Practical Radiation Oncology (2014) 4, 13–19

www.practicalradonc.org

Original Report

Radiation dose responses for chemoradiation therapy of pancreatic cancer: An analysis of compiled clinical data using biophysical models Ion C. Moraru PhD, An Tai PhD, Beth Erickson MD, X. Allen Li PhD ⁎ Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin Received 3 October 2012; revised 4 December 2012; accepted 15 January 2013

Abstract Purpose: We analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer (LAPC) in order to examine possible benefits from radiation therapy dose escalation. Methods and Materials: A modified linear quadratic model was used to fit clinical tumor response and survival data of chemoradiation treatments for LAPC reported from 20 institutions. Biophysical radiosensitivity parameters were extracted from the fits. Results: Examination of the clinical data demonstrated an enhancement in tumor response with higher irradiation dose, an important clinical result for palliation and quality of life. Little indication of improvement in 1-year survival with increased radiation dose was observed. Possible dose escalation schemes are proposed based on calculations of the biologically effective dose required for a 50% tumor response rate. Conclusions: Based on the evaluation of tumor response data, the escalation of radiation dose presents potential clinical benefits which when combined with normal tissue complication analyses may result in improved treatment outcome for locally advanced pancreatic cancer patients. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Introduction In 2010, an estimated 43,140 new cases were reported and 36,800 deaths were caused by pancreatic cancer 1 and despite treatment intensification outcomes remain poor. The majority of diagnosed cases are Sources of support: This study was partially supported by the MCW Cancer Center Meinerz Foundation. Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail address: [email protected] (X.A. Li).

typically advanced stages due to the vague symptoms produced early in the disease course, resulting in 75% mortality in the first year of diagnosis and a 5-year survival of 6%. With the number of cases expected to increase, investigations into more effective treatments are essential for improving outcomes. Surgical intervention is the most effective tool for disease management, 2 yet this option is available to only 15%-20% of patients, 3 with significant risk of morbidity and mortality. Presurgery treatment and restaging is performed for resectable and borderline resectable patients, as they have the best chances for survival. However, 30% of patients present with locally advanced unresectable tumors and 50% with metastases. 4 Although

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combined modalities of chemotherapy and radiation therapy (RT) have shown improved outcome in some cases, 5 the median survival remains at 6-11 months and efforts toward new treatment strategies are ongoing. 6 Certain patients may benefit from high-dose radiation treatment, and hence escalation trials have been attempted using conformal RT techniques including intraoperative radiation therapy (IORT) 7 and stereotactic body radiation therapy (SBRT). 8 In conjunction with the respiration motion management, 9 recent methods seeking improvements in image guided RT planning for higher dose radiation delivery with tighter margins and better normal tissue sparing are online adaptive RT strategies. 10,11 This work aims to examine theoretical benefits associated with radiation dose escalation by analyzing recent clinical data from RT treatment of unresectable locally advanced disease. Estimates of appropriate radiobiologic parameters used in biophysical models were obtained to quantify the potential benefits of the radiation dose increases. Fractionation schemes that may be used in dose escalation trials were designed based on the newly derived model parameters.

Table 1

Methods and materials Clinical data selection We evaluated the benefits of higher radiation doses from clinical observations of tumor response reported in the literature after 1997, summarized in Table 1. In the studies selected, patients had histologically or cytologically confirmed unresectable pancreatic cancer with good performance status, no distant metastases, and in most cases, no prior history of chemoradiation therapy treatment was explicitly stated in the trial inclusion criteria. Endpoints under investigation included feasibility, efficacy and toxicity of treatment modalities combining RT and chemotherapy. 12,15-20,22-25 Survival, palliation, and quality of life were also studied, 14,26 and a few cases involving high-dose or hyperfractionated RT approaches were evaluated for tolerability. 13,28-31 In addition, comparison studies were performed to determine efficacy and discern between treatment arms. 21,22 To ensure patient uniformity and to eliminate the possibility of population subgroups outside the different treatment specifications, we examined and found no correlation between tumor control, response or survival

Recent clinical data from treatment of advanced unresectable pancreatic cancer using radiation therapy and chemotherapy

