|Ahead of print publication
Comparative study of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone in locally advanced head and neck cancer
Saroj Dhaka, Shankar Lal Jakhar, Neeti Sharma, Harvinder Singh Kumar, Rajesh Kumar
Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, SP Medical College, Bikaner, Rajasthan, India
|Date of Submission||17-Jul-2020|
|Date of Decision||16-Dec-2020|
|Date of Acceptance||25-Dec-2020|
|Date of Web Publication||28-May-2021|
Shankar Lal Jakhar,
Acharya Tulsi Regional Cancer Treatment and Research Institute, SP Medical College, Bikaner, Rajasthan
Source of Support: None, Conflict of Interest: None
Objective: Concurrent chemoradiotherapy (CTRT) is the standard treatment for patients with unresectable, nonmetastatic Locally advanced squamous cell cancer of head and neck (LASCCHN). The aim of this study to compare the efficacy and toxicity of induction chemotherapy (ICT) followed by CTRT versus standard CTRT alone in patients with LASCCHN.
Materials and Methods: Between January 2017 and September 2017, 100 patients with LASCCHN (Stage III and IV) were randomly assigned to two arms: 50 patients in each. Arm A treated by standard CTRT alone (a total 66 Gy in 33fr 2 Gy/# administered daily 5 days/week with 3 weekly inj. cisplatin 100 mg/m2 divided in two days) and Arm B received two cycles of ICT (TPF - inj. paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 divided in 2 days and inj. 5FU 1 gm/m2 iv d1 and d2 ) followed by same CTRT. Assessment was done weekly during RT and 1, 3, 6, 12, and 18 months posttreatment for treatment response, toxicities, and progression-free survival (PFS).
Results: Total response was observed 79.1% and 82.1% in Arm A and Arm B, respectively (P = 0.705) at 6–8 weeks after the completion of treatment. Acute toxicities were significantly higher in ICT arm. The 18 months PFS was 57% versus 55% in Arm A and Arm B, respectively (x2 = 0.039, P = 0.8414).
Conclusion: Among the patients followed, this study failed to show benefit of ICT-CTRT over CTRT alone in patients of LASCCHN.
Keywords: Chemoradiotherapy, induction chemotherapy, unresectable locally advanced head and neck cancer
|How to cite this URL:|
Dhaka S, Jakhar SL, Sharma N, Kumar HS, Kumar R. Comparative study of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone in locally advanced head and neck cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=317069
| > Introduction|| |
The incidence of squamous cell carcinoma of the head and neck (SCCHN) is increasing, and it is the sixth most common malignancy worldwide, with more than 70% of cases occurring in the developing world. It is the third most common cancer in India, over 200,000 new cases are registered every year in India. The male-female ratio ranges from 2:1 to 4:1. About 90% of all head and neck cancers (HNCs) are squamous cell carcinomas, may be due to higher indulgence of alcohol, tobacco, and betel nut chewing. In our institute, Acharya Tulsi Regional Cancer Training and Research Institute 3671 new head and neck cases were registered in 2016.
SCCHN is a locoregional disease; distant metastases are rarely seen at the time of diagnosis. Radiotherapy and surgery are the treatments of choice, with radiotherapy being the favored treatment if organ conservation is concerned. One of the most important biological factors related to the outcome of radiotherapy in squamous cell carcinoma is the proliferation of tumor stem cells during the treatment. A prolonged overall treatment time might reduce the chance of tumor control,,, and a substantial number of clinical reports show a reduction in overall treatment time might improve tumor control.,, A shorter treatment time can be obtained by applying a concurrent chemoradiotherapy alone in advanced HNC. Various randomized trials have been investigated the efficacy of chemotherapy in locally advanced HNCs (LASCCHN). Chemotherapy has been used as induction treatment, concurrent with radiotherapy, or as adjuvant treatment after radiotherapy, surgery or both.,,,,,,
The prognosis of patients with locally advanced squamous cell cancer of the head and neck is generally poor. Despite multimodality of treatment such as surgery and/or radical radiation therapy (RT), 50%–60% of patients recur within 2 years, and an additional 20%–30% of them develop distant metastasis.
Concurrent chemo-radiotherapy improves survival over RT and generally attributed to improved locoregional control. Induction chemotherapy (ICT) reduces metastasis incidences and cisplatin-based ICT and induces response rate of 80%–90%, with complete response rate (CR) rate to 20%–40% in LASCCHN.,,,
To compare the efficacy and toxicity of ICT followed by CTRT versus standard CTRT alone in patients with LASCCHN. Primary end point is progression-free survival (PFS) and toxicity profile.
| > Materials and Methods|| |
This was a randomized, prospective study conducted at Acharya Tulsi Regional Cancer Treatment and Research Institute, Sardar Patel Medical College and associated group of hospitals, Bikaner.
The study protocol included 100 patients of histologically proven previously untreated locally advanced squamous cell carcinoma of head and neck (LASCCHN) who were enrolled from January 2017 to September 2017.
