|Year : 2017 | Volume
| Issue : 2 | Page : 224-229
Five versus ten fractions per week radiotherapy in locally advanced head and neck cancer
Ramanjis Viranna Tallari, OP Singh, Veenita Yogi, Suresh Yadav
Department of Radiation Oncology, Gandhi Medical College, Bhopal, Madhya Pradesh, India
|Date of Web Publication||23-Jun-2017|
Ramanjis Viranna Tallari
Department of Radiation Oncology, Gandhi Medical College, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Conventional fractionated radiotherapy (CFRT) is in use since a long time, but the invention of altered fractionation such as hyperfractionation has improved survival in head and neck squamous cell cancer (HNSCC).
Aims: Our aim of this prospective randomized study is to compare conventional 5 fractions per week (CFRT) with hyperfractionation 10 fractions per week (hyperfractionated radiotherapy [HFRT]) in locally advanced head and neck cancer.
Patients and Methods: The study period is from November 2013 to April 2015. Totally, 100 patients with proven head and neck cancer were submitted to radiotherapy on theratron 780 (cobalt 60) machine. Fifty patients in each CFRT group and HFRT group randomized to receive radiotherapy following induction chemotherapy. Patients in CFRT group have received 66–70 Gy/33–35 fractions Monday to Friday, while HFRT group have received 70.4 Gy/64 fractions Monday to Friday.
Results: Our results show manageable toxicity profile of a combined therapy consisting of cisplatin and paclitaxel, followed by concomitant chemoradiotherapy in the form of either CFRT or HFRT with cisplatin as a radiosensitizer in both treatment groups. The overall response at the completion of radiotherapy was 95.7% in HFRT versus 89.5% in CFRT with 76.6% complete response in HFRT versus 64.6% in CFRT.
Conclusions: After induction chemotherapy, HFRT seems to be more efficacious than CFRT in locally advanced HNSCC, by increasing significantly the probability of progression-free survival and locoregional control.
Keywords: Conventional fractionation (conventional fractionated radiotherapy), head and neck cancer, hyperfractionation (hyperfractionated radiotherapy)
|How to cite this article:|
Tallari RV, Singh O P, Yogi V, Yadav S. Five versus ten fractions per week radiotherapy in locally advanced head and neck cancer. J Can Res Ther 2017;13:224-9
| > Introduction|| |
The annual incidence of head and neck cancer worldwide is more than 550,000 cases with around 300,000 deaths each year. Head and neck squamous cell cancer (HNSCC) is the sixth leading cancer by incidence worldwide. Most HNSCCs arise in the epithelial lining of the oral cavity, oropharynx, larynx, and hypopharynx., These cancers are strongly associated with certain environmental and lifestyle risk factors such as tobacco and alcohol consumption. More recently, a new disease has emerged related to several strains of human papillomavirus 16, 18. The prognosis of these patients is substantially better than those associated with tobacco. The 5-year overall survival rate of patients with HNSCC is about 40%–50%. About one-third of patients present with early-stage disease (T1–2, N0) and remaining present with locally advanced stage.
The aim of this study is to evaluate whether after preceding induction chemotherapy, hyperfractionated radiotherapy (HFRT) is better than conventional fractionated radiotherapy (CFRT) and to assess the locoregional response and progression-free survival of the patients and the toxicity profile.
Altered fractionation and concurrent chemoradiotherapy have consistently shown superiority over conventional fractionation regimes. This has generated interest to test the combinations of altered fractionation regimens with chemotherapy in the treatment of advanced HNSCC. Most trials show that combinations of modified fractionation regimens with chemotherapy achieve better local control and in several trials, improved survival compared with standard or altered fractionation alone.
During the past two decades, definitive concurrent chemoradiation has shown to improve survival and organ preservation in locally advanced head and neck cancer.
In most patients with advanced head and neck cancer, conventional radiotherapy does not result in long-term locoregional control of the tumor, and this failure ultimately proves fatal.
Conventional radiotherapy alone is not sufficient to successfully treat most HNSCC cancers at locoregionally advanced stages. Hence, to improve locoregional control, altered fractionation regimen has evolved. These newer strategies lead to a 7%–10% improvement in locoregional control relative to conventional RT. Nonetheless, even the most effective RT regimens result in the local control rates of 50%–70% and dynamic foot stimulation of 30%–40%. All these have stimulated the investigation of treatments combining RT and chemotherapy. Hence, multimodality treatment has become the standard of care for the management of locally advanced HNSCC.
