|Year : 2016 | Volume
| Issue : 2 | Page : 265-269
Comparison of two different radiation fractionation schedules with concurrent chemotherapy in head and neck malignancy
MS Alam1, R Perween2, SA Siddiqui1
1 Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Obstetrics and Gynecology, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Web Publication||6-Jan-2017|
M S Alam
Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: The worldwide incidence of head and neck malignancy exceeds half a million cases annually. In radiotherapy (RT), conventional fractionation comprises giving five fractions per week from Monday to Friday. Accelerated RT includes administration of six fractions per week is being advocated. It gives better locoregional control and the median overall treatment time is 39 days as compared to 46 days in conventional group. Our study involved comparison of conventional versus accelerated RT with concurrent chemotherapy, in evaluation of local control and toxicity in the two arms. Materials and Methods: Sixty patients of locally advanced squamous cell carcinoma head and neck region were studied. All the patients received cisplatin (30 mg/m2) weekly during the therapy. The patients received RT dose of 70 Gray (Gy) in 35 fractions (#). The patients were randomly assorted into two groups: Group 1 - Study group (n = 30) - Six fractions RT per week (Monday–Saturday). Group 2 - Control group (n = 30) - Five fractions RT per week (Monday–Friday). During and after the treatment, locoregional control, acute and late radiation toxicity were assessed. Results and Observation: There was no significant difference between the two schedules regarding locoregional control rate. The Grade 3 or higher acute toxicities were significantly higher in the accelerated arm although there was no significant difference in late toxicities between the two arms. Conclusion: Accelerated fractionation regimen was not more efficacious than conventional fractionation in the treatment of previously untreated head and neck carcinoma.
Keywords: Accelerated radiotherapy, head and neck carcinoma, radiation therapy, radiotherapy fractionation schedules
|How to cite this article:|
Alam M S, Perween R, Siddiqui S A. Comparison of two different radiation fractionation schedules with concurrent chemotherapy in head and neck malignancy. Indian J Cancer 2016;53:265-9
|How to cite this URL:|
Alam M S, Perween R, Siddiqui S A. Comparison of two different radiation fractionation schedules with concurrent chemotherapy in head and neck malignancy. Indian J Cancer [serial online] 2016 [cited 2020 Apr 5];53:265-9. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/265/197740
| » Introduction|| |
The worldwide incidence of head and neck malignancy exceeds half a million cases annually. The number of new cases of head and neck cancer (HNC) in the United States was 40,500 in 2006 accounting for about 3% of adult malignancy. Nearly, 60% of this population presents with locally advanced disease, but not metastatic disease. In India, the most common HNCs are those of oral cavity and pharynx. The age-adjusted incidence for these sites in the Indian males range from 10.8 to 38.8/100,000 males, and for females it is 6.4–14.9/100,000 females. Mouth and pharynx cancers stand as third most common cancer in males and as fourth most common in females in developing countries. At the Institute Rotary Cancer Hospital, AIIMS, New Delhi, the HNCs represent 25% of all registered new cases. Oral cancer is a major problem in India, and accounts for 50%–70% of all cancers diagnosed as compared to 2%–3% in the UK and the USA. The age-standardized incidence rate of HNC in males exceeds 30/100,000 in the regions of France, Hong Kong, the Indian subcontinent, Central and Eastern Europe, Spain, Italy, Brazil, and among US Blacks. High rates of HNC (>10/100,000) even in females are found in the Indian subcontinent, Hong Kong, and the Philippines. Most, but not all, HNCs are associated with smoking. Those associated with smoking are carcinoma tongue, floor of mouth, tonsil, base of tongue, larynx, and pyriform sinus. Cancers not associated with smoking are malignancy of parotid. HNCs invade locally, spread to regional lymph nodes, and tend to remain confined to its site of origin and regional lymphatics. A locally advanced cancer means that cancer has spread to nearby tissue or lymph nodes but not elsewhere. The three modalities of treatment in head and neck malignancy are surgery, chemotherapy, and radiotherapy (RT). Out of these modalities, HNCs are predominantly treated by surgery and/or RT. However, concomitant chemotherapy and RT appear to be the most effective approach for the treatment of HNCs. Chemotherapy is the treatment modality for metastatic cervical lymph node with unknown primary, carcinoma pyriform fossa, and nasopharynx because of their high rate of lymph node metastasis.
