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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 12-16

Early initiation of radiotherapy in patients diagnosed with gliomas: A retrospective analysis of patient in a single institution a tertiary care center


1 Department of Radiation Oncology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
2 Department of Neurosurgery, Fortis Memorial Research Institute, Gurgaon, Haryana, India
3 Department of Radiology, Fortis Memorial Research Institute, Gurgaon, Haryana, India

Date of Submission06-Feb-2019
Date of Acceptance13-Feb-2019
Date of Web Publication3-Jun-2019

Correspondence Address:
Dr. Anusheel Munshi
Department of Radiation Oncology, Manipal Hospital, Dwarka, New Delhi - 110 075
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_1_19

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  Abstract 


Objective: Evaluation of effect of interval between surgery to adjuvant radiotherapy (Sx-ART) start and its early tolerance in glioma patients.
Method: A retrospective study of 155 adult glioma patients (WHO Grade II-IV) who underwent adjuvant radiotherapy (ART) post-surgery with confirmed histopathology was done in our institution from Sept, 2012 to May,2017. Results were analysed in 3 parts: Sx-ART interval, ART schedule, ART course tolerance.
Results: Sx-ART interval ranged from 1-8wks. Seventy-eight percent (121/155) patients started ART within 4wks of surgery, 30/155(19.4%) started within 2wks and 89/155 (57.4%) within 3wks of surgery. ART schedule was conventional fractionation (CF) in 121 (78%) while 34/155 (22%) patients received hypofractionated (HF) course. CF schedules varied between 54Gy-61Gy in 28-33 fractions and HF ranged 50Gy-55Gy in 20-25 fractions. Duration of ART ranged 24-50 days (median 41days). Sixty-five percent (101/155) patients completed ART <6wks and 147/155 (95%) <7wks. Seventy-eight percent (121/155) patients had concurrent Temozolomide (TMZ) including 28/34 (82%) HF patients. ART course interruption was recorded in 11/155 (7%) patients. Interruptions for Sx-ART interval <3wks & >3wks was 3 & 8 patients respectively. None had Grade 3/4 skin reactions or post-treatment scar infection/gaping at ART conclusion.
Conclusion: Early start of ART in this analysis showed no difference in tolerance to radiotherapy, including patients receiving HF radiotherapy or concomitant temozolomide. Decrease in time interval from surgery to start of radiotherapy may improve compliance to radiotherapy and reduce overall duration of treatment time (ODT). Long term data of such approaches to reduce ODT and its effect on disease free and overall survival require future studies.

Keywords: Early initiation, gliomas, radiotherapy


How to cite this article:
Munshi A, Agrawal S, Vaishya S, Patir R, Gupta R, Sarkar B, Ganesh T, Mohanti BK. Early initiation of radiotherapy in patients diagnosed with gliomas: A retrospective analysis of patient in a single institution a tertiary care center. Int J Neurooncol 2019;2:12-6

How to cite this URL:
Munshi A, Agrawal S, Vaishya S, Patir R, Gupta R, Sarkar B, Ganesh T, Mohanti BK. Early initiation of radiotherapy in patients diagnosed with gliomas: A retrospective analysis of patient in a single institution a tertiary care center. Int J Neurooncol [serial online] 2019 [cited 2019 Aug 19];2:12-6. Available from: http://www.Internationaljneurooncology.com/text.asp?2019/2/1/12/259554




  Introduction Top


Gliomas constitute a majority of primary malignant brain tumors and include lesions of different grades and subtypes.[1] Management of these tumors is varied depending on grade, performance status, and molecular markers. The current standard therapy for gliomas consists of radical surgical resection, followed by radiotherapy combined with concomitant and adjuvant chemotherapy using temozolomide (TMZ).[2] Postsurgical treatment options for patients with newly diagnosed WHO Grade II gliomas include watchful waiting, radiotherapy, and/or chemotherapy. For patients with Grade III and Grade IV tumor, concurrent chemoradiotherapy is considered a standard of care.[2],[3],[4]

A time factor of radiotherapy-related outcomes has been demonstrated for several tumor sites in the body, most prominently for head-and-neck squamous cell carcinoma and lung cancer. It is well-known fact that delayed radiotherapy after radical surgery or extended total radiotherapy treatment time has adverse effect, mostly seen not only head-and-neck squamous cell carcinoma and lung cancer which are rapidly proliferating but also in slow-growing tumor as breast and prostate cancer.[5],[6],[7],[8],[9],[10] Many mechanisms have been proposed for this, including repopulation before or during treatment.[9],[11]

In gliomas, the impact of postoperative waiting times before initiation of radiotherapy or radiochemotherapy (RCT) has not been systematically evaluated.[12] It is intuitive to believe that overall decrease in treatment time which includes time from radiological evidence to surgery and surgery to radiotherapy/RCT will have a positive outcome. We aimed to ascertain whether it is feasible to start early radiotherapy in glioma patients after surgery.


