Radiation Oncology (London, England)

Radiat Oncol. 6: 177-177

Radiotherapy and "new" drugs-new side effects?

Maximilian Niyazi¹, Cornelius Maihoefer¹, Mechthild Krause², Claus Rödel³, Wilfried Budach⁴, Claus Belka¹

1. Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 München, Germany

2. Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany

3. Klinik für Strahlentherapie und Onkologie, Johann Wolfgang Goethe Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

4. Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Heinrich Heine Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany

Copyright ©2011 Niyazi et al; licensee BioMed Central Ltd.

DOI: 10.1186/1748-717X-6-177

Published online: 21 December 2011

Abstract

Background and purpose

Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments.

Materials and methods

Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms.

Results

Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported.

Conclusions

The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.

Background and purpose

Several new anti-cancer drugs have recently entered clinical practice in oncology. Among those, especially targeted drugs are promising therapeutic candidates with a comparatively low toxicity profile. At present, these drugs are often applied in palliative treatment situations for metastasized diseases. In addition, targeted agents are a substantial part of many multimodal oncologic treatment schedules. Thus the risk of parallel use of both radiotherapy and targeted drug is given. With few exceptions, the toxicity of any combination of targeted drugs with radiotherapy has not yet been studied in detail.

Key cellular signalling pathways [1] are responsible for the response of normal tissue and tumour cells to radiation therapy [2]. Although some of the anti-cancer targets are specific for neoplastic signalling, there is considerable overlap between neoplastic signalling and normal cellular signalling. In this regard, several putative interactions with radiation triggered signalling in normal issues exist and thus [3,4] influences of targeted drugs on normal tissue reactions cannot be excluded [5-7].

The present article reviews the existing data on the toxicity profile and efficacy (if available) of targeted drugs when applied concurrently to radiotherapy.

Methods and materials

Using the following MESH headings and combinations of these terms, pubmed database was searched for randomized, prospective and retrospective trials as well as case reports (all sample sizes were considered):

1. Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab

2. Radiotherapy AND bevacizumab

3. Radiotherapy AND sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus

4. Radiotherapy AND thalidomide/lenalidomide.

5. Radiotherapy AND erythropoietin

For citation crosscheck, the ISI web of science database was used employing the same search terms. A focus was put on prospective or phase I/II trials; if available, some smaller case studies or case reports were included if higher toxicities were reported.

In general, grade III + IV toxicities are reported. For cetuximab, focus was set on larger phase III trials and those reporting trials specifically reporting toxicities. In addition, key reviews focusing on the use of targeted drug in oncology were screened in order to identify clinically relevant drugs [8].

Results

Antibodies

Cetuximab

Cetuximab is a monoclonal chimeric antibody directed against the epidermal growth-factor receptor (EGF-R). It has first been approved for treatment of locally advanced or metastatic colorectal cancer (k-ras wildtype) refractory to irinotecan [9]. Regarding radiotherapy, it has been approved for head-and-neck cancer as an alternative to concomitant chemotherapy [10]; in the given phase III trial overall survival of patients who were treated by radiotherapy and cetuximab was improved compared to patients who underwent radiotherapy alone. Cetuximab also has a proven efficacy in locally advanced or metastatic head-and-neck cancer in combination with 5-FU/cisplatin [11].

Thus several pre-clinical and clinical studies have provided evidence for the efficacy of cetuximab in combination with radiotherapy [12-17]. Nevertheless, several reports are available pointing to increased skin toxicity after combining cetuximab with radiotherapy [18-27] (a complete overview is given in Table 1). The initial publication on the combined use by Bonner and colleagues reported an increased incidence of an acneiform rash [10]. However, in single cases more severe complications occurred [19]. A recent retrospective matched-pair evaluation of acute toxicity during cis-platinum-based radio-chemotherapy versus radiotherapy with simultaneous cetuximab treatment showed significantly higher grade 3 oral mucositis and dermatitis as well as a higher risk of weight loss (> 10%) and of enteral feeding requirement in the cetuximab-group. However, this may be outweighed by the higher risk of haematological toxicity by radio-chemotherapy. In keeping with this, higher compliance rate with less treatment interruptions in the cetuximab-treated group was described [26]. In trials on thoracic [28,29] or pelvic radiotherapy with cetuximab increased rates of skin toxicity were not observed.

