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| ORIGINAL ARTICLE |
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| Year : 2014 | Volume
: 51
| Issue : 1 | Page : 69-72 |
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Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center
VM Patil1, S Chakraborty2, PK Shenoy1, A Manuprasad1, TP Sajith Babu3, T Shivkumar4, S Babu4, A Bhatterjee5, S Balasubramanian4
1 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Thalassery, Kannur, Kerala, India
2 Department of Radiation Oncology, Malabar Cancer Center, Thalassery, Kannur, Kerala, India
3 Department of Cancer Imaging, Malabar Cancer Center, Thalassery, Kannur, Kerala, India
4 Department of Surgical Oncology, Malabar Cancer Center, Thalassery, Kannur, Kerala, India
5 Department of Cancer Registry and Clinical Statistics, Malabar Cancer Center, Thalassery, Kannur, Kerala, India
| Date of Web Publication | 18-Jun-2014 |
Correspondence Address:
V M Patil
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Thalassery, Kannur, Kerala
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0019-509X.134649
Background: Recent studies indicate neoadjuvant chemotherapy (NACT) can result in R0 resection in a substantial proportion of patients with technically unresectable oral cavity cancers. However, data regarding the efficacy and safety of docetaxel, cisplatin and 5 fluorouracil (TPF) NACT in our setting is lacking. The present audit was proposed to evaluate the toxicities encountered during administration of this regimen. It was hypothesized that TPF NACT would be considered feasible for routine administration if an average relative dose intensity (ARDI) of ≥0.90 or more in at least 70% of the patients. Materials and Methods: Technically unresectable oral cancers with Eastern Cooperative Oncology Group PS 0-2, with biopsy proven squamous cell carcinoma underwent two cycles of NACT with TPF regimen. Toxicity and response rates were noted following the CTCAE 4.03 and RECIST criteria. Descriptive analysis of completion rates (completing 2 cycles of planned chemotherapy with ARDI of 0.85 or more), reason for delay, toxicity, and response are presented. Results: The NACT was completed by all patients. The number of subjects who completed all planned cycles of chemotherapy are with the ARDI of the delivered chemotherapy been equal to or >0.85 was 11 (91.67%). All toxicity inclusive Grade 3-5 toxicity was seen in 11 patients (91.67%). The response rate of chemotherapy was 83.33%. There were three complete response, seven partial response, and two stable disease seen post NACT in this study. Conclusion: Docetaxel, cisplatin and 5 fluorouracil regimen can be routinely administered at our center with the supportive care methods and precautionary methods used in our study.
Keywords: Induction, neoadjuvant chemotherapy, oral cancer, technically unresectable, toxicity
How to cite this article:
Patil V M, Chakraborty S, Shenoy P K, Manuprasad A, Sajith Babu T P, Shivkumar T, Babu S, Bhatterjee A, Balasubramanian S. Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center. Indian J Cancer 2014;51:69-72 |
How to cite this URL:
Patil V M, Chakraborty S, Shenoy P K, Manuprasad A, Sajith Babu T P, Shivkumar T, Babu S, Bhatterjee A, Balasubramanian S. Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center. Indian J Cancer [serial online] 2014 [cited 2022 Aug 15];51:69-72. Available from: https://www.indianjcancer.com/text.asp?2014/51/1/69/134649 |
| » Introduction | |  |
Technically unresectable oral cancer management is a clinical dilemma. [1],[2] Reports of nonsurgical treatment, neoadjuvant chemotherapy (NACT) followed by surgical treatment and upfront surgery in certain subsets have been published. However, the outcomes seen with nonsurgical series are dismal. [3],[4],[5] This led to a development of strategy of administration of neoadjuvant therapy followed by assessment of surgical resection. [1],[6] According to a report published by from TMH, Mumbai the median survival associated with such a strategy in oral cancer patients undergoing surgical resection post NACT was not reached for a median follow-up of 15 months. [1] Similar sequence of administration of NACT followed by surgical excision has been published for laryngopharyngeal cancers, maxillary sinus cancers and T4b oral cancers. [7],[8],[9] However, in these studies three quarters of the patient were treated with a doublet of platinum and taxane. [1],[6],[7],[8],[10]
Results from several randomized trials have shown that use of docetaxel, cisplatin and 5 fluorouracil (TPF) results in a significant improvement in response rates as well as survival when compared to a platinum doublet. [11],[12] Simultaneously, TPF is associated with more toxicity, in-patient admissions and supportive care. [1],[6],[11],[12] Administration of such regimens therefore requires greater financial and logistical support. There is little data on the use of TPF in such resource limited settings. Hence, this audit was planned to study the tolerance and efficacy of TPF regimen NACT when used in technically unresectable oral cancers. We have hypothesized that TPF NACT would be considered feasible for routine administration if an average relative dose intensity (ARDI) of ≥0.90 or more in at least 70% of the patients.
