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2012-01-23 13:06



Haidenberger A., Rinecker H.
Therapyproblem Pancreatic Carcinoma
13.000 people in Germany are diagnosed with pancreatic carcinoma every year. Pancreatic cancer is ranked fourth in the list of cancer induced deaths in men and women. At the same time it poses an enormous therapeutic problem: this type of cancer can remain entirely without any symptoms, and thus undetected, until the stage where it has already metastasized. Clinical symptoms such as jaundice caused by a compression of the biliary duct, which runs through the pancreas, often occur only at such a late stage that a cure of this cancer is no longer possible. More than 80% of these cases cannot be healed; therapy merely prolongs life for a few months.  
Today, an increasing number of examinations are undertaken, which can detect an early stage, yet symptomless and curable pancreatic carcinoma: image-guided examinations in the context of targeted screenings or unrelated examinations of the upper abdomen such as magnetic resonance imaging, computed tomography or sonography, which is in some cases able of an analysis of the pancreas. Thus, therapists are increasingly often confronted with pancreatic carcinomas that can still be cured. Chemotherapy as stand-alone treatment method cannot, as it is generally the case with any “solid” tumor, cure the cancer but merely extends life for a few months. Despite the introduction of new chemotherapeutics and targeted-therapy, this method remains restricted to prolonging life. The curative surgery is, in cases where the cancer is located in the so called head of the pancreas close to the duodenum, one of the most extensive abdominal surgeries possible: the “Whipple operation” named after its developer. This surgery is not only of very high risk; it is also prone to cause numerous complications and has more or less negative effects on the functionality of the gastrointestinal tract. Even though current surgery methods are highly advanced, only 10%-25% of the pancreatic carcinomas are primarily operable and even of those cases a total resection of the carcinoma without any tumor tissue remaining is possible in only 60%. Nevertheless, radical surgical resection of the carcinoma and surrounding lymphatic nodes so far remains the only potentially curative therapy in the early stage.  The risk associated with the surgery remains, however, with 5% - even in highly experienced surgical centers – very high.
Any radiation method with X-rays that is presently available is no satisfactory alternative. Indeed, X-rays can be aimed at the tumor laterally, as can be seen in detail below. However, with X-rays being a “shoot-through” method, the healthy tissue is exposed to a multiple of the dose – up to five times the tumor dose – in front of and behind the tumor.  
Indeed, radiation technology with X-rays has advanced rapidly over the past years. With the help of intensity modulated radio therapy (IMRT), tomotheraphy, or stereotactic ARC irradiation it is possible to better adapt the radiation dose distribution to the respective tumor shape. Yet, regardless of which x-ray radiation method is chosen, or from how many different directions the tumor is irradiated, the parts of the small intestine in front of the pancreas are always irradiated with a high dose. In the case of radiation with X-rays, there is further a high radiation exposure of other critical organs such as liver, kidneys, stomach or spinal cord. This necessitates a restriction of the tumor dose since every additional increase in this dose would only be possible at the expense of the healthy tissue and would surpass the dose that is maximally tolerated by the above mentioned critical organs.
Solution: Proton Therapy
With protons, their three-times better concentration of the radiation within the tumor, the absence of any radiation behind the tumor (in the direction of the beam) and a dose in front of the tumor, which is far lower than with X-rays, it is finally possible to irradiate pancreatic carcinomas with a curative dose.
The following is a description of our first experiences with the radiation of pancreatic carcinomas with proton scanning at the RINECKER PROTON THERAPY CENTER in Munich:
Between the summer of 2009 and the summer of 2011 a total of 26 patients with an inoperable, histologically confirmed, pancreatic carcinoma with varying pretreatments (chemotherapy and surgical attempts) has been irradiated with protons at our facility. Since the summer of 2010, 13 patients, who have received standardized proton radiation. 10 of these patients (77%) have been irradiated with a RPTC-standard dose of 18 x 3 Gy (RBE), in one case (8%) the dose has been reduced to 15 x 3 Gy (RBE) due to the side effects from concurrent chemotherapy, 2 patients (16%) with simultaneous liver metastasis have been irradiated with 10 x 4 Gy (RBE) in the area of the pancreas and 3 x 14 Gy (RBE) to the liver metastases, this irradiation taking place under anesthesia in apnea (Table 1).