See full tableTable 1. Studies on monoclonal EGFR antibodies

No other risks regarding additional or increased side effects concerning connective tissue, CNS [30-32] or peripheral nerves have been described so far in small early-phase clinical trials.

Panitumumab

Similar to cetuximab, panitumumab is a monoclonal antibody directed against EGF-R with a putatively higher affinity and less toxicity due to its non-chimeric design. It has been approved for stage IV colorectal cancer refractory to FOLFOX or FOLFIRI [33].

Only data from a single phase I study [34] and a single phase II trial described effects of a combination of panitumumab with a 5-FU/oxaliplatin-containing radio-chemotherapy for rectal cancer [35]. Pre-clinical data suggest a comparable efficacy to cetuximab [36]. Concerning toxicity, no additional toxicity was observed when combined with radiotherapy. The phase II trial reported one toxic death from diarrhea and a relatively high rate of grade III/IV diarrhea (39%) compared to the classical CAO/ARO/AIO-94 trial [37]. However, based on the design of the trial it is not possible to precisely attribute the side effects to any of the components of the given protocol.

Nimotuzumab

Nimotuzumab is another humanized therapeutic monoclonal antibody directed against EGF-R not yet been approved by the authorities in Europe. There are three small phase I trials testing radiotherapy and nimotuzumab in head-and-neck cancer as well as NSCLC patients; an increased rate of skin toxicity was observed [38-40]. The other larger phase II trial by Rodríguez and colleagues was prospectively randomized and 106 head-and-neck cancer patients were included [38]. No grade III or IV toxicity has been observed.

The data available suggest that the combination of cetuximab with radiation may lead to an increased rate of mucosal- and skin toxicity when applied together with radiation for the treatment of head-and-neck cancer. No such problems have been reported in other organ regions. It is unclear in how far this is an epitope-specific side effect-only limited data are available regarding similar effects after the combined use of panitumumab and nimotuzumab.

Anti -Her2/neu antibody trastuzumab

Trastuzumab is a humanized monoclonal antibody directed against the epidermal growth-factor-receptor Her-2/neu. It is approved for the treatment of metastatic her-2/neu-positive breast cancer as well as for the adjuvant treatment of her-2/neu-positive breast cancer in combination with chemotherapy [41-44].

Cardiac toxicity is a rare, but well described adverse effect of trastuzumab-especially with or after the treatment with anthracyclins [45-47]. As cardiac toxicity is also of concern in thoracic radiotherapy, the question of an increased toxicity has been raised. The largest trial focusing on side effects of the combined use of radiotherapy and trastuzumab is the phase III NLCCTG trial N9831 for adjuvant trastuzumab and radiotherapy including 1503 patients [48]. The trial did not reveal any significant differences in toxicity regarding skin, pneumonitis or cardiac events. Also, a French multicentric study [49] including 146 patients did not observe an increased cardiac toxicity. Another study retrospectively investigated the combinational approach of trastuzumab and radiotherapy including the internal mammary lymph nodes [50]. Again, no increased cardiac toxicity has been observed.

Thus, at present there are no strong indicators for an increased cardiac toxicity. However, follow-up periods are only sufficient for an estimation of early cardiac toxicity caused by trastuzumab, but not for an in-depth assessment of late radiation-induced cardiac effects.

Altogether, the current data suggest that the use of trastuzumab in a close time frame with radiotherapy may be safe. However, the reported studies might still reveal an increased cardiac toxicity, as minor vascular changes might lead to an increased mortality in long-term follow-up [51].

