|Year : 2012 | Volume
| Issue : 6 | Page : 106-110
Metronomic chemotherapy in advanced oral cancers
Vijay Patil1, Vanita Noronha1, AK D'cruz2, SD Banavali1, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
2 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, India
|Date of Web Publication||24-Jan-2012|
Department of Surgical Oncology, Tata Memorial Hospital, Mumbai
Source of Support: None, Conflict of Interest: None
Context: To assess the feasibility of metronomic chemotherapy in the palliative care setting.
Aims: To study the toxicity profile and efficacy of metronomic chemotherapy for palliation in oral cavity cancers.
Settings and Design: Retrospective analysis of prospectively collected data.
Materials and Methods: Subjects receiving metronomic chemotherapy from August 2010 to January 2011 for palliation in oral cancers subjected to certain criteria were included. Metronomic chemotherapy offered was a combination of twice daily celecoxib 200 mg and weekly methotrexate 15 mg/m 2 .The chemotherapy was continued till disease progression, intolerable side effects or patients' desire to stop. The toxicity profile was reported in accordance with common terminology criteria for adverse events (CTCAE) version 4.02. The efficacy was noted in terms of symptom control, response rates, progression free survival (PFS) and overall survival (OS).
Statistical analysis used: SPSS version 16 has been utilized. Descriptive analysis has been presented. The Kaplan-Meier survival analysis was performed for estimation of the PFS and OS.
Results: Eighteen patients with a median age of 50.5 years, 13 males and 5 females, participated in the study. Five patients had received no previous treatment while the rest had some form of previous treatment. ECOG performance status was 1 in 14 patients and 2 in 4 patients. Grade 3-4 mucositis was seen in one patient. Clinical benefit rate was 66.67%. The estimated median PFS and median OS were 5.2 months and not reached respectively.
Conclusions: Use of metronomic chemotherapy seems promising and well tolerated in this setting. Large trials are warranted to confirm these results.
Keywords: Chemotherapy, metronomic, oral cavity cancer, palliative
|How to cite this article:|
Patil V, Noronha V, D'cruz A K, Banavali S D, Prabhash K. Metronomic chemotherapy in advanced oral cancers. J Can Res Ther 2012;8, Suppl S2:106-10
| > Introduction|| |
Oral cancers form a major contributor toward the burden of cancer in India. Most of these patients (60-70%) present in locally advanced stages.  Curative treatment in these cases utilizes combination modality of surgery, radiation and chemotherapy. Despite adequate treatment, incidence of recurrence is nearly 30-40%. ,,, Distant recurrences and loco-regional recurrences not amenable to further local treatment is a common occurrence as both radiation and surgery have been optimally utilized in most of these patients. Further 10-30% of patients according to various series present with upfront metastasis and chemotherapy is the only option. 
The use of cytotoxic chemotherapy in such metastatic, recurrent or advanced cases has been extensively reported. , The use of single agent cisplatin prolonged survival over best supportive care alone. Since then, many combination chemotherapy with platinum as one of the agents have been utilized; however, none of them were clearly superior and the overall survival was not increased with respect to the increase in the number of agents utilized. The response rates were however better with combination chemotherapy. The use of cetuximab in combination with cisplatin and 5 FU lead to an improvement in overall survival with respect to cisplatin and 5FU combination. This lead to FDA approval of cetuximab for use in recurrent and metastatic settings. ,,,, It has been recommended in the NCCN and the ESMO guidelines for the above-mentioned indication as the category one recommendation. However, the utilization of this combination in our country is hampered by the financial and logistic considerations.
