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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 654-657
 

Hypofractionated radiotherapy for localized prostate cancer using three-dimensional conformal radiotherapy technique: 3 years toxicity analysis


Department of Clinical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom

Date of Web Publication10-Mar-2016

Correspondence Address:
R White
Department of Clinical Oncology, Mount Vernon Cancer Centre, Northwood
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178409

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 » Abstract 

BACKGROUND: Hypofractionated radiotherapy in the radical treatment of localized prostate cancer has potential biological advantages relative to conventional fractionation. We report prospectively collected toxicity data from a cohort of patients treated with a 3D conformal technique (3DCRT). MATERIALS AND METHODS: 90 patients receiving curative intent hypofractionated radiotherapy with 57Gy in 19 daily fractions over 3.8 weeks were evaluated prospectively for the development of radiation related toxicity over a 3 year period. RESULTS: All patients completed treatment. Maximal acute toxicity experienced was 58.6, 10 and 1.1% for grade 1, 2 and 3 genitourinary (GU) toxicity respectively and 75.6, 9 and 0% for gastrointestinal (GI) toxicity. For late toxicity the three year actuarial rates of grade 1, 2 and 3 GU and GI toxicity respectively were 47.3, 2.4 and 0%; and 40, 9.3 and 4.7%. There were no grade 4 or worse acute or late toxicities. 97.6% of evaluable patients remained free of biochemical failure 36 months post radiotherapy. CONCLUSIONS: A 57Gy in 19 daily fraction radiotherapy schedule using 3D conformal radiotherapy for the definitive treatment of localized prostate cancer has acceptable early and late toxicity.


Keywords: Hypofractionation, prostate cancer, radiotherapy, toxicity


How to cite this article:
White R, Woolf D, Li S, Alonzi R, Osler P, Hoskin P, Hughes R. Hypofractionated radiotherapy for localized prostate cancer using three-dimensional conformal radiotherapy technique: 3 years toxicity analysis. Indian J Cancer 2015;52:654-7

How to cite this URL:
White R, Woolf D, Li S, Alonzi R, Osler P, Hoskin P, Hughes R. Hypofractionated radiotherapy for localized prostate cancer using three-dimensional conformal radiotherapy technique: 3 years toxicity analysis. Indian J Cancer [serial online] 2015 [cited 2019 Dec 9];52:654-7. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/654/178409





 » Introduction Top


There are a number of hypofractionated radiotherapy protocols under investigation for the treatment of localized prostate cancer. These schedules are attractive as they are more convenient for patients, reduce treatment costs and free radiotherapy resources. In addition, there is an increasing body of evidence from preclinical and clinical studies supporting a low α/β ratio of prostate cancer relative to the nearby organs at risk (OAR) and hence potential radiobiological advantages with hypofractionated regimens.[1],[2]

In 2008, our center used a computerized tomography (CT) based three-dimensional conformal, forward planned radiotherapy (3DCRT) approach to deliver a hypofractionated external beam radiotherapy (EBRT) regimen of 57Gy in 19 fractions as definitive treatment of localized prostate cancer. This consisted of once daily treatment, 5 days/week over a total duration of 3. 8 weeks. It was given with or without the use of androgen deprivation therapy (ADT) of varying duration depending on prostate cancer risk stratification. The dose fractionation schedule was based on the assumption of an α/β ratio of around 1.5 for prostate cancer, translating to an isoeffective dose in conventional daily 2Gy fractions (DEQ21.5) of 74Gy. These 2 regimes are currently under comparison as part of the three arm CHHIP phase III randomized control trial, which recently reported 2 years toxicity data utilizing intensity modulated radiotherapy technique (IMRT).[3]

The rapid dose gradients, which are able to be generated with IMRT have been demonstrated to reduce OAR dose relative to 3DCRT resulting in well-established reductions in toxicity in the conventionally fractionated, dose escalated prostate cancer radiotherapy setting.[5] The benefits in toxicity reduction with IMRT relative to 3DCRT in a hypofractionated setting, however, are less clear. These findings may hence be of particular interest in developing regions where IMRT is not available or in already developed regions where IMRT is not always available due to resource restrictions. The primary aim of this study was to prospectively report the acute and late toxicity of the 57Gy in 19 daily fractions prostate radiotherapy regimen at 3 years utilizing a 3DCRT technique.


