Journal of Pharmaceutical Care & Health Systems
Open Access

Pharmaco-Economic Comparison of Various Palliative Cancer Chemotherapies in Head and Neck Cancers: India's Need

Aditi Chaturvedi^{* *}Correspondence: Aditi Chaturvedi, Department of Pharmacology, Suman Subharti Medical College, Dehradun, Uttarakhand, India, Email:

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Introduction

Cancer is a major cause of disastrous health expenditures, morbidity and mortality in both the developing and developed countries1. World Bank reported, India to have the largest number of people (800 million; 30% of India’s population) living below international poverty line. India’s middle class is not far above the International Poverty line and illness makes our population vulnerable to fall back into poverty. Annually, in India approximately 1 million people are newly diagnosed with cancer and over 700,000 die as a result of their malignancies. There is an urgent need for India and other countries for developing and applying the principles of Pharmaco-economics to Cancer Chemotherapy medicines to prevent bankrupting the patient or the health care system [1]. It becomes further important to address that when chemotherapy is of palliative intent the patient and relatives must clearly understand the goals of care and the unrealistic hopes and expectations of the patients and relatives regarding prognosis must be addressed and explained well with the benefits and risks as there seems a difference in understanding of the doctors and the patients and their relatives when highly expensive palliative chemotherapy medicines are prescribed. It is therefore important to identify Pharmaco-economically valuable palliative chemotherapy for various cancers and prioritize them in the cancer care guidelines in Indian Scenario. One of the reasons for patient drop outs from the Radiotherapy or Chemotherapy treatment is cost constraints. Also as Radiotherapy centres in our country are limited and far away from the reach of a patient living in a village it further adds to the indirect costs for the patients (stay and travel). There is a pressing need to identify cost effective palliative chemotherapy medicines for the common man in India and apply the principles of Pharmacoeconomics as an important priority in deciding the palliative chemotherapy medicines for the cancer patients. Head and neck cancers account for more than 550,000 cases and 380,000 deaths annually worldwide and are the 6th most common cancer type and in India Head and neck cancers constitute one third of the cancer burden [2].

Hence the need to review the data available on Pharmacoeconomically valuable or cost effective palliative chemotherapy medicines available for various common cancers like Head and Neck cancers in our country. This review article aims at compiling the current data available on the Pharmaco-economic or cost effective palliative chemotherapy available for head and neck cancers and might serve as a basis for conducting further research in the same area. This review is not meant to exhaustively enumerate every palliative chemotherapeutic agent used in Head and Neck cancers, but rather is meant to highlight important palliative chemotherapy medicines and its Pharmacoeconomic advantage comparing its cost and improvement in quality of life, twist score/symptom control, response rate, survival advantage.

Materials and Methods

Palliative chemotherapy

It is chemotherapy given in the non-curative setting to optimize symptom control, improve quality of life, and sometimes to improve survival [3].

Pharmaco-economics

Pharmacoeconomics identifies, measures, and compares the costs and consequences of drug therapy to healthcare systems and society. The two fundamental components of Pharmacoeconomics studies are measures of costs and measures of outcomes that are combined into a quantitative measure or ratio. It can be done using various methods like Cost- Minimization Analysis (CMA), Cost-Effectiveness Analysis (CEA), Cost-Utility Analysis (CUA), and Cost-Benefit Analysis (CBA). Authors of this article have made an attempt to compare the research studies of palliative chemotherapy in a tabular format using various parameters via improvement in symptom control, quality of life, response rates and overall survival advantage and cost of medicines used for 6 months and not specifically conducted a CMA,CEA, CUA, CBA analysis as multiple parameters were involved.

Overall survival (OS)

Broadly the duration between dates of treatment start (for the first palliative, systemic, Non-trial treatment) and date of death as registered in the hospital record. It is defined as the time from random assignment to the date of death due to any cause, or to the date of censoring at the last time the subject was known to be alive in intention-to-treat populations [4].

