Abstract
A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In gastrointestinal cancers, it is assessed that at least 345 patients, mainly non-resectable rectal cancers, oesophageal and liver cancers, are eligible. Great uncertainties do however exist both in the number of patients with gastrointestinal cancers suitable for radiation therapy, and in the proportion of those where proton beams may give sufficiently better results.
Cancers in the gastrointestinal tract and associated organs, chiefly the liver, biliary tracts and pancreas are common, and constitute with almost 9 000 new cases a year in Sweden almost one-fifth of the total number of cancers. Due to a generally less favourable prognosis than for other common tumour types, more than a quarter of all cancer deaths in Sweden are ascribed to a gastrointestinal cancer. Except for the most proximal, oesophagus, and distal, rectum and anus cancers, radiotherapy has traditionally played a minor role in treatment of these malignancies. Reasons for this are mainly the localization in or adjacent to radiosensitive organs and a tendency to metastasize early.
Oesophageal cancer
Every year slightly less than 400 patients in Sweden are diagnosed with oesophageal cancer Citation[1]. The majority are men with a median age of 72 years. There is a shift in histologic type and tumour location, with an increasing proportion of adenocarcinomas in the lower part on behalf of squamous cell carcinomas in the upper parts Citation[2]. The early cases are operated upon, while the more advanced cases are irradiated, more and more frequently in combination with chemotherapy Citation[3], Citation[4]. The disease, however, is often so advanced that only palliative treatments are possible. The survival rate in the western world is less than 10% after five years. In Japan, where screening is performed with oesophagoscopy on symptomless persons, early detection of oesophageal cancer leads to surgery which can cure about 45% of the patients.
Radiotherapy is often performed as conformal radiotherapy (3D-CRT) against the primary tumour with a 5 cm margin cranially and caudally and the lymph nodes in mediastinum. For cancer located in the upper third, the supraclavicular fossae are included. For cancer in the lower third of oesophagus the coeliacus region is generally included. The optimal target is, however, poorly defined Citation[5]. There is a potential role for FDG-PET in radiotherapy planning in oesophageal cancer Citation[6]. The doses to the spinal cord, the lungs, heart, liver and kidneys must be limited. Thus, the challenges in irradiation of oesophageal cancer are many, making this site an ideal candidate for the application of sophisticated technologies Citation[7–10]. Sometimes intraluminal brachytherapy is performed when the patient has low lung capacity or as a complement to laser treatment or stenting. In Japan, brachytherapy is used as a boost to the external radiation therapy in early cases, with increased survival Citation[11].
Acute oesophagitis is mandatory to a greater or lesser extent. Long-term side-effects like pneumonitis or lung fibrosis can develop, but this has seldom been a clinical problem, since most of the patients die of their cancer before these side-effects appear. Improved long-term survival after multimodal therapies may change this.
Clinical experience of proton treatment
A few case-reports exist from Japan Citation[12], Citation[13]. Doses around 80 – 88 Gy have then been given, which have resulted in a substantial number of oesophageal ulcerations. Heterogeneous cancer manifestations and heterogeneous treatments make it impossible to evaluate the benefits of protons compared to photons.
Model studies
Model studies have indicated quite a substantial benefit for proton treatment compared to photon treatment in avoiding high radiation doses in several risk organs surrounding the oesophagus Citation[14], Citation[15].
Assessment of the number of patients eligible for proton beam therapy
In the second SBU radiotherapy report about 19 patients received curative radiation treatment against the primary tumour, extrapolating to about 80 patients yearly Citation[16]. It was estimated that 20% of all patients with oesophageal cancer would have potential benefit of the higher doses that can be given with protons. The expected number of patients per year would then be about 80.
Research needed
There is an urgent need for randomized trials comparing photons and protons in order to substantiate the potential benefit that dose modelling studies indicate. With the most recent advances in radiation therapy delivery, there is also a need for further dose modelling studies to better define the patient groups that would potentially benefit the most.