In RT conventional fractionation (according to current practice in the United States), for the curative treatment of most cancers comprises a fractional dose of 1.8–2.0 Gy given once daily from Monday through Friday. Now, a new regimen of RT which includes administration of six fractions per week is being advocated. It has shown better tumor control (76% vs. 64% for six and five fractions, respectively). In 6 day RT, there is a better locoregional control, and the median overall treatment times (OTTs) are 40 days as compared to 47 days in five-fraction groups, which is a major advantage in developing countries like India. Our study involved comparison of five radiation fractions per week versus six fractions per week with concurrent chemotherapy, in terms of locoregional control, acute and late radiation toxicities in the two arms.
Aims and objectives
The aim of this study is to compare conventional (5DRT) versus accelerated (6DRT) radiation with concurrent chemotherapy in locoregionally advanced head and neck malignancy in terms of locoregional control rate, acute and late radiation toxicities, and OTT.
| » Materials and Methods|| |
Sixty patients of locally advanced squamous cell carcinoma head and neck region were studied. Only the patients where external radical RT was the primary line of management were included in the study. After complete history taking and complete physical examination, the patient underwent baseline investigations including complete blood counts (CBCs), renal function, and liver function tests. Chest X-ray and X-ray soft tissue neck (lateral view), X-ray peripheral nervous system (depending on the site of the primary tumor), ultrasonography abdomen, and computed tomography scan were done if required to rule out distant metastasis or to assess the extent of the disease. After examination and investigations, all patients were staged according to international tumor-node-metastasis classification of the American Joint Committee on Cancer 2002. The exclusion criteria included patients previously operated or treated with RT or chemotherapy, tumors classified as stage I and II, distant metastasis, and patients having some associated medical condition making them unfit for chemotherapy or RT. The patients received external beam irradiation on cobalt-60 teletherapy machine. The patients received 70 Gy in 35 fractions with each fraction being 2 Gy. All the patients received cisplatin (30 mg/m 2)-based chemotherapy once every week before RT for the entire course of radiation therapy.
The patients were randomly assorted into two groups by computer-based randomization procedure:
- Group 1 (6DRT) - Study group (n = 30) - Six fractions RT per week (Monday–Saturday)
- Group 2 (5DRT) - Control group (n = 30) - Five fractions RT per week (Monday–Friday).
On the 1st day of RT setup was checked followed by weekly assessment as per protocol. Chemotherapy was given once in a week (preferably on Monday) before radiation. It was given with adequate hydration and pre- and post-medications. Weekly CBC and release from treatment were done before chemotherapy administration.
During and after the treatment, locoregional control, 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 3 month in the 1st year, every 6 month in the 2nd year, and then on yearly basis.
Acute toxicity was assessed using Radiation Therapy Oncology Group (RTOG) scoring and chronic reaction by RTOG-European Organization for Research and Treatment of Cancer combined toxicity criteria.
It was done using statistical tool SPSS 11.0. Two-tailed corrected Chi-square test and unpaired t-test were used. The results were studied on an intention to treat basis.
| » Results and Observations|| |
In total, sixty patients were evaluated (thirty in each arm). Mean follow-up period was 18 months (range 8–32 months). All the patients completed their treatment according to the protocol. The patient and tumor-related details are given in [Table 1]. There was no significant difference between the two schedules regarding locoregional control rate. The locoregional failure details are given in [Table 2]. The Grade 3 or higher acute and late toxicities were significantly higher in the accelerated arm although there was no significant difference in lower grade toxicities between the two arms. The acute and late radiation toxicities are detailed in [Table 3] and [Table 4]. The median OTT in accelerated radiation arm was 40 days (range: 38–44 days) and conventional radiation arm was 47 days (range: 45–53 days). There was a significant difference in OTT between the two arms, and this is one of the most important advantages with accelerated radiation.
