Efficacy of dose escalation on TCP, recurrence and second cancer risks: a mathematical study

Abstract

VSK Manem and A Dhawan contributed equally to this article.Objective: We investigated the effects of conventional and hypofractionation protocols by modelling tumour control probability (TCP) and tumour recurrence time, and examined their impact on second cancer risks. The main objectives of this study include the following: (a) incorporate tumour recurrence time and second cancer risks into the TCP framework and analyse the effects of variable doses and (b) investigate an efficient protocol to reduce the risk of a secondary malignancy while maximizing disease-free survival and tumour control. Methods: A generalized mathematical formalism was developed that incorporated recurrence and second cancer risk models into the TCP dynamics. Results: Our results suggest that TCP and relapse time are almost identical for conventional and hypofractionated regimens; however, second cancer risks resulting from hypofractionation were reduced by 22% when compared with the second cancer risk associated with a conventional protocol. The hypofractionated regimen appears to be sensitive to dose escalation and the corresponding impact on tumour recurrence time and reduction in second cancer risks. The reduction in second cancer risks is approximately 20% when the dose is increased from 60 to 72 Gy in a hypofractionated protocol. Conclusion: Our results suggest that hypofractionation may be a more efficient regimen in the context of TCP, relapse time and second cancer risks. Overall, our study demonstrates the importance of including a second cancer risk model in designing an efficient radiation regimen. Advances in knowledge: The impact of various fractionation protocols on TCP and relapse in conjunction with second cancer risks is an important clinical question that is as yet unexplored Clinically, it is observed that over half of all cancer patients undergo radiotherapy over the course of their treatment, either as a primary treatment modality or in an adjuvant or a neoadjuvant context. In current radiotherapy treatments, tumours are often irradiated with a heterogeneous dose distribution throughout the treatment volume. The probability that all cancerous cells are removed from the system immediately post treatment is known as tumour control probability (TCP).1 The design and complexity of any treatment regimen in terms of improving therapeutic efficacy can be deduced (to some extent) from TCP values. Although a given heterogeneous dose distribution to the target volume locally controls the disease to a large extent (for a given radiation regimen), there are still shortcomings associated with the currently used radiation protocol. Of these, side effects are of great importance and can be classified based on the time to clinical presentation, with shorter-acting side effects arising from irritation of the skin or mucosa, or irradiation of tissues with sensitive adjacent structures. Late toxicities of radiation are known to manifest after a period of 10-15 years, and one of the major late toxicities is the appearance of a secondary...

Estimation of second cancer risk after radiotherapy for rectal cancer: comparison of 3D conformal radiotherapy and volumetric modulated arc therapy using different high dose fractionation schemes

“…These conclusions would favor hypofractionated RT regimens in reducing SCR, as seen in our study. Manem et al showed in their work modeling tumor control probability and tumor recurrence time on the basis of the linear quadratic model and SCR on the basis of the IIP model [11] that with hypofractionation, SCR was reduced by 22 % compared to a conventional (2Gy) fractionation schedule [34]. Schneider et al also reported that SCR decreases linearly by around 10–15 % per 1 Gy for both carcinoma and sarcoma induction with increasing fractionation dose, and using conventional rather than stereotactic RT, where this effect has not been detected [35].…”

Development and validation of genomic predictors of radiation sensitivity using preclinical data

“…Through our previous works, we characterized the biological imprecision of one-size-fits-all radiation dosing regimens by assessing patient-specific radiation-induced toxicities [ 6 , 8 ]. Furthermore, we curated a repertoire of published radiation response gene signatures [ 10 ], and reported that all the genomic signatures of radiation sensitivity were built using the NCI-60 dataset with limited to no independent external validation raising concerns about their reproducibility.…”

“…In recent years, we have witnessed a rapid evolution of technological advancements in radiotherapy treatment delivery and dose conformity through particle therapies, image-guided techniques [ 3 , 4 ] and the latest addition being the flash radiotherapy technique [ 5 ]. These significant advances have allowed the adaptation of radiation treatment planning fields based on anatomical changes of the gross tumor volume (in maximizing tumor control probability [ 6 ] and minimizing late toxicities either alone [ 7 , 8 ] or in combination with chemotherapy [ 9 ]). However, designing personalized radiotherapeutic regimens based on the tumor’s biological features is still hindered by the lack of appropriate clinical biomarkers [ 10 ].…”

Modeling age-dependent radiation-induced second cancer risks and estimation of mutation rate: an evolutionary approach

“…Several cohort and case control studies have indicated that there is an increased risk of second malignancies with young Hodgkin's Lymphoma survivors post irradiation (Bhatia and Sklar, 2002) (Hodgson et al, 2007b). Recently, several clinical and modeling studies have described the risk of of second malignancies for various neighboring organs (Sachs and Brenner, 2005) (Xu et al, 2008) (Moteabbed et al, 2014) (Paganetti et al, 2012) (Athar and Paganetti, 2011) (Hall, 2006) (Manem et al, 2014a). Some of these clinical studies have suggested that there is a high incidence rate of breast cancer among young Hodgkin's Lymphoma survivors compared to women treated in middle age (Travis et al, 2005).…”

“…Several clinical findings indicate that second cancer risks change with respect to age at exposure and also with respect to time since exposure (Travis et al, 2005) (Dores et al, 2002). Some authors studied the efficacy of dose escalation on secondary cancer induction (Manem et al, 2014b) (Schneider et al, 2007). It has also been noted that the latency period is typically between 10 to 20 years for solid tumors, and around 5 years for leukemia post irradiation (Zhang et al, 2012) (Wang et al, 2014) (Schneider et al, 2014) (van Leeuwen et al, 2003) (Yeoh and Mikhaeel, 2010) (Yahalom, 2009) (Hodgson et al, 2007a).…”