|Year : 2020 | Volume
| Issue : 3 | Page : 105-109
Induction chemotherapy in locally advanced head-and-neck squamous cell carcinoma: Real-world outcome
Vijay Gnanaguru1, Manikandan Dhanushkodi1, Venkatraman Radhakrishnan1, Jayachandran Perumal Kalaiarasi1, Arun Kumar Rajan1, Gangothri Selvarajan1, Sivasree Kesana1, Srikamakshi Kothandaraman2, Shobana Sekhar2, Venktesh Vaidhyalingam2, Arvind Krishnamurthi2, Aswin Nagarajan3, Kuluvoya Ramanaiah3, Harish Kumar3, Arun Kumar3, Ram Madhavan3, Alexander John3, Rama Ranganathan4, Trivadi Sundaram Ganesan1, Tenali Gnana Sagar1
1 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Radiation Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
4 Department of Epidemiology Biostatistics and Tumor Registry, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Submission||02-May-2020|
|Date of Decision||27-Jun-2020|
|Date of Acceptance||31-Oct-2020|
|Date of Web Publication||26-Nov-2020|
Department of Medical Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600 036, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Patients with locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) have a poor prognosis despite multimodality treatment. Aim: This study was done to assess the efficacy and toxicity of induction chemotherapy (IC) in patients with LAHNSCC. Materials and Methods: This was a retrospective study of patients with LAHNSCC who were treated with IC from May 2016 to July 2019 from a tertiary care cancer center in India. Results: A total of 26 patients were included in this analysis, with a median follow-up of 9.5 months. The majority of the patients had carcinoma of the oral cavity (96.2%, n = 25) and 1 (3.8%) had oropharyngeal cancer. The most common oral cavity subsites were buccal mucosa (65.4%) and gingivum (11.5%). Fifteen patients received a triplet regimen of IC and 11 patients received a doublet IC regimen. Among patients with an evaluable disease for response assessment (n = 21), complete response, partial response, stable disease, and progressive disease were seen in 9.5%, 66.7%, 19%, and 4.8%, respectively. Among patients with unresectable (Stage IVB) Oral squamous cell cancer (OSCCs), 40% underwent surgery. The median progression-free survival (PFS) was 8 months. Patients who underwent surgery after IC had a better PFS as compared to those who underwent nonoperative local therapy (12 months vs. 8 months). IC-induced Grade 3 or more toxicity occurred in 45% of the patients and mortality occurred in 2 patients (7.7%) due to neutropenic sepsis. Conclusion: IC is feasible in patients with inoperable LAHNSCC. Patients who underwent surgery after IC had a trend towards better PFS as compared to those who underwent nonsurgical local therapy after IC.
Keywords: Head-and-neck squamous cell carcinoma, induction chemotherapy, locally advanced
|How to cite this article:|
Gnanaguru V, Dhanushkodi M, Radhakrishnan V, Kalaiarasi JP, Rajan AK, Selvarajan G, Kesana S, Kothandaraman S, Sekhar S, Vaidhyalingam V, Krishnamurthi A, Nagarajan A, Ramanaiah K, Kumar H, Kumar A, Madhavan R, John A, Ranganathan R, Ganesan TS, Sagar TG. Induction chemotherapy in locally advanced head-and-neck squamous cell carcinoma: Real-world outcome. Oncol J India 2020;4:105-9
|How to cite this URL:|
Gnanaguru V, Dhanushkodi M, Radhakrishnan V, Kalaiarasi JP, Rajan AK, Selvarajan G, Kesana S, Kothandaraman S, Sekhar S, Vaidhyalingam V, Krishnamurthi A, Nagarajan A, Ramanaiah K, Kumar H, Kumar A, Madhavan R, John A, Ranganathan R, Ganesan TS, Sagar TG. Induction chemotherapy in locally advanced head-and-neck squamous cell carcinoma: Real-world outcome. Oncol J India [serial online] 2020 [cited 2021 Apr 10];4:105-9. Available from: https://www.ojionline.org/text.asp?2020/4/3/105/301579
| Introduction|| |
According to the Indian Council of Medical Research (ICMR) registry and GLOBOCAN 2018, carcinoma of the lip and oral cavity in men is the second most common cancer in India (10.4% of all cancers). The majority of the patients present with a locally advanced stage. The most common histology is squamous cell carcinoma. In India, the entire spectrum of head-and-neck cancer presents as a continual challenge in management.
Locally advanced unresectable oral squamous cell carcinoma (OSCC) is defined by the American Joint Committee on Cancer, 8th edition as the tumor invading the masticator space, pterygoid plates, skull base, and encasement of the internal carotid artery. The management of locally advanced disease mandates a multimodality approach and has a 5-year overall survival of <50%. The definition of resectability of OSCC is debatable with limited consensus. To achieve a negative pathological margin, extensive surgical procedures are warranted that significantly affect the functional and cosmetic outcome. Chemoradiation is a nonsurgical option to treat inoperable disease, but the survival remains poor with predominantly local recurrence.