Our analysis after a follow-up of 6 months shows an excellent tolerance of proton therapy. During therapy and up to 6 months after completion of therapy no grade 3 side-effects (for example weight loss over 15% or frequent nausea) have been registered. During therapy grade 2 side effects (for example modest weight loss less than 15% or modest abdominal pain) have been observed in 38% of the cases. These side effects have however disappeared entirely within 8 weeks after completion of therapy. One patient developed a grade 1 side effect in the form of a mild radio-dermatitis. In the follow-up period of 6 months only one patient (8%) experienced a grade 1 side effect (such as nonrecurring sickness) (Table 2). Obstruction of the biliary tract was not observed.
Not only tolerance but also early therapeutic results are excellent: 6 months after the therapy a remission (a receding of the tumor visible under MRI-scans or computer tomography) has been observed in all patients. This results in a local tumor control rate of 100%. In two-thirds of the patients, a remission of as much as 60-70% of the original tumor volume was measured.
The Advantage of Proton-scanning with Pancreatic Carcinomas
These clinical results correspond with and confirm the specifications of the treatment plans that were developed at the RPTC. An ideal homogeneous coverage of the tumor region with a high effective dose was achieved in all cases. At the same time, the proton scanning method at the RPTC made it possible to perfectly protect the surrounding critical organs. This becomes evident from the fact that there have been no grade 3 side effects and a control rate of 100% has been obtained.
The decisive advantage of proton scanning, compared to any other radiation-method of the pancreas with X-rays, is caused by the significantly better dose distribution:
Figure 1 shows a CT-cross section image for one of our patients with pancreatic carcinoma. Visible on the image are the tumor-expansion (red line) as well as the planning target volume, i.e. the target area which is to be irradiated with a high dose (PTV, blue line). Both areas have been defined by a radiotherapist. Likewise visible in this cross-sectional image are the highlighted critical areas of organs such as liver (yellow line), spinal cord (green line) and the left and right kidney (pink and light blue lines). In order to explain the physical differences of irradiation with X-rays and protons in clinical situations, we demonstrate a theoretical dose analysis for a single beam direction. Figure 2 compares the dose distribution resulting from an irradiation with X-rays with a single beam direction radiation field from the front (Figure 2a) with the dose distribution from irradiation with protons, likewise with a single field (Figure 2b). The fundamental advantage of proton therapy becomes apparent from the dose distribution: in front of the tumor, there is less dose than within the tumor, and none behind the tumor in the case of protons. In contrast, with X-rays there is a higher dose in front of the tumor in beam direction than within the tumor, and likewise a high exposure to radiation of the critical organs behind the tumor.
Even the method, common with X-rays, to irradiate from numerous direction fields and thus achieve an overlap of the doses in the target area, cannot compensate the physical disadvantage of X-rays that is illustrated in Figure 2. This can be seen in Figure 3, where a modern IMRT based treatment plan for irradiation with X-rays from 5 directions (3a) is compared with the proton-scanning-treatment plan that was actually used at the RPTC (Figure 3b). It can clearly be seen that the dose in the critical organs is too high in the x-ray treatment plan and thus precludes the radiation with an adequate tumor dose. In comparison, it was possible with protons to achieve the desired, high dose within the tumor while at the same time protecting the surrounding healthy tissue. The substantial advantage of an irradiation with protons with an only marginal dose exposure of critical organs can once again be seen from the case presented in Figure 4. In a so called dose-volume-histogram (DVH) it is demonstrated, for the planning target volume (PTV, blue line) as well as for the different critical structures, which parts of the respective areas are exposed to how much radiation. For comparison, the results from the proton therapy conducted at the RPTC (solid lines) and the theoretical IMRT treatment plan (dotted lines) are displayed. It shows that a much smaller volume of any critical structures is exposed to radiation and that the dose to which this smaller volume is exposed is likewise much lower than with X-rays. Thus, in the case of an IMRT treatment plan the stomach would be exposed to 3,6-times the average dose, the liver to 2,3-times the average dose and the right kidney to 2-times the average dose when compared to the realized proton therapy. The left kidney remains radiation free with proton therapy.
The experiences with the irradiation of pancreatic carcinomas that have been made at the RPTC so far show an excellent tolerance of proton therapy by the patients with a local tumor control rate of 100%. Given the high tumor dose a continuously good local tumor control rate beyond the 6 months observation period is to be hoped for.
With proton scanning it is finally possible to apply an effective tumor dose for pancreatic carcinomas.

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