A hyperfractionated course of radiotherapy is one in which more than one fraction is delivered each day, but the overall treatment time remains similar to that for conventional fractionation, uses an increased total dose, with the size of dose per fraction significantly reduced and the number of fractions increased. Overall time is relatively unchanged. Typically, this means 1.1–1.3 Gy/fraction, two fractions a day, with an increase in total dose of the order of 20%–30% to account for increased repair at the lower dose per fraction.
The major rationale for hyperfractionation is to take maximal advantage of the difference in repair capacity of late-reacting normal tissues compared with tumors.
| > Patients and Methods|| |
Between November 2013 and April 2015, a total number of 100 patients with advanced HNSCC who have attended radiotherapy department of our institute were assigned randomly in this study.
- Patients with age <70 years, both sexes
- Patients with histologically proven locally advanced HNSCC - Stage III and IV
- Karnofsky performance scores/scale more than 70
- Normal hematological investigations
- Normal renal function test
- Normal liver function test
- Normal chest X-ray.
- Patients with age >70 years
- Patients with distant metastasis
- Hemoglobin <10 g%
- Prior head neck irradiation
- Histology other than squamous cell carcinoma.
- A complete detailed history which includes presenting complaints, past history, personal history, family history with emphasis on personal habits such as tobacco and alcohol consumption
- General physical examination
- Systemic examination
- Local examination
- Complete blood investigations
- Biopsy from the primary tumor and/or fine needle aspiration cytology of metastatic lymph nodes (in case of trismus)
- Dental evaluation
- Chest X-ray posteroanterior view
- X-ray mandible (panorex/lateral oblique view)
- Computed tomography scan.
Informed written consent of the patient was taken after explaining the nature of the disease, its treatment, and side effects in his/her own vernacular language.
During RT, the patients were examined for acute toxicity every week. Toxicity of RT developing within 90 days from the beginning of RT (acute toxicity) assessed according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) criteria. RT toxicity developing after 90 days (chronic/late toxicity) is graded with the same scale for late sequelae and evaluated every 6 months.
Response assessed 4 weeks after the completion of radiotherapy by clinical examination, indirect laryngoscopy/endoscopic examination. Thereafter, monthly follow-up was advised during the 1st year and once in 2 months for the 2nd year. Both the primary and node responses were assessed separately at 4 weeks after the completion of treatment.
The response was assessed as per the WHO Tumor Response Criteria. Acute mucosal and skin toxicity was assessed as per the RTOG Acute Radiation Morbidity Scoring system. Chemotherapy-induced toxicities such as renal and hematological toxicities were assessed as per the Common Toxicity Criteria for Adverse Events.
Treatment plan scheme
Patients with locally advanced squamous cell head and neck cancer had received induction chemotherapy with 3 cycles of injection paclitaxel (175 mg/m 2 D1) and injection cisplatin (75 mg/m 2 D1), repeated every 3 weeks. Then patients were randomized to receive either conventional fractionation (CFRT) at 1.8–2 Gy/fraction/day, 5 days/week to 66–70 Gy/33–35 fractions/6.5 weeks or hyperfractionation (HFRT) at 1.1 Gy/fraction, twice daily with a 6-h interfraction interval, 5 days/week to 70.4 Gy/64 fractions/6.5 weeks.
All patients in both treatment arms received concomitant chemotherapy in the form of weekly injection of cisplatin (40 mg/m 2).
The primary end-points were local control and progression-free survival.
All patients were treated with Cobalt-60 Teletherapy unit (Theratron 780) with a source-to-surface or source-to-isocenter distance of 80 cm.
Initial tumor volume consisted of primary tumor, involved lymph nodes, and probable subclinical disease. The irradiation field was reduced after 46 Gy to spare the spinal cord.
All patients were treated in the supine position with shoulder retraction. Depending on the primary tumor site, patients were treated with two parallel-opposed lateral fields.