Induction chemotherapy (IC) followed by surgery is a potential option in patients with inoperable locally advanced OSCC. The advantages of IC include early control of micrometastases, assessment of response to chemotherapy, and tumor regression that could increase the operability. However, randomized controlled studies with IC in OSCC have not shown a survival advantage. IC has allowed organ conservation in laryngeal cancers., Triple-drug (docetaxel, cisplatin, and 5-fluorouracil [TPF]) IC has shown to improve survival as compared to a doublet regimen (cisplatin and 5-fluorouracil [PF]) in locally advanced head-and-neck cancers., Studies from India have shown that IC in locally advanced carcinoma of the oral cavity is feasible with improved resectability and manageable toxicity., This study was done to assess the efficacy and toxicity of IC in patients with locally advanced head-and-neck cancers.
| Materials and Methods|| |
Data were captured from individual case records of consecutive patients with untreated locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) who received IC from May 2016 to July 2019 in a tertiary care cancer center. Patients were evaluated with detailed history and clinical examination and staged along with contrast-enhanced computed tomography (CECT) of the head and neck. The inclusion criteria were patients with inoperable Stage IVB and Stage III/IVA who had moderate-to-severe trismus. The exclusion criteria were patients with Eastern Cooperative Oncology Group performance status >2, sensorineural hearing loss, neuropathy grade > 2, and calculated creatinine clearance <60 ml/min. The criteria of the inoperability of oral cancers included tumor involvement of masticator space, pterygoid plates, skull base, and encasement of the internal carotid artery (Stage IVB). Patients were started on IC after discussion in the multidisciplinary head-and-neck tumor board. The IC was administered either as a triplet regimen (TPF) or as a doublet regimen (PF/docetaxel-cisplatin [TP]). TPF regimen consisted of injection docetaxel 75 mg/m2 administered on day 1, followed by injection cisplatin 75 mg/m2 administered on day 1 and injection 5-fluorouracil 750 mg/m2/day administered by continuous intravenous infusion for days 1–5. PF regimen consisted of injection cisplatin 75 mg/m2 administered on day 1 followed by injection 5-fluorouracil 750 mg/m2/day administered by continuous intravenous infusion for days 1–5. TP regimen consisted of injection docetaxel 75 mg/m2 on day 1 followed by injection cisplatin 75 mg/m2 on day 1. All the chemotherapy regimen were given at 3-weekly interval up to 3 cycles. Following chemotherapy, patients received pegylated granulocyte colony-stimulating factor (GCSF) as indicated and levofloxacin prophylaxis (500 mg OD) from D5 to D15 in the triplet regimen. Trismus was graded as Grade 1 (35-26 mm), Grade 2 (25-16 mm), and Grade 3 (15-0 mm).
Patients were monitored with hemogram, renal function, liver function, and electrolytes before each cycle. Clinical examination was performed before each cycle, and imaging with a CECT scan of the head and neck was repeated after 3 cycles of IC to assess treatment response. Adverse effects were captured as per Common Toxicity Criteria for Adverse Events Version (CTCAE) version 4.0 (US Department of Health and Human Services).
The study was conducted according to various guidelines for the ethical conduct of studies, including the Declaration of Helsinki, good clinical practice guidelines, and the ICMR.
Baseline characteristics were analyzed using descriptive statistics. Progression-free survival (PFS) was calculated from the date of starting IC until the date of progression, death, or date of the last follow-up. Survival outcomes were analyzed by Kaplan–Meier's analysis by the Statistical Package for the Social Sciences (SPSS) software version 15 (SPSS, Chicago, IL, USA), and P < 0.05 was considered statistically significant.
| Results|| |
A total of 26 patients were included in this analysis, with a median follow-up of 9.5 months (range: 1–32 months). The median age was 45 years with predominantly males. The majority of the patients had carcinoma of the oral cavity (96.2%, n = 25) and 1 (3.8%) had oropharyngeal cancer. The most common oral cavity subsites were buccal mucosa (65.4%) and gingivum (11.5%). Trismus of Grade 2 or 3 was present in 70%. The majority of the patients had Stage IVB at the time of presentation (57.7%, n = 15) followed by Stage IVA (n = 9) and Stage III (n = 2) [Table 1].
