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Modeling Combined Chemotherapy and Particle Therapy for Locally Advanced Pancreatic Cancer.

Durante M, Tommasino F, Yamada S - Front Oncol (2015)

Bottom Line: Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond.We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose.We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung , Darmstadt , Germany ; Department of Physics, Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), University of Trento , Trento , Italy.

ABSTRACT
Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond. Combined radiochemotherapy protocols using gemcitabine and hypofractionated X-rays are ongoing in several clinical trials. Recent results indicate that charged particle therapy substantially increases local control of resectable and unresectable pancreas cancer, as predicted from previous radiobiology studies considering the high tumor hypoxia. Combination with chemotherapy improves the overall survival (OS). We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose. We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules. Further hypofractionation using charged particles may result in improved local control and survival. A comparative clinical trial using the standard X-ray scheme vs. the best current standard with carbon ions is crucial and may open new opportunities for this deadly disease.

No MeSH data available.


Related in: MedlinePlus

4DCT analysis of the movement of the critical organs during treatment of LAUPC at NIRS with C-ions. T0 is the peak inhalation and T50 the peak exhalation phases. Stomach and duodenum move in and out the PTV in the two phases.
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Figure 8: 4DCT analysis of the movement of the critical organs during treatment of LAUPC at NIRS with C-ions. T0 is the peak inhalation and T50 the peak exhalation phases. Stomach and duodenum move in and out the PTV in the two phases.

Mentions: Modeling chemotherapy in terms of equivalent radiation dose is an effective method to predict outcomes of dose-escalation trials (12, 16). The large scatter in the chemoradiation data leads, however, to a poor goodness-of-fit in Figures 3 and 4. This is due in part to the many different protocols used in chemotherapy for LAUPC, and to inclusion of data published in over 30 years using very different methods both for drug and radiation delivery. In this paper, we have decided to analyze all the data available in the literature, without including the treatment year as a function in the model. We have also assumed no synergistic interaction between chemicals and radiation. Finally, Eq. 4 should be modified for protons or carbon ions, where α/β is higher than for X-rays leading to a lower dependence on fractionation. Due to the lack of sufficient information leading to an educated guess for other parameters and models, we decided to stick to the conventional logistic function, replacing Gy with Gy(RBE) in Table 6. The basic assumption remains that a higher BED will result in a higher OS in LAUPC patients, an assumption clearly supported by the analysis of the several trials included in our data mining. Our analysis supports the concept that a dose escalation will improve OS, and toxicity is the limiting factor. In Table 7, we have calculated with the logistic model (Eq. 3) the expected survival in hypofractionated dose-escalation trials and compared with the standard chemoradiation treatment and other schedules proposed for SBRT using X-rays (15, 27). The standard at NIRS is 12 fractions in 3 weeks, and with the current maximum dose/fraction the OS at 1 year is expected to improve from 40 to 70% compared to the standard X-ray regime (50.4 Gy in 28 fractions). Reaching 18 fractions with the same dose/fraction, it could be possible to double the survival. Further hypofractionation, down to a single dose of 25 Gy(RBE) is very attractive in terms of expected survival, but raises concerns for the GI toxicity. C-ions delivered by raster scanning should provide the optimal dose distributions (Figure 7) compared to CIRT with passive scattering and protons, where the lateral scattering unavoidably leads to a dose penumbra around the PTV. However, for beam scanning, the issue of motion mitigation must be tackled very carefully, because of the known problem of the interplay. Currently, NIRS is using respiratory gating to compensate especially the movements of stomach and duodenum in the PTV (Figure 8). A treatment with high number of fractions compensates the interplay between beam scanning and organ motion, but this compensation is lost in radiosurgery (29). In the treatment of hepatocellular carcinoma with 12C-ions at the HIT facility in Heidelberg, it has been shown that the simple increase from 1 to 4 fractions substantially improved the dose target coverage and reduced overdosage (V107 from 32 to 4%) (30), this means that keeping the hypofractionation schemes above 4 fractions, major inhomogeneities should be avoided. Nevertheless, the range uncertainties due to bowel movement, stomach peristalsis, and breathing, have to be solved to reduce toxicity to the many critical organs surrounding the pancreas. Motion mitigation strategy include respiratory gating or layer stacking boost irradiation, such as used at NIRS for treating PC (31), and 4D optimization of the plan based on 4DCT (32). Patients with tumors in a favorable location, preferably >1 cm from the closest luminal organ, should be selected for the dose escalation.


