METHODS: Sixty patients with metastatic/recurrent head and neck squamous cell cancer treated with weekly paclitaxel (80 mg/m2) and cetuximab were matched with sixty patients treated with oral metronomic chemotherapy consisting of methotrexate and celecoxib. The progression-free survival (PFS) and overall survival (OS) between the cohorts were compared using log-rank test. Cox proportional regression model was used to identify independent factors affecting PFS and OS. RESULTS: The median OS was 191 days (95% confidence interval [CI]: 122.2–259.8 days) in metronomic cohort and 256 days (95% CI 177.0–334.9 days) in cetuximab cohort (hazard ratio: 0.58, 95% CI: 0.35–0.95, P = 0.031). On Cox proportional hazard model, Eastern Cooperative Oncology Group Performance Status (0–1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on OS. CONCLUSION: Cetuximab-based chemotherapy leads to a significant improvement in OS in the match pair analysis in comparison to metronomic chemotherapy.


Keywords: Chemotherapy, head and neck cancer, metronomic, metronomic administration, metronomic dosing, Palliative


How to cite this article:
Patil V M, Noronha V, Joshi A, Agarwala V, Muddu V, Ramaswamy A, Chandrasekharan A, Dhumal S, Juvekar S, Arya A, Bhattacharjee A, Prabhash K. Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers. Indian J Cancer 2017;54:20-4

How to cite this URL:
Patil V M, Noronha V, Joshi A, Agarwala V, Muddu V, Ramaswamy A, Chandrasekharan A, Dhumal S, Juvekar S, Arya A, Bhattacharjee A, Prabhash K. Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers. Indian J Cancer [serial online] 2017 [cited 2020 Mar 31];54:20-4. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/20/219546



 » Introduction Top


Cetuximab-based chemotherapy is the standard of care in palliative treatment of head and neck cancers.[1],[2] In a major Phase 3 randomized study by Vermorken et al., the combination of cisplatin, 5-fluorouracil (5 FU), and cetuximab significantly prolonged both progression-free survival (PFS) and overall survival (OS), in comparison to cisplatin and 5 FU alone.[3] However, very few patients in developing countries, including India and countries in the African region, can afford cetuximab.[4] Unfortunately, these countries also contribute maximally to the global burden of head and neck cancers.[5]

Metronomic chemotherapy is defined as continuously administered low-dose oral chemotherapy which has antiangiogenic and antitumor effect.[6] A metronomic combination of oral methotrexate and celecoxib was developed in head and neck cancers and is useful to overcome these socioeconomic issues.[6] The selection of these drugs was based on biological rationale. Methotrexate is an active agent in head and neck cancers and is used in palliative setting in a dose 40 mg/m 2 weekly.[7] A dose approximately one-third of this dose, i.e., 15 mg/m 2 weekly was selected as drugs have metronomic action at one-third to one-tenth of maximum tolerable dose. Celecoxib was selected as Cox expression is frequent in head and neck cancers, and in vitro data suggest its antiproliferative effect on cancer.[8] Initial pilot studies done at our center with metronomic chemotherapy confirmed its promising activity in the palliative setting. Retrospective studies have shown the efficacy of this regimen as palliative therapy.[9],[10] A recent Phase 2 study comparing metronomic chemotherapy (methotrexate 15 mg/m 2 weekly PO and celecoxib 200 mg PO twice daily) to single agent cisplatin confirmed the superiority of metronomic chemotherapy in terms of PFS and OS.[11] However, as highlighted in the first paragraph, the current standard of treatment for head and neck cancers in the palliative setting is a cetuximab-based chemotherapy regimen. The combination of oral methotrexate and celecoxib has never been compared against a standard cetuximab-based regimen. Hence, the present study was formulated to compare the efficacy of metronomic chemotherapy to a cetuximab-based regimen as palliative chemotherapy in head and neck cancers.


 » Materials and Methods Top


Selection of patients

This was an Institutional Review Board approved match pair analysis of patients receiving palliative chemotherapy in head and neck cancer. The data of patients treated with cetuximab-based chemotherapy were obtained from a prospectively maintained database and electronic medical records. We used the following selection criteria.

  • Primary in oral cavity or pharynx (oropharynx or hypopharynx) or larynx
  • Histopathology showing squamous cell carcinoma
  • Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2.


A total of 100 patients fulfilled the criteria. We randomly selected sixty patients as per the sample size requirement. These sixty patients were then matched with sixty patients who had received palliative metronomic chemotherapy (oral weekly methotrexate and celecoxib). The matching was done on 1:1 basis for following variables.