Study Conventional RT Ishii et al 1997 12 Ceha et al 2000 13 Andre et al 2000 14 Boz et al 2001 15 Wolff et al 2001 16 Safran et al 2001 17 Epelbaum et al 2002 18 Ashamalla et al 2003 19 Okusaka et al 2004 20 Morganti et al 2004 21

Cohen et al 2005 22 Murphyet al 2007 23 Saif et al 2007 24 Hong et al 2008 25 Crane et al 2009 26 Sudo et al 2011 27 SBRT De Lange et al 2002 28 Mahadevan et al 2010 29 Polistina et al 2010 30 Goyal et al 2011 31

Dose (Gy)

Dose/Fx (Gy)

Treatment time (d)

No. of patients

1-year survival (%)

Local control (%)

Tumor response (%)

Concurrent chemotherapy

41.8 47.0 31.0 26.0 66.0 30.0 30.0 45.0 28.0

10.0 27.0 16.0 23.0 24.0 26.0 20.0 30.0 21.0 6.7 13.3 5.0 6.0 9.0 15.0 20.0 24.4 26.0 12.0

5-FU NONE 5-FU, CIS 5-FU GEM PAC GEM PAC GEM 5-FU 5-FU 5-FU NONE MIT C, 5-FU GEM CAP GEM, CIS BEV, CAP S-1

29.2 61.0 69.6 44.0

GEM GEM GEM GEM

50.4 72.0 45.0 59.4 30.0 50.4 50.4 63.8 50.4 39.6 50.4 59.4 59.4 59.4 36.0 50.4 45.0 50.4 50.4

1.8 2.0 1.8 1.8 3.0 1.8 1.8 1.1 1.8 1.8 1.8 1.8 1.8 1.8 2.4 1.8 1.8 1.8 1.8

39 47 35 46 14 39 39 40 39 30 39 46 46 46 21 39 35 39 39

20 44 32 42 42 44 20 20 42 15 15 20 49 55 74 20 41 82 34

20.0 32.0 47.0 58.0 63.3 47.0 70.6

90.0 47.0 66.0 100.0 48.0 76.0 50.0 89.0 83.0 66.7 93.3 80.0 — — 88.0 85.0 87.8 87.0 97.0

24.0 29.3 30.0 25.0

8.0 9.8 10.0 10.4 a

14 3 3 2a

24 36 23 19

46.0 50.0 39.1 56.0

79.2 78.0 82.6 82.0

31.3 a

5-FU, 5-fluorouracil; BEV, bevacizumab; CAP, capecitabine; CIS, cisplatin; fx, fraction; GEM, gemcitabine; MIT C, mitomycin; PAC, paclitaxel; RT, radiation therapy; SBRT, stereotactic body radiation therapy. Tumor response includes complete response (CR) + partial response (PR) values, as indicated in the text. a Averaged over entire trial population.

Practical Radiation Oncology: January-February 2014

with several patient parameters including the mean age, gender, tumor location and staging for the studies collected.

Tumor local control and response Decreased tumor size or growth arrest are important steps in disease management, and clinical trial reports often detail tumor local control (LC) figures in addition to treatment tolerability, toxicity and survival. Patients with LC, describing the fraction of the population that does not experience progressive disease (PD), exhibit either a response (complete or partial) or no measurable change; ie, stable disease (SD). The complete disappearance of all target lesions is designated as complete response (CR) while partial response (PR) is assessed using the RECIST [Response Evaluation Criteria In Solid Tumors] criteria 32 on computed tomography, and sometimes magnetic resonance images. For the data in this study, reports detailed the number of patients (or percentage of the patient cohort) exhibiting CR, PR, and SD, from which LC was extracted using LC = CR + PR + SD. We compared published LC data as a function of a biologically effective dose (BED) using dose fractionation schemes and reliable radiobiologic parameters. However, although LC is a useful cumulative indicator for acute treatment efficacy, incorporating SD may overestimate treatment efficacy since most pancreatic cancer cases are diagnosed with advanced disease, when likely tumor size has reached maximal dimensions. Clinically reported high LC and SD rates, coupled with poor survival, seem to support this claim. Therefore, for our theoretical analysis we separated the tumor response rate (RR) from LC, and examined solely CR+PR as a function of BED.