| » Materials and Methods | | |
Since August 2013, patients with locally advanced and technically unrespectable oral cavity cancers were treated with three drugs NACT. Patients were considered eligible for the chemotherapy if they fulfilled the following criteria.
Selection criteria
- Age >18 years
- Pathologically proved squamous cell carcinoma of the oral cavity
- Eastern Cooperative Oncology Group PS 0-2
- Treatment naive except for biopsy or cytology
- Technically unresectable oral cancers. [1]
Exclusion criteria
- Patients with uncontrolled co morbidity
- Pregnant patients
- Those patients with >180° encasement of carotid vessels or involvement of prevertebral fascia or involvement of high ITF with involvement of base of the skull.
Intervention
These patients were discussed in the institutional tumor board and were considered as technically unresectable in accordance with previously published criteria's. [1] Patients underwent axial imaging within 4 weeks of starting of NACT. All patients were individually counseled regarding the benefits and side-effects of the proposed treatment. Pretreatment dental prophylaxis, dietary evaluation and nutritional counseling were provided to all patients. In patients above 60 years of age triage risk screening tool Flemish version geriatric screening was done. [13]
Neoadjuvant chemotherapy administered was docetaxel 75 mg/m 2 on D1, cisplatin 75 mg/m 2 on D1 and 5 FU 750 mg/m 2 continuous 24 h intravenous (IV) infusion D1-D5. In patients with serum creatinine clearance (calculated by modified Crock ford and Gault formula) below 60 ml/min cisplatin was replaced by carboplatin area under the curve (AUC-6). Two cycles were administered 21 days apart.
Supportive care
Antiemetic prophylaxis given was tablet aprepitant 125 mg PO D1 followed by 80 mg PO on D2-D3, injection Ondansetron 8 mg IV on D1 and injection dexamethasone 8 mg on D1-D5. Hydration provided was 2000 ml of 0.9% NS with 20 mEq of 15% KCl and 1 g of MgSO 4 on D1. Pegylated granulocyte colony-stimulating factor (G-CSF) 6 mg SC was administered on D7. Tablet levofloxacin 750 mg PO OD was administered from D6 to D14.
All patients had complete hemogram, renal function test and serum electrolytes monitored every day from D2 until count recovery. All patients were kept indoor until count recovery. If the patient had a Grade 3 weight loss (10% or more of baseline weight) than initially oral nutritional supplementation was provided. However, if weight loss until continued than parenteral nutrition was added. Below knee compression stockings were provided for the entire duration of indoor admission.
Toxicity and efficacy
Toxicity with CTCAE version 4.02 was noted. Response rate were assessed both clinically before the start of each cycle. RECIST version 1.1 was used for assessment of response.
Data collection
For the purpose of this study, details of basic demographic profile, staging details, NACT details, ARDI, maximum toxicity details (CTCAE version 4.02) and response (RECIST version 1.1) were noted from the database in medical oncology outpatient department and case records. SPSS version 16 was used for analysis. Descriptive statistics has been presented. As this is an audit formal sample size calculations were not done. The primary endpoint of this audit was to see the proportion of patients achieving an ARDI ≥0.90. Secondary endpoints were to see for toxicity and response rate.
| » Results | | |
Baseline details
There were patients 12 patients who were planned for TPF drug regimen in the above-mentioned stipulated time period. The median age of the patient was 52.5 (28-83 years). Patients with age 60 years and above were 5. The baseline details of these patients are shown in [Table 1].