 » Patients and Methods Top


Between July and December of 2008, 90 consecutive patients with histologically proven adenocarcinoma of the prostate were treated with the hypofractionated schedule and 3DCRT technique. Patients of all prostate cancer risk strata and ages without evidence of distant or nodal metastases on pretreatment imaging and considered suitable for EBRT of curative intent were eligible.

Simulation, planning and treatment

All patients were planned and treated using a CT based 3DCRT technique. A low residue diet was commenced prior to simulation and continued throughout treatment. Protocol further involved a standardized regimen of bowel emptying and bladder filling prior to simulation CT and each radiotherapy fraction.

At CT simulation, the region of interest was imaged in 3 mm slices with the patient immobilized in the supine position using neck rest, knee bolsters and ankle supports. The outlined clinical target volume (CTV) contained the whole prostate for those deemed at low risk of seminal vesicle involvement or prostate and seminal vesicles for those deemed at high risk as predicted by the use of the Roach equation. Elective nodal radiation was not part of the protocol. A planning target volume (PTV) was constructed with a further 1 cm expansion on CTV in all directions except posterior where 0.5 cm was used. The OAR's contoured were the bladder and rectum. The latter was outlined from the anal canal to the rectosigmoid junction. All patients were forward computer planned to cover the PTV by at least 95% of the prescribed dose, but respecting the dose constraints for rectum and bladder.[4] Typical approved plans consisted of a single phase utilizing three to four fields of beam energies between 6 and 15 MV with beam wedging as required for dose homogeneity. IMRT was not utilized.

Treatment set up verification involved an electronic portal imaging protocol with matching to bony landmarks from the digitally reconstructed radiographs constructed from simulation CT. This study predated the adoption of modern image guided radiotherapy (IGRT) systems at our institution such as intra-prostatic fiducial markers or cone beam computed tomography (CBCT).

Endpoints and statistical analysis

Radiotherapy toxicity data were collected prospectively via a structured telephone interview by therapeutic radiographers and graded as per the Common Toxicity Criteria for Adverse Events version 3.0.[6] Genitourinary (GU) symptoms assessed were hematuria, pelvic pain, bladder spasm, dysuria, incontinence and urinary frequency. Gastrointestinal (GI) symptoms assessed were anorexia, constipation, diarrhea, proctitis and vomiting. Recommended modifications to better differentiate grade 2 and 3 late radiation proctitis associated bleeding were adopted such that per rectal bleeding posttreatment responding to a single coagulation procedure was classified as grade 2 but if requiring a blood transfusion or multiple coagulations became classifiable as grade 3 radiation proctitis.[7] Skin toxicity and erectile function (EF) were also scored. Time points for data collection were weekly during radiotherapy and 2 and 6 weeks postradiotherapy to assess for acute toxicity. Late toxicity data were collected at 6, 12, 24 and 36 months postradiotherapy. Prostate specific antigen (PSA), biochemical failure (using the Phoenix definition) and subsequent therapy information was also collected at these time points.

The point prevalence of the varying grades of toxicity for each system was and maximal acute toxicity experienced over the relevant period (day 1–69) scored. Kaplan–Meier methods were used to construct an actuarial curve for late GU and GI to characterize cumulative rates. Patients were censored in this analysis if they reached the toxicity grade being measured, were lost to follow-up or died.


 » Results Top


The characteristics and treatment details of the 90 patients undergoing radical radiotherapy for localized prostate cancer between July and December 2008 at our center are summarized in [Table 1].
Table 1: Patient, disease and treatment characteristics

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All patients recruited to this study completed the planned radiotherapy course, and all were available for assessment of acute toxicity. 84 patients (93.3%) were available for evaluation of late toxicity at 2 years and 74 (82.2%) at 3 years. 7 (7.8%) had died from nonprostate cancer causes, and 9 (10%) had been lost to follow-up. Of the 90 patients, more than half (51%) were classified as having high risk disease based on the National Comprehensive Cancer Network classification.[8] 12 patients (13.3%) had baseline grade 1 GU toxicity and one patient (1.1%) had baseline grade 1 GI toxicity. There was nothing of higher severity. The vast majority (86%) of patients received ADT as a component of curative intent therapy, all commenced prior to radiotherapy. The median duration of ADT was 6 months (range 0–36 months) with 14.4% of all patients receiving between 24 and 36 months.

