|Ahead of print publication
Metronomic palliative chemotherapy in locally advanced, recurrent and metastatic head-and-neck cancer: A single-arm, retrospective study of a regional cancer center of North India (Asia)
Kamlesh Kumar Harsh1, Sita Ram Maharia1, Raj Kumar Nirban2, Pramila Khatri1, Surenderkumar Beniwal3, Harvinder Singh Kumar1, Shankar Lal Jakhar1
1 Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India
2 Department of Palliative Medicine, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India
3 Department of Medical Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India
|Date of Submission||24-Oct-2018|
|Date of Decision||25-Dec-2018|
|Date of Acceptance||11-May-2019|
|Date of Web Publication||29-Jan-2020|
Shankar Lal Jakhar,
Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner - 334 001, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Head-and-neck cancer is the most common cancer in developing countries of Southeast Asia. Most of the patients present to the hospital in advanced stage and have a poor prognosis. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of methotrexate and celecoxib in locally advanced, recurrent and metastatic head-and-neck cancers.
Materials and Methods: This was a single-arm retrospective observational study that included posttreatment patients with locally advanced, recurrent and metastatic disease in the year 2016 (January 1, to December 31, 2016). A total of 84 patients warranting palliative chemotherapy but not willing to take intravenous chemotherapy were included in the study. The oral MCT schedule consisted of oral celecoxib (200 mg twice daily) and oral methotrexate (15 mg/m2/week). Response evaluation was done using the Response Evaluation Criteria in Solid Tumors criteria version 1.1, and toxicity profile was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Descriptive statistics and Kaplan–Meier analysis were performed.
Results: Eighty-four patients, 68 males and 16 females, with a median age of 62 years (range: 35–80 years), were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group performance status was 0–1 in 62 patients and 2–3 in 22 patients. The primary sites of disease were buccal mucosa (18), tongue (22), tonsil (24), lower alveolus (7), hypopharynx (10), and soft palate (3). The best clinical response rate in post oral MCT was seen in the first 4 months (120 days). Objective response was observed in 67% of patients in the form of stable disease (56%) and partial response (11%). Disease progression was observed in 27% of patients. The median follow-up was 192 (6.4 months) days. The median estimated overall survival was 195 (6.5 months) days. The median estimated progression-free survival was 110 (3.6 months) days. Symptomatic relief with respect to pain was reported in about 75% of patients. Eighteen (21%) patients had Grade I–II mucosal reactions. Grade III–IV mucosal reactions were observed in five (6%) patients. Seventy-eight (93%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (18%) patients.
Conclusion: Oral MCT using celecoxib and methotrexate is an effective, economical, and well-tolerated regimen with good pain control and low toxicity profile in patients with locally advanced, recurrent and metastatic head-and-neck cancer.
Keywords: Celecoxib, head-and-neck cancers, methotrexate, oral metronomic chemotherapy
|How to cite this URL:|
Harsh KK, Maharia SR, Nirban RK, Khatri P, Beniwal S, Kumar HS, Jakhar SL. Metronomic palliative chemotherapy in locally advanced, recurrent and metastatic head-and-neck cancer: A single-arm, retrospective study of a regional cancer center of North India (Asia). J Can Res Ther [Epub ahead of print] [cited 2020 Apr 2]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=277280
| > Introduction|| |
Head-and-neck cancer has been reported to be the third (including thyroid cancer)-most common malignancy seen in both sexes across the world. It is the second-most common malignancy encountered in Indian males. In developing countries, most of the patients present to the health-care facilities in locally advanced stage (Stage III and IVa/IVb). These patients have a poor prognosis due to the high frequency of recurrences even after taking complete treatment.,
Locally advanced head-and-neck cancer patients are subjected to a multimodality approach involving a combination of surgery, chemotherapy, or chemoradiation at some step of treatment. Despite such an exhausting approach, most of the patients end up in recurrent or metastatic disease, qualifying only for palliative treatment. The chemotherapy already received by these patients is based on the concept of maximum tolerance dose (MTD) which has a sufficient rest period in between cycles to overcome the toxicities of the drugs. This rest period may lead to re-growth of tumor cells and also of certain clones of cells that are resistant to chemotherapy.