Summary assessment
It is estimated that about 80 patients per year with oesophageal cancer might benefit from proton treatment. This figure, however, is highly uncertain. The chances of local control would then increase. At the same time, radiation toxicity, especially from the lungs would diminish. As many as possible of these treatments should be within properly controlled trials.
Gastric cancer
Incidence of gastric cancer in Sweden has declined, with some 1 000 patients diagnosed in recent years Citation[1]. Surgery is the only established treatment, resulting in long-term cure for about 20% of the patients Citation[17], Citation[18]. In cases where radical surgery is possible, the long-term survival rate is approximately 40%. Until recently, chemotherapy had only modest effects for palliation, with no proofs of significant gains as adjuvant therapy Citation[19]. Pre- and postoperative therapy improved survival in one trial including 503 patients with operable gastric and lower oesophageal cancer Citation[20].
A randomised study Citation[21] has shown improved survival following the addition of chemoradiotherapy to radical surgery at stages IB-IV (MO). Apart from this study Citation[21], very limited use has been made of radiotherapy for treating gastric cancer. In the American study, survival rose by 10% after five years’ follow-up. The post-operative radiotherapy was given to the operation bed and to all lymph nodes at risk. The target volume is large and located close to several risk organs, lower parts of the heart and lungs, liver, kidneys and small intestine. The study showed substantial acute morbidity from the chemoradiotherapy. In a recent comparative model planning study, it was shown that 3D conformal photon therapy resulted in superior dose distributions compared with antero-posterior-posteroanterior (AP-PA) beams potential reducing toxicity Citation[22]. The results of the study have been criticised above all on account of poor-quality surgery. It is impossible to tell whether the improved survival is due to compensation for poor surgery or whether the same or possibly a better effect would be seen with good surgery including a more adequate lymph node dissection Citation[23].
Clinical experience of proton beam therapy, model studies for gastric cancer
None available.
Assessment of the number of cases eligible for proton beam therapy
Chemoradiotherapy after surgery for gastric cancer is not clinical routine in Sweden. This treatment has come to be routine at many centres in the USA Citation[24] and is being widely discussed in Europe. Even though comparative model studies using proton beams are lacking, it is reasonable to assume that protons give better dose distribution and, consequently, less impact on normal tissue than photons. This is probably the case even if varying quantities of air in the remaining ventricle/ventricle substitute have more effect on the proton than on the photon dose distribution.
If protons are to be given in primary gastric cancer, this must be done within a controlled clinical study. All patients who have undergone a radical resection for a gastric cancer below 75 years of age are potentially eligible for inclusion in a controlled study.
Research needed
Given the complete lack of model studies, these will have to be undertaken so as to provide a sounder basis for the potential advantage of proton irradiation against the tumour bed and remaining lymph nodes at risk. When a clinical proton facility is available, gastric cancer should be a suitable diagnosis for a controlled study.
Summary assessment
Radiotherapy is not being routinely used in Sweden for treating gastric cancer. Therefore, an adequate assessment of the number of potential patients is not easy. Potentially, though, many patients can be eligible for inclusion in a randomised study if treatment routines are altered, and it should also be possible for a very limited number of patients with local relapse without any other known spread to be treated with a view to better dose distribution.
Pancreatic cancer
The incidence of pancreatic cancer is declining, with upwards of 800 new cases diagnosed recently Citation[1]. Between 10 and 15% of these cases are operable when discovered and about 30% have locally irresectable tumours and no known distant metastases. Even in case where this cancer is radically resectable, it recurs in the majority of patients and long-term cure can only be achieved in a minute percentage of the cases diagnosed Citation[17].