| » Discussion|| |
RT along with concurrent chemotherapy has long been the standard nonsurgical therapy for locally advanced disease. State of the art regarding radiation dose fractionation has evolved from once daily treatment to hyper fractionation and accelerated fractionation.,,, These newer strategies lead to a 7%–10% improvement in locoregional control relative to once daily treatment scheme. Most randomized clinical trials show the superiority of combined RT and chemotherapy to RT alone for the treatment of locally advanced, nonmetastatic squamous carcinoma of head and neck. A meta-analysis of individual patient data from >10,000 participants in 63 trials conducted before 1993 (meta-analysis of chemotherapy on HNC) demonstrating that adding chemotherapy to RT in both definitive and adjuvant postoperative settings resulted in a 12% reduction in the risk of death from HNC corresponding to an absolute improvement of 4% in 5-year survival. An update that included an additional 24 trials revealed that the majority of this benefit resulted from the use of concurrent chemotherapy, a 19% reduction in the risk of death, and an overall 8% improvement in 5-year survival compared to treatment with RT alone (P < 0.0001). The RTOG conducted a three-arm trial of radiation alone versus radiation and concurrent cisplatin versus induction cisplatin followed by irradiation in larynx carcinoma. Concurrent therapy clearly constituted the most effective means of larynx preservation and provided the best disease control, albeit without a statistically significant survival benefit. Typically, the acute mucositis arising from radiation and concurrent chemotherapy regimen is greater than that seen with RT alone. It is the most significant impediment to timely delivery of concurrent therapy. Because prolongation of total treatment time adversely affects the success of RT in HNC, a major challenge has been the development of treatment schedules that integrate RT and chemotherapy and yet do not excessively increase total treatment time.,, The Christie Hospital in Great Britain evaluated RT and 100 mg/m 2 of single agent methotrexate (MTX) given at the commencement of and after 2 weeks of 3 weeks course of treatment. Most of the 313 patients in this protocol received 50–55 Gy in 15 or 16 fractions. Mucositis was significantly greater in the patients receiving MTX, but there was no difference in long-term toxicity. The addition of MTX increased local control from 50% to 70% (P = 0.02) and survival from 37% to 47% (P = 0.07). The greatest benefit was seen in patients with oropharyngeal primaries which constituted one-third of study population. Local control rate with RT/MTX was 78% versus 38% with RT alone (0.002) in this patient subset. Survival was 25% with RT alone and 50% with RT/MTX (P = 0.009). Browman et al. compared RT and continuous infusion fluorouracil (5-FU) against RT alone in a placebo-controlled randomized trial sponsored by the National Cancer Institute of Canada. All 175 patients received 66 Gy in 2 Gy fractions. 5-FU was given in a dose of 1200 mg/m 2/day for the first 3 days of the 1st and 3rd week of irradiation. Confluent mucositis was more frequent in the 5-FU arm than in the placebo arm (32% vs. 11%; P = 0.001) as was weight loss >15% from pretreatment baseline (41% vs. 11%; P < 0.0001). This increased acute toxicity did not prolong the delivery of RT in the RT/5-FU arm relative to the RT/placebo arm. The multiinstitutional French trial, GORTEC 94-01, was performed with patients who had stage 3/4 oropharyngeal carcinoma., RT was given in both arms through conventional 2 Gy, once daily fractions to a total dose of 70 Gy. Patients on the combined modality arm also received three cycles of concurrent carboplatin (70 mg/m 2) and continuous infusion 5-FU (600 mg/m 2/day × 4 days). Combined modality treatment resulted in significant improvement in 5-year locoregional control (48% vs. 25%; P = 0.002) disease-free survival (DFS) (27% vs. 15%; P = 0.01), and survival (23% vs. 16%; P = 0.05). This improvement in efficacy was accompanied by a significant increase in acute mucositis (grade >2) for 39–72% (P = 0.05). The DAHANCA trial which tested an acceleration of 70 Gy/6 weeks against 70 Gy/7 weeks. In the two treatment groups, patients received fractions of 2 Gy. Patient's assigned five fractions (conventional) per week were given one daily fraction from Monday to Friday. Patient's assigned six fractions (accelerated RT) per week were given one fraction daily from Monday to Friday, and the sixth fraction was given on Saturday or Sunday, or as an extra fraction on weekdays at least 6 h after the first fraction. More than 97% of the patients received the planned total dose. Median OTTs were 39 days (six-fraction group) and 46 days. Overall, 5-year locoregional control rates were 70% and 60% for the six fraction and five fraction groups, respectively (0.0005). The whole benefit of shortening of treatment time was seen for primary tumor control (76% vs. 66% for six and five fractions, P = 0.0001), but was nonsignificant for neck node control. Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer (80% vs. 68%, P = 0.007). Disease-specific survival improved (73% vs. 66% for six and five fractions, P = 0.01) but not overall survival. Acute morbidity was significantly more frequent with six than with five fractions but was transient.
