|Year : 2013 | Volume
| Issue : 3 | Page : 392-396
Concurrent chemoradiation with weekly Cisplatin, Docetaxel and Gefitinib: A study to assess feasibility, toxicity and immediate response
Prasad Eswaran1, Kumaravelu S Azmi2
1 Department of Medical Oncology, Madras Medical College, Chennai, Tamil Nadu, India
2 Department of Oncology, Vinayaka Missions Kirupananda Variyar Medical College & Research Institute, Salem, Tamil Nadu, India
|Date of Web Publication||8-Oct-2013|
Department of Medical Oncology, Madras Medical College, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objectives: Addition of docetaxel in the treatment regimen has shown improvement in survival of head and neck squamous cell carcinoma (HNSCC) patients. This study was conducted to evaluate the maximum tolerated dose of weekly docetaxel when combined with concurrent administration of weekly cisplatin, daily gefitinib, and radiation therapy.
Materials and Methods: 21 patients with newly diagnosed HNSCC were included. Radiation therapy was planned to a dose of 66 Gy/33 fractions. Doses of cisplatin and gefitinib were kept constant at 30 mg/m 2 and 250 mg respectively. Dose of weekly docetaxel started with 5 mg/m 2 and escalated 5 mg/m 2 up to a maximum of 20 mg/m 2 . Serious adverse event was defined as grade 3/4 hematological and non-hematological toxicities.
Results: All patients (three in dose level 1 [5 mg/m 2 ], level 2 [10 mg/m 2 ] and level 3 [15 mg/m 2 ]) did not experience any hematological serious adverse events. Weekly docetaxel of 20 mg/m 2 could not be tolerated with the combination, and we encountered two hematological (neutropenia) serious grade 4 adverse event and one grade 3 mucositis at level 4. Six patients were treated by omitting week 3 chemotherapy reducing the number of weekly cycles to a minimum of four. Gefitinib was continued throughout the treatment period. All patients tolerated the treatment well although with grade 2 hematological/non hematological toxicities.
Conclusion: The maximal tolerated dose of weekly docetaxel added to weekly cisplatin and daily gefitinib during concurrent chemoradiation is 15 mg/m 2 . Toxicity profile is tolerable with a break in the chemotherapy regimen during radiation therapy. Aggressive nutritional support is essential prior to this regimen.
Keywords: Cisplatin, docetaxel, gefitinib, head and neck neoplasm, radiation therapy
|How to cite this article:|
Eswaran P, Azmi KS. Concurrent chemoradiation with weekly Cisplatin, Docetaxel and Gefitinib: A study to assess feasibility, toxicity and immediate response. J Can Res Ther 2013;9:392-6
|How to cite this URL:|
Eswaran P, Azmi KS. Concurrent chemoradiation with weekly Cisplatin, Docetaxel and Gefitinib: A study to assess feasibility, toxicity and immediate response. J Can Res Ther [serial online] 2013 [cited 2020 Nov 30];9:392-6. Available from: https://www.cancerjournal.net/text.asp?2013/9/3/392/119313
| > Introduction|| |
Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy in developing countries commonly presenting as advanced loco-regional disease. Concurrent Chemoradiation has shown a survival benefit of 4% at 2 years and 5 years compared to radiotherapy alone.  Meta-analysis of all chemoradiation trials showed the superiority of concurrent chemotherapy over induction chemotherapy. ,, Analysis of cisplatin based chemotherapy trials showed a survival benefit favoring the practice of induction chemotherapy. ,, TAX 323 and 324 trials had demonstrated the benefit of addition of docetaxel in induction chemotherapy (TPF) with significant improvement in progression free and overall survival. , Newer trials demonstrated negative results, but the results are considered with caution due to the smaller sample size and shorter induction cycles. , However, with delaying a definitive loco-regional modality, the theoretical possibility of emergence of resistant clones exists with induction chemotherapy.