Radiotherapy for pancreatic cancer has been used both pre-, intra- and post-operatively and as sole treatment, usually combined with chemotherapy for unresectable cancer. Pre- and/or intraoperative irradiation can increase respectability, but has in some reports only had minor impact on short-term survival and unfortunately no impact on long-term survival Citation[25–28]. Post-operatively, chemoradiotherapy has been given in isolated randomised studies. The results, taken together, are inconclusive, a positive effect having been seen in some studies but not in others Citation[29–31]. Chemoradiotherapy as sole treatment has achieved long-term relapse-free survival in a handful of patients with morphologically verified pancreatic cancer, and it is possible that the results achieved with chemoradiotherapy for locally advanced cancer are no worse than those achieved with surgery for operable cancer Citation[30], Citation[32], Citation[33]. One small randomised trial, however, found that for patients judged to be resectable, radiochemotherapy was inferior to surgery Citation[34].
Clinical experience of proton beam therapy, model studies for pancreatic cancer
None available.
Model studies
Since, on account of adjacent risk organs such as the medulla, liver, duodenum and small intestines and kidneys, adequate coverage of the primary tumour and the adjuvant lymph nodes is difficult and complicated to achieve, a modality is needed which can deliver a higher radiation dose to the tumour target. In a study by Zurlo and co-workers Citation[35], proton beam therapy has yielded a better physical dose distribution.
Assessment of the number of cases eligible for proton beam therapy
Since the value of radiotherapy for treating pancreatic cancer has not been shown, it is impossible to make a really firm estimate of the number of cases eligible for proton beam therapy, but it is possible, with reasonable morbidity, to deliver an adequate radiation dose with photons to the pancreas and adjacent tissues where there is a high risk of tumour infiltration. Adequate assessment of the value of radiotherapy calls, for example, for proton beam therapy, in which case up to 240 patients, i.e. those aged under about 70 and with non-metastasing disease, are potentially eligible for inclusion in a clinical study. That study, in order to be conclusive, will probably have to be randomised. In the SBU survey, 12 treatments, corresponding to roughly 50 patients, were given in Sweden in the course of a year.
Summary assessment
Potentially up to 240 patients annually can be considered for a clinical study to evaluate proton beam therapy. Realistically speaking, however, this figure is probably far too high in relation to the present state of knowledge and therapy tradition. Pancreatic cancer, however, is a diagnosis for which a clinical proton facility in Sweden can facilitate randomised studies aimed at judging whether long-term survival can be increased for one of the diagnoses having the worst prognosis of any kind of cancer.
Cancer of the liver
Most liver cancer cases in Sweden are secondary, and so surgery, radiotherapy and other local treatment methods seldom come into question, except for colorectal cancer and perhaps a few other kinds of cancer. In future, therefore, the improvement undergone in recent years by the systematic treatment of colorectal cancer Citation[36], Citation[37] may drastically influence the feasibility of local treatment as “consolidation”, e.g. for relatively limited tumours following good effect with the systematic treatment.
Surgery is the only established curative treatment for primary cancer of the liver, mainly hepatocellular and cholangiocellular cancer. But it is seldom possible to remove the tumours (perhaps in 30 – 60 of the 370 new cases diagnosed in Sweden annually), either because inadequate function of the remaining liver, e.g. in cases of liver cirrhosis, or owing to proximity to great vessels. In cases of this kind, various local methods such as radiofrequency therapy, cryotherapy, interstitial laser therapy, ethanol therapy and radiotherapy have been tested Citation[38], Citation[39]. Long-term survival has been reported, mostly in small series, but the value of these methods remains unproven, one possible reason being that the practitioners of a technique have lacked the capacity, knowledge or interest to carry out conclusive studies.
The liver is a relatively radiosensitive organ which cannot tolerate elevated doses to large volumes Citation[40]. This has made it impossible to deliver an elevated dose to any tumour, with the result that radiotherapy has been mainly palliative Citation[41]. A dose-response relationship appears to exist for primary hepatocellular cancer Citation[42]. Using a stereotactic frame and many radiation fields, it has been possible to deliver relatively high doses in a small number of fractions to individual tumours measuring up to 6 – 7 cm. Experience of this stereotactic irradiation is limited. Most experience has been reported from Radiumhemmet, Stockholm Sweden Citation[43]. As mentioned above, long-term survival has been reported with primary hepatocellular, cholangiocellular and secondary colorectal cancer.