  Materials and Methods Top


Between September 2012 and May 2017, all patients who had been treated with radiotherapy or RCT for newly diagnosed glioma WHO Grade II–IV in our hospital were taken for the study. In all, 155 patients were included. The patients were managed according to the current standard of care, including interdisciplinary tumor board recommendations. Inclusion criteria were as follows: Age ≥18 years at start of RCT, performance status better or equal to the Eastern Cooperative Oncology Group performance status 2 (complying with Karnofsky performance status ≥50), histologically proven glioma WHO Grade II–IV who underwent tumor resection, and patients treated by hypofractionation or conventional fractionation (CF) with or without concurrent/adjuvant chemotherapy. Patients were divided into two groups: one group in which radiotherapy started earlier within 3 weeks early radiotherapy (ERT) and other started later after 3 weeks late radiotherapy (LRT) postsurgery.

Total dose was prescribed to a clinical target volume including the surgical cavity and contrast-enhancing lesions visible in postoperative Magnetic resonance imaging which was co-registered with planning computed tomography scan and used for treatment planning. Radiotherapy was delivered with linear accelerators providing photons of energies ≥6 MV. The field-shaping device was multileaf collimator. All patients were treated by volumetric modulated arc therapy technique.


  Results Top


Baseline patient characteristics are shown in [Table 1]. All patients had supratentorial glioma. Out of 155 patients, 139 (89%) had Grade 1 skin reactions while rest had Grade 2 reactions. No patient had Grade 3/4 skin reactions. No patients had posttreatment scar infection or wound gaping at adjuvant radiotherapy (ART) conclusion.
Table 1: Baseline patient characteristics

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Sixty-five percent (101/155) patients completed ART <6 weeks and 147/155 (95%) <7 weeks. Radiation schedule was CF in 121 (78%) while 34/155 (22%) patients received hypofractionated hypofractionated (HF) course. CF schedules varied between 54 and 61 Gy in 28–33 fractions and HF ranged 50–55 Gy in 20–25 fractions. Seventy-eight percent (121/155) patients had concurrent TMZ including 28/34 (82%) HF patients. Eighty-nine (57.4%) patients were in ERT group and 66 (42.6%) in LRT group [Figure 1].
Figure 1: Cumulative number of patients per week

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Time interval (TI) from surgery to start of RCT was from 7 to 56 days, and total radiation treatment time (RTT) was 24–50 days. TI for ERT and LRT was median of 16 and 29 days, respectively [Table 2]. Overall duration of treatment time (ODT) is from start of surgery to end of RCT was 35–106 days with median of 61 days. There was no impact of both TI and RTT, and no significant difference could be seen between the groups with short versus long ODT (35–106 days, median 61 days). Radiation treatment time (RTT) ranged from 24 to 50 days with a median of 41 days. Treatment interruptions for surgery to adjuvant radiotherapy (Sx-ART) interval in ERT and LRT were 3 and 8 patients, respectively [Table 3].
Table 2: Result range (median)

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Table 3: Cause of gap during radiotherapy

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  Discussion Top


Our study demonstrates that patients who are started on radiotherapy <3 weeks after surgery do equally well as compared to those starting after 3 weeks. We did not observe any difference with respect to skin reaction, blood counts, or any adverse effect between the two groups. In many countries where resources are limited and places where cost is an issue, early institution of treatment decreases the overall cost to the patient and has the potential to reduce their overall cost of living during treatment. Further, an early institution of treatment alleviates the anxiety and fear in patients and family and thus has a positive psychological benefit.[13] Finally, this approach may decrease the chances of tumor proliferation in view of early start, and in near future, a prospective study may enable us to show positive outcome for initiation of early treatment in gliomas in terms of overall survival (OS) and disease-free survival (DFS).

The other issue analyzed in our study was the radiation treatment time (RTT). In our participants, the primary reasons for prolongations of radiation treatment time (RTT) were patient-related factors. In many patients, shorter interruptions was compensated by applying additional treatment fraction on Saturdays, thus keeping the radiation treatment time as minimal as possible. Compensation was not possible if longer prolongations occurred, for example, due to low blood count of the patient, social commitment for which patient did not report for treatment, and urinary infection requiring intensive management. ART course interruption was recorded in 11/155 (7%) patients in which no compensation was possible.

