Aspects of chemotherapy and photon and proton radiotherapy in patients with gastric cancer

Gastric cancer remains a major health problem worldwide. The addition of chemotherapy alone or in combination with radiotherapy to surgery in local gastric cancer improves outcome. In more advanced stages, the optimal palliative chemotherapy remains unknown, as well as the effect of different regimens on the patients’ quality of life. The aim of this thesis was to explore a new concept in chemotherapy, i.e. the sequential approach, and a new modality in radiotherapy, i.e. proton therapy, in the treatment of patients with gastric cancer. Quality of life (QoL) in patients treated with chemotherapy, and target delineation in radiotherapy of gastric cancer, were also studied.

In Paper I, we evaluated the efficacy of sequential chemotherapy in patients with locally advanced and/or metastatic gastric cancer, with alternating irinotecan and docetaxel in combination with infusion 5-Fu. Eighty-one patients were randomized. No differences favoring either arm were found with respect to response rate, overall survival (OS), or toxicity. The median OS of 11 months indicated that the sequential approach was effective and similar to triple combinations, with potentially less toxicity. In Paper II, we evaluated the effect of sequential chemotherapy on the QoL in the same cohort. It was measured before, during, and after treatment. There were no statistically significant differences in QoL scores between the two treatment arms and no changes in mean scores during treatment. During the last 8 weeks of treatment, a significantly larger portion of patients with radiological response reported sustained or better QoL scores than those with no radiological response.

In Paper III, we investigated the effect of inter physician variation on the delineation of target volumes in gastric cancer patients treated with perioperative chemoradiotherapy (CRT). Despite the use of a delineation atlas, we found a large variation in CTV and PTV volumes. There was only a small variation in target coverage and doses to organs at risk (OARs) in the corresponding plans. In Paper IV, we compared proton therapy to modern photon radiotherapy with respect to doses to OARs in gastric cancer patients treated with perioperative CRT. Protons offered significantly lower doses to the left kidney, liver, and spinal cord, and statistically lower risks for all types and malignant secondary neoplasms compared to photons. In Paper V, we evaluated the importance of daily anatomical variations, i.e. intestinal gas filling, on the dose distribution of proton beam therapy. The effect of intestinal gas variations on the PTV/CTV coverage was large. The sparing effect of protons was, however, sustained or the dose to the OARs did not significantly exceed the dose delivered with photons.

In conclusion, sequential chemotherapy and proton radiotherapy are attractive alternatives in the treatment of gastric cancer. Standardization of target definitions in CRT, e.g. by reducing the inter physician variation, is important and should also be further investigated.

List of scientific papers

I. Randomized phase II study of sequential docetaxel and irinotecan with 5- fluorouracil/folinic acid (leucovorin) in patients with advanced gastric cancer: the GATAC trial. Gubanski M, Johnsson A, Fernebro E, Kadar L, Karlberg I, Flygare P, Berglund A, Glimelius B, Lind PA; Gastric Cancer. 2010 Aug; 13(3): 155-61.
https://doi.org/10.1007/s10120-010-0553-4

II. Quality of life in patients with advanced gastric cancer sequentially treated with docetaxel and irinotecan with 5-fluorouracil and folinic acid (leucovorin). Gubanski M, Glimelius B, Lind PA. Med Oncol. 2014 Apr; 31(4): 906.
https://doi.org/10.1007/s12032-014-0906-7

III. Interobserver variation of CTV delineation in Gastric Cancer. Jansen EP, Nijkamp J, Gubanski M, Lind PA, Verheij M. Int J Radiat Oncol Biol Phys. 2009 Oct 14; 77(4): 1166-1170.
https://doi.org/10.1016/j.ijrobp.2009.06.023

IV. Influence of scanned proton treatment on doses to organs at risk and secondary cancer in patients with gastric cancer. Gubanski M, Siegbahn A, Mondlane G, Lind PA [Manuscript]

V. Variation in gastrointestinal gas filling and dosimetric feasibility of proton radiotherapy in patients with gastric cancer. Gubanski M, Siegbahn A, Mondlane G, Lind PA [Manuscript]