|Year : 2010 | Volume
| Issue : 4 | Page : 442-447
Dosimetric risk estimates of radiation-induced malignancies after intensity modulated radiotherapy
Vijay M Patil, Rakesh Kapoor, Santam Chakraborty, Sushmita Ghoshal, Arun S Oinam, Suresh C Sharma
Department of Radiotherapy and Regional Cancer Center, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, India
|Date of Web Publication||24-Feb-2011|
Vijay M Patil
Department of Radiotherapy and Regional Cancer Center, Cobalt Block, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Context: The increasing popularity of intensity-modulated radiotherapy (IMRT) stems from its ability to generate a more conformal plan than hitherto possible with conventional planning. As a result, IMRT is in widespread use across diverse indications. However, the inherent nature of IMRT delivery makes it monitor unit inefficient and leads to increased normal tissue integral dose. This in turn may result in an increased risk of radiation-induced second malignancies.
Aim: To calculate the risk of second malignancy post-IMRT.
Settings and Design: Observational study in a tertiary care institute.
Materials and Methods: Eighteen previously untreated patients with head and neck cancers (n = 10) and prostate cancer (n = 8) were selected. In these patients, selected infield organs around the planning target volume were contoured, viz. brain and thyroid in patients with head and neck cancer and bladder, rectum and small intestine in patients with carcinoma prostate. The estimates of radiation-induced malignancies in these organs and the whole of the body were derived using the concept of Organ Equivalent Dose.
Statistical Analysis Used: Descriptive statistics (SPSS version 12).
Results: The modal estimated incidence of radiation-induced malignancies was 129.87, 1.4, 0.10, 3.42, 7.789 and 129.85 per 10,000 person-years for the brain, thyroid, bladder, rectum, small intestine and whole body respectively.
Conclusions: The estimated risk of radiation-induced malignancies in the thyroid and rectum was similar to the available literature, while the risk for bladder carcinomas was lower than that reported. However, the calculated risk of radiation-induced tumors of the brain was more than that reported with conventional radiation therapy. We propose that estimation of the risk of radiation-induced malignancies should be a part of the plan evaluation process and special care should be taken before using this modality in young patients with benign tumors in the head and neck region.
Keywords: Dose-response relationship, intensity-modulated radiotherapy, radiation-induced cancer, risk assessment, therapy-related cancer
|How to cite this article:|
Patil VM, Kapoor R, Chakraborty S, Ghoshal S, Oinam AS, Sharma SC. Dosimetric risk estimates of radiation-induced malignancies after intensity modulated radiotherapy. J Can Res Ther 2010;6:442-7
|How to cite this URL:|
Patil VM, Kapoor R, Chakraborty S, Ghoshal S, Oinam AS, Sharma SC. Dosimetric risk estimates of radiation-induced malignancies after intensity modulated radiotherapy. J Can Res Ther [serial online] 2010 [cited 2019 Nov 13];6:442-7. Available from: http://www.cancerjournal.net/text.asp?2010/6/4/442/77082
| > Introduction|| |
Successive improvements in radiotherapy techniques over the decades have resulted in an improved survival in cancer patients.  The improved survival however increases the probability of observing a relatively rare but potentially lethal late effect, i.e. radiation-induced second malignancy (RIM).
In recent years, the use of conformal radiotherapy techniques like intensity-modulated radiotherapy (IMRT) is gaining popularity. The better confomality with the use of IMRT plans has resulted in improved outcome along with reduction in the late normal tissue complications. ,, This, in turn, has lead to the widespread use of IMRT in the treatment of head and neck cancers and prostate cancers, where dose escalation is of primary concern. However, the inherent monitor unit inefficiency of the IMRT delivery process along with the use of multiple coplanar or non-coplanar beams, significantly increases the volume of normal tissue that is exposed to low doses of radiation. These factors can potentially lead to an increased risk of RIM. ,,,,
Till date, to the best of our knowledge, no study has documented any actual increase in the incidence of RIMs with the use of IMRT. However, as IMRT has come into extensive clinical use in the past decade only, long-term follow-up data will take time to accumulate. Therefore, several authors have used mathematical models to predict the risk of RIM with the use of IMRT. ,,, The available RIM risk estimates from atomic bomb survivors and patients treated with radiation therapy have been extrapolated for this purpose.  Most of these studies used point-dose estimates and primarily evaluated the impact of scattered radiation. However, the importance of RIM in the primary radiation field cannot be neglected, and it has been shown that 79% of RIM occur within the margins of the irradiated volume, defined as the volume 2.5 cm inside to 5 cm outside the field margin.  In addition, the inherently inhomogeneous dose distribution in the IMRT plans is difficult to be quantified by simple point doses. The concept of Organ equivalent dose (OED) described by Scheinder et al. overcomes this shortcoming. 