Progression-free survival (PFS)

Progression-Free Survival (PFS) is defined as the time from random assignment in a clinical trial to disease progression or death from any cause. It is broadly the time from treatment start to disease progression, defined as:

• Clinical or radiological progression of recurrent tumor and/or distant metastases.

• Start of new treatment (with the exception of treatment change due to toxicity).

• Death, whichever occurred first. A second primary tumor was not classified as disease progression.

Response rate (RR)

Response rate determinations reflect tumors that exhibit a complete regression or show a defined reduction for a specified time period. Stable tumors are excluded from response rate determinations. Questions regarding the relationship between response rate and survival are increasingly complicated. With novel agents that do not exert their effect through tumor reduction, response rates may be of little value to accurately assess biologic activity and predict clinical benefit [5].

Clinical benefit

A regulatory end point used in traditional drug approval, has generally been characterized by an increase in patient survival, an unambiguous gold standard of efficacy, or by relieving or delaying the onset of disease-related symptoms. The demonstration of improving survival may be obscured by subsequent therapies after disease progression in randomized trials. Relief of tumor-related symptoms has been difficult to document in oncology trials because of traditionally restrictive eligibility criteria that allow only asymptomatic or early symptomatic patients into the trials.

Results and Discussion

Time without symptoms or toxicities

It was calculated by deducting the sum of time spent with complications/worsening of the baseline symptoms, and for treatment from the overall survival of the patients from the initial diagnosis of metastatic head and neck cancer8. Therefore an attempt has been made by authors to compare the cost of the palliative chemotherapy medicines available for various head and neck cancers with the benefit in symptom control, improvement in quality of life, better response rates, improved survival so as to help the health care policy makers to decide for best value for money of patients for palliative chemotherapy drugs [6].

Palliative chemotherapies in head and neck cancers

For palliation of patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC), the major classes of commonly used cytotoxic chemotherapeutic agents are platinum agents {cisplatin-(CIP), carboplatin}, taxanes (paclitaxel, docetaxel), antimetabolic agents {methotrexate, 5- fluorouracil-(5FU)}, methotrexete, cetuximab etc [7]. They can be used as monotherapy or in various combination regimens. The first-line treatment for incurable R/M HNSCC has been combination chemotherapy with cisplatin and 5FU due to better response rates. Methotrexete (MXT) is another agent that is considered as an appropriate initial treatment for the majority of the patients. A number of trials analyzed individually in 1980s concluded that cisplatin as a single agent is not superior to methotrexete in terms of response or median survival.

The taxanes (paclitaxel, docitaxel) are certainly more difficult to administer and more costly. Taxanes may be the treatment of choice for patients whose renal dysfunction precludes the use of MTX or CIP. Unfortunately, it is unclear to what extent the useof these agents has brought about meaningful improvement in symptom control, quality of life and clinically relevant outcomes in these settings. Cisplatin has been associated with increased survival versus supportive care in only one small study. It is thought provoking that though cisplatin based regimens did not demonstrate improved survival, offer better quality of life or better control of symptoms; this palliative chemotherapy regimen is preferred on the basis of response rate at the cost of greater toxicity for the patient and hence could compromise the quality of life of the patient further. Therefore a need for thorough discussion with the patients about the benefit they are expecting with the palliative chemotherapy and why was a particular palliative chemotherapy regimen chosen for that patient is very important?. As most of the palliative chemotherapy regimens offered a comparable median survival advantage and studies comparing these chemotherapy medicines for symptom control and quality of life is limited it becomes important to compare the direct and indirect costs involved in the overall palliative chemotherapy treatment decided for any patient. Further studies comparing various palliative chemotherapy medicines for symptom control, quality of life and median survival need to be done to actually do justice to the definition of palliative chemotherapy where priority is symptom control and quality of life and sometimes improve survival. A study conducted recently demonstrated good palliation and improved progression free survival with Methotrexate, gefitinib, and combination arms, which is superior to 5-FU+cisplatin arm and were better tolerated. Lately, Geftinib has been considered as an effective chemotherapeutic agent which lacks any serious adverse reactions and has offered improved quality of life even in patients with poor performance status.Yet another study comparing Gefitinib, Methotrexate and Methotrexate plus 5-FU revealed higher QOL of Geftinib at after 2 month and after 4 month as compared to MTX, however the mean quality of life was statistically same in all the groups. The median overall survival was not statistically different in all the groups. In summary, when using response rates as the clinical trial end point for recurrent disease, cisplatin-based combinations appeared to be superior to single agents, but at a cost of greater toxicity and without demonstrating improved survival or other indicators of clinical benefit [8].