- Age <70 years
- Eastern Cooperative Oncology Group (ECOG) 0–2
- No previous history of malignancy oriented treatment
- Adequate baseline haematological, cardiac, renal or liver functions tests.
- Distant metastasis
- Recurrent lesions
- Concurrent malignancies
- Associated severe comorbidities
- History of previous treatment with any of the following modalities: Surgery, radiotherapy, and chemotherapy
- Pregnant and lactating women.
The protocol was approved by hospital's institutional ethical committee, and all patients were properly informed and consented for the treatment study. Study design was intent to treat.
One hundred patients who fit the inclusion criteria were randomized into two arms of 50 each, by using the website (http:/www.randomisation.com). The arms were:
Arm A (CTRT alone)
A total 66Gy in 33fr (2Gy per fraction), administered daily (5 days per week) for 7 weeks (conventional fractionated radiotherapy) with 3 weekly inj. Cisplatin 100mg/m2 divided in two doses on D1, D22, and D43.
Arm B (ICT f/b CTRT)
Two cycles of induction chemotherapy each consisting of inj. Paclitaxel 175mg/m2 on day1, inj. Cisplatin 100mg/m2 divided in two doses on D1 and D2 and inj. 5FU 1gm/m2 on day 1 and 2; followed by 7 weeks of concurrent CTRT consist of standard RTOG regime with 3 weekly inj. Cisplatin 100 mg/m2 in two divided doses on D1, 22, 43 Plus RT by conventional fractionation.
Treatment volume was included primary tumor site plus neck node regions. Parallel opposed bilateral fields were planned. The dose was prescribed at midline. External-beam radiotherapy was given with RT parameter on cobalt-60 machines Theratron 780E/780C/Bhabhatron II with photon energies of 1.25MeV. Minimum treatment distance was ≥80 cm source to surface distance. Prophylactic granulocyte colony-stimulating factor (G-CSF) administration after 48 h of TPF chemotherapy cycle was implemented in the study. Prophylactic ciprofloxacin (500 mg PO bid) was given to TPF arm from days 6 to 12 after TPF chemotherapy cycle.
Patients were under monitoring after every course of chemotherapy and prior to and during radiotherapy. In each monitoring, patients were assessed for treatment response, control of symptoms, and any treatment-related morbidity by doing complete blood counts, biochemistry profile consisting of renal function test (RFT) and liver function test (LFT), ear, nose, throat (ENT) examination, chest X-ray, and ultrasonography (USG) abdomen. Toxicities including hematological, renal, biochemical, skin reactions, and disease response were assessed. After 6–8 weeks of completion of radiotherapy, patients were called for first follow-up visit and were assessed for treatment response and symptoms relief. Treatment response was assessed as per the RECIST criteria- Response Evaluation Criteria in Solid Tumors (V 1.1). Acute toxicities were assessed as per the RTOG/EORTC acute radiation morbidity scoring system. On first follow-up visit, complete general-physical examination, ENT examination, hemogram, RFT, RBS, and contrast-enhanced computed tomography head and neck were done for treatment response, and toxicity evaluation and metastatic workup were consist of chest X-ray, USG abdomen, and LFT. Statistical analysis was performed using the Chi-square test to compare tumor response and treatment-related toxicities between the study arm and control arm. P < 0.05 was considered statistically significant.
| > Results|| |
The baseline patients and tumor characteristics are described in [Table 1]. All characteristics were balanced. The treatment-related toxicities are described in [Table 2]. The treatment response on different follow-up visits is shown in [Table 3], [Table 4], [Table 5], [Table 6] to evaluate local control and PFS. The median follow-up was 18 months (6 months, 12 months, and 18 months).
Most of patients had ECOG performance status 1 and 2, median age 59 years, male gender, median weight 53 kg, and Stage III and IV in both arms. During the treatment, 2 and 4 patients lost from follow-up in Arm A and Arm B, respectively; while 1 patient expired after receiving two cycles of chemotherapy. A total of 48 and 45 patients were received CTRT in Arm A and Arm B, respectively. Sixteen patients showed >5% of weight loss during study; 7(14.6%) and 9(20%) patients from arm A and arm B respectively.
The follow-up was done after 6–8 weeks after completion of chemoradiotherapy, 18 and 24 patients had CR in study and control arm for any stage (X2 = 2.38, P = 0.126), which was insignificant. Although total 38 and 37 patients had regression (x2 = 0.14, P = 0.705), 7 and 5 patients had stable disease and 3 and 3 patients had progression of disease in Arm A and Arm B, respectively.
There was no Grade 4 hematological and nonhematological toxicities found in both arms. During the induction TPF, hematological toxicities in terms of anemia and neutropenia were higher in TPF arm. Grade 3 neuropathy was found only in two patients of TPF arm (4.4%). Stomatitis and skin reactions of Grade 3 were also higher in TPF arm. The symptoms relief was slightly better and earlier achieved in the control arm.
The subsequent follow-ups done at 3 months, 6 months, 12 months, and 18 months were done to evaluate PFS. Few patients were lost to follow-up at different visits. Although the patients those followed, 6 months' PFS was found 77% v/s 75.6% (P = 0.853), 12 months PFS was found 67.4% versus 66% (P = 0.126), and 18 months PFS was found 57% versus 55% (x2 = 0.039, P = 0.8414) in Arm A and Arm B, respectively.