Docetaxel has a good response rate (35%) in recurrent HNSCC as a single agent.  Trials have demonstrated mitotic arrest (G2/M arrest) and potent radiosensitization in preclinical models and its toxicity and efficacy in phase I/II trials. ,,, Cisplatin inhibits radiation induced deoxyribonucleic acid (DNA) double strand damage. Gefitinib had been shown to radiosensitize tumor by a variety of mechanisms by inducing G0/G1 cell arrest and induction of apoptosis. , Moreover, epidermal growth factor receptor (EGFR) kinase expression promotes the acquisition of stem cell like properties in cancer cells. These cells when treated with gefitinib had lesser potential to invade and become more sensitive to cisplatin induced cytotoxicity.  Hence, combination treatment with chemotherapy and EGFR inhibition might be an effective strategy in HNSCC. ,
Our previous experience with gefitinib and cisplatin showed that the combination is feasible and tolerable with better response rates.  We tried to incorporate docetaxel along with cisplatin, gefitinib and radiation therapy in HNSCC to assess its feasibility, toxicity, and immediate response rate as this combination is not reported in the literature.
| > Materials and Methods|| |
Patients aged 18-65 years with good performance status (Eastern Cooperative Oncology Group (ECOG) 0, 1) and histologically confirmed unresectable advanced HNSCC (except oral cavity) were included [Table 1]. Distribution per Tumor (T) and Node (N) status is given in [Table 2]. All had adequate renal and hepatic functions. Institutional review board approved the proposal (Research and Ethical Committee). A detailed explanation of the trial was given to patients before obtaining written consent for participation in the trial.
All patients were evaluated with blood investigations (complete blood count, liver function test and renal function test), chest X-ray and computed tomography of the head and neck region. Patients were advised to undergo percutaneous endoscopic gastrostomy (PEG) tube insertion before treatment, but it was not necessary for the trial.
After simulation, external beam radiation therapy (EBRT) was delivered with Linear accelerator up to a total dose of 66 Gy/33 fractions. Phase I was up to 40 Gy after which radiation portals were modified for shielding spinal cord. Phase II was up to 60 Gy. Final 6 Gy was delivered to gross residual disease.
Dexamethasone 4 mg was given twice daily for 3 days with adequate anti emetics. Docetaxel was started at 5 mg/m 2 and given in incremental doses of 5 mg/m 2 at each cohort level. Weekly cisplatin was given at a dose of 30 mg/m 2 . Gefitinib was given at fixed daily doses of 250 mg. Granulocyte Colony Stimulating Factor was not given. Patients were initially planned to receive a minimum of five cycles of weekly chemotherapy.
Assessment of toxicity
During EBRT, all patients were assessed for toxicity weekly during treatment as per National Cancer Institute - Common Terminology Criteria for Adverse Events v3. They were assessed again 6 weeks after completion of EBRT for toxicity and response.
The study was designed to be conducted as per modified Fibonacci series. All cohorts received 30 mg/m 2 of weekly cisplatin and gefitinib 250 mg daily. Weekly docetaxel was started at 5 mg/m 2 and escalated 5 mg/m 2 every cohort level until serious adverse events (SAE) are encountered in a given level. SAE is defined as grade 3/4 hematological toxicity (neutropenia and thrombocytopenia) and non-hematological toxicity (except nausea, vomiting and mucositis) persisting more than a week. Chemoradiation was suspended if the neutrophils or platelet count were less than 1,000 cells/mm 3 and 75,000 cells/mm 3 respectively. Treatment was continued once the counts normalized. If one SAE occurred, additional cohorts of three patients were enrolled at that level. If no patient developed an SAE in this second cohort, dose escalation continued. If two or more cases of SAEs were observed in a given cohort, dose escalation was stopped. This was designated as the dose-limiting toxicity. The maximal tolerated dose (MTD) was defined as the dose level before the dose that induced two or more SAEs. Although mucositis was considered in weekly assessment for treatment purposes, it was not considered as SAE in this study. A treatment break of 1 week was allowed for relief of mucositis.
| > Results|| |
All patients at levels 1 and 2 (docetaxel 5-10 mg/m 2 , cisplatin 30 mg/m 2 and gefitinib 250 mg) had grade 1 and 2 hematological and non-hematological toxicities. One patient in level 2 and two in level 3 had grade 3 mucositis, but was not considered SAE as per the pre-defined criteria. No other SAEs encountered in these levels. Treatment breaks were more common in level 3 due to mucositis [Figure 1], [Figure 2] and [Figure 3].
Of the three patients in level 4, two patients developed grade 3 febrile neutropenia. One patient had severe pain (grade 4) due to mucositis at 42 Gy and needed injectable morphine/fentanyl patch for pain control. He discontinued further treatment and was lost for follow-up. Another patient had grade 3 pain due to mucositis [Figure 4]. One patient had grade 3 diarrhea during neutropenic episode probably due to infection [Figure 5]. These events were considered SAEs and the MTD was considered at dose level 3 [Table 3].