Simulation X-ray film with lead wire markings was taken for verification of radiation portals, and necessary corrections according to the standard portals were made before the start of treatment.
Radiation therapy was given as conventional RT (CFRT) in arm-I, treatment commenced on Monday, continued up to Friday, Saturday, Sunday being the rest days. Patients received a total of 66 Gy–70 Gy/33–35Fr, 200cGy/Fr/day over 6.5 weeks.
In arm-II (HFRT), treatment commenced on Monday, continued up to Friday, Saturday, Sunday being the rest days. Patients received a total of 70.4 Gy/64Fr, 110cGy/Fr twice daily over 6.5 weeks with an interfraction interval of 6 h.
Primary and involved nodes received a dose of 66–70 Gy in CFRT arm and 70.4 Gy in HFRT arm. The primary treatment fields were reduced off the spinal cord at 46 Gy.
The tumor dose was defined as the mid-line dose on the central axis for the parallel-opposed fields.
All patients completed the schedule of radiotherapy irrespective of the delay and received minimum 4 cycles of chemotherapy were evaluated for response and follow-up.
| > Results|| |
A total of 100 patients with locally advanced head and neck cancer were recruited from November 2013 to April 2015 for this study. The patients were selected according to the inclusion and exclusion criteria as mentioned earlier. After the completion of chemotherapy, the patients were divided into two arms randomly, 50 in each arm, i.e., arm-I conventional fractionation (CFRT) and arm-II hyperfractionation (HFRT). Forty-eight patients in arm-I and 47 patients in arm-II completed the full course of radiotherapy and were evaluated for response.
The age of the patients ranged between 20 and 70 years with maximum patients in the age group of 51–60 years. Of 100 patients, 89 were male and 11 were female. T3 stage patients were maximum in both arms. N1 patients were maximum in arm-I and N2c patients were maximum in arm-II. Stage IVa patients were maximum in both arms. Distribution according to histology is well differentiated (WD) 64.6%, moderately differentiated (MD) 29.1%, and poorly differentiated (PD) 6.3% in arm-I and 61.7%, 34%, and 4.35% in arm-II, respectively [Table 1].
Overall response after induction chemotherapy for primary and lymph node was good, but the complete response is less than expected [Table 2].
After concurrent chemoradiotherapy, the complete response rate was significantly increased in both arms, more in case of HFRT arm-II [Table 3].
A significant observation was the association between the histology of squamous cell carcinoma and complete response with 67.7% (21/31) and 79.3% (23/29) of WD, 57.2% (8/14) and 81.3% (4/16) of MD, and 66.7% (2/3) and 0% of PD carcinomas showing complete response in arm-I and arm-II, respectively. HFRT arm has shown higher complete response rate in WD and MD cancers as compared with CFRT arm [Table 4].
Site-wise 90% (7/8) and 66.7% (4/6) of oropharyngeal cancers and 0% and 100% (2/2) of hypopharyngeal cancers and 90.9% (10/11) and 90% (9/10) of laryngeal cancers showed complete response; while in oral cavity cancer, it was 53.5% (15/28) and 72.4% (21/29) in arm-I (CFRT) and in arm-II (HFRT), respectively. Higher complete nodal response was observed in arm-II (HFRT) among patients with N1 and N2a lesions, N2b and N2c lesions as compared with arm-I (CFRT).
Tumor, node, metastasis stage-wise 85.7% (12/14) and 90% (9/10) of Stage III, 57.6% (19/33) and 74.3% (26/35) of Stage IVa showed a complete response in arm-I (CFRT) and arm-II (HFRT), respectively. None of the Stage IVb patients had shown a complete response in either arm.
[Table 5] and [Table 6] show the acute and late toxicity of radiotherapy in both treatment arms. The most common sites of Grade III toxicity were the mucous membrane. HFRT arm had increased Grade III mucositis and other toxicities such as dysphagia, xerostomia, and skin toxicity. Moderate and severe degrees of dysphagia necessitated placement of a nasogastric tube in 4.2% (2/48) and 10.7% (5/47) in arm-I and arm-II patients, respectively. None of the patients had Grade II or Grade III xerostomia during radiotherapy but developed Grade II xerostomia in the post-RT period at the end of the 1st month in 47.9% and 48% of patients. All patients in both arms had weight loss less than 10% of their pretreatment body weight and two (4.2%) patients in arm-I and five (10.6%) patients in arm-II required either IV fluids, tube feeding, or both.