Metronomic chemotherapy is a new modality of drug administration coined by Douglas Hanahan.  The aim of treatment is to induce and maintain tumor dormancy (angiogenic dormancy), thus leading to long-term asymptomatic control of the disease. The expression of COX-2 enzyme is increased in head and neck cancers and it is an important mediator of angiogenesis.  The use of low doses of methotrexate have been shown in in-vivo and in-vitro to be antiangiogenic.  The combination of celecoxib and methotrexate has been reported in a small study by Gluck et al, in chemo-resistant head and neck cancers to have good efficacy without significant toxicity.  A similar modified protocol of metronomic chemotherapy is followed in our institution in those patients who cannot afford or are not willing for intravenous chemotherapy with or without cetuximab. In this report, we report our early results and the safety profile of use of metronomic chemotherapy in head and neck cancer patients with metastatic, recurrent and locally advanced patients who are not amenable to local treatment.
| > Materials and Methods|| |
This is an analysis of prospectively collected data. Patients with metastatic, recurrent and locally advanced oral cavity cancers which were not amenable to local treatments were offered the combination of chemotherapy and cetuximab. Those patients who refused intravenous chemotherapy were given the option of oral metronomic chemotherapy. Patients with uncontrolled comorbidities and with a disease free interval of less than three months were excluded.
These patients received daily oral celecoxib 200 mg twice daily and weekly oral low dose methotrexate 15 mg/m 2 . These patients prior to start of chemotherapy underwent a complete physical examination, complete hemogram, biochemical evaluation and chest radiographs. A CT scan of the affected part was done prior to start of the chemotherapy. These patients were then followed up after seven days for documentation of toxicity and then monthly for two months and then two monthly thereafter. The toxicity was graded according to the CTCAE version 4.02 (common terminology criteria for adverse events) and response was evaluated according to the RECIST criteria version 1.1 (response evaluation criteria in solid tumors). Symptom control was also documented. In addition, CT scan was repeated in every two months to document the response. Chemotherapy was stopped in the event of disease progression or intolerable side effects. The data was collected in a predesigned data collection form. In this report, the patients included were those who received metronomic chemotherapy from August 2010 to January 2011.
The statistical analysis was done with SPSS version 16. Descriptive analysis was performed. The progression free survival (PFS) was calculated from the date of histopathological proof of malignancy or recurrence (which ever was later) to the date of progression of disease, discontinuation of chemotherapy (due to any cause) or death due to any cause which ever occurred the earliest. The overall survival (OS) was calculated from the date of histopathological proof of malignancy or recurrence (which ever was later) to the date of death due to any cause which ever occurred the earliest. Kaplan-Meir method was used to obtain actuarial estimates of these survival related endpoints.
| > Results|| |
Between the period of August 2010 to January 2011, 18 patients with oral cavity cancers received oral metronomic chemotherapy. The median age was 50.5 years (30-68 years). The sex distribution was skewed with 13 males (72.2 %) and only 5 females (17.8%). The median income was 3500 INR per month. Majority of patients 11 (61.1%) were from outstation. The performance status was ECOG PS 1 in 14 patients (77.80%) and it was PS 2 in 4 patients (22.22%). Seven patients (38.88%) had received platinum or platinum-based chemotherapy as a component of initial treatment, five patients (27.78%) had received no previous treatment and rest had received only local treatment. The details of treatment are shown in [Table 1]. The median event free interval from previously received treatments was six months (range 3-40 months). Median cumulative exposure to cisplatin was 200 mg.
|Table 1: Details of previously received treatments, patients who had received chemoradiation were exposed|
to cisplatinum and those who had received neoadjuvant chemotherapy had received DCF regimen (docetaxel, cisplatin and 5-fluorouracil)
Click here to view
The disease-related parameters are shown in [Table 2]. The staging shown is at the start of palliative chemotherapy. Most of these patients were with a primary cancer arising from buccal mucosa (61.11%). The indication of oral metronomic chemotherapy was metastatic diseases in 1 patient and local disease not amenable to loco-regional treatment in 17 patients.
The toxicity noted was minimal. There was one episode grade 4 mucositis in one patient requiring discontinuation of metronomic chemotherapy. The other episodes of mucositis seen were either grade 1 or grade 2 in 12 patients (66.67%). In hematological toxicity, only one patient had grade 3 anemia; it was a heartening fact that there was no evidence of any febrile neutropenia. The details of other toxicities are shown in [Table 3].
|Table 3: Toxicity details, where only the highest grade of toxicity per patient is depicted|
Click here to view
The response rates at the end of two months and at last follow up are depicted in [Table 4]. Clinical benefit rate was 66.67% at the end of two months and at respective last follow up, it was 44.48%. The most common cause of discontinuation of chemotherapy was progression of disease (9 patients) and intolerable side effects in one.