The retrospective study like ours has its own drawbacks. These include bias from selection, uncontrolled patient and tumor factors, and physician treatment bias. However, it would be difficult to design a prospective randomized study to examine the effect of prolonged waiting time on this group of patients. It needs to be noted that our cohort is of appreciable size and is also heterogeneous which included different dose levels and different histologies including Grade II–IV and use of TMZ.

A study on this issue showed that a significant association between longer waiting time from presentation to radiotherapy and reduced OS.[14] The hazard of death increased by 2% per day of delay time from presentation to radiotherapy department to the commencement of radiotherapy in Grade III/IV gliomas.

In another related study, the authors devised complex mathematical model using pathological and radiobiological concepts, based on survival data from 154 glioblastoma patients treated with radiation therapy after surgery.[15] Timing was taken from the date of the first oncology consultation rather than surgery. Their model showed a steep in median survival after a delay of 40 days. An interesting study suggested that longer than 37 days' delay in receiving radiotherapy after surgery decreases survival of patients with malignant supratentorial gliomas (glioblastoma and anaplastic astrocytoma [AA]).[16]

Irwin et al. found that a delay in radiotherapy results in a clinically significant reduction in survival.[17] In a group of 172 patients with a histological diagnosis of supratentorial AA or glioblastoma multiforme, time to radiotherapy after surgery varied from 7 days to over 16 weeks. Every additional week of delay until the start of radiotherapy increases the risk of death by 8.9%. A 6-week delay in starting radiotherapy (from 2 weeks to 8 weeks) reduces median survival by 11 weeks. In the group of patients having anaplastic gliomas and Glioblastoma, treated with surgical resection, Radiotherapy (RT), and chemotherapy, Graus et al. showed that a delay of ≥42 days to initiate RT was associated with a shorter progression-free survival (PFS).[18] In all the preceding studies, only Grade III/IV gliomas were evaluated for survival outcomes. The treatment technique varied from two-dimensional to intensity-modulated RT with patients in early studies not receiving any chemotherapy/TMZ. In all these studies, TI was considered as an ordinal variable rather than continuous variable in which patients were grouped on basis of per week delay and not on number of days. A published analysis of 198 patients treated within 4 prospective trials in the TMZ era confirmed prolonged OS and PFS after short delay with start of postoperative RCT at 30–34 days, after adjusting for prognostic factors in multivariate analysis.[19]

There is also some evidence for lack of impact of the TI before adjuvant treatment. A study aggregating large prospective multicenter data of patients treated within the EORTC-NCIC trial analyzed TI between surgery and radiotherapy. Patients were assessed on basis of starting of radiotherapy between ≤ 2–4, >5, 6, and 7, and ≥8 weeks after surgery with concurrent and adjuvant TMZ. No effect was demonstrated with respect to patient survival.[20]

It is still possible that larger variations of treatment time could have an effect on survival after all. From our patient cohort, we cannot draw conclusions based on such very long radiation treatment times because only 5.1% of all patients had overall treatment times longer than 50 days. The policy in our department is to compensate unintended treatment interruptions by application of treatment fractions at weekends.[10],[21]

We were not able to find any specific study even after extensive literature review which deals regarding feasibility of early start of radiotherapy postsurgery in WHO Grade II–IV glioma patients. The studies which we discussed had patients started on radiotherapy postsurgery ranging from ≤2 to ≥8 weeks; however, they have not specifically seen feasibility of doing early radiotherapy but have evaluated the survival outcome with respect to various TIs such as diagnosis to surgery, surgery to radiotherapy, diagnosis to radiotherapy, diagnosis to end of radiotherapy treatment, and use of concurrent/adjuvant TMZ in later studies. They have not evaluated patients during radiotherapy for parameters such as skin reaction, blood count, and any adverse effect.

There is no clear result regarding time effect on radiotherapy treatment in gliomas; however, no study has demonstrated any adverse effect depending on TI between surgery and radiotherapy; hence, our study demonstrates that whatever may be the final outcome over long period of time, the early institution of radiotherapy postsurgery is possible and may even be practical as it may show overall improvement in DFS and OS. In our analysis, 57.4% of all patients had waiting time <3 weeks and 22% of all patients had waiting times >4 weeks and 7.8% >6 weeks.


