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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 25-29
 

Retrospective analysis of palliative metronomic chemotherapy in head and neck cancer


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Division of Clinical Research and Biostatistics, Malabar Cancer Centre, 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_161_17

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 » Abstract 

BACKGROUND: Metronomic chemotherapy has shown promising results in selected patients of head and neck cancer in a small randomized study. This retrospective analysis was done to see whether the efficacy of metronomic chemotherapy in an unselected cohort of head and neck cancer patients is similar to that reported in the randomized study and the influence of the site and subsite of head and neck cancer on survival. MATERIALS AND METHODS: This was a retrospective analysis of head and neck cancer patients who received palliative metronomic chemotherapy between January 2013 and February 2015. The data of these patients were collected from our palliative chemotherapy database maintained in medical oncology outpatient department. The overall survival (OS) was calculated in days from the date of start of chemotherapy to the date of death. Patients who had not expired at last follow-up were censored during estimation of OS by Kaplan–Meier method. Factors affecting OS were identified by COX regression analysis. RESULTS: Over the stipulated time period, 340 patients received palliative metronomic chemotherapy. The median age of these patients was 48 years (22–90 years). The sites of tumor origin were oral cavity in 281 patients (82.6%), oropharynx in 33 patients (9.7%), larynx in seven patients (2.1%), hypopharynx in 12 patients (3.5%), and maxilla in seven patients (2.1%). Previous treatment was received by 286 patients (84.1%). The median time to failure was 3.5 months (interquartile range 2.0–6.0 months). The overall median survival was 155 days (95% confidence interval 140.2–169.8 days). Failure within 6 months of previous treatment was the most important factor influencing OS. There was a trend toward lower OS in patients with oral cancers (139 days vs. 210 days). Among the various oral cancer subsites, oral tongue primary had a lower OS. CONCLUSION: Oral metronomic chemotherapy has promising results when used in a selected cohort of patients but has dismal results in patients who failed within 6 months of previous treatment.


Keywords: Chemotherapy, head and neck cancer, metronomic, palliative


How to cite this article:
Patil V M, Noronha V, Joshi A, Nayak L, Pande N, Chandrashekharan A, Dhumal S, Bhattacharjee A, Banavali S, Prabhash K. Retrospective analysis of palliative metronomic chemotherapy in head and neck cancer. Indian J Cancer 2017;54:25-9

How to cite this URL:
Patil V M, Noronha V, Joshi A, Nayak L, Pande N, Chandrashekharan A, Dhumal S, Bhattacharjee A, Banavali S, Prabhash K. Retrospective analysis of palliative metronomic chemotherapy in head and neck cancer. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:25-9. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/25/219547



 » Introduction Top


Traditional maximum tolerable dose, single-agent palliative chemotherapy in head and neck cancer has improved survival but at best can be considered marginal.[1],[2] The effect of this treatment on quality of life (QOL) is an issue considering the side effects. Efforts of improving survival by use of combination chemotherapy have not been successful. The median overall survival (OS) is similar, whether a single-agent platinum or a platinum-based combination chemotherapy is used.[3],[4],[5] In addition, these combination chemotherapy regimens have added to the toxicity.[3],[4],[5] However, the addition of epidermal growth factor receptor targeting agent cetuximab to the combination chemotherapy of cisplatin and 5-fluorouracil (5FU) has improved survival.[6] However, in countries like ours, head and neck cancers are seen in the low socioeconomic groups, and unfortunately, most patients do not have access to cetuximab.[7] Metronomic chemotherapy was developed as an option in this situation for improvement in efficacy.[8]

The efficacy of metronomic chemotherapy consisting of low-dose methotrexate (15 mg/m 2 weekly) and celecoxib, in terms of progression-free survival (PFS), QOL, and OS, was better than single-agent cisplatin with a favorable toxicity profile. These results were obtained in a small randomized study consisting of a selected patient cohort.[9] This study lead to the routine use of metronomic chemotherapy in the palliative setting of head and neck cancer in our hospital. This retrospective analysis was done to assess the efficacy of metronomic chemotherapy in an unselected cohort of head and neck cancer patients. In addition, the influence of site and subsite on OS was studied.


 » Materials and Methods Top


Selection of cohort

This was a retrospective analysis of palliative metronomic chemotherapy administered in head and neck cancer. The study protocol was approved by the Institutional Ethics Committee (IEC). In view of the retrospective nature of the study, IEC gave a waiver for consent. Patients who received metronomic chemotherapy from January 2013 to February 2015 were selected for this analysis. All of these patients received oral metronomic chemotherapy (OMCT) which was a combination of celecoxib and methotrexate. The dose of methotrexate was 15 mg/m 2 weekly and that of celecoxib was 200 mg BD. This chemotherapy was continued till progression of disease or intolerable side effects. These patients were followed up till death.

