Abstract

Introduction 5-fluorouracil (5-FU) is a crucial agent in treating various types of cancer, particularly recurrent head and neck cancers (HNCs). According to prior studies, individuals who underwent therapeutic drug monitoring (TDM) based 5-FU dosage adjustments showed significantly higher response rates and experienced fewer adverse events compared with those who received the standard 5-FU administration. This study aims to enhance our understanding of the overall clinical outcomes in patients with recurrent HNCs who received 500 mg of 5-FU through a pharmacokinetic (PK) analysis.

Objectives Our objectives are to conduct TDM in selected HNC patients and observe individual PK responses, efficacy, tolerability, and drug toxicity.

Materials and Methods We enrolled a total of 12 patients with recurrent metastatic HNC, and all of them received a fixed dose of 500 mg with cisplatin in a 21-day cycle. During cycle II or III, we analyzed the blood concentrations and PK parameters of 5-FU using the liquid chromatography and mass spectrometry (LC–MS) technique. Notably, we calculated the Concentration maximum (Cmax), time at which the concentration reaches maxiumum (Tmax), Half life of the drug (T1/2), and area under the curve (AUC) for the 500-mg dose of 5-FU, as the PK data for this particular dose were unavailable, making our study uniquely valuable for assessing efficacy and toxicity.

Results Within the study group, 83.33%-obtained an average AUC range of 1,000 to 3,000 h/µg/mL. Out of this group, 41.66%-showed a partial response, 33.33%-experienced disease progression, and 25%-remained stable during the therapy. One patient had an AUC below the expected value (832.21 h/µg/mL), while another had an overexposed AUC value (5726.87 h/µg/mL), resulting in a poor clinical outcome. After interpreting the results, suggestions for dosage adjustments were made to the clinician.

Conclusion From our interventional study, it is evident that at a flat dose of 500 mg, PK-based individual dosage regimens play a superior role in managing advanced cancer patients with minimal toxicities. This PK analysis showed us clarity on the outcomes of 5-FU at a 500-mg dose.

Introduction

An antimetabolite chemotherapeutic molecule, 5-fluorouracil (5-FU), has been used in the last six decades to treat multiple cancers, including gastrointestinal (GI), breast, ovarian, and head and neck cancers (HNCs). Head and neck squamous cell carcinoma (HNSCC) refers to the majority of head and neck malignancies, which are generated from the mucosal epithelium in the oral cavity, pharynx, and larynx. In most of these, quantifying the efficacy and establishing an individualized dose is still challenging for health care professionals and researchers. 5-FU is the primary component of combination chemotherapy in patients with metastatic HNCs. Like other anticancer drugs, 5-FU is administered by body surface area (BSA) based dosing in most practices.[1] Numerous studies have clinically proven suboptimal and poor outcomes in colorectal cancers (CRCs) treated with 5-FU in different regimens, such as folinic acid, fluorouracil and oxaliplatin chemotherapy drugs (FOLFOX)[2] and folinic acid, fluorouracil and irinotecan chemotherapy drugs (FOLFIRI).[3] But evaluating the efficacy of 5-FU in HNC has been stated in very few studies. Notably, stage III and IV locoregionally progressed tumors were found in roughly 60%-of HNC patients.[4] [5] Many patients had stage IV (stage IVA) tumors out of the two stages. The typical patient survival time for stage IV HNC patients with metastatic and locoregionally progressed HNC was approximately 10 months, whereas nonmetastatic stage IV HNCs were treatable.[6]

Therapeutic drug monitoring (TDM) is a part of clinical therapy in which a patient's drug level is continuously monitored for the concentration of a specific medicine to ensure that their dose regimens are working as effectively as possible.[7] TDM should be considered and recommended for improving the safety and efficacy of drugs with a narrow therapeutic index.[8]