Bevacizumab

Bevacizumab is a humanized monoclonal antibody against the vascular endothelial growth-factor (VEGF). So far, bevacizumab has been approved for the treatment of metastatic colorectal carcinoma, in combination with standard chemotherapy (5-FU, irinotecan, oxaliplatin or capecitabine). Bevacizumab has been approved for the treatment of metastatic non-squamous-cell bronchial carcinoma, for the treatment of renal cell cancer and for the treatment of glioblastoma multiforme (US only). The FDA has withdrawn the approval for first line treatment of metastatic HER-2/neu-negative breast cancer-however, the drug still is approved in Europe.

The most common side effects of bevacizumab alone include impaired wound healing, hypertension, bleeding problems as well as an increased risk of thromboembolic events.

One of the first publications to describe an increased risk of combining bevacizumab with radiotherapy reported on patients with ischemic bowel complications after the administration of radiotherapy followed by bevacizumab [52].

A phase II study combining neoadjuvant bevacizumab, capecitabine and radiotherapy for locally advanced rectal cancer revealed an increased rate of wound complications such as delayed healing and wound dehiscence [53]. The data are in line with a number of similar reports and case studies, supporting the interpretation that the combined use of bevacizumab with neoadjuvant radiotherapy is associated with an increased risk of postoperative complications [54-57]. However, this interpretation is not homogenously supported by all available data [58-61]. In terms of tumour response, the rate of pathological complete responses seems to be enhanced [53].

The use of bevacizumab, capecitabine and radiotherapy in patients with locally advanced pancreatic cancer was associated with an increased rate GI-bleeding and ulcerations (12%) [62]. These complications preferentially occurred in patients with a mucosal infiltration of the tumour. In a consecutive study -after excluding patients with mucosa infiltration-no such side effects were reported [63]. A similar study reported the combination of radiotherapy with bevacizumab-partly in a neoadjuvant setting- as "feasible" [64].

The combination of radiotherapy with simultaneous administration of bevacizumab was also tested for lung cancer [65,66]. In this setting, the occurrence of severe fistula leading to a discontinuation of both trials has been described [66].

In case of breast cancer the parallel combination of radiotherapy and bevacizumab had no significant side-effects in regard to lung and skin toxicity [65].

The treatment of malignant tumours of the brain has been subject to a variety of studies combining radiotherapy with bevacizumab with or without temozolomide; regarding progression-free survival, these trials suggest a benefit of the combined use [67]. No intra-cerebral bleeding has been reported, however cases of wound dehiscence of the previous operation have been documented [68-70]. A collection of case reports points towards increased late toxicity such as optic neuropathy and a single case of Brown-Séquard syndrome after a combination of bevacizumab with radiotherapy [71]. (a complete overview is given in Table 2).

See full tableTable 2. Studies on VEGF antibodies.

Altogether, the combined use of bevacizumab and radiotherapy seems to be associated with a considerable risk of side effects (wound dehiscence, bleeding, fistula or GI complications). However, in selected cases the combination was feasible and even favourable concerning overall survival (retrospective) [69] and progression-free survival [72].

Anti CD20 monoclonal antibody-rituximab

Rituximab is a monoclonal antibody directed against the CD20 antigen. It was initially developed and approved as a targeted agent for the treatment of CD20-positive non-Hodgkin lymphoma. In this setting, rituximab is mostly used in combination with chemotherapy (e. g. CHOP). Apart from the use of rituximab in oncology, its use has been extended to the treatment of refractory autoimmune diseases (e. g. rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and idiopathic thrombocytopenic purpura among others).

The application of rituximab in combination with or shortly before/after radiotherapy of non-Hodgkin lymphoma has been prospectively studied [73-75]. So far no significant additional toxicities have been reported. All side effects seen in the trials have been attributed to the individual therapeutic modalities respectively [76]. Thus, at present the combination of rituximab with radiation does not seem to harbour any relevant risks.