Dose response of pancreas RT

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This modified linear-quadratic formalism with long follow-up time, 34 although designed for tumor LC, can be directly applied to calculate tumor RR by adjusting assumptions related to the Gaussian distribution of the critical volume required to achieve response according to the RECIST criteria. 32 The population-averaged response rate is then 1 x2 RRðD; d; τÞ ¼ 1− pffiffiffiffiffiffi ∫t−∞ e− 2 dx 2π h  i − α

where t ¼

e

f d 1þ c α=β

f cD−γT −ðγðτ−T ÞÞ

σk =K 0

ð2Þ

δ

−K 50 =K 0

:

In this case, K50 is the critical tumor volume corresponding to 50% of nonresponse and σk is the Gaussian width for the distribution of critical tumor cell numbers. A factor, fc, is introduced to account for the effect of concurrent chemotherapy on BED due to dose sensitization. 35 Of the independent parameters of Eq (2), outcomes from different dose fractionations determine α, α/β, Td, and fc, while K50/K0, σk/K0, and δ are established by the follow-up time dependence of RR. Because we are not investigating follow-up time dependence, the dimensionless parameter t is simplified to   f d  D−γT c −B ð3Þ t ¼ Ae− α 1þ α=β f c Using determined values for the radiobiologic parameters, the BED is calculated using 36

fc  d ln2 T ⋅ BED ¼ f c D⋅ 1 þ ; ð4Þ − α=β α Td ensuring proper comparison between studies with different prescription dose, treatment time, and dose per fraction.

Modeling Goodness of fit In a previous lung tumor study 33 a model linking LC probability to prescription and fractional dose was employed to compare published clinical data. The model assumed that the following: (1) a tumor is not controlled for an individual patient if the number of tumor cells exceeds a critical volume (Kcr); (2) the distribution of Kcr follows a Gaussian distribution for the patient population; and (3) the regression of population-averaged tumor cells can be described by     d − α 1þα=β D−γT −ðγðτ−T ÞÞδ ; ð1Þ K ¼ K 0e where γ = ln 2/Td, α, β are radiobiologic parameters. D, d, K0, Td, and T are the prescription dose, dose per fraction, number of tumor cells at beginning of radiation treatment, tumor doubling time, and total radiation treatment time, respectively. The δ characterizes the speed of tumor cell growth after radiation and τ is the follow-up time starting from the beginning of the treatment.

A least χ 2 method was utilized to generate a fit to the response data. In order to avoid model over-specification we set α/β = 10 Gy and Td = 42 days 37 and fixed fc = 1 for studies employing RT-only. Using treatment outcomes from a phase 3 trial 22 and formalism from reference 35, we calculated fc = 1.188 for those employing 5-FU-based chemoRT. For all remaining chemo drugs, fc was left as a single free parameter, along with α, A, B, to be determined by minimizing  theory 2 n X RR ðDi ; d i Þ−RRclinical ðD i ; d i Þ 2 χ ¼ ; ð5Þ σ2i i¼1 using a method developed at the European Organization for Nuclear Research (CERN; MINUIT), 38 which calculates best-fit parameter values and uncertainties, including nonlinearities and correlations between parameters. Here RR clinic (Di di) and RR theory (Di di) are the ith clinically-

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Figure 1 (A) Tumor local control versus biologically effective dose for radiation therapy of advanced unresectable pancreatic cancer. (B) Tumor response rate vs biologically effective dose for radiation therapy of advanced unresectable pancreatic cancer. The data are fitted with a modified linear quadratic (LQ) model. The points (pink star), (green star), and (blue star) show the expected response for potential dose escalation schemes. (For color version, see online at www.practicalradonc.org).

observed data point and corresponding response rate obtained using Eqs (2) and (3), respectively. The statistical error, σi, is calculated using 39 sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 1−RRclinic i ; ð6Þ σi ¼ RRclinic i Ni where Ni is the number of lesions at risk for the ith data point, taken for simplicity as the number of responding lesions at the time the data point is obtained. The goodness of fit was determined by the condition χ 2/dof ~ 1. The degree of freedom, dof, was defined as the total number of clinically observed RR data points minus the number of free parameters.

et al 18 investigated the efficacy of gemcitabine (GEM) combined with RT in a phase 2 study, where induction phase GEM was administered for 7 weeks in order to maximize the palliative effect on disease-related symptoms and select patients who were unlikely to tolerate the combined modality. The fraction of patients with SD was 30%, which likely resulted in reduced LC. Similarly, Wolff et al 16 and Ceha et al 13 also reported lower SD values, namely 24% and 20%, respectively. In fact, the studies reporting poor LC had SD values much lower than the 54% average observed in this analysis. In the work by Ceha et al, RT was the sole treatment modality, with 72 Gy administered in 2.0 Gy daily fractions, the highest cumulative dose reported using conventional conformal treatment. The authors concluded that the approach was feasible, with good palliation. No other dissimilarities between the data were apparent.