All the patients were discussed in a multidisciplinary team before the initiation of the IC. The IC was administered as either a triplet regimen in 15 patients or a doublet regimen in 11 patients. Among the 11 patients who received doublet, 10 received PF regimen and 1 patient received TP regimen. Primary prophylaxis with pegylated GCSF was used in 50% of the patients. The majority of the patients (n = 19/26; 73.1%) received 3 cycles of IC. Patients received lesser than 3 cycles if they have had chemotherapy-induced toxicity. Among the 26 patients who received IC, 21 patients had an evaluable disease. Five patients were not evaluable as 2 patients had IC-related toxic death, 2 patients were lost to follow-up, and 1 patient had toxicity (cerebrovascular accident and renal dysfunction) after day 1 of the 1st cycle of IC and subsequently did not receive further chemotherapy. The response assessment to IC showed a complete response, partial response, stable disease, and progressive disease (PD) in 9.5%, 66.7%, 19%, and 4.8%, respectively [Table 2].
Among the 21 evaluable patients who received IC, surgery was performed in 52.4% (n = 11). Among patients with inoperable OSCC (Stage IVB, n = 15) who received IC, surgery was performed in 40% (n = 6). The pathological stage of patients who were operated (n = 11) was T4a in 63.6% and T1–2 in 36.4% of the patients. The histopathology showed cervical node involvement in 7 out of 11 operated cases (63.6%). The surgical margin was free of tumor in all patients.
Among the patients who underwent surgery (n = 11) after IC, 6 patients received adjuvant radiation and 5 patients received adjuvant chemoradiation with weekly carboplatin (area under the curve: 2). A total of 11 patients received nonoperative local therapy after IC that included 10 inoperable patients who received chemoradiation and 1 patient who had toxicity during the 1st cycle of IC and then received only radiation.
The median PFS was 8 months [Figure 1]. The median PFS [Figure 2] for patients who underwent surgery and who underwent nonoperative therapy was 12 months and 8 months, respectively (P = 0.16). At a median follow-up of 9.5 months, 13 patients had PD (n = 5/11 postsurgery; n = 8/11 nonoperative local therapy). Among the patients who had PD, 2 underwent salvage surgery, 1 received palliative radiation, 6 received palliative systemic therapy (oral methotrexate 15 mg/m2 weekly), and 4 opted for best supportive care.
|Figure 1: Kaplan–Meier analysis showing the overall progression-free survival|
Click here to view
|Figure 2: Kaplan–Meier analysis comparing progression-free survival of patients who underwent surgery after induction chemotherapy and those who underwent nonoperative local therapy after induction chemotherapy|
Click here to view
The most common toxicity due to IC was mucositis, followed by chemotherapy-induced nausea and vomiting. Grade 3 or more toxicity occurred in 45% of the patients. Febrile neutropenia was seen in 15% of the patients. IC-related mortality was seen in 2 patients (7.7%) due to neutropenic septicemia leading to multi-organ dysfunction and septic shock [Table 3].
| Discussion|| |
The majority of the patients in India present with locally advanced disease as compared to developed countries where the majority present with early stage. In our study, operable patients had either severe trismus or relative inoperability due to a morbid surgery. A matched pair analysis from Mumbai showed that the use of IC does not preclude subsequent delivery of locoregional therapy in OSCC.
Triple-drug regimen (TPF) has shown a survival advantage as compared to a doublet regimen (PF)., In our study, only 57.7% received the triplet regimen and the rest received a doublet regimen. The rate of completion of all 3 cycles of planned IC was 73.1% which was similar to the TAX 323 trial where 75.7% in the TPF group and 65.7% in the PF group completed the planned chemotherapy.
The overall response rate in our study with IC was 76.2% and was comparable to the TAX 323 trial where it was 68%. In our study, among patients with inoperable OSCC (Stage IVB), 40% were operable after IC. A study by Rudresha et al. from Kidwai Memorial Institute of Oncology, Bengaluru, on IC in locally advanced T4b OSCC reported post-IC resectability in 19% of the patients. A similar study on IC in T4b OSCC conducted by Joshi et al. from TMH, Mumbai, had a post-IC resectability in 30.9% of the patients. A retrospective study by Malik et al. showed a favorable nodal response to IC in 64.7% of the patients with unresectable cervical nodes and up to 87.9% of the nodal responders underwent curative surgery leading to improved survival.
Patients in our study who underwent surgery had a better PFS (12 months) as compared to those who underwent nonsurgical local therapy (8 months). However, the difference was not statistically significant, possibly because of a small sample size. Studies by Rudresha et al. on IC in locally advanced T4b OSCC and Patil et al. on IC in unresectable locally advanced oral cavity cancers have shown better outcomes in patients who underwent surgery.
As compared to the DeCIDE trial by Cohen et al., our study had a higher Grade 3 or more mucositis (26.9% vs. 11%) and higher febrile neutropenia (15.4% vs. 9%). Furthermore, 2 patients in our study died of IC-related neutropenic sepsis. A study from a rural tertiary care center showed that Grade 4 toxicity (febrile neutropenia, thrombocytopenia, electrolyte disturbance, mucositis, and diarrhea) occurred in 33% of the patients who received triple-regimen IC without any toxic death. Given the toxicity, individualized IC protocols are warranted, especially in elderly patients.