Clinical experience using proton beam therapy
Protons have been used with alleged success, mainly in Japanese or Asian series, but no good reports exist Citation[44–46]. At the Tsukuba Cancer Center, 236 medically and technically inoperable patients with hepatocellular cancer were treated with protons (5 CGEx16). Several of these patients had multiple tumours. Local control was achieved in 85% of the patients Citation[47]. Most of the patients relapsed in other parts of the liver. Thus clinical treatment studies cannot constitute good evidence for proton beam treatment of many patients with liver cancer. Carbon ion therapy has also been used in patients with hepatocellular carcinoma with liver cirrhosis Citation[48].
Model studies
Advanced radiation technology is needed in order to attain an elevated dose against cancer of the liver. Protons are capable of achieving, with fewer fields, better dose distributions than are possible, for example, with stereotactic techniques, though this has not been studied more closely. Physical dose advantages have been described in abstract terms, mainly from Asia. The demand for good fixation and control over the respiratory movements is probably greater with protons than when using photons.
Assessment of the number of cases eligible for proton beam therapy
Despite the lack of good evidence from clinical treatment studies or model studies, liver cancer is an interesting group of tumours which should be made a subject of clinical studies with protons. Protons can present an interesting alternative to surgery in cases where there is doubt concerning the remaining liver function or proximity to great vessels. They can also be an alternative to other local treatment methods such as radiofrequency therapy, interstitial laser therapy or stereotactic radiotherapy using photons. These techniques are developing relatively fast, but good evidence is still lacking. It is reasonable to suppose that protons can achieve an effect comparable to that of the above methods. At the same time larger tumours can probably be treated with protons than presently with these other techniques. Fifty cases annually in Sweden, equally divided between primary and secondary cases, is a very conservative estimate of the number of potential patients.
Research needed
Adequate comparative dose planning studies with many patients and optimal algorithms are desirable and should be feasible relatively soon. Clinical experience of proton beam radiotherapy for cancer of the liver should be systematically canvassed. Studies may possibly be reported between now and 2008, even though, to our knowledge, none of the studies in progress is randomised.
Clinical studies will have to be initiated when a facility is available. In the western world, randomised studies will probably be required in order to prove the value of protons. Depending on the type of cancer, the occurrence of simultaneous liver cirrhosis etc., the arms of comparison may be surgery, some other local method of tumour destruction or stereotactic irradiation with photons. The endpoint should then be local tumour control and survival. If 20% of liver cancer patients in Sweden are includable, this means a potential of 65 patients annually for studies.
Similar studies should be feasible for secondary colorectal cancer of the liver. These cases are considerably more numerous than those of primary cancer of the liver, and it is estimated that up to at least 200 patients annually may be includable in randomised studies. In these studies, survival must be the primary endpoint.
Summary assessment
It is estimated that in the first instance 65 Swedish patients annually may be eligible for proton beam therapy, given the possibility. The chances of local tumour control and, survival prospects with them should then increase. The treatments should take place within randomised studies. There is a future potential here of many more patients than indicated above. According to the SBU report, radiotherapy was given to about 75 patients in Sweden annually for primary cancer of the liver and bile ducts. It is not known how many patients were treated for colorectal cancer metastases in the liver.
Rectal cancer
Radiotherapy is widely used for rectal cancer, which is diagnosed in about 1 800 new Swedish patients annually Citation[1]. In case of primarily operable rectal cancer, radiotherapy is used to reduce the risk of local relapse and to influence survival somewhat. In cases of primarily unresectable rectal cancer or in case of local relapse without previous irradiation, radiotherapy is given with or without cytostatics to achieve tumour reduction, to make surgery possible and, consequently, long-term cure.