In order to overcome the above-stated drawbacks of traditional chemotherapeutic regimens, a new-era approach of drug administration was proposed by Douglas Hanahan called “metronomic chemotherapy (MCT).” In this approach, a low dose of various chemotherapeutic agents is administered over a long period, without any extended rest period. The novelty of such a treatment modality lies in its antitumor efficacy along with very low toxicity.
The aim of this study was to evaluate the efficacy and toxicity profile of MCT using oral methotrexate and oral celecoxib in patients with locally advanced, recurrent and metastatic head-and-neck cancer.
| > Materials and Methods|| |
Over a period of 1 year (January 1, to December 31, 2016), a total of 10,063 new cancer cases were registered in 2016 at our center, out of which 2658 cases were of head-and-neck cancer (26.57%). A total of 84 histologically confirmed squamous cell carcinoma patients with locally advanced, recurrent/metastatic head-and-neck cancer in the year 2016 were included in the study. These patients had already received treatment in the form of surgery or chemoradiotherapy or only radiotherapy or both and now presented with local failure or distant metastasis. These patients were warranted to receive palliative chemotherapy but were not willing to take intravenous chemotherapy.
- Age >35 years
- Histopathologically proven squamous cell carcinoma
- Controlled comorbid condition such as hypertension, diabetes mellitus, and chronic obstructive pulmonary disease (COPD)
- Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) 0–3
- Unaffordable for cetuximab (epidermal growth factor receptor [EGFR]-target agent)
- Unwilling for intravenous chemotherapy.
- Patients with viral infections such as HIV, HBC, and HCV
- Uncontrolled comorbid condition such as hypertension, diabetes mellitus, and COPD
- Age <35 years
- Primary in nasopharynx.
All the selected patients were prescribed oral MCT consisting of oral methotrexate at a dose of 15 mg/m2 once a week and celecoxib at a dose of 200-mg tablets twice daily. All these patients were assessed fortnightly, and the treatment was continued until disease progression or unacceptable toxicities or death. The toxicities were assessed using the National Cancer Institute Common Terminology Criteria for adverse events (CTCAE) version 4.03. In case of Grade III/IV (CTCAE) toxicities, the drug dose was adjusted or stopped. Routine hematological and radiological investigations were done as per the standard schedule. The patients were followed up monthly up to 1 year.
Response assessment for all the patients was done on the basis of clinical and symptomatic relief. This assessment was also supported with radiological evidences, and grading was done according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The disease response was graded as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Any response other than disease progression was considered as objective/clinical response. Improvement in clinical symptoms such as pain and swelling or clinical signs such as decrease in tenderness and size of tumor was considered under clinical response. Worsening of these signs or symptoms was denoted as progression of disease.
Statistical analysis was done using SPSS software version 17.0, and survival curves were plotted using Kaplan–Meier product limit method. Overall survival (OS) was defined as the duration between the initiation of oral metronomics till the last follow-up and the death of patient. Patients who were alive at the last follow-up were censored during the estimation of OS by Kaplan–Meier methods. Progression-free survival (PFS) was evaluated from the initiation of oral metronomics till documented clinical/radiological progression of disease.
| > Results|| |
Eighty-four patients with locally advanced, recurrent/metastatic head-and-neck cancer were enrolled in the study to receive oral MCT. The median age was 62 years (range: 35–80 years), and gender distribution was 68 males (81%) and 16 females (19%). All had a poor socioeconomic status with an average monthly income of Rs. 4500 (Indian currency). Sixty-two (74%) patients belong to rural area and 22 (26%) patients belong to urban area. Eighteen (21%) patients were literate and 66 (79%) patients were illiterate. Thirty-six (43%) patients were chronic smokers, 21 (25%) patients were tobacco chewers, 14 (17%) patients were pan masala or supari (betel nut) chewers, and 5 (6%) patients were nonsmokers. The ECOG-PS was 0–1 in 62 patients (74%) and 2–3 in 22 patients (26%). Comorbid conditions associated with cancer were hypertension in 30 (36%) patients, diabetes mellitus in 16 (21%), COPD in 21 (25%), and other diseases in 15 (18%) patients. Fifty-two (62%) patients had unresectable locally advanced disease, 1 (1.2%) had metastatic disease, and 31 (37%) had recurrence. Twenty-four (29%) patients belonged to Stage III, 35 (42%) to Stage IVa, 24 (28%) to Stage IVb, and 1 (1%) to Stage IVc disease.
