Pancreatic cancer is a highly lethal cancer. Despite all effort, the five-year overall survival rate is currently at merely 5–10% [
1]. In 2018, the global mortality to incidence ratio was at 94% [
2]. So far, operation is the solely curative therapy option but even the postoperative five-year overall survival rate is at only 20% [
3]. Often diagnosed in a late stage of disease, approximately one third of all patients initially present with non-metastasized but inoperable locally advanced pancreatic cancer (LAPC) [
4]. In the last decades, different neoadjuvant and definitive treatment schemes were evaluated and optimal care is still in discussion. In 2016, Hammel et al. published the prospective, international LAP 07 trial, in which patients underwent chemotherapy and only those who did not show tumor progression after 4 months were randomized in further treatment with chemotherapy (
n = 136) or chemoradiotherapy (
n = 133) [
5]. Although, there was no difference in overall survival, chemoradiotherapy was shown to improve local tumor control compared to chemotherapy alone. Altogether, the role of photon radiotherapy in LAPC is still inconclusive. Recently, Icaobuzio-Donahue et al. could show that local tumor progression is related with approximately one third of all pancreatic cancer deaths [
6], highlighting the necessity of effective treatment schemes for patients suffering from LAPC and from non-metastasized locally recurrent pancreatic cancer. To improve efficacy of radiotherapy in pancreatic cancer therapy, different approaches are made. On the one hand, radiation dose prescription is limited due to the organs at risk (OAR) nearby. The duodenum and the stomach as well as the small intestine in total are sensitive tissues with a high risk of ulceration or perforation in case of overdosing [
7,
8]. Higher conformity and consequently higher doses in the target volume without the risk of OAR-overdosing could try to be reached by modern radiation techniques. On the other hand, there are pancreatic cancer-tissue specific properties that could explain the missing effect on overall-survival of radiotherapy. Predominantly, hypoxic tissue is relatively resistant to photon radiotherapy because photon radiation damage is mainly induced by the production of reactive oxygen species and pancreatic cancer is known to be hypoxic [
9]. An approach to overcome this gap of efficacy of photon irradiation is the use of particle therapy, which induces more direct radiation damage to the deoxyribonucleic acid (DNA) due to the known higher linear energy transfer (LET) corresponding with a higher relative biological effectiveness (RBE). Hence, particle therapy is supposed to be more effective in hypoxic tumors. In vitro, carbon ion radiotherapy shows higher RBE-values in pancreatic cancer than those commonly known from protons [
10‐
12]. Therefore, it could be an effective treatment scheme for patients suffering from LAPC or non-metastasized locally recurrent pancreatic cancer.
Recently, Shinoto et al. presented promising results of a prospective Phase I/II dose-escalation study investigating carbon ion radiotherapy in combination with gemcitabine [
13]. Seventy-two patients were irradiated from 43.2 Gy (RBE) up to 55.2 Gy (RBE) in twelve fractions over 3 weeks. The described median overall survival (OS) was at 19.6 months. There was a tendency to improved results in the higher-dosed irradiations. The twelve-months overall survival rate was at 73%. The CT-based local control rate after 2 years was at 83%. Apart from six cases of grade 3 anorexia, only one clearly radiation-induced grade 3 toxicity was observed: a gastrointestinal ulceration.
In our facility, Combs et al. retrospectively evaluated the oncological response of 57 patients suffering from LAPC receiving neoadjuvant chemoradiotherapy with photons (intensity modulated radiotherapy: IMRT) and gemcitabine [
14]. The dose prescription was divided in a primary treatment plan (including tumor + lymphatic drainage) of a median total dose of 45.0 Gy in single doses of 1.8 Gy and in a boost irradiation (including tumor only) up to a median total dose of 54.0 Gy in single doses of median 2.2 Gy. The observed median OS was at 11 months and the twelve-months OS rate was at 36%. The local progression free survival (LPFS) rate after 2 years was at 13%. Toxicity rates were low.
Compared to the prospective patient cohort treated with photon radiotherapy of Hammel et al. [
5] and especially compared to our in-house data from Combs et al. [
14], the findings of Shinoto et al. seem very promising (see Table
1). To our knowledge, there is no prospective trial investigating carbon ion radiotherapy in locally recurrent pancreatic cancer. Retrospective data of carbon ion radiotherapy in Japanese patients suffering from locoregional recurrent pancreatic cancer are very promising, too. Kawashiro et al. observed a median overall survival of 25.9 months in this patient cohort [
15]. Our in-house data from Habermehl et al. showed a median overall survival of 16.1 months of locally recurrent pancreatic cancer patients treated with photon radiotherapy [
16].
Table 1
Comparison of a retrospective analysis of neoadjuvant treated pancreatic cancer patients with photon radiotherapy (IMRT) in our facility by Combs et al. [
14] with a Phase I/II prospective trial investigating carbon ion radiotherapy in pancreatic cancer by Shinoto et al. [
13]
Photons | Combs et al. | 57 | 25 | 54 | 2.2 | 36 | 8 | 11 | 300 mg/m2, weekly |
Carbon ions | Shinoto et al. | 72 | 12 | 43.2–55.2 | 3.6–4.6 | 73 | 35 | 19,6 | 400–1000 mg/m2; days 1, 8, 15 |
Concerning carbon ion radiotherapy, different facilities use different RBE-calculation models as well as different radiation techniques (active scanning vs. passive scattering) [
17]. Furthermore, apart from the results of Shinoto et al., there are no other published data of prospective trials evaluating carbon ion radiotherapy in pancreatic cancer. Therefore, the present PACK-study will investigate carbon ion radiotherapy in patients suffering from LAPC or locally recurrent pancreatic cancer at HIT, Germany.