In cases of operable rectal cancer, one week's irradiation together with good surgery produces outstandingly good results, with only isolated patients suffering a symptomatic local relapse Citation[49]. Although long-term side-effects have been described following rectal cancer irradiation Citation[50–52] and the risk of these effects can probably be reduced by using protons instead of photons, it is not reasonable to suppose that protons will replace conventional radiotherapy for primarily operable rectal cancer.
A combination of preoperative irradiation and cytostatics can facilitate surgery in 60 – 70% of patients, and long-term cure is achieved for one patient in every three Citation[49], Citation[53], Citation[54]. Some patients who are apparently operated radically, however, suffer local relapses and greater tumour control is desirable. Present-day irradiation, which covers the primary tumour region and the regional lymph nodes, gives acute morbidity, especially when combined with cytostatics, and if the radiation load to adjacent organs, especially the small intestine and bladder, can be reduced, this will be an advantage. Chemotherapy is likely to be increasingly used in the light of recent studies showing a comparatively large number of patients with considerable down-staging and down-sizing, even if results from randomised trials are still limited Citation[55–59]. In that case it should also be possible to raise the dose delivered to the primary tumour target.
Although the risk of local recurrence after primarily combined irradiation and good surgery of a primarily operable rectal cancer is very low, the local recurrences occurring are a major clinical problem. In these cases it is almost impossible, using conventional radiotherapy, to provide further adequate supplementary irradiation which, combined with surgery, can facilitate cure. IORT or brachytherapy has been tried without its value being amenable to proof Citation[60], Citation[61]. Attempts are made with external radiotherapy, but in limited doses.
Clinical experience of proton beam therapy for rectal cancer
No proton irradiation has, to our knowledge, been given for primary rectal cancer, but a comparative IMXT-IMPT study is being planned in Boston.
Model studies
Irradiation for rectal cancer has for the most part been fairly standardised, for a long time without three-dimensional dose planning. Since both acute and long-term side-effects have been noted, increasing demands have been made for a better-defined target and more adequate radiotherapy. These demands are likely to be increased, not least because the trend favours combination with increasingly intensive cytostatic therapy for the achievement of better anti-tumour effect. Comparative dose planning studies have been made of various conventional techniques Citation[62]. The importance of IMRT has only recently been studied Citation[63]. One study, comparing protons with conventional irradiation for locally unresectable rectal cancer, found clear physical advantages and less risk of complications from the intestines Citation[64]. These differences were greatest for rectal cancers located high up, where the volume of small intestine is greater, but it is also essential for tumours located low down that an adequate radiation dose should be deliverable to the lateral lymph nodes up towards the internal iliac vessels.
Potential number of patients
About 15% of rectal cancers are primarily unresectable, and half of these have no metastases at diagnosis. These patients, then, numbering about 150 annually, are potential candidates for radiotherapy. In the SBU survey, prolonged irradiation to about 50 Gy was given to 21 patients, 91 on an annual basis. To these are added a number of cases of local recurrence which are also in need of more advanced radiotherapy in order to achieve a better outcome. About 50 such patients are judged eligible for radiotherapy. Since the median age for rectal cancer is relatively high, not all these 200 patients are expected to be eligible for protons; 150 patients annually is a more conservative estimate.
Further research needed
The tools available for planning at the time of the 1995 comparative model study Citation[64] were limited, and further model studies are needed. Needless to say, IMRT must then also be included in the comparison even if not yet used clinically Citation[65].
Apart from the above mentioned model studies, it is doubtful whether further knowledge can be obtained before there is a facility available. Patients can be irradiated at the centres which now have access to protons with a gantry system and acute toxicity recorded. When a clinical facility is available, a controlled study will be desirable, comparing conventional pre-operative radiotherapy with proton beam therapy, both being combined with cytostatics. The endpoint of the study should be local tumour control, acute toxicity and long-term survival.
Summary assessment
It is estimated that in the first instance 150 Swedish patients annually may be eligible for proton beam therapy. Treatment of this kind can then provide greater tumour control, at the same time as the acute and long-term side-effects can be limited.