Modeling Combined Chemotherapy and Particle Therapy for Locally Advanced Pancreatic Cancer.

Durante M, Tommasino F, Yamada S - Front Oncol (2015)

4DCT analysis of the movement of the critical organs during treatment of LAUPC at NIRS with C-ions. T0 is the peak inhalation and T50 the peak exhalation phases. Stomach and duodenum move in and out the PTV in the two phases.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492201&req=5

Figure 8: 4DCT analysis of the movement of the critical organs during treatment of LAUPC at NIRS with C-ions. T0 is the peak inhalation and T50 the peak exhalation phases. Stomach and duodenum move in and out the PTV in the two phases.
Mentions: Modeling chemotherapy in terms of equivalent radiation dose is an effective method to predict outcomes of dose-escalation trials (12, 16). The large scatter in the chemoradiation data leads, however, to a poor goodness-of-fit in Figures 3 and 4. This is due in part to the many different protocols used in chemotherapy for LAUPC, and to inclusion of data published in over 30 years using very different methods both for drug and radiation delivery. In this paper, we have decided to analyze all the data available in the literature, without including the treatment year as a function in the model. We have also assumed no synergistic interaction between chemicals and radiation. Finally, Eq. 4 should be modified for protons or carbon ions, where α/β is higher than for X-rays leading to a lower dependence on fractionation. Due to the lack of sufficient information leading to an educated guess for other parameters and models, we decided to stick to the conventional logistic function, replacing Gy with Gy(RBE) in Table 6. The basic assumption remains that a higher BED will result in a higher OS in LAUPC patients, an assumption clearly supported by the analysis of the several trials included in our data mining. Our analysis supports the concept that a dose escalation will improve OS, and toxicity is the limiting factor. In Table 7, we have calculated with the logistic model (Eq. 3) the expected survival in hypofractionated dose-escalation trials and compared with the standard chemoradiation treatment and other schedules proposed for SBRT using X-rays (15, 27). The standard at NIRS is 12 fractions in 3 weeks, and with the current maximum dose/fraction the OS at 1 year is expected to improve from 40 to 70% compared to the standard X-ray regime (50.4 Gy in 28 fractions). Reaching 18 fractions with the same dose/fraction, it could be possible to double the survival. Further hypofractionation, down to a single dose of 25 Gy(RBE) is very attractive in terms of expected survival, but raises concerns for the GI toxicity. C-ions delivered by raster scanning should provide the optimal dose distributions (Figure 7) compared to CIRT with passive scattering and protons, where the lateral scattering unavoidably leads to a dose penumbra around the PTV. However, for beam scanning, the issue of motion mitigation must be tackled very carefully, because of the known problem of the interplay. Currently, NIRS is using respiratory gating to compensate especially the movements of stomach and duodenum in the PTV (Figure 8). A treatment with high number of fractions compensates the interplay between beam scanning and organ motion, but this compensation is lost in radiosurgery (29). In the treatment of hepatocellular carcinoma with 12C-ions at the HIT facility in Heidelberg, it has been shown that the simple increase from 1 to 4 fractions substantially improved the dose target coverage and reduced overdosage (V107 from 32 to 4%) (30), this means that keeping the hypofractionation schemes above 4 fractions, major inhomogeneities should be avoided. Nevertheless, the range uncertainties due to bowel movement, stomach peristalsis, and breathing, have to be solved to reduce toxicity to the many critical organs surrounding the pancreas. Motion mitigation strategy include respiratory gating or layer stacking boost irradiation, such as used at NIRS for treating PC (31), and 4D optimization of the plan based on 4DCT (32). Patients with tumors in a favorable location, preferably >1 cm from the closest luminal organ, should be selected for the dose escalation.

Bottom Line: Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond.We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose.We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung , Darmstadt , Germany ; Department of Physics, Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), University of Trento , Trento , Italy.

ABSTRACT
Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond. Combined radiochemotherapy protocols using gemcitabine and hypofractionated X-rays are ongoing in several clinical trials. Recent results indicate that charged particle therapy substantially increases local control of resectable and unresectable pancreas cancer, as predicted from previous radiobiology studies considering the high tumor hypoxia. Combination with chemotherapy improves the overall survival (OS). We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose. We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules. Further hypofractionation using charged particles may result in improved local control and survival. A comparative clinical trial using the standard X-ray scheme vs. the best current standard with carbon ions is crucial and may open new opportunities for this deadly disease.

No MeSH data available.


Related in: MedlinePlus