Tumor details
All patients had oral cancers. All patients had squamous cell carcinoma. The grade of the tumor were Grade 1 in 5 (42.7%), Grade 2 in 5 (42.7%) and Grade 3 in 2 patients (14.6%). The subsite were buccal mucosa in 5 patients (42.7%), lower alveolus in 1 patient (08.3%), and anterior two-third of tongue in 6 patients (50.0%). The indication of NACT were in buccal mucosa primary tumor related edema up to or above the level of zygoma in four patients and disease going up to hyoid in 1 patients and in anterior two-third primary disease going into base of tongue in 5 patients and disease reaching up to hyoid in 2 patients. While the patient having primary in lower alveolus the reason for NACT was disease going up to hyoid. Clinically, the maximum size in one-dimension in superior-inferior direction on external examination was 8 cm (4-10 cm) while maximum size in one-dimension in mediolateral direction on external examination was 5 cm (3-8 cm). The maximum size in one-dimension measurement internally (mucosal aspect of the oral cavity) was 7 cm (3-10 cm). The staging details are shown in [Table 2].
Neoadjuvant chemotherapy details
The regimen delivered were TPF (Cisplatin as the platinum) in 9 patients (75%) while TPF (Carboplatin as the platinum) in 3 patients (25%). The median numbers of cycles delivered were 2 (2-3). The relative dose intensity delivered of docetaxel, platinum and 5 FU were 0.97, 0.97 and 0.97, respectively. The median ARDI was 0.97 (range: 0.84-1). >2 cycles were delivered in 2 patients. This was due to delay in surgical date. The NACT was completed by all patients. The number of subjects who achieved an ARDI ≥0.90 was 9 (75%).
A delay of >2 days in start of subsequent cycle was seen 4 patients. Three of these patients had a delay of 4 days while one had a delay of 7 days. The reasons for delay were logistical issues in patient, delayed referral from surgical department (3 rd cycle as surgical date was delayed) in 1 patient and toxicity in 3 patients. None of the patients had required a dose reduction in subsequent cycles.
The median duration of indoor stay in the first cycle was 14 days (9-22 days) while that in second or subsequent cycle was 11 days (8-31 days). The median time to Grade 3 or more neutropenia post start of chemotherapy was 8 days (5-10 days). The median time to recovery of Grade 3 or more neutropenia to Grade 2 or less neutropenia was 4 days (1-7 days).
Toxicity details
The maximum cumulative toxicity has been shown in [Table 3]. All toxicity inclusive Grades 3-5 toxicity was seen in 11 patients (91.67%). Life-threatening Grade 4 toxicity (inclusive of febrile neutropenia, thrombocytopenia, electrolyte disturbance, mucositis, and loose motions) was seen in 4 patients (33.3%). No treatment related mortality was observed. The median time for development of Grade 3 hyponatremia was 6 days from start of TPF regimen (2-10 days). The median time for recovery of Grade 3 or above hyponatremia was 3 days (1-7 days). Grade 4 kidney dysfunction was seen in 1 patient. The serum creatinine started rising after first cycle from day 2 onward. It went up to a maximum of 6 mg/dl. However, he responded to hydration alone. The serum creatinine returned to its normal value by day 28 of the first cycle. Cycle 2 was started on D22 in this patient with replacement of cisplatin by carboplatin AUC-6. 1 patient had Grade 4 weight loss for which partial parenteral nutrition supplementation had to be given for 5 days. Pneumonia with febrile neutropenia was seen in 2 patients these were the 2 patients who had a delay in chemotherapy because of this toxicity these were the only patients who had ARDI below 0.9.
Efficacy details
The response rates post two cycles of NACT in accordance with RECIST version 1.1 are shown in [Table 4]. The clinically median decrement in size of the tumor on external examination and internal examination were 75% (20-100%) and 75% (20-100%), respectively. Radiologically, the median decrement in size of the tumor was 60% (0-100%). Of 12 patients, 11 patients were considered resectable by the surgeons after NACT.
| » Discussion | | |
Triplet chemotherapy based on TPF results in improved outcomes over platinum doublet. [11],[12] Data from randomized controlled trial has shown a gain of 14% in 3 years overall survival over platinum based doublet chemotherapy regimens. [12] However, in these studies the proportion of oral cavity patients was <15%. [11],[12] In the trial conducted by Zhong et al., evaluating the use of TPF in resectable oral cavity cancers, a response rate of 80.7% was obtained. [14] The present study confirms the activity of this regimen in our patient population with oral cavity cancers, with a response rate of 83.3%.