Data collection

The data of these patients were collected from our palliative chemotherapy database. Clinical records and electronic medical records were utilized for acquisition of details when necessary. The data regarding demographic characteristics, previous treatment details, site of tumor, stage of tumor, comorbidities, baseline hematological parameters, and baseline biochemical parameters were collected.

Statistical analysis

SPSS version 16 was used for analysis (SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). Descriptive statistics was performed. Proportions and frequencies were mentioned for categorical variables while median with interquartile range (IQR) was used for continuous variables. The OS was calculated in days from the date of start of chemotherapy to the date of death. Patients who had not expired at last follow-up were censored during estimation of OS by Kaplan–Meier method. Factors affecting OS were identified by COX regression analysis.


 » Results Top


Demographic features

Over the stipulated time period, 340 patients received palliative metronomic chemotherapy. The median age of these patients was 48 years (22–90 years), and 312 patients (91.8%) were males. Comorbidities seen were hypertension in 43 patients (12.7%), diabetes mellitus in 33 patients (8.7%), and ischemic heart disease in four patients (1.2%). Two hundred and fifty-six (75.3%) patients had a history of tobacco use. The median tobacco pack-years were twenty. The baseline hemoglobin and serum albumin levels were 11.9 g/dl and 3.9 g/dl, respectively. The Eastern Cooperative Oncology Group performance status was 0–1 in 307 patients (89.4%), two in 23 patients (6.8%), three in one patient (0.3%), and it was not documented in nine patients (2.6%).

Tumor details

The site of tumor origin was oral cavity in 281 patients (82.6%), oropharynx in 33 patients (9.7%), larynx in seven patients (2.1%), hypopharynx in 12 patients (3.5%), and maxilla in seven patients (2.1%). The subsites of tumor in oral cavity were anterior two-third of the tongue in 131 patients (38.5%), buccal mucosa in 121 patients (35.6%), and alveolus in 29 patients (8.5%). The indications of chemotherapy were upfront locally advanced disease unsuitable for locoregional treatment in 37 patients (10.9%), upfront metastatic disease in 17 patients (5.0%), and recurrent disease in 286 patients (84.1%).

Previous treatment

Previous treatment was received by 286 patients. Out of these patients, 190 patients (55.9%) were exposed to platinum therapy, and 238 patients (70.0%) were exposed to radiation treatment. The median time to failure was 3.5 months (IQR 2.0–6.0 months). The details of previous treatment received are shown in [Table 1].
Table 1: Depicting previous treatment details

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Overall survival

Overall median survival

The mean follow-up was 7.4 months in patients who had not experienced an event. The overall median survival was 155 days (95% confidence interval [CI] 140.2–169.8 days) [Figure 1]. The proportion of patients surviving at 6 months, 1 year, and 2 years was 41.1%, 15.4%, and 4.3%, respectively. [Table 2] provides the details of the impact of different factors on OS.
Figure 1: Estimated overall survival in days

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Table 2: Impact of different factors on overall survival

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Impact of time to failure

The median OS in patients with failure within 6 months was 137 days (119.3–154.7 days) versus 195 days (150.8–239.2 days) in patients with either time to failure ≥6 months or upfront-treated patients. On multivariate analysis, failure within 6 months of previous treatment was an independent negative prognostic factor with a hazard ratio of 1.48 (1.13–1.95). The median survival in patients with time to failure below 0–3 months, between 3 and 6 months, above 6 months, and upfront-treated patients was 139 days (95% CI 112.2–165.8 days), 134 days (95% CI 118.7–149.3 days), 187 days (137.1.1–236.9 days), and 226 days (130.7–321.3 days), respectively.

Different sites

The median OS was 139 days (122.1–155.9 days) in oral carcinomas, 204 days (143.0–265 days) in oropharyngeal carcinoma, 167 days (25.9–308.1 days) in laryngeal carcinomas, 210 days (90.3–329.7 days) in hypopharyngeal cancers, and 320 days (257.7–382.3 days) in maxillary sinus carcinomas (P = 0.083). The comparison of survival between hypopharynx and oral cancers showed a trend toward improved survival with the former (P = 0.086). Similar trend toward better survival was seen in maxillary sinus carcinomas in comparison with oral cancers (P = 0.127).