|Table 5: Acute adverse effects of radiation therapy reported within 90 days after start of radiotherapy.|
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|Table 6: Late adverse effects of radiation therapy reported after 90 days after start of radiotherapy|
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At the end of 1-year locoregional control, progression-free survival and overall survival were highest in hyperfractionation arm [Table 7]. Six patients in arm-I (CFRT) and three patients in arm-II (HFRT) died in the 1st year after the treatment completion.
| > Discussion|| |
Our results show manageable toxicity profile of a combined therapy consisting of cisplatin and paclitaxel followed by concomitant chemoradiotherapy in the form of either CFRT or HFRT with cisplatin as a radiosensitizer in both treatment groups. The overall response at the completion of radiotherapy was 95.7% in HFRT versus 89.5% in CFRT with 76.6% CR in HFRT versus 64.6% in CFRT. Such a response rate has been seen in the previous studies including induction cisplatin-fluorouracil regimens.
Locoregional control represents the major end-point of any curative radiotherapy. This randomized trial demonstrates a significant 12-month locoregional control rate benefit of an HFRT regimen over a conventional regimen in locally advanced head and neck cancer. These findings had been seen in many large randomized trials that had compared HFRT with CFRT.,,,,,
[Table 8], shows the comparison of our study results with different other studies. In this study, there was a trend in favor of HFRT, especially for the most unfavorable T and N combinations. In our study, we found that the locoregional control benefit of HFRT is of a larger magnitude in patients with unfavorable prognostic factors. Neoadjuvant chemotherapy followed by concomitant chemoradiotherapy resulted in reduction of tumor lesions as well as eradication of micrometastases outside the irradiated field; this resulted in high local control and low incidence of both local failure and distant metastases. Moreover, in hyperfractionated irradiation, the overall treatment time is reduced with respect to the increased total dose (70.4 Gy/6.5 weeks). This lead to an increase in locoregional control, as the hypothesis that tumor repopulation during therapy is a major cause of treatment failure. Our findings go ahead with EORTC trial, in which patients with locally advanced head and neck cancer recur more often and sooner with conventional regimen than those with hyperfractionated one.
|Table 8: Results of randomized controlled trials of hyperfractionated versus conventional radiotherapy in locally advanced head and neck squamous cell cancer|
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The improvement in locoregional control was responsible for better progression-free survival in HFRT arm than those in CFRT arm. These findings are in agreement with the finding of Santamaria et al. and Adelstein et al. and the improvement in locoregional control was responsible for improved 12-month overall survival in the HFRT arm than those of CFRT arm; however, it did not reach a statistically significant level, but the progression-free survival has attained a statistically significant level in the hyperfractionated arm.
In our study, hyperfractionated schedules resulted in increased acute toxicity more than standard fractionation which go ahead with RTOG trial. The most common sites of Grade III acute reactions were the mucous membrane and the pharynx, which was in accordance with other studies.,, In our study, most of the late effects (reported >90 days) resolved with time, and there was no significant difference in the frequency of reported late effects at 6–18 months after treatment starts among the two treatment groups. Most common late effects observed were mucositis, xerostomia, and fibrosis.
At the present time, the major limitation of HFRT or combined radiotherapy and chemotherapy for head and neck is increased acute reaction primarily acute mucositis. Several toxicity antagonists are under active investigation.
In the future, some of these agents may decrease the acute and late effects of cancer therapy. The therapeutic ratio may also be improved by conformal and intensity-modulated radiotherapy, which has the capability of the high-dose tumor target coverage while minimizing the dose to the volume of the surrounding normal tissues irradiated.
| > Conclusions|| |
After induction chemotherapy, HFRT seems to be more efficacious than CFRT (CR: 76.6% vs. 64.6%) in locally advanced squamous cell carcinoma of the head and neck, by increasing significantly the probability of progression-free survival and locoregional control.
The study showed a good locoregional response rate and survival with acceptable toxicity profile.
This study has demonstrated that hyperfractionation is more efficacious in locally advanced head and neck cancer and needs to be used more often than actually used.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]
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