This audit met its primary endpoint. An ARDI ≥0.9 was achieved in 75% of the patients. All patients could complete two cycles of chemotherapy and none of the patients had a delay exceeding 7 days due to toxicity. This is comparable to the results reported in the TAX 323 trial. [11] The selection criteria of our patients were similar to a similar larger report published from Mumbai. [1] As the same group had obtained better response rates with TPF regimen than a platinum and taxane doublet, this TPF regimen was selected for our patients. [15] The authors had reported rate of febrile neutropenia was 34% with TPF despite routine G-CSF prophylaxis. [1] In the present study, also the rate of febrile neutropenia was 58% despite use of routine pegylated G-CSF prophylaxis. This justifies the routine administration of G-CSF in our patient population.
Although routine antibiotic prophylaxis is not recommended by ASCO guidelines in solid tumor patients, most authors have used routine quinolone prophylaxis with TPF. [11],[12] In our setting, the high incidence of febrile neutropenia, mucositis, diarrhea, and Gram-negative bacteremia justifies the continued use of antibiotic prophylaxis. However, the rates of these complications are higher than that reported in western literature possibly secondary to the high rates of quinolone resistance in India. [16]
Hyponatremia is a complication which is poorly reported in literature. The incidence of hyponatremia in our study and NACT studies reported from TMH is 83% and 44.5%, respectively. [17] This hyponatremia may due to syndrome of inappropriate secretion of antidiuretic hormone or platinum induced salt wasting.
The median time for development of severe complications like Grades 3-5 neutropenia and Grades 3-5 hyponatremia in our study was 8 days (5-10 days) and was 6 days (2-10 days) from start of TPF regimen. In view of this complication routine monitoring of counts and serum electrolytes should be practiced at least for 4-5 days post completion of TPF chemotherapy. This fact should also be taken into consideration, while counseling the patients regarding the side-effects, especially if they are discharged after completion of TPF regimen.
The aim of NACT in this situation is to make tumor resectable and our study shows that this objective can be achieved in majority of patients (91.67%). There exists a risk of deterioration of nutritional status of patients. Despite regular nutritional counseling weight loss >10% was seen in 1 patient (8.3%), while Grade 2 hypoalbuminemia was observed in 2 (16.7%). Poor nutritional status is a negative prognostic factor in Head and neck cancers and is associated with poor tolerance to surgery and radiation. Hence, routine nutritional supplementation and regular dietician reference should be encouraged during this treatment.
While TPF chemotherapy is associated with better outcomes, it also requires extensive supportive care. As a result, in our part of the world platinum taxane doublets are used in most patients. [1],[6],[7],[8],[10],[18],[19] In some centers, a modified dose schedule of TPF is also practiced. [20] Our center was devoid of expert medical oncology services until August 2013. Since August 2013, the corresponding author joined the institute and the medical oncology services were established. Moreover, the division had an indoor patient to nurse ratio of 8:1 and the institute was predominantly catering to a rural population. Due to the limited availability of trained manpower there was a concern that use of standard dose TPF may lead to increased morbidity and loss of dose intensity. Hence, in this study as a protocol all patients were kept indoors until count recovery or decrement of all life-threatening toxicity to Grade 2 or less, which ever was later. Despite the high rate of life-threatening toxicity seen in the present study (33.3%), no mortality was observed which justifies our decision. However, despite the limited manpower available an ARDI of ≥0.9 was achieved in 75% of the patients. This encouraging finding lets us to routinely administer TPF at our center.
| » Conclusion | | |
Docetaxel, cisplatin and 5 fluorouracil regimen can be routinely administered at a tertiary level center with the supportive care methods and precautionary methods used in our study.
| » References | | |
| 1. | Patil VM, Noronha V, Muddu VK, Gulia S, Bhosale B, Arya S, et al. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference? Indian J Cancer 2013;50:1-8. 