The typical routine for administering 5-FU in concomitance with many anticancer drugs has been based on BSA, regardless of the regimen used.[9] Sadly, BSA dosing cannot fit the needs of different body types and leads to a wide range of 5-FU exposure. A study with 81 patients with metastatic CRC documented a lack of association between BSA and 5-FU.[10] An algorithm for 5-FU dosage adjustments was introduced by Wilhelm et al[11] in a study conducted in 14 HNC patients administered with cisplatin and a 5-day continuous infusion of 5-FU. Hillcoat et al reported a strong association between 5-FU plasma concentrations and tumor response in patients with GI malignancies in the 1970s.[9] All the patients got nitrosourea 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) 150 mg/m2 on the first day, followed by a 5-day continuous infusion of 5-FU at a rate of 1,200 mg/m2/d on days 1 to 5, delivered every 6 weeks. Measurements of plasma 5-FU concentrations revealed significant interpatient variability. Furthermore, the area under the curve (AUC) was found to be considerably larger in patients with either partial response (PR) or stable disease (SD) compared with those who did not have a tumor response. This first instance linked clinical data on 5-FU plasma exposure to clinical action. 5-FU is a highly saturable, narrow therapeutic index with a very short half-life of 8 to 20 minutes. This favors the trend to adopt a pharmacokinetic (PK) based dosing in cancer patients. Clinical investigations from the past few decades have demonstrated that individual 5-FU dose titration with PK monitoring results in a high and effective survival rate, a high positive response, and good tolerability in CRC and HNC patients.[12] [13] The adverse event system of voluntary postmarketing reporting reviewed data from the U.S. Food and Drug Administration (FDA) suggested severe toxicities. Nausea, diarrhea, vomiting, mucositis, neutropenia, and palmar–plantar erythrodysesthesia (PPE) are examples of systemic Fluoropyrimidines (FP)-associated toxicities (FP-TOX).[14]

This pilot investigation enhances comprehension of disease progression, survival rate, and efficacy of chemotherapy in certain populations while providing updated information to clinicians on the safe and effective utilization of 5-FU. The main focus of this study is to examine the correlation between PK data and its impact on both treatment effectiveness and potential side effects when administering a constant 500-mg dose of 5-FU through intravenous infusion over 8 hours.

It is important to note that the actual treatment regimen involves a 2-day intravenous infusion of 5-FU + cisplatin, repeated every 21 days, with cisplatin playing a significant role in overall clinical outcomes. However, this evaluation specifically concentrates on observing the PK data of 5-FU at a flat dose of 500 mg.

Materials and Methods

Study Design

This is a prospective interventional study. Twelve patients diagnosed with advanced squamous cell carcinoma of the head and neck were studied in the Department of Clinical Research, Erode Cancer Centre, Tamil Nadu, India.

Inclusion and Exclusion Criteria

Recurrent HNC patients with normal renal, hepatic, and cardiac functions and good hematological status were included. Patients with renal failure or hepatic impairment, vulnerable populations (pediatrics and age above 75 years), obesity patients, medication histories, and those using drugs and alcohol that interfere with 5FU were excluded.

| Fig 1 : Toxicity assessment of study population. Toxicity changes occurred in patient while on 5-fluorouracil treatment. Nausea and dizziness were predominant. ADR, adverse drug reaction.

| Figure 2: Concentration versus time graph. A 64-year-old female patient of was on 5-fluorouracil treatment. Samples were collected and the concentration versus time graph was plotted and displayed. The graph shows the area under the curve concentration is increased, indicating the patient requires low dose.

| Figure 3:Concentration versus time graph. A 53-year-old male patient was on 5-fluorouracil treatment. Samples were collected and the concentration versus time graph was plotted and displayed.

Comparison of Pharmacokinetics

Deviated samples: The AUC and tumor reduction were plotted in a normal probability plot using regression statistics ([Fig. 4]). The R-value from the correlation using regression statistics was 0.16, that is, the R-value is progressing toward a positive factor. In the case of a large sample population, the relation between AUC and tumor size reduction will be clearer.

|  Figure 4:The normal probability by regression statistics. The plot shows the regression graph of area under the curve concentration and tumor size reduction. The regression value is 0.16. It shows that the plot is moving toward a positive correlation.

Interpretation of the R value is as follows:

• 0: relation cannot be predicted.

• +1: positive relation between variables.

• –1: negative relation between variables.