Acute toxicity

A dataset comprising of 6480 separate entries was collected for the assessment of acute toxicity. This was generated from questions regarding the presence and severity of 12 potential symptoms across three domains (GI, GU and skin) for the 90 patients at six different time points in the acute toxicity period (weekly during treatment, 2 and 6 weeks posttreatment).

While 30% did not report any GU toxicity, the majority (58.6%) experienced grade 1 as the worst severity. This was predominantly dysuria and/or frequency. There were far fewer patients who experienced grade 2 toxicities (10%) and only 1 (1.1%) grade 3 with nothing more severe reported. The sole grade 3 acute GU toxicity was pelvic pain. This resolved by 6 weeks postradiotherapy. [Figure 1] represents the progression and resolution in acute GU toxicity over time with the peak incidence at 2 weeks posttreatment and near complete resolution at 6 weeks posttreatment.
Figure 1: Prevalence of acute genitourinary toxicities by timepoint

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The majority of patients experienced acutely GI toxicity. For 75.6%, grade 1 was the maximal severity and consisted of either proctitis and/or diarrhea. There were no reported grade 3 or worse acute GI toxicities. [Figure 2] demonstrates the progression and resolution of acute GI toxicity with time. Again, symptoms peak at 2 weeks postradiotherapy with resolution in the majority by 6 weeks posttreatment.
Figure 2: Prevalence of acute gastrointestinal toxicities by timepoint

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There was no reported acute skin toxicity of any grade.

Late toxicity

The point prevalence of 12 potential symptoms across three domains (GI, GU and EF) was collected at four different time points in the late toxicity period (6, 12, 24 and 36 months posttreatment). This resulted in a dataset of 3956 entries of a possible 4320 with the difference due to patients lost to follow-up or death.

The prevalence of late toxicity at the various data collection time points for both GU and GI systems are represented in [Figure 3] and the actuarial curve plotting the cumulative proportion of events against time in [Figure 4]. On actuarial analysis, the cumulative proportion of patients who experienced late grade 1, 2 and 3 GU toxicity was 47.3%, 2.4% and 0% respectively at 36 months.
Figure 3: Prevalence of late genitourinary and gastrointestinal toxicities

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Figure 4: Actuarial analysis of late genitourinary and gastrointestinal toxicities

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On actuarial analysis, the cumulative proportion of patients who experienced late grade 1, 2 and 3 GI toxicity was 40, 9.3 and 4.7% respectively at 36 months with no grade 4 or worse toxicity reported. Four patients in total experienced grade 3 late toxicity, all with radiation proctitis associated bleeding severe enough to require transfusion and/or multiple administrations of topical therapies. While one of these episodes had already occurred at 6 months postradiotherapy, the remaining instances all occurred between 12 and 24 months.

Seven patients in total were treated with argon plasma coagulation for grade 2 or 3 rectal bleeding. Two patients had persistent grade 3 radiation proctitis at the 36 months follow-up despite multiple topical therapies. Hence, the actual point prevalence of grade 3 GI toxicity at 36 months from those evaluable (n = 74) was 2.7%.

Erectile function was evaluated at 24 and 36 months postradiotherapy. At 24 months, patients who were still receiving adjuvant ADT as part of a curative intent treatment regimen were excluded from the evaluation. From the 76 evaluable patients, 68 answered EF questions and 76% noted impairment relative to baseline with one-quarter of these utilizing erectile aids. At 36 months, 63 patients responded to EF questions and again 76% reported compromise. About 18% were continuing with erectile aids, pharmaceutical or otherwise.

Prostate specific antigen follow-up data

There were PSA results for 83 patients at 36 months follow-up with the 7 missing patients all having died from nonprostate cancer causes. The mean PSA was 0.54 (range: 0–11) and the biochemical failure free percentage (BFF) at 3 years was 97.6%.


 » Discussion Top


Hypofractionated radiotherapy appears an attractive treatment option when the α/β of a tumor is lower than that of the surrounding OAR. The normal tissue complication probability (NTCP) can be reduced for an equivalent tumor control probability (TCP) or alternatively the NTCP kept constant for a higher TCP.

The results of this prospective study demonstrate both the feasibility and tolerability of the 57/19/5 regimen using a 3DCRT approach. While a BFF rate at 3 years follow-up of 97.6% appears promising it is too early to assess efficacy, particularly given the high rate of adjuvant ADT use.