  • Site of primary (oral versus nonoral)
  • Event-free period from previous treatment (below 6 months versus above 6 months)
    • Patients who were not treated previously were included in above 6 months category for this matching.


The metronomic database used for matching had a total of 200 patients. Since there were limited patient numbers for nonoral subgroup with an event-free period (EFP) from previous treatment above 6 months, we decided to do a 1:1 matching. If more than the required number of patients were available for selection in metronomic cohort than patients with similar site (oropharynx, larynx, and hypopharynx) were selected. If there was more than one patient matched, then the patient with similar subsite was selected. If there was still more than one matched patient, then EFP in months and finally random number allocation was used to select the matching patient.

Treatment

Patients in the metronomic cohort received oral weekly methotrexate at a dose of 15 mg/m 2 along with capsule celecoxib 200 mg orally twice daily. Patients in the cetuximab cohort received weekly paclitaxel (80 mg/m 2) along with weekly cetuximab (loading dose of 400 mg/m 2 followed by 250 mg/m 2). Patients were evaluated at each clinical visit for response and toxicity. Patients in both the cohorts underwent radiological assessment at every 2-month interval. The treatment was continued for all patients till either disease progression or intolerable side effects.

Sample size calculation

The primary endpoint of this analysis was 6-month OS. To demonstrate an improvement in 6-month OS from 65% in metronomic cohort (control group) to 85% in cetuximab cohort, with Type I and II error of 5% and 20%, respectively, with propensity score matching of 70%, a sample size of 120 patients was necessary, i.e., sixty patients in each group. However, the propensity matching was not feasible. Hence, simple matching for variables described above was used.

Statistical analysis

R Studio version 3.1.2 (R: A Language and Environment for Statistical Computing, R Core Team, Vienna, Austria) and SPSS for Windows, Version 16.0. Chicago, SPSS Inc. The primary analysis was on an intention-to-treat basis. The characteristics of the patients were measured and compared between groups with an exact Fisher's test or Chi-square for trends, as appropriate. Survival analysis was performed for PFS and OS.

PFS was calculated in days from the date of start of treatment to time of progression or last follow-up (DD-MM-YYYY). OS was calculated in days from the date of start of treatment to time of death or last follow-up (DD-MM-YYYY). Event rates and their 95% confidence intervals (CI) were calculated according to Kaplan–Meier method. Patients not experiencing any event (death for OS or progression for PFS) were censored at their last date of follow-up. Differences between cohorts were evaluated using the log-rank test. A univariate Cox proportional regression model was performed to obtain the hazard ratios (HRs) for PFS and OS for metronomic versus cetuximab. A multivariable Cox proportional regression model was used to identify independent factors associated with PFS and OS among patients treated with metronomic with reference to cetuximab arm.


 » Results Top


Baseline features

The median age of the whole cohort was 52 years (interquartile range [IQR]: 46–59.00 years). The gender distribution was 107 males (89.2%) and 13 females (10.8%). The ECOG PS was 0–1 in 97 patients (79.8%), whereas it was 2 in 23 patients (20.2%). The most common site of disease was oral cavity in 64 patients (53.3%). The distribution of nonoral cavity tumors was oropharynx, larynx, and hypopharynx in 26 (21.7%), 12 (10.0%), and 18 (15.0%) patients, respectively. The indication for chemotherapy was metastatic disease in 15 patients (12.5%), locoregional recurrence not amenable to surgery or radiation in 93 patients (77.5%), whereas it was locally very advanced disease in 12 patients (10.0%).

Previous treatment was received in 101 patients (84.2%). The treatment received was radical radiotherapy, surgery followed by adjuvant RT, surgery followed by adjuvant chemoradiation, neoadjuvant chemotherapy followed by surgery and then adjuvant chemoradiation, radical chemoradiation, neoadjuvant chemotherapy followed by radical chemoradiation, surgery, and chemotherapy in 5, 22, 12, 05, 38, 13, 5 patients, and 1 patient, respectively. The median EFP following previous treatment was 7.0 months (IQR 4.0–14.7 months).

The patients were well distributed in the cohorts. The cetuximab cohort had a higher percentage of patients with PS-2 status (25.0% vs. 13.3%) and a higher percentage of previously treated patients (90.0% vs. 78.3%). The baseline demographic and previous treatment characteristics in the two cohorts are shown in [Table 1].
Table 1: Baseline features comparison between the two cohorts

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Response

Radiological response assessment at 2 months was done in 106 patients and not documented in 14 patients. The response was complete response (CR) + partial response (PR) in 7 (11.7%, n = 60) and 16 patients (26.7%, n = 60) in metronomic and cetuximab cohort, respectively (Chi-square test, P = 0.002) as shown in [Table 2]. Clinical benefit rate defined as CR + PR + SD at 5 months was seen in 22 patients (36.7%) with metronomic chemotherapy and 45 patients (75.0%) with cetuximab chemotherapy (Chi-square test, P = 0.000).
Table 2: Comparison of radiological response rates at 2-month poststart of chemotherapy

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Toxicity

In both cohorts, the therapy was well tolerated. In metronomic cohort, three patients discontinued treatment, due to pneumonia (one patient) and oral mucositis (two patients). In the cetuximab cohort, three patients had severe toxicity leading to discontinuation, four due to sensory neuropathy, and one due to severe rash.