References
- Cancer Incidence in Sweden. Epidemiologiskt Centrum 2003; www.sos.se.
- Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83: 2049–53
- Albertsson M. Chemoradiotherapy of esophageal cancer. Acta Oncol 2002; 41: 118–23
- Ask A, Albertsson M, Järhult J, Cavallin-Ståhl E. A systematic overview of radiation therapy effects in oesophageal cancer. Acta Oncol 2003; 42: 462–75
- Tai P, Van Dyk J, Yu E, Battista J, Stitt L, Coad T. Variability of target volume delineation in cervical esophageal cancer. Int J Radiat Oncol Biol Phys 1998; 42: 277–88
- Vrieze O, Haustermans K, De Wever W, Lerut T, Van Cutsem E, Ectors N, et al. Is there a role for FGD-PET in radiotherapy planning in esophageal carcinoma?. Radiother Oncol 2004; 73: 269–75
- Bedford JL, Viviers L, Guzel Z, Childs PJ, Webb S, Tait DM. A quantitative treatment planning study evaluating the potential of dose escalation in conformal radiotherapy of the oesophagus. Radiother Oncol 2000; 57: 183–93
- Nutting CM, Bedford JL, Cosgrove VP, Tait DM, Dearnaley DP, Webb S. A comparison of conformal and intensity-modulated techniques for oesophageal radiotherapy. Radiother Oncol 2001; 61: 157–63
- Wu VW, Sham JS, Kwong DL. Inverse planning in three-dimensional conformal and intensity-modulated radiotherapy of mid-thoracic oesophageal cancer. Br J Radiol 2004; 77: 568–72
- Tait DM. Multi-modality treatment in oesophageal cancer: a curse for radiotherapy progress. Radiother Oncol 2004; 73: 115–7
- Okawa T, Dokiya T, Nishio M, Hishikawa Y, Morita K. Multi-institutional randomized trial of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan. Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group. Int J Radiat Oncol Biol Phys 1999; 45: 623–8
- Koyama S, Tsujii H, Yokota H, Hotta S, Miyo Y, Fukutomi H, et al. Proton beam therapy for patients with esophageal carcinoma. Jpn J Clin Oncol 1994; 24: 144–53
- Tsunemoto H, Ishikawa T, Morita S, Kitagawa T, Tsujii H. Indications of particle radiation therapy in the treatment of carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 1992; 22: 321–4
- Isacsson U, Lennernäs B, Grusell E, Jung B, Montelius A, Glimelius B. Comparative treatment planning between proton and x-ray therapy in esophageal cancer. Int J Radiat Oncol Biol Phys 1998; 41: 441–50
- Graffman S, Jung B. Clinical trials in radiotherapy and the merits of high energy protons. Acta Radiol Ther Phys Biol 1970; 9: 1–23
- Möller TR, Brorsson B, Ceberg J, Frodin JE, Lindholm C, Nylen U, et al. A prospective survey of radiotherapy practice in Sweden. Acta Oncol ;42 2001; 2003: 387–410
- Talbäck M, Stenbeck M, Rosén M, Glimelius B. Cancer survival in Sweden. Acta Oncol 2003; 42: 637–59
- Jansen EP, Boot H, Verheij M, van de Velde CJ. Optimal locoregional treatment in gastric cancer. J Clin Oncol 2005; 23: 4509–17
- Janunger K, Hafström Lo, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in gastric cancer. Acta Oncol 2001; 40: 309–26
- Cunningham D, Allum WH, Stenning SP, Weeden S. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 2005: Abstr 4001.
- MacDonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–30
- Leong T, Willis D, Joon DL, Condron S, Hui A, Ngan SY. 3D conformal radiotherapy for gastric cancer–results of a comparative planning study. Radiother Oncol 2005; 74: 301–6
- Glimelius B. Has progress been made in gastrointestinal cancer treatment?. Acta Oncol 2002; 41: 115–7
- Smalley SR, Gunderson L, Tepper J, Martenson JA, Minsky BD, Willett C, et al. Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation. Int J Radiat Oncol Biol Phys 2002; 52: 283–93
- White RR, Tyler DS Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am 2004;13:675–84, ix–x.
- White RR, Xie HB, Gottfried MR, Czito BG, Hurwitz HI, Morse MA, et al. Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer. Ann Surg Oncol 2005; 12: 214–21
- Yamaguchi K, Nakamura K, Kobayashi K, Nakano K, Konomi H, Mizumoto K, et al. ERT following IORT improves survival of patients with resectable pancreatic cancer. Hepatogastroenterology 2005; 52: 1244–9
- Ihse I, Andersson R, Ask A, Ewers SB, Lindell G, Tranberg KG. Intraoperative radiotherapy for patients with carcinoma of the pancreas. Pancreatology 2005;5:438–43.
- Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, et al. Adjuvant chemotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001; 358: 1576–85
- Glimelius B. Pancreatic and hepatobiliary cancers: adjuvant therapy and management of inoperable disease. Ann Oncol 2000; 11: 153–9
- Wilkowski R, Thoma M, Weingandt H, Duhmke E, Heinemann V. Chemoradiation for ductal pancreatic carcinoma: principles of combining chemotherapy with radiation, definition of target volume and radiation dose. JOP 2005; 6: 216–30
- Snady H, Bruckner H, Cooperman A, Paradiso J, Kiefer L. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial. Cancer 2000; 89: 314–27
- Willett CG, Czito BG, Bendell JC, Ryan DP. Locally advanced pancreatic cancer. J Clin Oncol 2005; 23: 4538–44
- Imamura M, Doi R, Imaizumi T, Funakoshi A, Wakasugi H, Sunamura M, et al. A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer. Surgery 2004; 136: 1003–11
- Zurlo A, Lomax A, Hoess A, Bortfeld T, Russo M, Goitein G, et al. The role of proton therapy in the treatment of large irradiation volumes: a comparative planning study of pancreatic and biliary tumors. Int J Radiat Oncol Biol Phys 2000; 48: 277–88
- Ragnhammar P, Hafström Lo, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 2001; 40: 282–308
- Glimelius B. Palliative treatment of patients with colorectal cancer. Scand J Surg 2003; 92: 74–83
- Johnson PJ. Primary liver tumours. Oxford Textbook of Oncology2nd edn, RL Souhami IT, P Hohenberger, J-C Horiot. Oxford University Press, Oxford 2002; 1627–40
- Glimelius B. Liver metastases. Oxford Textbook of Oncology2nd edn, RL Souhamiit, P Hohenberger, J-C Horiot. Oxford University Press, Oxford 2002; 1663–80
- Ingold JA, Reed GS, Kaplan HS, Bagshaw MA. Radiation hepatitis. Am J Roentgenol 1965; 93: 200
- Mohiuddin M, Chen E, Ahmad N. Combined liver radiation and chemotherapy for palliation of hepatic metastases from colorectal cancer. J Clin Oncol 1996; 14: 722–8
- Park HC, Seong J, Han KH, Chon CY, Moon YM, Suh CO. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002; 54: 150–5
- Blomgren H, Lax I, Göranson H, Kræpelien T, Nilsson B, Näslund I, et al. Radiosurgery for tumors in the body: Clinical experience using a new method. J Radiosurg 1998; 1: 63–75
- Matsuzaki Y. The efficacy of powerful proton radiotherapy for hepatocellular carcinoma – Long term effects and QOL. Ann Cancer Res Ther 1998; 8: 9–17
- Matsuzaki Y, Osuga T, Saito Y, Chuganji Y, Tanaka N, Shoda J, et al. A new, effective, and safe therapeutic option using proton irradiation for hepatocellular carcinoma. Gastroenterology 1994; 106: 1032–41
- Kawashima M, Furuse J, Nishio T, Konishi M, Ishii H, Kinoshita T, et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005; 23: 1839–46
- Tokuuye KYA, Hashimoto T, et al. Clinical results of proton radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2003; 383: (abstr)
- Kato H, Tsujii H, Miyamoto T, Mizoe JE, Kamada T, Tsuji H, et al. Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys 2004; 59: 1468–76
- Glimelius B, Grönberg H, Järhult J, Wallgren A, Cavallin-Ståhl E. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol 2003; 42: 476–92
- Glimelius B. Balancing gains and costs in radiation therapy of rectal cancer. Dis Colon Rectum 2005; in press.