In our study, there was no significant difference in locoregional control of HNC between conventional and accelerated fractionation of patients similar to the Toronto randomized trial. There are less consistent results of randomized trials of accelerated fractionation as accelerated treatment is given by different ways.,, We adopted the concept of pure acceleration using, six instead of 5 treatment days in a week because it has shown to significantly increase the locoregional control rate with a trend toward improved DFS. In our study, there was no significant difference between accelerated fractionation and conventional fractionation, which is similar to the previous findings. On the other hand, when Ang et al. and Johnson et al. compared accelerated fractionation with conventional fractionation, they concluded significantly better locoregional control and survival rates., The improvement in therapeutic gain with accelerated fractionated radiation was also confirmed by the results of RTOG 9003 trial. The patients who were treated with accelerated fractionation had significantly better locoregional control compared with standard fractionation although the overall survival was not significantly different. Similar to other studies, in our study also mucous membrane was the most common site of Grade 3 acute reactions.,,, Grade 3 mucosal toxicity was also the most common late side effect. Contrary to this, according to RTOG 9003 trial, the pharynx and the salivary gland were the most common sites to have Grade 3 late effects. In our study, Grade 2 and lower acute reactions of the skin and mucous membrane of patients in the accelerated fractionation group were not significantly different from those in the conventional fractionation group. Contrary to it, there was significant acute reaction related to mucous membrane in the altered fractionation groups of Horiot et al. and Johnson et al., In our study, both acute and late Grade 3 and high mucosal reactions were significantly more in the accelerated fractionation group as compared to the conventional group. Similarly, according to Fu et al. and Horiot et al., the difference in late mucosal reactions between altered fractionation group and conventional fractionation group was also significant., According to Antognoni et al. accelerated fractionation as compared to conventional radiation did not produce any significant reaction in normal tissues other than skin and salivary gland which showed slightly more mild complications. There is definite improvement in survival when chemotherapy is added concurrently with irradiation as compared to radiation alone. The severe acute normal tissue reactions are increased when more toxic concurrent radiochemotherapy protocols and altered fractionated schedules are used, and these become the limitation of the before mentioned treatment modalities. With the introduction of more conformal and intensity-modulated radiation techniques, these acute side effects in normal tissues are minimized. Conformal RT improves target coverage and also minimizes the dose to and volume of adjacent normal tissues. Intensity-modulated RT delivers higher doses per fraction to the target and lower doses per fraction to normal tissues, thus maximizes total doses in tumors while spares more of normal tissue resulting in increased therapeutic gain.
We used cobalt-60 machine for irradiation, and this may be one of the possible limitations related to our study. The use of new, more sophisticated linear accelerator machines may produce better results. Small sample size and short follow-up are also other limitations of our study.
| » Conclusion|| |
There is no significant difference in the therapeutic effects of accelerated fractionation schedule as compared to conventional treatment schedule. However, the use of conformal RT in previously untreated head and neck squamous cell carcinoma will increase the possibility of better outcome.
I am thankful and would like to acknowledge the contributions of the doctors and staffs of the Department of RT and Gynaecology, of J. N. Medical College and Hospital, Aligarh, Uttar Pradesh, India.
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]
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