The primary sites of tumor were buccal mucosa in 18 (21%), tongue in 22 (26%), tonsil in 24 (29%), lower alveolus in 7 (8%), hypopharynx in 10 (12%), and soft palate in 3 (4%) patients. Nearly 35% of the patients received platinum-based chemotherapy as initial treatment; 16 (19%) received surgery and chemotherapy; 22 (26%) patients received surgery, radiotherapy, and chemotherapy; 30 (36%) received chemoradiation; 10 (12%) received surgery and radiotherapy; and 6 (7%) patients received only radiation therapy. The demographic details of these patients are summarized in [Table 1].
Response to metronomic chemotherapy
All the patients included in the study were assessed in terms of survival and toxicity profile. The best clinical response rate post oral MCT was seen in the first 4 months (120 days). Objective response (SD + PR) was observed in 67% of patients in the form of SD (56%) and PR (11%). Disease progression was observed in 27% of patients [Table 2]. The mean follow-up was 192 (6.4 months) days. The median estimated OS was 195 (6.5 months) days. The median estimated PFS was 110 (3.6 months) days. The Kaplan–Meier graphs for estimated OS and PFS are depicted in [Figure 1] and [Figure 2], respectively. In our study, complete follow-up was done till 1 year (365 days). The total number of deaths was 78 (92.85%) at the end of the study. The benefits in terms of reduction of pain grade were seen in 58 out of 84 (69%) patients. Requirement of analgesics decreased in 63 (75%) patients. Although disease progression was not affected much, the patients showed significant pain relief and psychological benefit.
|Figure 2: Kaplan-Meier curve estimated progression free survival in days (0:-Censored)|
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Metronomic chemotherapy drug toxicity
Grade I and II mucosal toxicities were seen in 18 (21%) patients. Grade III and IV mucosal toxicities were seen in five (6%) patients. No Grade V toxicity was seen. Dose reduction was required in 15 (18%) patients due to mucositis. Two patients required admission in hospital for mucositis. Grade I and II nausea was seen in 14 (17%) patients. Ten (12%) patients developed anemia of Grade I/II, six (7%) required blood transfusion, four (5%) developed febrile neutropenia of Grade I–II, whereas two (3%) developed skin rashes of Grade I. Five (6%) patients had Grade I–II diarrhea. The details of the grade of toxicity occurring during MCT are shown in [Table 3]. Progression of no mortality was observed due to the toxicity of drugs. All patients expired due to progression disease.
| > Discussion|| |
All the traditional chemotherapy regimens were based on the concept of “MTD” until the year 2000 which was a turning point in cancer chemotherapy. In this year, a new concept was proposed by Fidler and Ellis who said that “cancer is a chronic disease and should be treated like other chronic diseases.” Based on this concept and also to combat the toxicities from traditional chemotherapeutic regimens, certain studies were conducted to evaluate a new modality of drug administration which was introduced by Douglas Hanahan called “metronomic therapy.”
A “metronome” is a musical device that produces an audible beat at regular intervals that the user can set in beats per minute. Similarly, in “MCT,” low doses of chemotherapeutic agents are given chronically in pulsed form to maintain a therapeutic effect without any drug-free interval along with decreased toxicity. The studies that were conducted to evaluate the efficacy of such chronically administered low-dose chemotherapeutic agents suggested an anti-angiogenic mode of action of these agents in tumor microenvironment., Angiogenesis in the tumor microenvironment plays an important role in disease progression, blocking of which may result in the cessation of tumor growth and sometimes also in disease regression. These metronomic agents thus act via a different cell target and may induce response in patients not responding to other hitherto-used chemotherapy.