This study was designed to estimate the risk of RIM in selected infield organs in patients undergoing IMRT for patients with head and neck and prostate cancer using the concept of OED. Also, the overall risk of RIM for the whole body is reported.
| > Materials and Methods|| |
In the period between January 2007 and December 2008, 18 previously untreated patients of head and neck cancer and prostate cancer, treated with IMRT in our institution, were selected for the present study. All patients were between the ages of 25 and 70 years and had a Karnofsky Performance Score ≥70. Informed consent was taken from each patient as part of the treatment protocol and prior ethical clearance for the study had been obtained from the institutional ethical review committee. None of the patients had been previously treated for cancer at any point of time.
Ten (55.55%) head and neck cancers and eight (44.44%) patients of carcinoma prostate were selected. In patients with head and neck cancers, the majority had primary cancer in the base of the tongue (33.33%), followed by the tonsil (16.67%) and supraglottic larynx (5.55%). A majority of the patients were male (88.89%). All but two patients (11.11%) had a history of addiction to tobacco or alcohol and four (22.22%) had a history of addiction to both. None of these patients had a family history of cancer or had received any chemotherapy prior to or during radiation.
All patients selected for the study underwent a planning contrast-enhanced computed tomography scan (CECT scan) of the affected region after requisite immobilization. Special attention was paid to include the entire body contour in the scan. Patients with head and neck cancer were scanned from the vertex of the skull to the thoracic inlet while patients with prostate cancer were scanned from the superior border of the fourth lumbar vertebra to the lower border of lesser trochanter of the femur. All CT scans were acquired in the departmental CT simulator Light Speed® RT-16 (GE Medical Systems, Waukesha, WI, USA) and the acquired image were transferred to the Eclipse® Treatment Planning System (Varian Medical Systems, Palo Alto, CA, USA) for further treatment planning.
The organs selected for estimation of RIM were the thyroid gland and brain for the head and neck patients. The thyroid gland was contoured as a solid structure including both lobes. The brain was also contoured as a single organ from the vertex to the foramen magnum after excluding the brainstem. In prostate cancer patients, the bladder, rectum and small intestine were contoured. The rectum was contoured from the lower border of the ischial tuberosity to the sigmoid flexure. Small intestine loops were not contoured individually; instead, the entire peritoneal cavity was contoured, starting 2 cm proximal to the highest extent of the planning target volume (PTV). The selection of these organs was based on results from retrospective series that had shown that these were at the highest risk of having a RIM. ,,,,,,
IMRT planning for all patients was carried out on the Eclipse® Treatment Planning System (Varian Medical Systems). Seven equispaced coplanar beams at angles of 51° were used for all patients. Plan optimization was carried out by the inverse planning technique using the Helios, IMRT software, with the help of the dose-volume optimizer (DVO) algorithm version 7.3.10. A sliding leaf technique was used for delivery of IMRT. Patients were treated after proper plan verification on a Clinac DHX (Varian Medical Systems) using 6 MV photons.
In patients of head and neck cancer, three target volumes were defined: gross tumor volume (GTV), high-risk clinical target volume (CTV1) and low-risk CTV (CTV2). Simultaneous integrated boost IMRT was planned to deliver a dose of 72 Gy, 66 Gy and 57 Gy to the PTV around GTV, CTV1 and CTV2, respectively, in 33 fractions.
In prostate cancer patients, the prostate and seminal vesicles with margins was taken in the GTV in six of eight patients based on patterns of involvement. The remaining two had seminal vesicles treated as part of high-risk CTV. Pelvic lymph nodes were irradiated in three patients as low-risk CTV. The PTV around GTV was given a dose ranging from 68 to 70 Gy. PTV around the high-risk CTV received a dose ranging from 60 to 66 Gy and the low-risk CTV received a dose ranging from 50 to 54 Gy. Treatment was planned for 25-30 fractions over 5-6 weeks.
The concept of OED proposed by Scheinder et al. was used for the estimation of risk of RIM.  The OED essentially reduces the inhomogeneous dose distribution in an organ to a single dose, which, if distributed homogeneously across the said organ, will result in the same risk of RIM induction as the original inhomogeneous dose distribution.
While the radiation dose-response for induction of RIM is essentially linear for doses <2 Gy, it is not very well known for doses more than 2 Gy. There are two extreme possibilities for the shape of the dose response curve at higher doses: A linear curve or a plateau curve.