The incidence of Grade 3–5 toxicity was 6.9% (four patients, n = 58) and 16.4% (nine patients, n = 55) in metronomic and cetuximab cohorts, respectively (Chi-square, P = 0.142). The comparison of all grades of toxicity is shown in [Table 3].
Table 3: Comparison of toxicity between metronomic and cetuximab cohort

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Progression-free survival

The median follow-up of the whole cohort was 228 days. The overall median PFS was 141 days (95% CI: 112.9–169.1 days). The median PFS was 101 days (95% CI: 64.6–137.4 days) in metronomic cohort and 173 days (95% CI 120.9–225.1 days) in cetuximab cohort [Figure 1]. On Cox proportional hazard model, ECOG PS (0–1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on PFS. The HR was 0.58 in favor of cetuximab cohort (95% CI: 0.38–0.91, P = 0.016). The HR was 0.58 in favor of patients with PS 0–1 (95% CI: 0.34–0.99, P = 0.046). The other factors tested were age, site of tumor, and event-free survival postprevious treatment. The impact of different prognostic factors on median PFS in each treatment cohort is shown in [Table 4].
Figure 1: Graph depicting the progression-free survival curves between the 2 cohorts

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Table 4: Impact of different prognostic factors on progression-free survival and overall survival

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Overall survival

The median OS was 249 days (95% CI: 206.5–291.5 days). The median OS was 191 days (95% CI: 122.2–259.8 days) in metronomic cohort and 256 days (95% CI: 177.0–334.9 days) in cetuximab cohort [Figure 2]. On Cox proportional hazard model, ECOG PS (0–1 vs. 2) and therapy (cetuximab vs. metronomic) had a statistically significant impact on OS. The HR was 0.58 in favor of cetuximab cohort (95% CI: 0.35–0.95, P = 0.031). The HR was 0.48 in favor of patients with PS 0–1 (95% CI: 0.27–0.86, P = 0.014). The other factors tested were age, site of tumor, and event-free survival postprevious treatment. The impact of different prognostic factors on median OS in each treatment cohort is shown in [Table 4].
Figure 2: Graph depicting the overall survival curves between the two cohorts

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 » Discussion Top


Cetuximab-based regimen is the standard treatment in recurrent/metastatic head and neck squamous cell cancers, and the results of the present match pair analysis reiterate the superiority of cetuximab-paclitaxel regimen in terms of superior overall median PFS and OS compared to oral metronomic therapy.

However, analysis of the data shows the variable impact of cetuximab depending on the type of tumor. Two notable factors are the site of tumor and EFP post last treatment. In the landmark EXTREME study, oral cancers had a median survival of 11.0 months in the cetuximab arm, whereas the survival was 4.4 months in the non-cetuximab arm with a HR of 0.42. Interestingly, in all other subsites (oropharynx, larynx, and hypopharynx), the 95% CIs of the HR crossed unity.[3] Similarly, in our analysis, oral cancers had a greater benefit with a HR of 0.56 and the HR for nonoral cancers was near unity. The majority of our patients had a primary in oral cavity (53.3%), and it is possible that the cetuximab benefit seen is due to the preponderance of oral cavity cancers. EFP or EFP from previous treatment is another factor which impacted OS differentially in between the two cohorts. Patients with EFP below 6 months benefitted from cetuximab therapy (HR 0.31) immensely as compared to patients with EFP equal to or above 6 months in the present analysis. Interestingly, this subset of patients was excluded in the EXTREME study, which included patients who had either failed after 1 month after definitive therapy or after 6 months of exposure to platinum as a part of multimodality treatment.[3] In our analysis, metronomic therapy seemed to have comparable efficacy to cetuximab in this subset. We need to stress that such subgroup analysis in a small population can only be considered as hypothesis generating. However, these intriguing results can help investigators select an appropriate population for conducting a randomized study between cetuximab-based chemotherapy and metronomic chemotherapy. Based on our analysis, it appears that nonoral primaries with EFP >6 months are the most appropriate population for such comparison.