Results Response rate versus BED Tumor local control versus BED We observed no clear benefit in LC with increased RT dose, with typically reported values around 85%, as illustrated in Fig 1A. Studies with LC lower than average were observed at 50%, 18 48%, 16 and 47%. 13 Epelbaum Table 2

We subtracted the SD contributions from the LC data in order to examine tumor response outcomes only. Figure 1B shows response as a function of BED for conventional and hypofractionated treatments, revealing an increased response for higher radiation doses, with RR varying from 6% to 70%

Radiobiologic parameters obtained from fitting published data with a modified linear quadratic model

α (Gy )

α/β (Gy)

Td (day)

fc

A

B

χ 2 / dof

0.021 ± 0.003

10

42

1.353 ± 0.047

6.155 ± 1.375

1.186 ± 0.325

1.8

-1

dof, degree of freedom.

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Figure 2 One-year survival versus (A) response rate and (B) biologically effective dose for radiation therapy treatment of unresectable pancreatic cancer using different chemotherapeutic agents. (For color version, see online at www.practicalradonc.org)

between 33 Gy and 92 Gy BED. The highest observed response rate was reported by Polistina et al, 30 in multimodal treatment involving neoadjuvant GEM and 10 Gy/fraction SBRT to 30 Gy over 3 consecutive days. The authors reported no grade 2 or higher acute or late toxicity, with achievable resectability. The biophysical model applied in this work generated a reasonable fit, with χ 2/dof ~ 1.8. Summarized in Table 2 are the extracted parameters of Eq (2): α = 0.021 ± 0.003 Gy - 1, A = 6.155 ± 1.375, and B = 1.186 ± 0.325, employing as fixed parameters α/β = 10 Gy, Td = 42 days, and fc = 1.188 for data with 5-FU-based chemoRT. The fitted chemo parameter was fc = 1.353 ± 0.047, confirming that 5-FU is indeed less effective than GEM and other drugs utilized in this study.

Survival versus BED We have also investigated 1-year survival data as a function of response and BED for both conventional and hypofractionated-SBRT treatments, distinguished in Fig 2A and B by chemotherapy agent, respectively. Using conventional RT treatment and an oral S-1, the highest 1-year survival rate reported was 70.6%, with a RR of 12% at 54.3 Gy BED. 27 The lowest survival rate of 20% was the result of the arm in the phase 3 trial that employed RT only, 22 exhibiting a RR of 6% at 34 Gy BED. Hypofractionated-SBRT treatments resulting in the highest RR at 61% 29 and 70% 30 reported only modest 1-year survival, namely 50% and 39%, respectively. Examining the data, 5-FU appears to be somewhat inferior for survival when compared with the other chemotherapy treatments. Ongoing clinical trials involving escalations to higher RT

dose regimes will provide additional data needed for definitive conclusions about the benefits to patient survival.

Discussion In the treatment of advanced pancreatic cancer, studies thus far have reported low survival rates with little Table 3 Potential hypofractionation regimens and biologically effective dose (BED) Fractions Treatment Dose/ Prescription Fractions BED time (d) fraction dose (Gy) per (Gy) (Gy) week 28 a 33 b 31 c 29 d 20 15 10 10 10 5 5 3 3 1

39 46 43 39 28 21 14 22 35 10 15 21 7 1

1.80 2.25 2.25 2.25 2.7 3.3 4.2 4.5 4.8 6.7 6.9 10.0 9.2 17.4

50.4 74.3 69.8 65.3 54.7 49.1 42.3 44.5 48.1 33.6 34.6 30.0 27.7 17.4

5 5 5 5 5 5 5 3 2 3 2 1 3 1

52.8 93.2 87.6 82.0 78.4 78.4 78.4 78.4 78.4 78.4 78.4 78.4 78.4 78.4

Hypofractionation schemes are designed to achieve approximately 50% tumor response; ie, 78.4 Gy BED, with parameters from our fit. a Current standard fractionation scheme for radiation therapy treatment. b,c,d Proposed treatment regimen for an in-house clinical dose escalation trial.