A linear curve is unlikely because the radiation-induced cell kill at high doses removes the mutated cell population secondary to the radiotherapy treatment. The implication of the plateau dose response curve is that for organs receiving higher radiation doses, the probability of RIM will be lower than that calculated assuming a linear dose-response curve. Each fraction of radiation eliminates a constant fraction of the mutated cells as a function of the dose delivered and the organ irradiated. Assuming that the risk of RIM induction at low doses (I 0) is a constant linear function of the dose, the risk for higher doses is a product of this risk (I 0) and the cell kill induced by radiation for the given organ. Assuming a plateau dose-response relationship and using the model parameter δ (model parameter for specified organs), we calculated the OED for individual organs and the volume of body imaged by the following formulae.
For any given organ, the risk of occurrence of a second malignancy was given by the formula:
where, I 0 is the irradiation-induced cancer risk from low-dose radiation exposure, expressed as the absolute excess risk per 10,000 patients/year/Gy from the UNSCEAR report (2000) on the epidemiological evaluation of radiation-induced second cancers.
The OED for a given organ was calculated from the CT data using the formula:
where, D V is the volume corresponding to the dose D i cTorg for the specified organ obtained from the differential dose volume histogram, delta(δ) is the model parameter for the specified organ (Appendix 1) and VCT is the volume of the concerned organ (ml).
Statistical analysis was performed using SPSS software (Statistical Package for Social Sciences, USA) version 12.0. Descriptive statistics and range are provided.
| > Results and Discussion|| |
The mean volumes of the contoured organs were 984.14 cc,13.92 cc, 220.4 cc, 82.88 cc and 2191.23 cc for the brain, thyroid, bladder, rectum and small intestine, respectively.
The mean, modal organ doses, modal OED (vide Formula 2) and the estimated incidence of RIMs are enlisted in [Table 1].
|Table 1: Organ equivalent dose and estimated incidence in 10,000 person-years. Mean and modal doses were calculated from the dose volume histogram data|
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Radiation is a well-known carcinogen, and the prognosis of a second radiation-induced malignancy is often poor.  Therefore, despite the rarity of the event, careful consideration has to be given to the risk of this complication whenever a patient is exposed to medical radiation. This is particularly true in patients likely to survive longer. 
There is a large body of literature on the estimation of the risk of development of a RIM after radiotherapy. Several of these have used thermoluminescent dosimetry in a phantom for dose estimation. They have primarily reported the scattered doses at pre-defined points at a distance from the irradiated volume. ,,,, The estimate of the risk of development of a RIM for a given dose was then calculated for the data obtained from low-dose radiation exposure in the UNSCEAR data. In most of these studies, the impact of the primary infield radiation on the risk of second malignancy was neglected. The use of a linear dose-response curve in these regions of higher dose overestimates the risk of second malignancy.
Some studies have also used thermoluminescent dosimeters placed on surface landmarks over the skin, which was taken as a surrogate of the internal organ dose. However, how closely this skin dose can represent the internal organ dose remains an unanswered question. The uncertainties in using point doses as surrogates of the whole organ dose is higher in IMRT, which is characterized by steep dose gradients.
The concept of OED by Scheinder et al. overcomes these problems and it also takes into account the inhomogeneous dose distribution in the surrounding organs.  In the present study, the dosimetric estimates were obtained from planning CT scan and took into account the dose received by the whole organ. In order to put the results into perspective, the risk estimates seen in this study have been compared against the risk estimates from large retrospective studies [Table 2].
|Table 2: Table showing the comparison of the risk estimated in the present study against the observed risk in retrospective studies of radiation-induced second malignancies in various organs. All risk estimates are in per 10,000 person-years. Data for the small intestine is not shown as sparse data were available. The mean observed risk is the average of the risk observed in the studies is quoted|
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In the present study, the incidence of RIM in the brain is more than that detailed in the literature. ,,, It is noteworthy that a majority of the radiation-induced second tumors in the brain are benign tumors, with nerve sheath tumors and meningiomas being encountered most commonly.  However, a higher risk of malignant gliomas have also been seen, with Tsang et al. reporting the risk of gliomas to be 16-times higher than a comparable non-irradiated cohort for patients treated in childhood.  Higher risks of benign tumors have also been seen in patients of pituitary tumor treated with radiation after conservative surgery.
In IMRT in head and neck cancer, a larger volume of brain is exposed to radiation than in conventional radiation therapy due to the use of multiple beams arrayed around the patient. As can be seen from [Table 1], the brain was the organ that had received the lowest doses among all the organs studied. The plateau dose-response curve model chosen for the present study showed an elevated risk of RIM in areas receiving low-dose radiation as sterilization of the mutated cell population was not seen. While the actual risk can only be calculated from actual observational studies with sufficient follow-up, the increased risk from the use of IMRT in the head and neck region should be kept in mind, especially for young patients with good expected survival.