[PUBMED]  |
| 2. | Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Surgical outcome of T4a and resected T4b oral cavity cancer. Cancer 2006;107:337-44.
|
| 3. | 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.
|
| 4. | Das S, Thomas S, Pal SK, Isiah R, John S. Hypofractionated palliative radiotherapy in locally advanced inoperable head and neck cancer: CMC Vellore experience. Indian J Palliat Care 2013;19:93-8.
[PUBMED] |
| 5. | 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.
|
| 6. | Joshi A, Patil VM, Noronha V, Juvekar S, Deshmukh A, Chatturvedi P, et al. Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers? Indian J Cancer 2013;50:349-55.
[PUBMED] |
| 7. | Patil VM, Noronha V, Joshi A, Muddu V, Poladia B, Chauhan B, et al. Induction chemotherapy in locally advanced pharyngolaryngeal cancers with stridor: Is it feasible and safe? Chemother Res Pract 2012;2012:549170.
|
| 8. | Joshi P, Patil V, Joshi A, Norohna V, Chaturvedi P, Chaukar D, et al. Neo-adjuvant chemotherapy in advanced hypopharyngeal carcinoma. Indian J Cancer 2013;50:25-30.
[PUBMED] |
| 9. | Hanna EY, Cardenas AD, DeMonte F, Roberts D, Kupferman M, Weber R, et al. Induction chemotherapy for advanced squamous cell carcinoma of the paranasal sinuses. Arch Otolaryngol Head Neck Surg 2011;137:78-81.
|
| 10. | Patil V, Noronha V, Joshi A, Muddu Krishna V, Juvekar S, Pantvaidya G, et al. Is there a limitation of recist criteria in prediction of pathological response, in head and neck cancers, to postinduction chemotherapy? ISRN Oncol 2013;2013:259154.
|
| 11. | 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.
|
| 12. | 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.
|
| 13. | Deschodt M, Wellens NI, Braes T, De Vuyst A, Boonen S, Flamaing J, et al. Prediction of functional decline in older hospitalized patients: A comparative multicenter study of three screening tools. Aging Clin Exp Res 2011;23:421-6.
|
| 14. | 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.
|
| 15. | Noronha V, Patil V, Joshi A, Juvekar S, Bhosale BB, Poladia B, et al. Are three drugs better than two and does docetaxel trump paclitaxel in induction therapy for locally advanced oral cavity cancers? J Clin Oncol 2013;31. [Suppl; Abstr 6085]. Available from: http://www.meetinglibrary.asco.org/content/116720-132. [Last cited on 2014 May 04].
|
| 16. | Ghafur A, Mathai D, Muruganathan A, Jayalal JA, Kant R, Chaudhary D, et al. The Chennai declaration: A roadmap to tackle the challenge of antimicrobial resistance. Indian J Cancer 2013;50:71-3.
[PUBMED] |
| 17. | Poladia B, Patil V, Noronha V. Development of hyponatremia on neoadjuvant chemotherapy in locally advanced head and neck cancers. ECCO Website. Available from: http://www.eccamsterdam2013.ecco-org.eu/Scientific-Programme/Abstract-search.aspx#. [Last cited on 2014 May 04].
|
| 18. | Salama JK, Stenson KM, Kistner EO, Mittal BB, Argiris A, Witt ME, et al. Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: A multi-institutional phase II trial investigating three radiotherapy dose levels. Ann Oncol 2008;19:1787-94.
|
| 19. | Patil V, Prabhash K, Noronha V, Joshi A, Muddu V, Chauhan B, et al. Neoadjuvant chemotherapy followed by definitive local treatment in locally advanced carcinoma maxillary sinus. J Clin Oncol 2012;30. [Suppl; Abstr 5585]. Available from: http://www.meetinglibrary.asco.org/content/99898-114. [Last cited on 2014 May 04].
|
| 20. | Somani N, Goyal S, Pasricha R, Khuteta N, Agarwal P, Garg AK, et al. Sequential therapy (triple drug-based induction chemotherapy followed by concurrent chemoradiotherapy) in locally advanced inoperable head and neck cancer patients-Single institute experience. Indian J Med Paediatr Oncol 2011;32:86-91.
[PUBMED] |
[Table 1], [Table 2], [Table 3], [Table 4]
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