Confirmation of MTD
Three more patients were included at dose level 3 and were assessed for toxicity. There were no SAEs although overall treatment time was prolonged (Median - 68, Range - 62-72 days) by grade 3 mucositis in two more patients. A total of four patients had grade 3 mucositis in level 3 (66%).
Modification of MTD (Level 3A)
We continued our trial for six more patients with modification of the level 3 dose, skipping week 3 chemotherapy (2 weeks on and 1 week off) reducing the total number of weekly chemotherapy administration to a minimum of four cycles. However, gefitinib was continued throughout the treatment period. All patients tolerated the treatment well although we had grade 2 hematological/non hematological toxicities. Compliance was better with the modified MTD. One patient had grade 3 mucositis [Figure 6].
Although, this trial was not intended to measure response rates, it is reported as a secondary endpoint. The immediate response rate was 100% (Complete response - 18/21 [85.7%] and Partial response - 3/21 [14.3%]).
| > Discussion|| |
Many treatment modalities are being tried to improve survival in unresectable locally advanced HNSCC. Docetaxel enhances the effect of radiation by synchronization of cell cycle at the most sensitive phase (G2/M) and influences intracellular platinum metabolism.  Cisplatin enhances radiosensitivity by inhibition of radiation induced DNA repair. Gefitinib has a variety of mechanisms attributed to its activity. Preclinical studies showed a reduction of cisplatin dose when used along with gefitinib is acceptable without loss of anti-proliferative effects and reduced toxicity. , We tried to incorporate these three active agents along with radiation therapy and assess toxicity and tolerability as this combination in naïve in Indian population.
Incidence of mucositis in level 4 was 66% (two out of three patients). Grade 4 pain was secondary to mucositis in one patient and required PEG tube insertion for nutritional support. There were grade 3 mucositis in four patients (66%) in level 3. Although most patients undergoing radiation experience mucositis, it was substantial with this combination, probably accentuated by the addition of docetaxel and gefitinib. Increased incidence of mucositis had been reported with weekly docetaxel, weekly docetaxel/cisplatin (71%) and 3 weekly docetaxel/cisplatin/5 FU (79%). ,, Our results were comparable to data reported in the literature. Skipping week 3 chemotherapy dose had resulted in better mucosal tolerability (grade 3-0%) in level 3A.
The doublet (docetaxel/cisplatin) and triplet (docetaxel/cisplatin/5 FU) along with radiation had been tested in various trials. Hematological toxicity was most commonly reported. ,,, In this study, the dose limiting toxicities were neutropenia (66%) in level 4. Hematological toxicities in level 3/3A were manageable.
Tyrosine kinase inhibitors (TKI) had shown a response rate of 4-10% in recurrent/metastatic HNSCC as a single agent. A phase II study examining the combination of radiotherapy and gefitinib in HNSCC reported 32% complete remission and 53% partial remission.  The combination of gefitinib with chemotherapy had been a subject of debate for a long time. Preclinical studies showed synergistic cytotoxicity between cisplatin and gefitinib. The addition of gefitinib to docetaxel alone did not increase cell kill.  The definitive role of TKIs with chemoradiation needs to be defined in randomized controlled clinical trials.
We used PEG tube for nutritional support during acute toxicity. Long term tube dependence should be studied in our patients as most of the trials using docetaxel based chemoradiation had reported chronic toxicity and dysphagia. The effect of prolongation of an overall treatment duration and loss of local control should be studied further. Late radiation toxicity in newer combination chemotherapy needs to be evaluated in future trials.
| > Conclusion|| |
In this study, MTD of the weekly docetaxel is determined at 15 mg/m 2 along with weekly cisplatin (30 mg/m 2 ), daily gefitinib (250 mg) and conventional radiation therapy. This treatment is feasible although with manageable toxicity with modification of the regimen skipping week 3 cycle. Aggressive nutritional support must be planned prior to initiating docetaxel based chemoradiation protocols.
