|Year : 2017 | Volume
| Issue : 1 | Page : 6-10
Comparison of conventional fractionation (five fractions per week) and altered fractionation (six fractions per week) in stage I and II squamous cell carcinoma of oropharynx: An institutional study
J Poddar, AD Sharma, SU Kunikullaya, JP Neema
Department of Radiotherapy, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
|Date of Web Publication||1-Dec-2017|
Dr. J Poddar
Department of Radiotherapy, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
BACKGROUND: The radiotherapy (RT) dose and fractionation schedule for head and neck cancers for locoregional control and acceptable organ toxicity are still debatable. Accelerated RT includes administration of six fractions per week with the same dose per fraction. AIM: Comparison of conventional versus accelerated RT in terms of locoregional control, and acute and late radiation toxicity in squamous cell carcinoma oropharynx (stage I and II). SETTINGS AND DESIGN: Prospective, double arm, phase 2, randomized study. MATERIALS AND METHODS: Sixty patients of squamous cell carcinoma oropharynx (stage I and II) were randomized in two arms (accelerated fractionation, arm 1 and conventional fractionation, arm 2). All patients received RT dose of 66 Gray (Gy) in 33 fractions (#). The patients in arm 1 received six fractions per week with 2 Gy/# (Monday–Saturday) and in arm 2, five fractions per week with 2 Gy/# (Monday–Friday). No chemotherapy was administered. During and after the treatment, locoregional control, and acute and late radiation toxicity were assessed. RESULTS: At 1-year follow-up, 76% patients in arm 1 and 64% patients in arm 2 had complete response. The recurrence rate at the end of 1 year in arm 1 was 12% and it was 20% in arm 2.The acute Grade 2 and 3 toxicities were higher in the accelerated arm and no significant difference in late toxicities was found. SPSS version 4.0 was used for statistical analysis. CONCLUSION: Accelerated fractionation provides better locoregional control with higher but acceptable acute and equal late radiation toxicity in squamous cell carcinoma oropharynx.
Keywords: Accelerated fractionation, carcinoma oropharynx, radiotherapy
|How to cite this article:|
Poddar J, Sharma A D, Kunikullaya S U, Neema J P. Comparison of conventional fractionation (five fractions per week) and altered fractionation (six fractions per week) in stage I and II squamous cell carcinoma of oropharynx: An institutional study. Indian J Cancer 2017;54:6-10
|How to cite this URL:|
Poddar J, Sharma A D, Kunikullaya S U, Neema J P. Comparison of conventional fractionation (five fractions per week) and altered fractionation (six fractions per week) in stage I and II squamous cell carcinoma of oropharynx: An institutional study. Indian J Cancer [serial online] 2017 [cited 2021 Jul 24];54:6-10. Available from: https://www.indianjcancer.com/text.asp?2017/54/1/6/219539
| » Introduction|| |
Head and neck carcinoma is the sixth most common cancer. In Southeast Asia, it accounts for 20%–30% of all cases., Carcinoma oropharynx comprises 6%–8% of all head and neck cancers. Radiotherapy (RT) is the primary modality of treatment in carcinoma oropharynx as organ preservation is the major goal, but the fact that local recurrence is a major cause of failure, has led to a number of studies to investigate the role of dose intensification of radiation in head and neck cancers. The optimal dose and the fractionation schedule for head and neck cancers for locoregional control and acceptable organ toxicity is still debatable. While treating head and neck cancers with radiation, a balance is to be maintained between four parameters, i.e., total radiation dose, dose per fraction, overall treatment time, and the irradiated volume. A number of radiation treatment schedules have been proposed keeping all these parameters in view known as altered fractionation. The conventional system of fractionation (i.e., 60–70 Gray in 2 Gray/fraction, five times a week) as the optimal way of delivering RT in all circumstances is highly debatable.
One of the most important biological factors hindering the local control is accelerated repopulation of tumor cells after the initiation of treatment. Treatment with any chemotherapy agent or radiation triggers the surviving cells in the tumor to divide faster than before and a larger proportion of tumor clonogens come to the replicative pool. This can make the tumor resistant to conventional fractionation of radiation as well as to chemotherapy. Hence, the chances of tumor control decrease with increase in the overall treatment time which is clinically and biologically documented. There are a number of clinical reports which prove that decrease in treatment time has improved the clinical outcomes.,
A shorter treatment time can be achieved by applying a higher dose per fraction, but this change can increase the rate of late complications, disproportionately. Hence, a midpath is to be devised, i.e., the number of fractions delivered per week is increased without increasing the dose per fraction. This would shorten the overall treatment time and could limit the accelerated repopulation of tumor cells thereby increasing the local control rate with the same dose of radiation. This fractionation is called accelerated fractionation.