Small molecules/tyrosine-kinase inhibitors (TKI's)

TKI's are small molecules able to pass the cell membrane and to inhibit intracellular tyrosine kinases of several growth factor receptors. Relevant examples are sunitinib, sorafenib, erlotinib or gefitinib. At present, TKI are used for diverse cancer entities and various clinical settings. Key indications are: Metastasized lung cancer/renal cell cancer/pancreatic cancer, locally advanced and metastatic breast cancer as well as hepatocellular carcinoma.

Up to now, no TKI has been approved for the simultaneous use with radiotherapy.

All toxicity data on combined toxicity are limited to case reports or studies with small numbers of patients. The clinical indications and the most common adverse effects of clinically used TKI's are summarized in Table 3.

See full tableTable 3. Studies on small molecules.

When using sunitinib or sorafenib alone, mainly diarrhea, hypertension, fatigue, hand-foot syndrome, bleeding and hematotoxicity may occur as side effects. Concerning combined use with radiotherapy, one case report described a lethal small bowel perforation after 1x 8 Gy in a palliative setting, sorafenib had been stopped 2 days before and three days after radiotherapeutic treatment [77]. In another case, a lethal bronchial fistula occurred after radiation of the mediastinum [78]; as this phenomenon has been observed after sunitinib alone [79] no definite causality can be deduced. Furthermore, elevated bone-marrow toxicity was observed if large volumes of bones or liver were radiated; a phase I study concluded to avoid the combination with sunitinib when radiating volumes of more than 6 ccm of the liver. A dose reduction of sunitinib was advised for the following phase II study [80].

In patients with cerebral metastases increased intracerebral bleeding has been reported, this appears to happen with or without radiotherapy [81].

Concerning the simultaneous use of gefitinib/erlotinib and radiotherapy one case of fatal diarrhea after combining erlotinib with RT in the abdomen (2x8 Gy, q1w) has been reported [82]. And again, in patients with cerebral metastases increased intracerebral bleeding has been reported, however, this appears to happen with or without radiotherapy [83].

As long as no reliable data concerning the safety of the combination of TKI's and radiotherapy are available, such therapies should be used very carefully, especially if the above reported organs received relevant radiation doses. So far it is unclear if the increased intracerebral bleeding rates are induced by the combined treatment or by the drug alone. However, because of the severity of this adverse effect, special caution is warranted for combined treatment schedules. The same applies for tumours that tend to bleed outside of the brain. Radiotherapy in the abdomen or the pelvis together with TKI's might lead to an increased toxicity, including the occurrence of ulcera and bleeding.

mTOR inhibitors

According to pre-clinical data, an improvement of tumour growth by simultaneous administration of temsirolimus with radiotherapy seems possible [84-86]. However, the only study on long-term local tumor control revealed no beneficial effect regarding the combined treatment [84]. Preclinical data show an inhibition of vascular growth when combining everolimus with radiation, however a direct radio-sensitizing effect could not be consistently shown [85,86]. A recent study [87] showed evidence for a suppressed dsDNA break repair by everolimus.

Concerning toxicity, there is one phase I study using temsirolimus with topotecan in recurrent gynaecological malignancies [88]. Dose-limiting toxicity of this combination was myelo-suppression. Although this toxicity cannot be attributed to temsirolimus, we advise caution when combining mTOR-inhibitors with concomitant or sequential radiotherapy, especially if large volumes of bone are in-field as the latter is already known to potentially cause myelo-suppression.

Nevertheless there are no sufficient clinical data to adequately judge the risks and potential benefits of a combined use of mTOR-inhibitors with radiotherapy. As long as this is the case, it can be assumed that-similar to anti-angiogenic substances-the combinational use may lead to wound healing deficits, increased bleeding and thrombosis.