The underdosed sample showed reduced Cmax, Tmax, and AUC and increased clearance, while the overdosed sample showed increased Cmax, Tmax, and AUC and reduced clearance. We have attained the expected target in 10 samples (84.4%).

p = 0.615 (p > 0.05): The p value calculated for the AUC range and intercept was greater than 0.05. So the AUC range and the outcome were not statistically significant. The result shows nonsignificance of the p value due to small sample size and disease progression. The results indicated that one (8.3%) patient was underdosed and showed decreased maximum concentration (Cmax) and below the AUC range. One (8.3%) patient showed increased maximum concentration (Cmax) and AUC range. Ten (84.4%) patients were under an optimum range.

Response Rate

The response evaluation was represented using the RECIST criteria for 12 subjects. PR was observed in five (41.66%) patients, disease progression in four (33.33%) patients, and stable response in three (25%) patients. No complete responses were observed.

Discussion

In advanced HNC, the main goal of chemotherapy is to relieve symptoms. Slightest increase in their response rate can improve their quality of life. In general, when administered as first-line therapy, combination chemotherapy has response rates that are 10 to 15%-greater than those of single-agent chemotherapy (15–40%).[17] [18] Only a tiny proportion of patients with stage III or IV locoregionally progressed HNCs are treated by radiation or surgery. Concurrent radiation and chemotherapy treatment may yield better outcomes in terms of lifespan and disease-free life expectancies.[19]

Numerous studies have shown that an individual's response to chemotherapy is significantly influenced by the PK heterogeneity of 5-FU in them.[2] [20] Age-related changes in physiology and biological traits may affect the PK of medicines, alter plasma concentrations, and ultimately influence the acceptability and efficacy of chemotherapy. The variability in the steady-state concentration may also be due to changes in the infusion pump or drug collection. When therapy is based on BSA or a flat dose, the clearance of 5-FU exhibits significant intersubject variability that is not diminished. The BSA-based dose was personalized for individual patient dosing of chemotherapy drugs.[21] Another major point is that the drug is unstable in blood and plasma at room temperature, while the catabolism of 5-FU is handled by the DPD enzyme.[11] [22] [23] [24] Many studies have been conducted to evaluate the efficacy of a dose-modifying algorithm and demonstrate the advantages of a 5-FU PK-guided dosing pattern for reducing toxicity and enhancing therapeutic outcomes, although BSA is an accepted method for determining 5-FU dosage. TDM and adjustment of the 5-FU concentration significantly improved the efficacy of chemotherapy.[25]

In our study, we chose 12 recurrent HNC patients diagnosed with tongue cancer (4), oropharyngeal cancer (4), buccal mucosa cancer (2), tonsil cancer (1), and esophageal cancer (1) in palliative care who underwent combination chemotherapy of cisplatin and 5-FU. The age range was between 45 and 75 years. We found that increasing dosage in underdosed individuals may assist in minimizing toxicities and complaints from the present cycle to subsequent cycles in progressing malignancies. At the initial cycle, a flat 5-FU dose of 500 mg was administered. No difference in terms of the 5-FU combination was observed. However, all the patients received 500 mg of 5-FU + cisplatin on day 1 and 1,000 mg of 5-FU + cisplatin on day 2 as a cumulative total regimen for a 21-day cycle. As a reminder, for this study, individual dose adjustment was based on systemic exposure measured from TDM. An average AUC range of 1,000 to 3,000 h/µg/mL was obtained in 83.33%-of the group, with two exceptions. One was under the expected AUC (832.21 h/µg/mL) and one had an overexposed AUC value (5,726.87 h/µg/mL). Both cases showed wide variability in PK parameters.