Methotrexate is another single agent chemotherapy that is preferred as a palliative chemotherapy agent for squamous cell caricinoma of Head and neck cancer patients. Recently Geftinib has demonstrated good palliation with a better quality of life for the patients in the initial months of treatment for SCCHN. However Tab. Geftinib 250 mg (glenmark company) costs approximately Rs 2470 for 30 tablets is much more costlier than Tab. Methotrexete 10 mg (cipla company) which costs approximately Rs 375 for 30 tablets. Several chemotherapy drugs which are active in R/M HNSCC most notably the platinum compounds, taxanes, fluorouracil (5-FU), methotrexate, geftinib and cetuximab. Approximately 10-25% of patients will respond to treatment with one of these drugs.

The response rate is higher for combinations such as platinum plus a taxane, platinum plus 5-FU, a combination of the three, or one of more of these drugs plus cetuximab. Combination chemotherapy has not been shown to prolong survival over single-agent therapy, with the exception of the addition of cetuximab to a platinum and 5-FU combination16. The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil Chemotherapy (CT), followed by maintenance cetuximab (the "EXTREME" regimen). Cetuximab was the first targeted therapy approved in the first line for R/M SCCHN, conferring survival benefits in combination with platinum-based CT 20-23. The survival improvement with extreme regimen (Cetuximab+5FU+Cisplatin) was significant from 7.4 months to 10.1months with a cost of addition of cetuximab- six cycles for 6lakh Rs in comparision to the 5FU+cisplatin combination regimen which costed approximately Rs 9000 for six cycles. It is prudent to discuss here that the patient and the family must be informed about both the survival advantage at increased costs. Inadequate sharing of expected benefit and cost involved may sometimes leave the patient and the family in huge debts for small improvement of survival advantage in months. One study also concluded, that the EXTREME-regimen may not add as much to overall median survival and may be more toxic than expected when used in patients with R/M HNSCC outside clinical trials. The 11 of 22 pts ended the treatment due to side effects. Three patients died within the first months due to side effects of the treatment. Two patients died of febrile neutropenia after the first cycle of treatment. It also needs a consideration at this point that primary end point of many palliative chemotherapy studies is overall survival or response rates and a lot of times improvement in symptom control and quality of life of the patient is not included as an important evaluation parameter even when the definition of palliative chemotherapy states that it is the chemotherapy given in the non-curative setting to optimize symptom control, improve quality of life, and sometimes to improve survival. A thorough re-consideration of further conducting palliative chemotherapy studies with the intention to offer better symptom control and improved quality of life as primary end points must be a high priority future need [9].

Cost effectiveness of various chemotherapy medicines for head and neck cancers

Methotrexete, Cisplatin+5FU based regimens appear to be cost effective choices as compared to other anticancer chemotherapy medicines for advanced Head and Neck Cancers. Even though the Cetuximab based (extreme) regimen offers reduction in pain, improved quality of life and survival advantage of approximantely 2-3 months it needs a thorough discussion with the patients about the actual cost and benefits of this regimen before the chemotherapy regimen is decided so as to ensure that the patient and their relatives do not keep false hopes with this expensive cetuximab based chemotherapy treatment. Geftinib appears to be a promising new drug for advanced Head and Neck Cancer Patients offering improved quality of life.