Symptom control was achieved in at 12 (66.7%). The pain control is depicted in [Figure 1].
|Figure 1: (a) Pain grade at presentation, (b) Pain grade at seven days post start of metronomic chemotherapy, (c) Pain grade at one month, (d) Pain grade at two month|
Click here to view
The median follow up was five months. The crude median PFS and OS were 5 and 3.05 months respectively. The Kaplan-Meir graphs for estimated PFS and OS are depicted in [Figure 2] and [Figure 3] respectively.
| > Discussion|| |
The primary aim of treatment in palliative setting in oral cavity cancer is to provide symptomatic relief and secondary aim is to improve overall survival.  In a country like ours where the major burden of these cancers is seen in patients with poor socioeconomic status, use of therapies which are suitable to this population is warranted.
The most distressing symptom reported by most patients is pain. The symptom control with metronomic chemotherapy is depicted in [Figure 1]. All of these patients were on WHO step II analgesic (combination of NSAID and a weak opoid) when treatment was started and within a week it can be appreciated that the peak of the curve has fallen toward right side indicating a decrease in higher grades of pain. At this step in accordance with the grade of pain, they were given either step I (only NSAID), step II (combination of NSAID and a weak opoid), or step III (strong opiod) analgesic. At the end of one month, the requirement for analgesic had further decreased. The control of pain in this case with metronomic is effective. The symptomatic response rates seen are equivalent to those previously reported in a trial on palliative radiotherapy from the same institute. 
Though symptomatic response rates with metronomic chemotherapy and palliative radiation are similar, it would be worthwhile to compare the toxicity profile of these two modalities. The greater level of mucositis and xerostomia which these patients get is a topic of concern. The level of mucositis is a function of radiation field size, total dose, fraction size and duration of treatment. It has been shown that biologically equivalent doses which are equivalent to conventional regimen of 70 Gy/35#/7weeks provide better palliation and a better survival too.  However, it is a disheartening fact that these regimens are associated with a rate grade 3 mucositis as high as 70-80%. In a cancer where the best reported survival are in the range of 6-8 months, the quality of life after the completion of treatment is an important consideration.  A treatment which controls symptoms faster and without grade 3-4 side effects being more than 5% is required. Though the numbers in this study are small, these regimens seem to be showing promise with this respect. Even the use of palliative chemotherapy with or without cetuximab is not without side effects. In extreme trial, the rate of febrile neutropenia was 31% in chemotherapy arm and 26% in chemotherapy and cetuximab arm. The rates of sepsis were 2% in chemotherapy arm and 7% in chemotherapy and cetuximab arm. It is also important to consider that when cetuximab is given to these patients, they have to visit hospital each week till progression or intolerable side effects. Though the cohort of patients used in this study are not similar to those in extreme trial, it does seem that use of metronomic is unlikely to produce a high incidence of grade 3-4 life-threatening complications. 
The use of cetuximab in addition to chemotherapy is the regimen associated with survival advantage. ,,,, However, the progression free survival noted in various trials utilizing chemotherapy with or without cetuximab or utilizing radiation as sole modality for palliation seems similar to those seen in this trial. Further in a country, where this cancer is prevalent in low socioeconomic strata and mostly without any health insurance support, the use of cetuximab is restricted. Such a low cost metronomic regimen is an important treatment alternative. The requirement for outpatient administration of intravenous drugs is also minimized which benefits the over burdened health care system as well as the patients who are often too sick to travel frequently to the hospitals.