Since late reacting normal tissues have little or no effect of the overall treatment time, with respect to the late tissue injury, accelerated fractionation does not affect the late reacting normal tissues. Considering all these facts, we planned a clinical study to test the efficacy of accelerated fractionation by delivering six fractions per week, reducing the overall treatment time from 6 1/2 weeks to 5 1/2 weeks, in the patients of stage I and II carcinoma oropharynx, at our institute. We aimed to find out whether shortening of overall treatment time by use of this regimen improves the local response with acceptable toxicity and tolerability by the patients.
Aim and objectives
The aim of this study was to compare the response of accelerated fractionation (arm 1, 66 Gray/33 fractions with six fractions per week) and conventional fractionation (arm 2, 66 Gray/33 fractions with five fractions per week) in squamous cell carcinoma of oropharynx stage I and II (T1–T2 N0M0), AJCC 2007.
The primary objective of the study was local disease control rate. The secondary objective was evaluation of acute and late radiation-induced toxicity.
| » Materials and Methods|| |
In our institution, we conducted a prospective randomized study for 2.5 years from July 2012 to December 2014, in sixty untreated patients of squamous cell carcinoma of head and neck (oropharynx) with histologically confirmed diagnosis and no evidence of distant metastasis.
Inclusion criteria were age <70 years, Karnofsky Performance Status score >70, stage T1–T2, N0M0, invasive squamous cell carcinoma of the oropharynx, no previous treatment for the malignancy (surgery or Neo Adjuvant Chemo Therapy (NACT), normal hematological, and renal and hepatic function status.
Clinical history, physical examination, and local examination with direct laryngoscopic examination (DLE) and biopsy were done for all the patients. Routine blood investigations, orthopantomogram, chest X-ray, computed tomography (CT) scan of the head and neck and dental evaluation was done for all the patients. All patients underwent dental checkup before RT and in patients who had undergone dental procedure, a minimum gap of 2 weeks was maintained between procedure and beginning of RT. All patients were staged according to AJCC 2007 staging system into stage I and II. Thirty patients were randomized into each arm of the study.
The patients were randomly assorted into two arms:
- Study group: (Arm A): Received accelerated six fractions per week RT-66 Gray/5½ weeks/33# (Monday–Saturday; one fraction per day)
- Control group: (Arm B): Received conventional five fractions per week RT 66 Gray/6½ weeks/33# (Monday–Friday; one fraction per day).
Ethical clearance was obtained from the Institutional Ethical Committee. All the patients were informed regarding the intervention in the study and a written informed consent was taken from all the patients recruited in the study.
All the patients were treated with 6 MV photons on a linear accelerator. All patients were immobilized with an acrylic cast. Treatment was planned on a simulator with bilateral parallel opposed fields and an anterior lower neck field. Initially, the radiation portals encompassed primary disease, microscopic disease around primary, and the anticipated lymph node stations. In all the cases, whole neck along with primary disease was included in the initial radiation portals. After 46 Gray/23#, the posterior neck field was reduced to spare spinal cord. After the microscopic disease had received 50 Gray/25#, the field was reduced to include lymph node region with one level up. After 60 Gray, the field was reduced to include involved primary site. Same procedure was followed for both the arms.
Assessment for toxicity was done at every week during and at the end of treatment, toxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 4.0 proposed by National Cancer Institute, United States of America.
The scores were based on the patient's subjective symptoms, objective examination findings, and treatment of the symptoms. At the time of completion of treatment, toxicity status and locoregional disease status of all patients were recorded.
The response to treatment was considered to be complete if there was complete regression of disease with no visible or palpable lesion, partial (residual) if there was more than 50% regression in the lesion in maximal diameter, stable if lesion regressed <50% in maximal diameter, and recurrence if lesion reappeared after 3 months of treatment completion and the patient had achieved complete response (CR).
During and after the treatment, locoregional control and acute and late radiation toxicity were assessed at following intervals:
- Weekly during RT
- Within a week of termination of therapy
- One month after the termination of therapy
- Every month for the first 6 months, every 2 months in the next 6 months, every 3 months for the next 1 year.
During the treatment, tolerance to treatment was assessed by noting the weight, performance status, acute reactions, for example, mucositis, skin reactions, dysphagia, and pain.
During the follow-up evaluation, physical examination monthly for the first 6 months, then every two monthly for the next 6 months followed by three monthly for next 1 year. DLE was done three monthly for the first 1 year then six monthly for the next 1 year. CT scan was done at the end of 1 year or as and when required. Late tissue toxicity included dry mouth, subcutaneous fibrosis, and trismus which were graded.