Apart from anti-angiogenic action, these metronomic agents also have two other effects, namely, apoptotic cell death of neoplastic cells and immune modulation. The above-stated modes of actions form the basis of the use of MCT with methotrexate and celecoxib.
The dose of methotrexate selected was 15 mg/m2 in this study which was based on the fact that, at this dose, the dihydrofolate reductase gets saturated in head-and-neck cancers. Further, dose escalation had a limited value in terms of disease control but a higher toxicity occurrence. A similar dose was used in other studies conducted by other researchers with improvement in survival for patients.,, The rationale behind the use of celecoxib (cyclo-oxygenase 2 [COX-2] inhibitor) was to suppress cell proliferation and induce apoptosis in COX-2-independent manner. COX-2 expression is upregulated in neoplastic cells, which augments the release of angiogenic peptides, namely vascular endothelial growth factor, basic fibroblast growth factor, and nitric oxide. Thus, the inhibition of COX-2 results in decreased angiogenesis and downregulation of proangiogenic factors.
In a country like India, majority of patients belong to poor socioeconomic status, so our primary aim is to provide affordable drugs for symptomatic relief, increased OS, and better quality of life (QOL). Majority of our population cannot afford EGFR-targeting agents such as cetuximab, and oral cancers treated with a palliative intent with chemotherapeutic drugs such as cisplatin and 5-florouracil have poor survival. In the EXTREME study, the median OS of oral cancer was only 4.0 months with cisplatin and 5-florouracil in patients. MCT was developed as an option in this situation. Clinical studies from early-phase MCT have reported similar results. The results of MCT have been presented at the American society of clinical oncology (ASCO)-2014. The median PFS and OS in patients who received MCT were 101 days and 249 days, respectively, whereas the median PFS and OS in patients who received cisplatin chemotherapy were 66 days and 249 days, respectively. Patil et al. reported (n = 18) that the clinical benefit rate was 66.67%. The estimated median PFS and median OS were 5.2 months. The median follow-up was 5 months. Patil et al. reported (n = 57) CR in 2 patients (3.5%), PR in 7 (12.3%), SD in 41 (71.9%), and progression in 6 patients (10.5). The median PFS was 153 days, and median OS was 186 days. Kalaichelvi et al. reported (n = 30) that, at the end of 4 months, 60% of the patients had SD, 10% had PR, and 30% had PD. The clinical benefit rate (PR + SD) was 70%. The estimated median time to progression was 8 weeks (2 months). Mateen et al. reported (n = 72) that no patient showed CR. PR was seen in 17 (29%) patients, while 31 (54%) patients showed SD at 6-month follow-up. Two-year PFS and OS were 18% and 40%, respectively. Patil et al. reported (n = 5) that the proportion of patients surviving at 6 months, 12 months, and 18 months was 40%, 40%, and 20%, respectively. The estimated median OS was 126 days. Results of our study showed that the median estimated OS was 195 (6.5 months) days and the median estimated PFS was 110 (3.6 months) days. The median follow-up was 192 (6.4 months) days. The best clinical response rate post oral MCT was seen in the first 4 months (120 days). Objective response (SD + PR) was observed in 67% of patients in the form of SD (56%) and PR (11%). Disease progression was observed in 27% of patients, which was similar to that of the other studies mentioned above.
It has been asserted that MCT reactions occurring during treatment are mainly mucositis, diarrhea, anemia, skin rashes, and febrile neuropenia. Patil et al. reported (n = 18) Grade III/IV mucositis, anemia, and thrombocytopenia in three, one, and one patients, respectively. Patil et al. also reported (n = 57) Grade III/IV mucositis in one patient, Grade I/II mucositis in 12 patients (60.67%), and Grade III anemia in only one patient. In their study, Kalaichelvi et al. (n = 30) reported that only one patient had Grade III mucosal toxicity, 11 patients had Grade I/II mucosal toxicity, and 18 patients had no mucosal toxicity. Our study results showed Grade I and II mucosal toxicities in 18 (21%) patients, while Grade III and IV mucosal toxicities in five (6%) patients. No Grade V toxicity was seen. Dose reduction was required in 15 patients (18%) due to mucositis. Two patients required admission in hospital due to mucositis. Grade I and II nausea was seen in 14 (17%) patients, ten (12%) patients developed anemia, six (7%) patients required blood transfusion, four (5%) patients had febrile neutropenia of Grade I–II, two (3%) patients developed skin rashes of Grade I, and five (6%) patients developed diarrhea of Grade I–II. No mortality was observed due to the toxicity of drugs. Our study also showed results similar to those of other studies. Hence, important advantages of this oral metronomic therapy were its cost-effectiveness and patient convenience. Patients in palliative settings and other patients who have already received multiple cycles of intravenous chemotherapy and not willing for further such cycles tolerated such regimens with better QOL, better survival, and lesser toxicities.