The major limitations of the present study are the limited number of participants and the short follow up. A proper evaluation of this regimen in a prospective trial setting is warranted given the encouraging response rates and minimal side effects.
| > Conclusion|| |
Use of metronomic chemotherapy schedule used in the present study may be useful in palliative treatment of patients with advanced head and neck cancer. Large trials are warranted to confirm these results.
| > References|| |
|1.||Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80. |
|2.||Murthy V, Gupta T, Agarwal JP, Ghosh-Laskar S, Budrukkar A. Cautious optimism in advanced incurable head neck cancer. Radiother Oncol 2008;89:123-4. |
|3.||Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009;45:309-16. |
|4.||Spector GJ. Distant metastases from laryngeal and hypopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec 2001;63:224-8. |
|5.||Spector JG, Sessions DG, Haughey BH, Chao KS, Simpson J, El Mofty S, et al. Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope 2001;111:1079-87. |
|6.||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. |
|7.||Lamont EB, Vokes EE. Chemotherapy in the management of squamous-cell carcinoma of the head and neck. Lancet Oncol 2001;2:261-9. |
|8.||Vermorken J, Hitt R, Geoffrois L, Erfan J, Kawecki A, Zabolotnyy D, et al. Cetuximab plus platinum-based therapy first-line in recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Efficacy and safety results of a randomized phase III trial (EXTREME). Eur J Cancer 2007;5:324. |
|9.||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. |
|10.||Tejani MA, Cohen RB, Mehra R. The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics 2010;4:173-85. |
|11.||Rivera F, García-Castaño A, Vega N, Vega-Villegas ME, Gutiérrez-Sanz L. Cetuximab in metastatic or recurrent head and neck cancer: The EXTREME trial. Expert Rev Anticancer Ther 2009;9:1421-8. |
|12.||Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646-54. |
|13.||Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy: New rationale for new directions. Nat Rev Clin Oncol 2010;7:455-65. |
|14.||Gately S, Li WW. Multiple roles of COX-2 in tumor angiogenesis: A target for antiangiogenic therapy. Semin Oncol 2004;31 (2 Suppl 7):2-11. |
|15.||Pai RB, Lalitha RM, Pai SB, Kumaraswamy SV, Lalitha N, Bhargava MK. Analysis of in vitro and in vivo sensitivity of oral cancer cells to methotrexate. Exp Oncol 2009;31:118-20. |
|16.||Glück S. Metronomic therapy in recurrent and metastatic chemoresistant SCCHN: Data from a pilot study. Proc Am Soc Clin Oncol 2003;22:A2066. |
|17.||Agarwal JP, Nemade B, Murthy V, Ghosh-Laskar S, Budrukkar A, Gupta T, et al. Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6. |
|18.||Stevens CM, Huang SH, Fung S, Bayley AJ, Cho JB, Cummings BJ, et al. Retrospective study of palliative radiotherapy in newly diagnosed head and neck Carcinoma. Int J Radiat Oncol Biol Phys 2011;81:958-63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20950952 [Last cited on 2011 Jul 31]. |
|19.||Specenier PM, Vermorken JB. Recurrent head and neck cancer: Current treatment and future prospects. Expert Rev Anticancer Ther 2008;8:375-91. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Efficacy of schedule-dependent metronomic S-1 chemotherapy in human oral squamous cell carcinoma cells
| ||Ferdous, T., Harada, K., Kin, T., Harada, T., Ueyama, Y. |
| ||International Journal of Oncology. 2013; 43(1): 271-279 |
||Has the time come for metronomics in low-income and middle-income countries?
| ||André, N., Banavali, S., Snihur, Y., Pasquier, E. |
| ||The Lancet Oncology. 2013; 14(6): e239-e248 |
||Efficacy and safety of metronomic administration of paclitaxel for advanced recurrent non-small-cell lung cancer
| ||Noronha, V., Patil, V.M., Joshi, A., Prabhash, K. |
| ||Indian Journal of Cancer. 2013; 50(2): 122-127 |
||Metronomic therapy: Chemotherapy revisited
| ||Noronha, V., Krishna, M.V., Patil, V., (...), Banavali, S.D., Prabhash, K. |
| ||Indian Journal of Cancer. 2013; 50(2): 142-148 |
||Metronomic chemotherapy in progressive pediatric malignancies: Old drugs in new package
| ||Bahl, A., Bakhshi, S. |
| ||Indian Journal of Pediatrics. 2012; 79(12): 1617-1622 |