  Conclusion Top


Our analysis is one of a kind which has evaluated the feasibility of start of radiotherapy postsurgery at the earliest, as we have shown that start within 3 weeks has good feasibility and is no way inferior to a bigger gap between surgery and start of radiotherapy. This approach saves valuable time for the patient and has consequent logistic benefits. Long-term data of our study and similar studies need to be seen to see the impact of this approach in DFS and OS rates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97-109.  Back to cited text no. 1
    
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Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 2
    
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Soffietti R, Baumert BG, Bello L, von Deimling A, Duffau H, Frénay M, et al. Guidelines on management of low-grade gliomas: Report of an EFNS-EANO task force. Eur J Neurol 2010;17:1124-33.  Back to cited text no. 3
    
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Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 2014;15:e395-403.  Back to cited text no. 4
    
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Bese NS, Sut PA, Ober A. The effect of treatment interruptions in the postoperative irradiation of breast cancer. Oncology 2005;69:214-23.  Back to cited text no. 5
    
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Thames HD, Kuban D, Levy LB, Horwitz EM, Kupelian P, Martinez A, et al. The role of overall treatment time in the outcome of radiotherapy of prostate cancer: An analysis of biochemical failure in 4839 men treated between 1987 and 1995. Radiother Oncol 2010;96:6-12.  Back to cited text no. 6
    
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Withers HR, Peters LJ, Taylor JM, Owen JB, Morrison WH, Schultheiss TE, et al. Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions. Int J Radiat Oncol Biol Phys 1995;33:549-62.  Back to cited text no. 7
    
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Bütof R, Baumann M. Time in radiation oncology – Keep it short! Radiother Oncol 2013;106:271-5.  Back to cited text no. 8
    
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Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27:131-46.  Back to cited text no. 9
    
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Bese NS, Hendry J, Jeremic B. Effects of prolongation of overall treatment time due to unplanned interruptions during radiotherapy of different tumor sites and practical methods for compensation. Int J Radiat Oncol Biol Phys 2007;68:654-61.  Back to cited text no. 10
    
11.
Bentzen SM. Repopulation in radiation oncology: Perspectives of clinical research. Int J Radiat Biol 2003;79:581-5.  Back to cited text no. 11
    
12.
Lawrence YR, Blumenthal DT, Matceyevsky D, Kanner AA, Bokstein F, Corn BW, et al. Delayed initiation of radiotherapy for glioblastoma: How important is it to push to the front (or the back) of the line? J Neurooncol 2011;105:1-7.  Back to cited text no. 12
    
13.
Song H, Fang F, Valdimarsdóttir U, Lu D, Andersson TM, Hultman C, et al. Waiting time for cancer treatment and mental health among patients with newly diagnosed esophageal or gastric cancer: A nationwide cohort study. BMC Cancer 2017;17:2.  Back to cited text no. 13
    
14.
Do V, Gebski V, Barton MB. The effect of waiting for radiotherapy for grade III/IV gliomas. Radiother Oncol 2000;57:131-6.  Back to cited text no. 14
    
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Burnet NG, Jena R, Jefferies SJ, Stenning SP, Kirkby NF. Mathematical modelling of survival of glioblastoma patients suggests a role for radiotherapy dose escalation and predicts poorer outcome after delay to start treatment. Clin Oncol (R Coll Radiol) 2006;18:93-103.  Back to cited text no. 15
    
16.
Gliński B, Urbański J, Hetnał M, Małecki K, Jarosz M, Mucha-Małecka A, et al. Prognostic value of the interval from surgery to initiation of radiation therapy in correlation with some histo-clinical parameters in patients with malignant supratentorial gliomas. Contemp Oncol (Pozn) 2012;16:34-7.  Back to cited text no. 16
    
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Irwin C, Hunn M, Purdie G, Hamilton D. Delay in radiotherapy shortens survival in patients with high grade glioma. J Neurooncol 2007;85:339-43.  Back to cited text no. 17
    
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Graus F, Bruna J, Pardo J, Escudero D, Vilas D, Barceló I, et al. Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain. Neuro Oncol 2013;15:797-805.  Back to cited text no. 18
    
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Han SJ, Rutledge WC, Molinaro AM, Chang SM, Clarke JL, Prados MD, et al. The effect of timing of concurrent chemoradiation in patients with newly diagnosed glioblastoma. Neurosurgery 2015;77:248-53.  Back to cited text no. 19
    
20.
Noel G, Huchet A, Feuvret L, Maire JP, Verrelle P, Le Rhun E, et al. Waiting times before initiation of radiotherapy might not affect outcomes for patients with glioblastoma: A French retrospective analysis of patients treated in the era of concomitant temozolomide and radiotherapy. J Neurooncol 2012;109:167-75.  Back to cited text no. 20
    
21.
Herrmann T, Baumann M. Prolongation of latency or overall treatment time by unplanned radiation pauses. The clinical importance of compensation. Strahlenther Onkol 2005;181:65-76.  Back to cited text no. 21
    


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