| > Conclusion|| |
The data collected at our tertiary care center suggest that oral metronomic therapy using methotrexate and celecoxib is an effective method of disease control in patients with locally advanced, recurrent and metastatic head-and-neck cancers. The results of our study reflect survival benefits in patients in addition to less toxicities and good pain control. In addition to the above benefits, oral metronomic therapy is also cost-effective and convenient to patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Mishra A, Meherotra R. Head and neck cancer: Global burden and regional trends in India. Asian Pac J Cancer Prev 2014;15:537-50.
Gleich LL, Ryzenman J, Gluckman JL, Wilson KM, Barrett WL, Redmond KP, et al.
Recurrent advanced (T3 or T4) head and neck squamous cell carcinoma: Is salvage possible? Arch Otolaryngol Head Neck Surg 2004;130:35-8.
Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2644-52.
Hanahan D, Bergers G, Bergsland E. Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045-7.
US Department of Health and Human Services, National Institutes of Health, National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03; 2010. p. 6-14.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Fidler IJ, Ellis LM. Chemotherapeutic drugs – More really is not better. Nat Med 2000;6:500-2.
Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, et al.
Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878-86.
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15-24.
Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: New rationale for new directions. Nat Rev Clin Oncol 2010;7:455-65.
Schifeling DJ, George T, McGuirt F, Capizzi RL, Kamen BA. Methotrexate content in squamous cell carcinoma of the head and neck after low-dose methotrexate. Med Pediatr Oncol 1994;22:88-90.
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.
De Felice F, Musio D, Tombolini V. Head and neck cancer: Metronomic chemotherapy. BMC Cancer 2015;15:677.
Pai PS, Vaidya AD, Prabhash K, Banavali SD. Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis. Indian J Cancer 2013;50:135-41. [Full text]
Bock JM, Menon SG, Sinclair LL, Bedford NS, Goswami PC, Domann FE, et al.
Celecoxib toxicity is cell cycle phase specific. Cancer Res 2007;67:3801-8.
Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al.
Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000;60:1306-11.
Gately S, Kerbel R. Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. Prog Exp Tumor Res 2003;37:179-92.
Khan OA, Blann AD, Payne MJ, Middleton MR, Protheroe AS, Talbot DC, et al.
Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer. Br J Cancer 2011;104:1822-7.
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al.
Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N
Engl J Med 2007;357:1695-704.
Patil VM, Noronha V, Banavali SD, Joshi A, Dhumal S, Arya S. A 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. J Clin Oncol 2014;32.15_Suppl.e6017.
Patil VM, Noronha V, Krishna V, Prabhash K. Oral metronomic chemotherapy in recurrent metastatic and locally advanced head and neck cancers. J Clin Oncol 2017;400:219-22.
Kalaichelvi K, Suresh SK, Raja G, Senthikumar KS, Kharthik N. Metronomic chemotherapy in advanced/recurrent head and neck cancer: A tertiary centre experience. South Asian J Cancer 2016;5:37-47.
Mateen A, Adil AR, Maken RN, Khan SA, Arif M. Metronomic chemotherapy in recurrent head and neck cancer. J Clin Oncolo 2015;33:15_suppl.e17007.
Patil VM, Noronh V, Joshi A, Karpe A, Talreja V, Chandrasekharan A, et al.
Metronomic palliative chemotherapy in maxillary sinus tumor. South Asian J Cancer 2016;5:56-8.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]