The results of metronomic chemotherapy in patients with early failures, i.e., within 1 month of definitive therapy or within 6 months of exposure to platinum as a part of multimodality treatment are disappointing in this analysis and in other published reports to.[12] Cetuximab therapy, however, in this poor prognostic group to has shown promising survivals. In this analysis too, the median survival of patients with EFP below 6 months with cetuximab therapy was 314 days, which is similar to that seen in patients with EFP above 6 months.

However, unfortunately, medical oncologists working in low- and middle-income countries have to balance costs in attempting to provide standard therapies.[4] As an illustrative example, our institute is a premier cancer center in India serving patients referred from the entire country. Over the previous 5 years, we have treated 3720 head and neck cancer patients with palliative chemotherapy and only 111 patients (3.0%) could afford cetuximab. An important concern is whether cetuximab provides an incremental benefit in survival which validates the cost of cetuximab. The incremental cost-effectiveness ratio (ICER) of cetuximab is $386,000 per QALY gained according to an analysis by Hannouf et al. which is quite steep for lesser developed countries.[13] Similar concerns have been echoed by the expert review committee of National Institute for Health and Care Excellence (NICE) regarding the use of cetuximab in recurrent and metastatic setting.[14] Consequently, the NICE Appraisal Committee has recommended against the use of cetuximab. Oral metronomic chemotherapy costs around 30 USD per month and is an affordable treatment, especially in low- and middle-income countries.[6] We strongly believe that an effective cost–benefit needs to be established when expensive new therapies are being evaluated.

We plan to do a study comparing cetuximab-based regimen with oral metronomic chemotherapy. Nonoral primaries with diabetic foot infection >6 months would be recruited, and an ICER analysis would be one of the secondary end points. However, we feel that a decrement in the cost of cetuximab is the need of the hour so that until such study results are out, patients even in low- and middle-income countries can have access to this treatment. This fact becomes more important as the majority of cancer patients in the Indian subcontinent have oral cancers which derive the maximum benefit from this treatment.[15]


 » Conclusion Top


Our matched pair analysis shows a benefit for cetuximab-based chemotherapy over oral metronomic chemotherapy in both progression-free survival and OS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
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. 1
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Parikh P, Patil V, Agarwal JP, Chaturvedi P, Vaidya A, Rathod S, et al. Guidelines for treatment of recurrent or metastatic head and neck cancer. Indian J Cancer 2014;51:89-94.  Back to cited text no. 2
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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. 3
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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. 4
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Globocan 2012 – Home. Available from: http://www.globocan.iarc.fr/Default.aspx. [Last accessed on 2015 Aug 19].  Back to cited text no. 5
    
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André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013;14:e239-48.  Back to cited text no. 6
    
7.
A phase III randomised trial of cistplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Br J Cancer 1990;61:311-5.  Back to cited text no. 7
    
8.
Schiffmann S, Maier TJ, Wobst I, Janssen A, Corban-Wilhelm H, Angioni C, et al. The anti-proliferative potency of celecoxib is not a class effect of coxibs. Biochem Pharmacol 2008;76:179-87.  Back to cited text no. 8
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9.
Patil V, Noronha V, Krishna V, Joshi A, Prabhash K. Oral metronomic chemotherapy in recurrent, metastatic and locally advanced head and neck cancers. Clin Oncol (R Coll Radiol) 2013;25:388.  Back to cited text no. 9
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Patil V, Noronha V, D'cruz AK, Banavali SD, Prabhash K. Metronomic chemotherapy in advanced oral cancers. J Cancer Res Ther 2012;8 Suppl 1:S106-10.  Back to cited text no. 10
    
11.
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. 11
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12.
Patil VM, Noronha V, Joshi A, Pinninti R, Dhumal S, Bhattacharjee A, et al. Metronomic chemotherapy in platinum-insensitive failures and/or early failures postmultimodality management in oral cancers. Indian J Med Paediatr Oncol 2015;36:161-5.  Back to cited text no. 12
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13.
Hannouf MB, Sehgal C, Cao JQ, Mocanu JD, Winquist E, Zaric GS. Cost-effectiveness of adding cetuximab to platinum-based chemotherapy for first-line treatment of recurrent or metastatic head and neck cancer. PLoS One 2012;7:e38557.  Back to cited text no. 13
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14.
Bagust A, Greenhalgh J, Boland A, Fleeman N, McLeod C, Dickson R, et al. Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck: A NICE single technology appraisal. Pharmacoeconomics 2010;28:439-48.  Back to cited text no. 14
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Coelho KR. Challenges of the oral cancer burden in India. J Cancer Epidemiol 2012;2012:701932.  Back to cited text no. 15
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    Figures

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