Oral subsites

The median OS in tongue cancers was 124 days (106.6–141.4 days), in alveolar cancers was 138 days (101.7–174.3 days), and in buccal mucosa cancers was 171 days (147.7–194.3 days) (P = 0.000). Primary in the tongue in comparison to other oral subsites and other head and neck sites had a negative impact on OS. The tongue subsite and time to failure were the only factors impacting OS in oral cancers. The interaction between these two factors is shown in [Figure 2]. The median OS ranged from 326 days in buccal mucosa primary with time to failure above 6 months to a median OS of 106 days in tongue primary with time to failure below 6 months. In both buccal mucosa and tongue primaries, an event-free period below 6 months had a negative impact on OS [Figure 2].
Figure 2: Figure depicting impact of site and time to failure

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 » Discussion Top


Metronomic chemotherapy in head and neck cancers is one of the accepted treatment options at our center. This is a result of a recently published randomized study. In this study, OMCT was compared against single-agent cisplatin with OMCT showing a statistically significant improvement in median PFS and OS. The median PFS and OS reported in this study was 101 days (95% CI: 58.2–143.7 days) and 249 days (95% CI: 222.5–275.5 days), respectively.[9] These results were achieved at lower toxicity rates and better QOL gains in comparison to intravenous cisplatin.[10] The cost of OMCT is low (below 20 USD per month), and hence, it is an attractive option for low- and middle-income countries like India. However, whenever such results are published, these drugs are then used beyond the inclusion and exclusion criteria used in the study. Our study gives us the opportunity to evaluate the treatment in patients beyond the inclusion and exclusion criteria. 41.3% of patients (124 patients) had time to failure below 3 months. Patients who had failed within 3 months of chemotherapy exposure were excluded from the study. Failures within 6 months of exposure to platinum are considered as platinum-refractory disease. These patients were never included in treatment changing studies in view of their poor prognosis.[11] The current analysis also identifies time to failure below 6 months as a negative prognostic factor. The present analysis had 197 patients (65.7%) in this category. And hence, it is not a surprise that the median OS in this study was only 155 days.

Palliatively treated oral cancers have poor survival with chemotherapy. In the EXTREME study, the median OS of oral cancer patients was only 4.0 months with cisplatin and 5FU in patients with time to failure >6 months.[6] In the present study, 93.7% of patients had oral cancers. A median survival of 191 days (6.37 months) in patients with time to failure >6 months would be considered favorable to intravenous chemotherapy. These figures, however, seem inferior than the median OS seen in oral cancers treated with cetuximab and chemotherapy. The median OS in EXTREME study in oral cancer patients was 11.0 months.[6] However, the EXTREME study regimen of cetuximab, cisplatin, and 5FU is affordable by <1% of our population.

Head and neck cancers are commonly considered as a group, especially in the palliative setting. None of the studies published till date or still recruiting focus on the site or subsite in head and neck cancers. However, our data suggest that different sites in head and neck cancers respond differently to palliative metronomic chemotherapy and have different OS. This analysis, owing to the large number of patients, allowed us to evaluate the impact of metronomic chemotherapy on various sites and subsites. The OS was different for different sites. For example, the median OS was superior in hypopharyngeal cancers compared to oral cancers (median of 210 days vs. 139 days, P = 0.086). Not only the site but also the subsite seems to be an important factor. In our analysis, patients with tongue primary had a much worse OS than the other oral subsites [Figure 2]. The median OS (326 days) was most favorable in buccal mucosa cancers with time to failure >6 months. This suggests that probably each subsite in head and neck cancer behaves differently and might need a different strategy.

Data regarding toxicity and compliance were not extracted in this study. In general, however, monitoring and follow-up of patients in routine practice are not as thorough as that in trial settings. Furthermore, compliance to oral therapy in routine settings is an issue. Experience with oral drugs such as imatinib and tamoxifen attest to this fact.[12],[13],[14] Use of oral metronomic drugs needs detailed counseling of patients regarding the method of administration of drugs and importance of compliance.

The information gained from this study will help us in developing this modality in an innovative manner to improve outcome. We have planned for the development of metronomic chemotherapy combining intravenous chemotherapy or using another oral drug in specific subsites of the head and neck cancer.


 » Conclusion Top


OMCT has shown encouraging results, especially in the context of patients who are not able to take cetuximab-based therapy in the palliative setting for head and neck cancer. These results need to be improved with various innovative ways, considering the subsite as a factor. OMCT, however, has limited activity in platinum refractory patients. The site and subsite influence the outcomes to metronomic chemotherapy in head and neck cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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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. 1
    
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Morton RP, Rugman F, Dorman EB, Stoney PJ, Wilson JA, McCormick M, et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: A randomised factorial phase III controlled trial. Cancer Chemother Pharmacol 1985;15:283-9.  Back to cited text no. 2
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Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 1992;10:1245-51.  Back to cited text no. 3
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Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994;5:521-6.  Back to cited text no. 5
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Patil VM, Noronha V, Joshi A, Banavali SD, Muddu V, Prabhash K. Preoperative chemotherapy and metronomic scheduling of chemotherapy in locally advanced oral cancers. Oncology 2016;91 Suppl 1:35-40.  Back to cited text no. 8
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Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Bhosale B, et al. Aprospective 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. 9
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

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