Local control and PFS were calculated by using the Chi-square test. Differences in both arms were identified as statistically significant if P < 0.05.
| > Discussion|| |
Treatment of HNC is a multimodality approach, including surgery, chemotherapy, and radiotherapy according to the site and stage of the disease. More than 75% of HNC patients require RT, which can be given either alone or concurrently with chemotherapy., As per Delaney et al.'s study, RT was indicated at some point in 74% of all patients with head and neck carcinoma.
The purpose of this study was to verify the potential impact of ICT on treatment outcome, toxicity, and PFS in patients with locally advanced SCCHN. Our study showed 37.5% versus 53.3% CR rate and 79.1% versus 82.1% total response rate (CR + PR) (P = 0.705) at 6–8 weeks of treatment completion in CTRT versus ICT-CTRT arms respectively, which was similar to a study by Hitt et al. Published in annals of Oncology 2014. The 18 months' PFS was found 57% versus 55% in Arm A and Arm B, respectively (x2 = 0.039, P = 0.8414), which is also similar to this above study.
No any patient showed Grade 4 toxicities. The most reported Grade 2–3 hematologic toxicities was anemia and neutropenia, and the most reported non hematological toxicities included stomatitis, skin reactions, dysphagia, and nausea and vomiting. The toxicities were significantly higher in ICT-CTRT arm, which is also similar to above discussed study.
Four patients in TPF arm were lost to follow-up as they got relief by ICT, so they did not turn up for subsequent CTRT.
The prevalence of human papilloma virus (HPV) association in oropharyngeal cancers is roughly 25%. HPV status, which is a prognostic factor in HNCs, was unknown in our study and could be a confounding factor.
The expected higher proportion of febrile neutropenia in Arm B (ICT-CTRT) was controlled with prophylactic G-CSF. The toxicity-related deaths were zero in both arms.
| > Conclusion|| |
The present study represents the cohort of locally advanced head and neck cancer treated with induction CT and CTRT in single institute. The results of this study are matched with some previous studies cited in the literature. On basis of our findings, this study conclude that addition of induction TPF chemotherapy before concurrent CTRT in unresectable LASCCHN has failed to show any significant advantage in terms of CR rates, toxicity profiles, and PFS.
The authors would like to thank the doctors and support staff of the Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ferlay J, Shin HR, Bray F, et al
. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr
. [Last accessed on 2011 Dec 03].
Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T, et al
. Larynx preservation in pyriform sinus cancer: Preliminary results of a European organization for research and treatment of cancer phase III trial. EORTC head and neck cancer cooperative group. J Natl Cancer Inst 1996;88:890-9.
Posner MR, Haddad RI, Wirth L, Norris CM, Goguen LA, Mahadevan A, et al
. Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: Evolution of the sequential treatment approach. Semin Oncol 2004;31:778-85.
Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143-54.
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.
Brockstein B, Haraf DJ, Rademaker AW, Kies MS, Stenson KM, Rosen F, et al
. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: A 9-year, 337-patient, multi-institutional experience. Ann Oncol 2004;15:1179-86.
Argiris A. Induction chemotherapy for head and neck cancer: Will history repeat itself? J Natl Compr Canc Netw 2005;3:393-403.
Fu KK, Phillips TL, Silverberg IJ, Jacobs C, Goffinet DR, Chun C, et al
. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987;5:1410-8.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al
. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.
Bourhis J, Le Maître A, Baujat B, Audry H, Pignon JP, Meta-Analysis of Chemotherapy in Head, Neck Cancer Collaborative Group, et al
. Individual patients' data meta-analyses in head and neck cancer. Curr Opin Oncol 2007;19:188-94.
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.
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.
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.
Vermorken JB, Remenar E, van HC, 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.
Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, et al
. Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 2006;368:843-54.
Paccagnella A, Ghi MG, Loreggian L, Buffoli A, Koussis H, Mione CA, et al
. Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: A phase II randomized study. Ann Oncol 2010;21:1515-22.
Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, et al
. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 2014;25:216-25.
Ghi MG, Paccagnella A, Ferrari D, Foa P, Alterio D, Codecà C, et al
. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol 2017;28:2206-12.
Guan J, Zhang Y, Li Q, Zhang Y, Li L, Chen M, et al
. A meta-analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus concurrent radiotherapy (CRT) for advanced head and neck cancer (HNC). Oncotarget 2016;7:70185-93.
Verma V, Surkar SM, Moreno AC, Lin C, Simone CB 2nd
. Practice patterns and outcomes of chemoradiotherapy versus radiotherapy alone for older patients with nasopharyngeal cancer. Cancer Med 2018;7:1604-11.
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;S1808-8694(18):30759-6.
Ferrari D, Ghi MG, Franzese C, Codecà C, Gau M, Fayette J. The slippery role of induction chemotherapy in head and neck cancer: Myth and reality. Front Oncol 2020;10:7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]