This result led to an important variability in 5-FU steady-state concentrations, ranging from 130 to 541 mg/L for an identical total dose of 500 mg. The Css in two cases (16.66%) showed a significant change in their AUC and was subjected to poor clinical outcomes (i.e., disease progression). Similarly, the PK parameters of all the patients were interpreted according to the clinical outcome. PR was observed in 41.66%-of the patients, disease progression in 33.33%-patients, and SD in 25%-patients. Suggestions for dosage adjustments were made to the clinician after interpreting the results. In Saam et al,[2] the 5-FU AUC was recorded for 4 cycles in 64 CRC patients prescribed with any regimen in which 5-FU was administered throughout 44 to 48 hours. The first measurement indicated that 68%-of patients were underexposed, 13%-were under the therapeutic range, and 19% had a superior AUC target level. A clinical trial conducted by Macaire et al focused on assessing the benefit-to-risk ratio in elderly individuals. The study investigated the relationship between 5FU exposure and toxicity while also comparing the effectiveness of 5FU therapeutic drug monitoring (TDM). The drug was monitored on cycle 1, and blood samples were drawn. Further dosage adjustments were made. Results showed a percentage difference between older and younger patients. The AUC of 5-FU at cycle 2 was 64%-in older and 68%-in younger patients. The toxicity level decreased compared with the first cycle after dose adjustment. Their results demonstrate that the vast majority of patients are not in the expected therapeutic range after receiving a standard 5-FU BSA-based dose. The high interindividual variability after dose adaptation testifies to a very limited interest in 5-FU BSA-based dosing. Upon 5-FU PK-guided dose adjustment in subsequent cycles, a significant decrease in this variability was observed.[23] The clinical outcome was evaluated through imaging studies at the end of chemotherapy, and the interpretation revealed some publications describing increased rates of nausea, diarrhea, stomatitis, leukopenia, or neutropenia.[11] [23] In our investigation, after a standard flat dose of 500 mg, the following common toxicity symptoms were observed: nausea (91.66%), vomiting (25%), dizziness (83.33%), fatigue (75%), anorexia (41.66), diarrhea (50%) and moderate stomatitis (8.33%), anaphylactic reaction (16.66%), anemia (50%), thrombocytopenia (8.33%), and neutropenia (58.33%). However, both toxicity and clinical outcome depend on the activity of 5-FU given with cisplatin as a combination therapy. We observed that grade III and IV toxicities were associated with a higher AUC range than grade I and II toxicities. Conversely, almost twice as many toxicities were observed among overexposed patients compared to patients who were underexposed or well exposed.

The results show that the flat dose gives a significant positive response in most cases along with lower toxicity. All 12 recurrent HNC patients in the study underwent TDM, and all the PK parameters were assessed. The target AUC was obtained in approximately 83.33 %. Dose alterations were made for the under- and over-exposed patients. Toxicities were mild and moderate with manageable conditions. Out of 12 subjects, 41.66 %-showed PR, 33.33 %-showed disease progression, and 25%-were stable.

The main limitations of our study are the small sample size and the short study time. A multi-centered study with a large sample size might give more detailed and confirmatory reports of the relationship between dose and clinical response of 5-FU at a flat dose.

Future studies should come up with preemptive pharmacogenetic testing that confidently enhances 5-FU exposure in a significant number of patients. Despite the abundance of positive shreds of evidence supporting the 5-FU TDM, the clinical routine of PK tests has not been widely established. To fully enter the era of precision medicine, a model framework incorporating the PK and pharmacodynamics of 5-FU will be necessary. The use of model applications may also help clinicians determine the appropriate dose before beginning chemotherapy.

Conclusion

From our interventional study, it is evident that at a flat dose of 500 mg, PK-based individual dosage regimens play a superior role in managing advanced cancer patients with minimal toxicity. The study population involving 12 recurrent HNC patients underwent TDM, and all the PK parameters were assessed. The target AUC was obtained in approximately 83.33%-of patients. Two patients who deviated from the expected therapeutic window were considered for dosage adjustments. The dose was increased to 750 mg + 1 g in patient 6 in the next cycle and patient 5 was prescribed 350 mg + 750 mg by the clinician. PR was observed in 41.66%-patients, disease progression in 33.33%, and SD in 25%- patients. This PK analysis showed clarity on the outcomes of 5-FU at a 500-mg dose.

A small sample size and a non-PK-based dosage regimen before TDM may be the cause of the nonsignificance of our results. However, the significance of a sample size of 12 showed positive progress with a regression value of 0.16. Increasing the sample size to more than 30 with extended follow-up can have a greater impact by establishing a detailed PK response for 500 mg of 5-FU. This single-center pilot study gives hope for managing advanced HNC patients with flat doses for better tolerability while reducing toxicity. Its precise role in the management of HNC remains to be determined at a larger scale.