Statistical analysis included two-tailed Chi-square test. The P value was calculated and P < 0.05 was considered to be statistically significant. All calculations were done using SPSS 16.0 (Statistical Package for the Social Sciences version 16 produced by International Business Machines Corporation) software. The results were studied on an intention-to-treat basis.
| » Results|| |
Thirty patients were recruited in arm 1 and 2 each. In arm 1, four patients could not complete the treatment whereas two patients from arm 2 patients could not complete the treatment. One patient from arm 1 and three patients from arm 2 were lost to follow-up. At the end, a total of 25 patients were available for analysis in both the arms.
All the patients recruited in the study were males. The median age of presentation was 58 years ranging from 41 to 63 years. All the patients were of oropharynx and it included carcinoma base of tongue, soft palate, and tonsil. [Table 1] shows the patients' characteristics along with the presenting symptoms.
At the first follow-up, i.e., 1 month after treatment completion, 84% (21 patients) in arm 1 and 76% (19 patients) in arm 2 achieved CR. At 1-year follow-up, 76% (19 patients) in arm 1 and 64% (16 patients) in arm 2 had CR. The recurrence rate at the end of 1 year in arm 1 was 12% (three patients) and it was 20% (five patients) in arm 2. The recurrence rate was higher in the conventional arm as compared to the accelerated arm by the end of 1 year (P = 0.88). The results are shown in [Table 2].
All the recurrences in both the arms were local. No nodal recurrence was seen in any of the patient.
One patient in arm 2 had stable disease at first follow-up, who was referred for palliative chemotherapy. The patient showed partial response in subsequent follow-ups. At 1 year, 12% (three patients) in arm 1 and 16% (four patients) in arm 2 had residual disease. They were advised palliative chemotherapy. The median follow-up period was 20 months.
The rate of response was evaluated according to the tumor subsite which is shown in [Table 3].
Carcinoma base of tongue and tonsil showed better response as compared to carcinoma soft palate in both the arms. The result was statistically significant for base of tongue (P = 0.003) and tonsil (P = 0.003).
Acute mucositis was the most important toxicity observed in both the arms as depicted in [Table 4].
|Table 4: Acute mucosal reactions during treatment and at the end of 1 month|
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Grade 3 mucositis was higher in the accelerated RT (76%) arm as compared to conventional (64%) arm. Grade 2 toxicity in arm 1 was 24% and that in arm 2 was 36% (P value). Weekly assessment of the appearance and grading of the mucositis was done and it was concluded that acute mucositis appeared early and persisted longer in the accelerated fractionation arm but all healed within 3 months of the end of treatment.
Acute skin reactions were observed in the both the arms and were assessed at the end of the treatment and the end of 1 month. [Table 5] shows the skin reactions at the completion of treatment and at 1 month after treatment completion.
|Table 5: The skin reactions at the completion of treatment and at 1 month after treatment completion|
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There was no difference in Grade 3 skin reactions in both the treatment arms. However, the Grade 2 skin reactions were slightly higher (72%) in arm 1 as compared to arm 2 (64%).
Toxic death is defined as death resulting from treatment within 30 days of treatment completion. No toxic death was seen in either arm.
The more frequent mucosal reactions in the accelerated treatment group resulted in a significantly increased use of tube feeding during accelerated treatment (24%) compared with the conventional treatment group (8%). Two patients from arm 1 required intravenous fluids during treatment.
Similar to the other acute toxicity, the onset of dysphagia was earlier in arm 1 as compared to arm 2 during of the treatment though the severity was same by the end of the treatment. The severity of dysphagia at the end of treatment and at 1-month posttreatment was evaluated and it is as follows in [Table 6].
|Table 6: Acute dysphagia at the end of treatment and at the end of 1 month posttreatment|
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Late toxicity was evaluated at the end of 6 months and 1 year as shown in [Table 7], [Table 8], [Table 9]. It included xerostomia, subcutaneous fibrosis, and trismus. At the end of 1 year, Grade 3 xerostomia was equal in both the arms (16%) and there was no Grade 3 subcutaneous fibrosis or trismus.
Xerostomia at 6 months was equal in both the arms. No incidence of Grade 3 fibrosis or trismus was seen.
Xerostomia at 1 year improved in both the arms. No significant change was seen in pattern of fibrosis or trismus at 6 months and 1-year posttreatment.
| » Discussion|| |
Accelerated RT improves locoregional control in squamous cell carcinoma of head and neck is shown in different clinical studies. Although it increases treatment-associated acute morbidity, which when very severe, may lead to an increase in late radiation effects. This study was planned with the objectives that reducing overall treatment time would negate the effect of accelerated repopulation and would result in better locoregional control. As with reduction in overall treatment time, it is expected that patients will have more acute toxicity, therefore, to find out whether the patients would tolerate the new accelerated schedule and would they able to finish the treatment as planned.