- Birgisson H, Påhlman L, Gunnarsson U, Glimelius B. Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 2005;.
- Marijnen CA, van de Velde CJ, Putter H, van den Brink M, Maas CP, Martijn H, et al. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2005; 23: 1847–58
- Jansson-Frykholm G, Påhlman L, Glimelius B. Combined chemo- and radiotherapy vs radiotherapy alone in the treatment of primary, nonresectable adenocarcinoma of the rectum. Int J Radiat Oncol Biol Phys 2001; 50: 427–34
- Glimelius B. Chemoradiotherapy for rectal cancer-is there an optimal combination?. Ann Oncol 2001; 12: 1039–45
- Rodel C, Grabenbauer GG, Papadopoulos T, Hohenberger W, Schmoll HJ, Sauer R. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003; 21: 3098–104
- Chan AK, Wong A, Jenken D, Heine J, Buie D, Johnson D. Posttreatment TNM staging is a prognostic indicator of survival and recurrence in tethered or fixed rectal carcinoma after preoperative chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2005; 61: 665–77
- Diaz-Gonzalez JA, Calvo FA, Cortes J, de La Mata D, Gomez-Espi M, Lozano MA, et al. Preoperative chemoradiation with oral tegafur within a multidisciplinary therapeutic approach in patients with T3-4 rectal cancer. Int J Radiat Oncol Biol Phys 2005; 61: 1378–84
- Chapet O, Romestaing P, Mornex F, Souquet JC, Favrel V, Ardiet JM, et al. Preoperative radiotherapy for rectal adenocarcinoma: Which are strong prognostic factors?. Int J Radiat Oncol Biol Phys 2005; 61: 1371–7
- Hofheinz RD, von Gerstenberg-Helldorf B, Wenz F, Gnad U, Kraus-Tiefenbacher U, Muldner A, et al. Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer. J Clin Oncol 2005; 23: 1350–7
- Wiig JN, Poulsen JP, Tveit KM, Olsen DR, Giercksky KE. Intra-operative irradiation (IORT) for primary advanced and recurrent rectal cancer. a need for randomised studies. Eur J Cancer 2000; 36: 868–74
- Alektiar KM, Zelefsky MJ, Paty PB, Guillem J, Saltz LB, Cohen AM, et al. High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 2000; 48: 219–26
- Frykholm-Jansson G, Isacsson U, Sintorn K, Montelius A, Jung B, Påhlman L, et al. Preoperative radiotherapy in rectal carcinoma-aspects of adverse effects and radiation technique. Int J Radiat Oncol Biol Phys 1996; 35: 1039–1048
- Duthoy W, De Gersem W, Vergote K, Boterberg T, Derie C, Smeets P, et al. Clinical implementation of intensity-modulated arc therapy (IMAT) for rectal cancer. Int J Radiat Oncol Biol Phys 2004; 60: 794–806
- Isacsson U, Montelius A, Jung B, Glimelius B. Comparative treatment planning between proton and x-ray therapy in locally advanced rectal cancer. Radiother Oncol 1996; 41: 263–272
- Suit H, Goldberg S, Niemierko A, Trofimov A, Adams J, Paganetti H, et al. Proton beams to replace photon beams in radical dose treatments. Acta Oncol 2003; 42: 800–8