Conflict of Interest

None declared.

Acknowledgments

We express our sincere thanks to our honorable chairman of Vivekanandha Educational Institutions for allowing us to carry out this work and for providing us with all the facilities for the study. We are thankful to our Principal, Swamy Vivekanandha College of Pharmacy (SVCP) and the Department of Pharmacy Practice, SVCP for their support throughout the study. We thank all the physicians and nurses at the Erode Cancer Centre for their kind support. Our sincere thanks also go to INNOSPECS BIOANALYTICAL LABORATORY for the pharmacokinetic analysis.

Author Contributions

N.K.B, N.D., and S.D.B. were responsible for the concept and design of the study, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and literature search. Critical revision of the manuscript for important intellectual content was done by K.V. and P.S.N. They also provided administrative, technical, or logistic support. PSN contributed to design the study protocol and supervised the study.

Statement

The manuscript has been read and approved by all the authors, and the requirements for authorship have been met.

Patient Consent

The consent from the patient has been taken to participate on this study.

References

Baker SD, Verweij J, Rowinsky EK. et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002; 94 (24) 1883-1888
CrossrefPubMedGoogle Scholar
1. Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR. Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens. Clin Colorectal Cancer 2011; 10 (03) 203-206
   CrossrefPubMedGoogle Scholar
2. Maiello E, Gebbia V, Giuliani F. et al; Gruppo Oncologico dell'Italia Meridionale (GOIM). FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale (GOIM). Ann Oncol 2005; 16 (Suppl. 04) iv56-iv60
   CrossrefPubMedGoogle Scholar
3. Kim DH, Kim WT, Lee JH. et al. Analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer. Cancer Res Treat 2015; 47 (01) 46-54
   CrossrefPubMedGoogle Scholar
4. Lee JH, Song JH, Lee SN. et al. Adjuvant postoperative radiotherapy with or without chemotherapy for locally advanced squamous cell carcinoma of the head and neck: the importance of patient selection for the postoperative chemoradiotherapy. Cancer Res Treat 2013; 45 (01) 31-39
   CrossrefPubMedGoogle Scholar
5. Pisani P, Airoldi M, Allais A. et al. Metastatic disease in head & neck oncology. Acta Otorhinolaryngol Ital 2020; 40 (Suppl. 01) S1-S86
   CrossrefPubMedGoogle Scholar
6. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med (Korean Assoc Intern Med) 2009; 24 (01) 1-10
   PubMedGoogle Scholar
7. Hashimoto Y, Yoshida Y, Yamada T. et al. Current status of therapeutic drug monitoring of 5-fluorouracil prodrugs. Anticancer Res 2020; 40 (08) 4655-4661
   CrossrefPubMedGoogle Scholar
8. Hillcoat BL, McCulloch PB, Figueredo AT, Ehsan MH, Rosenfeld JM. Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. Br J Cancer 1978; 38 (06) 719-724
   CrossrefPubMedGoogle Scholar
9. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16 (04) 215-237