A doublet regimen (TP) without 5-fluorouracil is a patient-friendly option as it does not necessitate central line insertion and inpatient admission for chemotherapy., Docetaxel is the preferred taxane as compared to paclitaxel as part of IC. Patients who are ineligible for taxane- or 5-fluorouracil-based chemotherapy can be treated with ifosfamide- and cisplatin-based IC regimen. Weekly IC with paclitaxel and carboplatin is an option in patients who are unfit for upfront radical treatment.
The present study has limitations including the retrospective design, small sample size, and outcome from a single center.
| Conclusion|| |
IC is feasible in patients with LAHNSCC. Among patients with inoperable OSCC (Stage IVB), 40% underwent surgery after IC. Patients who underwent surgery after IC had a trend toward better PFS than those who underwent nonsurgical local therapy after IC. Among this cohort, 2 patients died of IC-related neutropenic sepsis. Hence, careful monitoring (blood counts, renal functions, and electrolytes) and good supportive care are needed for patients on IC. Further prospective randomized studies with IC are warranted from developing countries like India to assess the impact on survival.
We look like to thank the nurses in medical oncology who had delivered the chemotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45:301-8.
Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al
. Head and neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:122-37.
dos Santos FM, Viani, GA, Pavoni JF. Evaluation of survival of patients with locally advanced head and neck cancer treated in a single center. Braz J Otorhinolaryngol 2019, doi.org/10.1016/j.bjorl.2019.06.006, Epub ahead of print, PMID 31395491.
Yousem DM, Gad K, Tufano RP. Resectability issues with head and neck cancer. AJNR Am J Neuroradiol 2006;27:2024-36.
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.
Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, HuangCH, et al
. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735-43.
Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al
. Long-term results of RTOG 91-11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-52.
Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, et al
. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506.
Vermorken JB, Remenar E, Herpen CV, Gorlia T, Mesia R, DegardinM, et al
. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N
Engl J Med 2007;357:1695-704.
Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al
. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: Long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.
Rudresha AH, Chaudhuri T, Lakshmaiah KC, Babu KG, Dasappa L, Jacob LA, et al
. Induction chemotherapy in locally advanced T4b oral cavity squamous cell cancers: A regional cancer center experience. Indian J Cancer 2017;54:35-8.
] [Full text]
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.
] [Full text]
Shah SB, Sharma S, D'Cruz AK. Head and neck oncology: The Indian scenario. South Asian J Cancer 2016;5:104-5.
] [Full text]
Patil VM, Muttath G, Babu S, Kumar ST, Jones J, Sen S, et al
. Does the use of induction chemotherapy in oral cavity cancer compromise subsequent loco-regional treatment delivery: Results from a matched pair analysis. Indian J Cancer 2015;52:632-6.
] [Full text]
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.
] [Full text]
Malik A, Qayyumi BN, Mair M, Singhavi H, Mathur Y, Nair D, et al
. Outcome of patients following neo-adjuvant chemotherapy for unresectable cervical nodes in head and neck squamous cell carcinomas. Eur Arch Otorhinolaryngol 2019;276:567-74.
Patil VM, Chakraborty S, Shenoy PK, Manuprasad A, Sajith Babu TP, Shivkumar T, et al
. 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.
] [Full text]
Patil VM, Noronha V, Joshi A, Ramaswamy A, Dhumal S, Juvekar S, et al
. Neoadjuvant chemotherapy in geriatric head and neck cancers. Head Neck 2017;39:886-92.
Noronha V, Goswami C, Patil S, Joshi A, Patil VM, Murthy V, et al
. Response to docetaxel and cisplatin induction chemotherapy of locally advanced head and neck squamous cell carcinoma: A multicenter, non-comparative, open-label interventional pilot study. J Laryngol Otol 2016;130:833-42.
Lakshmaiah KC, Rudresha AH, Suresh TM, Lokanatha D, Babu GK, Jacob LA. A prospective study to assess the efficacy and toxicity of 5-flurouracil and cisplatin versus taxane and cisplatin as induction chemotherapy in locally advanced head and neck squamous cell cancer in a regional cancer center in India. Indian J Cancer 2015;52:65-8.
] [Full text]
Noronha V, Patil VM, Joshi A, Muddu V, Bhattacharjee A, JuvekarS, et al
. Is taxane/platinum/5 fluorouracil superior to taxane/platinum alone and does docetaxel trump paclitaxel in induction therapy for locally advanced oral cavity cancers? Indian J Cancer 2015;52:70-3.
] [Full text]
Zaheer S, Siddiqui SA, Akram M, Hasan SA. Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience. Indian J Cancer 2016;53:372-6.
] [Full text]
Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Arya S, et al
. Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy. Indian J Cancer 2014;51:20-4.
] [Full text]
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]