The estimates for RIM in the thyroid gland and rectum show good concordance with the observed risk obtained from the literature. ,,,,,, It is noteworthy that in one of the largest analysis of radiation-induced second thyroid cancers in childhood cancer survivors, Sigurdson et al. have demonstrated that there indeed exists an exponential risk relationship between radiation dose and the risk of development of second thyroid cancers, with the risk diminishing sharply after thyroid doses of more than 30 Gy.  In this respect, it is to be noted that the mean thyroid dose in the head and neck cancer patients in the present study was 65 Gy and hence a lower estimated risk is to be expected due to the phenomenon of radiation-induced cell killing at higher doses.
Contrary to expectation, the risk estimates for RIM in the bladder are much lower than that reported in the literature dealing with radiation treatment of pelvic malignancies. , The reason behind this discrepancy may be multifactorial. In the present study, six of the eight patients with prostate cancer were treated with IMRT to the prostate and seminal vesicles. The higher doses (mean dose 56 Gy) received by the bladder in the present study would have lowered the risk as the plateau dose-response model was used.
Liauw and Brenner et al. studied the risk of radiation-induced bladder cancers in patients treated for prostate cancer and found a higher value than that obtained in the present study. As patients primarily had low-risk disease, smaller and more localized radiation techniques (including brachytherapy) were used in their study. , This may have resulted in exposure of the large majority of the bladder to scatter irradiation only. In contrast, the studies by Travis et al., where patients of ovarian and testicular tumors were studied, a much lower risk of radiation-induced bladder cancers was found. , In these situations, use of large fields exposed the bladder to higher radiation doses, which can validate the assumption in our model.
In addition, it should be kept in mind that patients of prostate cancer are often considered to have a higher risk of development of radiation-induced bladder cancer. When age-matched cohorts of patients of prostate cancer patients were compared against patients with no prostate cancer, a SEER data analysis revealed a higher risk in patients with prostate cancer. Part of this increased incidence may be explained by the detection bias that exists in prostate cancer patients due to the use of frequent urological surveillance. 
The overall estimates in the whole body reported here are more than that seen by a study of second malignancies in Hodgkins disease, testicular tumor and cervical cancer. ,, However, a higher observed risk of RIM has been seen in a cohort of patients with prostate cancer as reported by Brenner et al. Thus, use of IMRT could result in excess risk of RIM in patients in this study, but the overall significance of this increase remains questionable in view of the much higher reported risk in patients treated for prostate cancer where patients were treated with conventional radiotherapy. We could not find any sizable study that had evaluated the incidence of RIM in patients treated with head and neck cancer.
It should be remembered that the issue of radiation-induced carcinogenesis is not without controversies. In particular, the phenomenon of radiation hormesis at low-radiation doses has attracted increasing attention.  Radiation hormesis is considered to be an adaptive response to the external stress of radiation exposure and is manifested in several cell lines in the form of reduced chromosomal aberrations and increased longevity. In addition to the issue of radiation hormesis, the disadvantages of extrapolating risk estimates generated in the present study to clinical studies should be kept in mind. Modeling risk of radiation-induced carcinogenesis is an exercise in uncertainty. Data on radiation carcinogenesis are mainly derived from retrospective studies, with variable patient populations exposed to variable radiation doses whose dosimetry is often uncertain. In addition, a heightened risk of second malignancies may exist in these patients. Further, different organs may have different risks of RIMs. In an extensive review of the literature, Suit et al. have opined that the greatest reduction in the risk of radiation-induced malignancies would be obtained by reducing the dose below 2 Gy and, above this dose, the magnitude of reduction in RIM is more uncertain.  The use of more conformal techniques can lower the risk of normal tissue injury consequent to high-dose radiation, which may be of greater benefit than an anticipated increase in the risk of RIM.
| > Conclusion|| |
The present study attempts to present an estimate of the risk of RIM incurred by a patient when IMRT is chosen for the treatment. A large majority of the risk stems from the low-dose irradiation of normal tissues due to IMRT. As the risk of radiation-induced cancers is influenced by the age of treatment, this fact should be kept in mind when young patients with early-stage diseases with a favorable prognosis are selected for IMRT. On the other hand, an unnecessary fear of second cancer should not deprive patients of a potentially conformal treatment, which, in turn, can reduce the normal tissue complication probability significantly.
However, till date, no predictive assay can isolate patients who would have an increased risk of RIM. In a country like India where patients with cancer often present at younger age and the absolute number of patient is large, an increased risk of RIM can be anticipated and hence modeling of risk estimates can be part of the plan evaluation process before blanket recommendation of IMRT in all patients, especially if equally good conventional alternatives are available.
| > Acknowledgments|| |
The authors declare no conflicts of interest. No external funding was required for the study. The authors express their heart felt thanks to the technical staff of the Radiotherapy Department, without whose cooperation the present study could not have been executed.
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[Table 1], [Table 2]
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