   CrossrefPubMedGoogle Scholar
10. Wilhelm M, Mueller L, Miller MC. et al. Prospective, multicenter study of 5-fluorouracil therapeutic drug monitoring in metastatic colorectal cancer treated in routine clinical practice. Clin Colorectal Cancer 2016; 15 (04) 381-388
    CrossrefPubMedGoogle Scholar
11. Santini J, Milano G, Thyss A. et al. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer 1989; 59 (02) 287-290
    CrossrefPubMedGoogle Scholar
12. Gamelin E, Boisdron-Celle M, Guérin-Meyer V. et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 1999; 17 (04) 1105
    CrossrefPubMedGoogle Scholar
13. Paulsen NH, Vojdeman F, Andersen SE. et al. DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview. Basic Clin Pharmacol Toxicol 2022; 131 (05) 325-346
    CrossrefPubMedGoogle Scholar
14. Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 2007; 60 (04) 503-507
    CrossrefPubMedGoogle Scholar
15. Saif MW, Syrigos K, Mehra R, Mattison LK, Diasio RB. Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: experience of 4-years. Pak J Med Sci 2007; 23 (06) 832-839
    PubMedGoogle Scholar
16. Hughes RS, Frenkel EP. The role of chemotherapy in head and neck cancer. Am J Clin Oncol 1997; 20 (05) 449-461
    CrossrefPubMedGoogle Scholar
17. Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol 1988; 15 (01) 70-85
    PubMedGoogle Scholar
18. Vokes EE, Haraf DJ, Weichselbaum RR, McEvilly JM, Sutton HG, Panje WR. Perspectives on combination chemotherapy with concomitant radiotherapy for poor-prognosis head and neck cancer. Semin Oncol 1992; 19 (4, Suppl 11): 47-56
    PubMedGoogle Scholar
19. Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL. Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist 2012; 17 (03) 296-302
    CrossrefPubMedGoogle Scholar
20. Beumer JH, Chu E, Allegra C. et al. Therapeutic drug monitoring in oncology: international association of therapeutic drug monitoring and clinical toxicology recommendations for 5-fluorouracil therapy. Clin Pharmacol Ther 2019; 105 (03) 598-613
    CrossrefPubMedGoogle Scholar
21. Wattanatorn W, McLeod HL, Macklon F, Reid M, Kendle KE, Cassidy J. Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. Pharmacotherapy 1997; 17 (05) 881-886
    CrossrefPubMedGoogle Scholar
22. Bertino J, Fleisher M, Beumer JH. et al. Highlights from: 5-fluorouracil drug management pharmacokinetics and pharmacogenomics workshop; Orlando, Florida; January 2007. Clin Colorectal Cancer 2007; 6 (06) 407-422
    CrossrefPubMedGoogle Scholar
23. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993; 53 (22) 5433-5438
    PubMedGoogle Scholar
24. Zhou X, Chang Y, Qian J. et al. Clinical benefit of therapeutic drug monitoring in colorectal cancer patients who received fluorouracil-based chemotherapy. Med Sci Monit 2021; 27: e929474
    CrossrefPubMedGoogle Scholar
25. Macaire P, Morawska K, Vincent J. et al. Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years. Eur J Cancer 2019; 111: 116-125