| > References|| |
|1.||Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8. |
|2.||Pignon JP, Baujat B, Bourhis J. Individual patient data meta-analyses in head and neck carcinoma: What have we learnt?. Cancer Radiother 2005;9:31-6. |
|3.||Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949-55. |
|4.||Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14. |
|5.||Paccagnella A, Orlando A, Marchiori C, Zorat PL, Cavaniglia G, Sileni VC, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265-72. |
|6.||Zorat PL, Paccagnella A, Cavaniglia G, Loreggian L, Gava A, Mione CA, et al. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J Natl Cancer Inst 2004;96:1714-7. |
|7.||Domenge C, Hill C, Lefebvre JL, De Raucourt D, Rhein B, Wibault P, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC). Br J Cancer 2000;83:1594-8. |
|8.||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. |
|9.||Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15. |
|10.||Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet Oncol 2013;14:257-64. |
|11.||Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 2013;31:744-51. |
|12.||Glisson BS. The role of docetaxel in the management of squamous cell cancer of the head and neck. Oncology (Williston Park) 2002;16:83-7. |
|13.||Milas L, Mason KA, Liao Z, Ang KK. Chemoradiotherapy: Emerging treatment improvement strategies. Head Neck 2003;25:152-67. |
|14.||Mauer AM, Masters GA, Haraf DJ, Hoffman PC, Watson SM, Golomb HM, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 1998;16:159-64. |
|15.||Tishler RB, Norris CM Jr, Colevas AD, Lamb CC, Karp D, Busse PM, et al. A Phase I/II trial of concurrent docetaxel and radiation after induction chemotherapy in patients with poor prognosis squamous cell carcinoma of the head and neck. Cancer 2002;95:1472-81. |
|16.||Tsao AS, Garden AS, Kies MS, Morrison W, Feng L, Lee JJ, et al. Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2006;24:4163-9. |
|17.||Shintani S, Li C, Mihara M, Terakado N, Yano J, Nakashiro K, et al. Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer. Int J Cancer 2003;107:1030-7. |
|18.||Al-Hazzaa A, Bowen ID, Randerson P, Birchall MA. The effect of ZD1839 (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin, on apoptosis in SCC-15 cells. Cell Prolif 2005;38:77-86. |
|19.||Abhold EL, Kiang A, Rahimy E, Kuo SZ, Wang-Rodriguez J, Lopez JP, et al. EGFR kinase promotes acquisition of stem cell-like properties: A potential therapeutic target in head and neck squamous cell carcinoma stem cells. PLoS One 2012;7:e32459. |
|20.||Morelli MP, Cascone T, Troiani T, De Vita F, Orditura M, Laus G, et al. Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors. Ann Oncol 2005;16 Suppl 4:iv61-8. |
|21.||Balaiyya N. Pilot study to assess safety and tolerance of gefitinib in combination with intensity modulated radiation therapy (IMRT) with or without concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC). Poster presented at Multidisciplinary Head and Neck Symposium. Pheonix, Arizona, USA; 2012. |
|22.||Maeda S, Sugiura T, Saikawa Y, Kubota T, Otani Y, Kumai K, et al. Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism. Cancer Sci 2004;95:679-84. |
|23.||Hambek M, Baghi M, Strebhardt K, Baumann H, Gstöttner W, Knecht R. Reduction of cisplatin dosage by ZD 1839. Anticancer Res 2005;25:3985-8. |
|24.||Magné N, Fischel JL, Tiffon C, Formento P, Dubreuil A, Renée N, et al. Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil. Br J Cancer 2003;89:585-92. |
|25.||Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91:2081-6. |
|26.||Katori H, Tsukuda M, Mochimatu I, Ishitoya J, Kawai S, Mikami Y, et al. Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Br J Cancer 2004;90:348-52. |
|27.||Schwartz DL, Montgomery RB, Yueh B, Donahue M, Anzai Y, Canby R, et al. Phase I and initial phase II results from a trial investigating weekly docetaxel and carboplatin given neoadjuvantly and then concurrently with concomitant boost radiotherapy for locally advanced squamous cell carcinoma of the head and neck. Cancer 2005;103:2534-43. |
|28.||Airoldi M, Cattel L, Cortesina G, Giordano C, Pedani F, Recalenda V, et al. Docetaxel, carboplatin and concomitant radiotherapy for unresectable squamous cell carcinoma of the head and neck: Pharmacokinetic and clinical data of a phase I-II study. Am J Clin Oncol 2004;27:155-63. |
|29.||Doss HH, Greco FA, Meluch AA, Gray JR, Spigel DR, Shipley DL, et al. Induction chemotherapy + gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients (pts) with locally advanced squamous carcinoma of the head and neck: A phase I/II trial of the minnie pearl cancer research network. J Clin Oncol (Meeting Abstracts) 2006;24:5543. |
|30.||Laytragoon-Lewin N, Ustun H, Castro J, Friesland S, Ghaderi M, Lundgren J, et al. In vitro effect of radiation, antibody to epidermal growth factor receptor and docetaxel in human head and neck squamous carcinoma cells with mutant P53 and over-expressed EGFR. J Cancer Res Clin Oncol 2009;135:203-9. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]