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indication of benefits from increased radiation. With modern chemotherapy methods improving, patients live longer with their disease and many have local symptoms, such as pain. Therefore, improvement in local tumor control is recognized as beneficial for palliation and quality of life. In addition, a rapid autopsy series study of patients with pancreatic cancer revealed that 30% of patients die of locally destructive disease, 40 and thus it is critical to take significant steps toward improvement of local tumor control. In this analysis we observed good LC rates from chemoradiation therapy treatment, even though patient survival remained poor, and so we analyzed tumor response and demonstrated a benefit with increased radiation dose. We made the argument that RR is a reasonable indicator for treatment effectiveness, given that pancreatic cancer is usually late-stage and treatment of some patients may be ineffective, even though considered to have attained SD. There are challenges when comparing the effects of radiation dose on response, given the diversity in treatment strategies, institutional experience, timing of assessment, and follow-up, and that studies employing RT as sole modality are uncommon. The aggressive nature of pancreatic cancer and constant pursuit of new agents and dose schemes limits the availability of similar data. Also, computed tomographic-based evaluations cannot distinguish between viable and nonviable cancer cells, even in the case of significant cell killing, making radiologic assessment of treatment difficult. Nonetheless, a systematic survey of published data is necessary when estimating the potential advantages of future prospective trials involving a RT dose escalation. Given that current RT treatment of 50.4 Gy in 1.8 Gy/ fraction appears ineffective in managing advanced pancreatic cancer, we have compiled a list of potential dose escalation schemes using parameters obtained from our fit (summarized in Table 3). Based on our estimates, conventionally fractionated doses administered in 2.25 Gy/fraction to 65.25 Gy (d), 69.75 Gy (c), and 74.25 Gy (b) could generate response rates of 55%, 60%, and 64%, respectively. This regimen offers a conservative approach to dose escalation, with potential improvement upon the 26% average response of standard treatment, while offering a course that physicians would be comfortable administering. In addition to conventional fractionation, results from experiences with SBRT 41 are promising for patients with unresectable disease who might benefit from high-dose ablative therapy with good local control that is relatively well tolerated. Therefore, more aggressive hypofractionated schemes are also listed in Table 3, intending for 50% tumor response rate based on our estimates at 78.4 Gy BED. However, all of these fractionation methods must be considered with caution as they examine the potential benefits purely from the point of view of tumor response, not taking into account normal tissue complications or toxicity-related effects.

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Selecting patients with advanced disease who would benefit most from a RT dose escalation is equally as important as assessing the benefits. For instance, although not shown in this analysis, examination of clinical data including stage IV populations exhibited no enhancement in survival, LC, or RR with increased RT dose, and hence those patients might not benefit from dose intensification. Also, it was recently demonstrated 42 that a local dominant pattern of disease progression can be shown by intact Smad4 expression, while a distant dominant pattern of disease progression by Smad4 loss. Because complications from local rather than distant progression are a significant source of disease-related mortality, differentiating patients through Smad4 expression prior to treatment offers promise in addition to systemic therapy.

Conclusions We have systematically examined recent clinical data from chemoradiation treatment of pancreatic cancer to explore possible benefits from radiation dose escalations. We have selected recent clinical data from patient groups possessing similar characteristics to investigate the effect of radiation therapy dose on patient outcome, including 1-year survival rate, local tumor control, and response rate. We observe that higher radiation doses result in increased tumor response with little evidence toward increased survival. From published data we extracted radiobiologic parameters that may be used to estimate possible radiation dose escalation schemes for unresectable advanced pancreatic cancer. Our results demonstrate that appropriate dose enhancement may be beneficial for a select group of patients; based on this analysis, a dose escalation trial up to 74.25 Gy in 2.25 Gy/fraction is initiated for unresectable pancreatic cancer at our institution.

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Radiation dose responses for chemoradiation therapy of pancreatic cancer: an analysis of compiled clinical data using biophysical models.

We analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer (LAPC) in order to examine possible ...
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