In Danish Head and Neck Cancer Study Group (DAHANCA) study, locoregional tumor control improved significantly in the accelerated fractionation group compared with that in the conventional RT group (70% vs. 60% 5 years actuarial rate, P = 0.0005). There was 10% statistically significant improvement in locoregional disease control in accelerated arm. In International Atomic Energy Agency (IAEA)-ACC study by Overgaard et al., the 5-year actuarial locoregional control was 42% in the accelerated versus 30% in the conventional group (P = 0.004). In our study, the statistical significance could not be achieved because of the smaller sample size and shorter follow-up.
We observed that acute treatment complications were considerably more severe in the accelerated RT arm than those of conventional fractionation arm. Grade 3 mucositis was significantly higher in the accelerated arm as compared to conventional 1 (76% vs. 64%, P = 0.354). Moreover, the mucositis appeared earlier and persisted longer in the accelerated fractionation arm but all healed within 3 months of the initiation of treatment. Similarly, the Grade 2 skin reactions were higher in arm 1 as compared to arm 2 (72% vs. 64%).
The higher rate of severe acute reactions seen in the accelerated RT arm was expected due to accumulated dose (AD) per week of 12 Gray in accelerated arm as compared to AD of 10 Gray in conventional RT arm, as acute toxicity is directly dependent on AD. All toxicities were effectively managed and did not lead to increased frequency of treatment interruptions in the accelerated RT arm patients. Our findings are comparable to DAHANCA trial, with respect to the acute radiation toxicity and time required for healing of acute reactions, where acute radiation-related morbidity was significantly higher in the accelerated RT group with 53% incidence of Grade 3 mucositis compared with 33% in the conventional treatment group (P< 0.0001). In our study, we observed radiation-induced late toxicity as xerostomia and subcutaneous fibrosis at anterior aspect of neck, which did not differ significantly in both groups. Comparably, late toxicities in two groups were expected as late morbidity depends on dose per fraction which was not different in the two treatment arms, that is, 2 Gray per fraction. In the DAHANCA trial and IAEA-ACC study too, the probability of developing a severe late radiation-related complication did not differ significantly between the two fractionation groups. The six fractions per week schedule, resulting in a 1-week reduction in treatment time relative to conventional treatment, seems to give a good balance between improved tumor control and avoidance of excess late morbidity.
| » Conclusion|| |
Based on our study, DAHANCA trial and IAEA-ACC study, we propose that six fractions per week treatment are a better treatment option for carcinoma oropharynx as compared to five fractions per week, especially in countries where working days are 6 in a week. The concept of fractionating the total dose of radiation and delivering five fractions per week was started in the West, almost a century back, when the logic of giving fractionated treatment was not clear. It was based on working convenience. As the standard fractionation of RT has evolved without any logic, biologic basis, and empiricism, we should definitely search for better treatment options. It is also clear from the trials on accelerated RT delivering seven fractions per week that 7-day treatment results into unacceptable early and late toxicities if the total radiation dose was not reduced., Hence, further acceleration of treatment is not recommended. Six fractions per week seem to be an ideal schedule in developing countries like ours. Hence, shortening of overall treatment time from 6½ weeks to 5½ weeks by use of six fractions per week instead of five fractions per week is feasible, tolerable, and results in better local outcome in the patients of carcinoma oropharynx.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008;371:1695-709.
GLOBOCAN 2008: Cancer Incidence, Mortality, and Prevalence Worldwide. In Version 2.0 IARC Cancer Base No. 5. Lyon: IARC Press; 2008.
Withers HR. Treatment-induced accelerated human tumor growth. Semin Radiat Oncol 1993;3:135-43.
Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27:131-46.
Nguyen LN, Ang KK. Radiotherapy for cancer of the head and neck: Altered fractionation regimens. Lancet Oncol 2002;3:693-701.
Bernier J, Bentzen SM. Altered fractionation and combined radio-chemotherapy approaches: Pioneering new opportunities in head and neck oncology. Eur J Cancer 2003;39:560-71.
Horiot JC, Bontemps P, van den Bogaert W, Le Fur R, van den Weijngaert D, Bolla M, et al.
Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: Results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111-21.
Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, et al.
Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933-40.
Overgaard J, Mohanti BK, Begum N, Ali R, Agarwal JP, Kuddu M, et al.
Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): A randomised, multicentre trial. Lancet Oncol 2010;11:553-60.
Skladowski K, Maciejewski B, Golen M, Pilecki B, Przeorek W, Tarnawski R. Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer – Report on 3-year tumour control and normal tissue toxicity. Radiother Oncol 2000;55:101-10.
Jackson SM, Weir LM, Hay JH, Tsang VH, Durham JS. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;43:39-46.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]