| Fig 1 : Toxicity assessment of study population. Toxicity changes occurred in patient while on 5-fluorouracil treatment. Nausea and dizziness were predominant. ADR, adverse drug reaction.

| Figure 2: Concentration versus time graph. A 64-year-old female patient of was on 5-fluorouracil treatment. Samples were collected and the concentration versus time graph was plotted and displayed. The graph shows the area under the curve concentration is increased, indicating the patient requires low dose.

| Figure 3:Concentration versus time graph. A 53-year-old male patient was on 5-fluorouracil treatment. Samples were collected and the concentration versus time graph was plotted and displayed.

|  Figure 4:The normal probability by regression statistics. The plot shows the regression graph of area under the curve concentration and tumor size reduction. The regression value is 0.16. It shows that the plot is moving toward a positive correlation.

References

Baker SD, Verweij J, Rowinsky EK. et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002; 94 (24) 1883-1888
CrossrefPubMedGoogle Scholar
1. Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR. Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens. Clin Colorectal Cancer 2011; 10 (03) 203-206
   CrossrefPubMedGoogle Scholar
2. Maiello E, Gebbia V, Giuliani F. et al; Gruppo Oncologico dell'Italia Meridionale (GOIM). FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale (GOIM). Ann Oncol 2005; 16 (Suppl. 04) iv56-iv60
   CrossrefPubMedGoogle Scholar
3. Kim DH, Kim WT, Lee JH. et al. Analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer. Cancer Res Treat 2015; 47 (01) 46-54
   CrossrefPubMedGoogle Scholar
4. Lee JH, Song JH, Lee SN. et al. Adjuvant postoperative radiotherapy with or without chemotherapy for locally advanced squamous cell carcinoma of the head and neck: the importance of patient selection for the postoperative chemoradiotherapy. Cancer Res Treat 2013; 45 (01) 31-39
   CrossrefPubMedGoogle Scholar
5. Pisani P, Airoldi M, Allais A. et al. Metastatic disease in head & neck oncology. Acta Otorhinolaryngol Ital 2020; 40 (Suppl. 01) S1-S86
   CrossrefPubMedGoogle Scholar
6. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med (Korean Assoc Intern Med) 2009; 24 (01) 1-10
   PubMedGoogle Scholar
7. Hashimoto Y, Yoshida Y, Yamada T. et al. Current status of therapeutic drug monitoring of 5-fluorouracil prodrugs. Anticancer Res 2020; 40 (08) 4655-4661
   CrossrefPubMedGoogle Scholar
8. Hillcoat BL, McCulloch PB, Figueredo AT, Ehsan MH, Rosenfeld JM. Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. Br J Cancer 1978; 38 (06) 719-724
   CrossrefPubMedGoogle Scholar
9. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16 (04) 215-237
   CrossrefPubMedGoogle Scholar
10. Wilhelm M, Mueller L, Miller MC. et al. Prospective, multicenter study of 5-fluorouracil therapeutic drug monitoring in metastatic colorectal cancer treated in routine clinical practice. Clin Colorectal Cancer 2016; 15 (04) 381-388
    CrossrefPubMedGoogle Scholar
11. Santini J, Milano G, Thyss A. et al. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer 1989; 59 (02) 287-290
    CrossrefPubMedGoogle Scholar
12. Gamelin E, Boisdron-Celle M, Guérin-Meyer V. et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 1999; 17 (04) 1105
    CrossrefPubMedGoogle Scholar
13. Paulsen NH, Vojdeman F, Andersen SE. et al. DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview. Basic Clin Pharmacol Toxicol 2022; 131 (05) 325-346
    CrossrefPubMedGoogle Scholar
14. Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 2007; 60 (04) 503-507
    CrossrefPubMedGoogle Scholar
15. Saif MW, Syrigos K, Mehra R, Mattison LK, Diasio RB. Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: experience of 4-years. Pak J Med Sci 2007; 23 (06) 832-839
    PubMedGoogle Scholar
16. Hughes RS, Frenkel EP. The role of chemotherapy in head and neck cancer. Am J Clin Oncol 1997; 20 (05) 449-461
    CrossrefPubMedGoogle Scholar
17. Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol 1988; 15 (01) 70-85
    PubMedGoogle Scholar
18. Vokes EE, Haraf DJ, Weichselbaum RR, McEvilly JM, Sutton HG, Panje WR. Perspectives on combination chemotherapy with concomitant radiotherapy for poor-prognosis head and neck cancer. Semin Oncol 1992; 19 (4, Suppl 11): 47-56
    PubMedGoogle Scholar
19. Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL. Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist 2012; 17 (03) 296-302
    CrossrefPubMedGoogle Scholar
20. Beumer JH, Chu E, Allegra C. et al. Therapeutic drug monitoring in oncology: international association of therapeutic drug monitoring and clinical toxicology recommendations for 5-fluorouracil therapy. Clin Pharmacol Ther 2019; 105 (03) 598-613
    CrossrefPubMedGoogle Scholar
21. Wattanatorn W, McLeod HL, Macklon F, Reid M, Kendle KE, Cassidy J. Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. Pharmacotherapy 1997; 17 (05) 881-886
    CrossrefPubMedGoogle Scholar
22. Bertino J, Fleisher M, Beumer JH. et al. Highlights from: 5-fluorouracil drug management pharmacokinetics and pharmacogenomics workshop; Orlando, Florida; January 2007. Clin Colorectal Cancer 2007; 6 (06) 407-422
    CrossrefPubMedGoogle Scholar
23. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993; 53 (22) 5433-5438
    PubMedGoogle Scholar
24. Zhou X, Chang Y, Qian J. et al. Clinical benefit of therapeutic drug monitoring in colorectal cancer patients who received fluorouracil-based chemotherapy. Med Sci Monit 2021; 27: e929474
    CrossrefPubMedGoogle Scholar
25. Macaire P, Morawska K, Vincent J. et al. Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years. Eur J Cancer 2019; 111: 116-125