The overall rates of acute toxicity are low and the tolerability of this schedule is further supported by the fact that all patients completed the prescribed radiotherapy course. The actuarial rates of late GU toxicity to 36 months posttreatment is also low with no grade 3 or worse events.

The actuarial rate of grade 2 and 3 late GI toxicity events of 9.3 and 4.7% respectively at 36 months in this study warrants further discussion. The available literature on rectal toxicity rates using isoeffective, conventionally fractionated, 3DCRT schedules suggest late GI toxicity to be lower in our study consistent with the lower predicted NTCP.[9],[10],[11] The United Kingdom based RT-01 study, using the hypothesized isoeffective schedule of 74/37/5 reported cumulative grade 2 and 3 late GI toxicity events at 24 months of 20 and 6%, respectively. This rose to 33 and 10% respectively at 5 years.[10] However, studies utilizing similarly isoeffective, conventionally fractionated regimens, but with IMRT and modern IGRT report lower toxicity.[3],[12],[13]

Erectile function assessment is likely clouded in this cohort by the high use of adjuvant ADT. Prolonged suppression of testosterone well beyond cessation of ADT is common, particularly in an elderly group, and in this cohort many patients received prolonged therapy.


 » Conclusion Top


This study has found that a 57Gy in 19 daily fractions, single phase 3DCRT regimen is well tolerated with low rates of both acute and late toxicity. While our hospital adopted IMRT with daily on-line IGRT using intra-prostatic fiducial markers (or CBCT) in 2010, centers in more resource challenged environments with limited access to these technologies may find the 3DCRT 57/19/5 schedule preferable to the conventionally fractionated, isoeffective alternative for its improved toxicity profile in addition to the more obvious planning, patient and departmental advantages associated with a single phase, shortened treatment schedule.

 
 » References Top

1.
Vogelius IR, Bentzen SM. Meta-analysis of the alpha/beta ratio for prostate cancer in the presence of an overall time factor: Bad news, good news, or no news? Int J Radiat Oncol Biol Phys 2013;85:89-94.  Back to cited text no. 1
    
2.
Dasu A, Toma-Dasu I. Prostate alpha/beta revisited – An analysis of clinical results from 14 168 patients. Acta Oncol 2012;51:963-74.  Back to cited text no. 2
    
3.
Dearnaley D, Syndikus I, Sumo G, Bidmead M, Bloomfield D, Clark C, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: Preliminary safety results from the CHHiP randomised controlled trial. Lancet Oncol 2012;13:43-54.  Back to cited text no. 3
    
4.
Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:S10-9.  Back to cited text no. 4
    
5.
Cahlon O, Hunt M, Zelefsky MJ. Intensity-modulated radiation therapy: Supportive data for prostate cancer. Semin Radiat Oncol 2008;18:48-57.  Back to cited text no. 5
    
6.
Trotti A, Colevas A, Setser A, Rusch V, Jaques D et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in radiation oncology 2003;13;176-81.  Back to cited text no. 6
    
7.
Hanlon AL, Schultheiss TE, Hunt MA, Movsas B, Peter RS, Hanks GE. Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 1997;38:59-63.  Back to cited text no. 7
    
8.
Mohler JL. Updating the prostate cancer guidelines. J Natl Compr Canc Netw 2007;5:647-8.  Back to cited text no. 8
[PUBMED]    
9.
Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al. Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61:1019-34.  Back to cited text no. 9
    
10.
Dearnaley DP, Sydes MR, Graham JD, Aird EG, Bottomley D, Cowan RA, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer:First results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475-87.  Back to cited text no. 10
    
11.
Kok D, Gill S, Bressel M, Byrne K, Kron T, Fox C, et al. Late toxicity and biochemical control in 554 prostate cancer patients treated with and without dose escalated image guided radiotherapy. Radiother Oncol 2013;107:140-6.  Back to cited text no. 11
    
12.
Zelefsky MJ, Kollmeier M, Cox B, Fidaleo A, Sperling D, Pei X, et al. Improved clinical outcomes with high-dose image guided radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2012;84:125-9.  Back to cited text no. 12
    
13.
Al-Mamgani A, Heemsbergen WD, Peeters ST, Lebesque JV. Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;73:685-91.  Back to cited text no. 13
    


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