Theadvanced Head and Neck Cancers and this information needs a clear sharing with the patients and relatives. It is suggested that the patients could be guided by standard set questionnaires about their queries to the oncologists on extent of disease, patient symptomatology, performance status, affordability, available logistic/social support and various palliative chemotherapy regimens available. Considering the poor Oncologist and patient ratios in India, medical oncology trained palliative care professionals or medical officers could be appointed to assist the oncologists for counseling the patients on deciding the best possible palliative chemotherapy plan for the patient. Please find below a proposed questionnaire for patients undergoing Palliative Chemotherapy for advanced Head and Neck Cancers (Table 1).

Table 1: Proposed Questionnaire format for Specific Information needed/Questions to be asked by Patients undergoing Palliative Chemotherapy (these questions are in addition to the general set of questions to be used to guide your patient about cancer chemotherapy).

As Palliative chemotherapy states that it is the chemotherapy given in the non-curative setting to optimize symptom control, improve quality of life, and sometimes to improve survival, therefore a discussion on palliative chemotherapy options available for Head and Neck Cancers for offering good symptom control and quality of life at a reasonable cost needs to be done. The comparative studies of various palliative chemotherapy options for Head and Neck Cancers on basis of improvement in symptom control, quality of life, overall survival, response rates and cost comparison reveal that Geftinib, Methotrexate and 5FU+Cisplatin, are good options for consideration in Palliative Chemotherapy for Head and Neck Cancer Patients. Combination of Methotrexate and Geftinib was inferior in terms of symptom control/Twist scores and quality of life of patients; however response rates appeared higher as compared to Geftinib treatment alone. The decreasing order of twist score Geftinib (216days), Geftinib+Methotrexete (185days), Methotrexete (163days) and 5FU+Cisplatin (102 days) reveal that Geftinib alone offers good symptom control over other chemotherapy medicines however a six monthly cost of treatment of Geftinib is approximately 14820 Rs which might not be affordable by a patient from low socioeconomic strata in India and then weekly intramuscular methotrexate injections might be a good option available for such patients which is around Rs 831 for 6 months. It will be good to open up discussions with the patients and allow patient autonomy for making such informed decisions on which medicine to choose for the patient for palliative chemotherapy promoting personalized and individualized pharmacotherapy. Twist scores of 5FU+Cisplatin were less than Methotrexete and might be considered inferior to Methotrexete in improving symptom control. For those who can afford Cetuximab based- extreme regimen (cetuximab+5FU+Cisplatin) which offered significant improvement in pain, problems with swallowing, speech and social eating and does not adversely affect the quality of life of patients. It has also shown significant survival advantage from 7.4 months to 10.1 months. However the six cycle treatmentcosts approximately Rs 6,35,937.6 which might be beyond the scope of an average Indian and needs to be discussed with the patient.

No patient should be kept in dark and spends such a huge amount hoping of cure when studies have revealed survival benefit of months with the extreme regimen of Cetuximab. Docetaxel based palliative chemotherapy offered a twist score of 61 days which was much below other palliative chemotherapy regimens for Head and Neck cancers and the cost of treatment for 6 cycles was approximately Rs 86,000, therefore Docetaxel based regimens may not be a good option to consider for palliative chemotherapy. Tablet Geftinib and Injection/Tablets of Methotrexete gives the patient an added advantage that they may continue their palliative chemotherapies from the comfort of their homes and added costs of travel, hospitalization may be saved which has not been considered in the Table 1 [10].

Conclusion

There seems an overall need to open up discussions with the patient and family member to plan and individualize the Pharmaco-economically cost effective palliative chemotherapy plan in Head and Neck Cancers. The end point that will be achievable should be clearly stated right from the beginning and the families and the patients must be appropriately guided and prepared and be assured of support in all situations. Oncologists might be concerned about the huge patient load and paucity of time to open up such discussions, therefore the authors suggest that based on individualised hospital settings a proper plan of training/appointing junior doctors trained in palliative care may be utilized.

Conflict of Interest

The authors declare that they have no competing interests.

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