Lenalidomide/thalidomide

Data on available studies combining radiotherapy and lenalidomide or thalidomide treatment are shown in Table 4. Thalidomide was initially used and approved as sedative drug until the early 1960s when it became clear that the intake of "Contergan" during pregnancy could lead to severe deformities. It was only in the late 1990s that thalidomide was rediscovered for its anti-angiogenic properties in cancer therapy [89]. Thalidomide is clinically used in the treatment of multiple myeloma; other areas of possible clinical use and ongoing clinical trials include leprosy, erythema nodosum leprosum and myelodysplastic syndrome.

See full tableTable 4. Studies on thalidomide and derivatives.

The most common side effects of thalidomide-besides somnolence-are thromboembolic events as well as peripheral polyneuropathy.

In vitro studies with cells of squamous cell carcinoma and of multiple myeloma showed no evidence for any radio-sensitizing quality of thalidomide. However, a radio-sensitizing effect has been observed in normal hematopoietic bone marrow [90]. Experiments in mice showed thalidomide induced tumour re-oxygenation pointing to a possible radio-sensitizing effect in vivo [91]. Experiments in rats indicate that thalidomide might be protective against radiation-induced proctitis when given 7 days after a single-RT [92].

In humans, thalidomide has been tested in combination with radiotherapy in phase I-III studies. Most data exist for radiation of the CNS combined with the administration of thalidomide.

The largest study so far was conducted by Knisely and co-workers [93]. In this phase III study 183 patients with multiple cerebral metastases were randomized for palliative WBRT (37,5 Gy in 15 fx) vs. WBRT (same dose and number of fractions) with thalidomide. In this study, only the known side effects of thalidomide occurred in the usual frequency. Hints to a possible interaction with radiotherapy have not been reported. Nearly half of the patients discontinued the study in the thalidomide arm due to side effects. The major limiting side effect was somnolence [93].

In malignant glioma, thalidomide was used in combination with radiotherapy or radiotherapy plus temozolomide in primary or recurrent settings [94]. Intratumoural bleeding and thromboembolic complications have been reported. However, the rate of complications was not higher than the reported rates for thalidomide alone [95-97].

Other studies, combining radiotherapy of soft tissue/bone metastasis as well as pelvic tumours with thalidomide simultaneously or sequentially revealed no evidence for increased risks of acute or late side effects [99].

However, a single study using radiotherapy (66 Gy in 33 fx) combined with vinorelbine and thalidomide in NSCLC stage III was abrogated after 10 patients due to side effects (thromboembolic, 1 bradycardia II°) [100]. As in this study only known side effects of thalidomide occurred, it still remains unclear whether radiation including the lung or the heart leads to increased side effects when combined with thalidomide.

Altogether the combination of thalidomide with simultaneous or sequential RT does not seem to be critical. Only in cases when large volumes of the heart or the lung are exposed, a certain level of cautiousness should be advised.

Lenalidomide

Lenalidomide is a derivative of thalidomide. Thus, the anti-angiogenic effect and the adverse effects are to a large extent similar to thalidomide. However, it largely lacks the sedative side effect, making it better tolerable for patients. Leukopenia and thrombocytopenia have also been reported.

In Europe and the US it is only approved in combination with dexamethasone for the treatment of multiple myeloma as 2nd line therapy. There is only very limited data regarding the combination of lenalidomide and radiotherapy. A single phase I trial [101] in glioblastoma used lenalidomide with RT (60 Gy, 30 fx). Thromboembolic events, pneumonitis and elevation of transaminases have been reported. The maximal tolerable dose was reported to be 15 mg/m², corresponding to the respective dose for monotherapy. Being chemically similar to thalidomide and having a similar profile of side effects, one can indirectly assume a similar pattern of interaction with radiation.

Imatinib

Imatinib is a tyrosine-kinase inhibitor (TKI) of bcr-abl, PDGFR alpha/beta and c-kit. The first successful clinical application of imatinib was in chronic myeloid leukaemia as the bcr-abl-fusion gene plays a crucial role in this disease. As GIS-tumours display a high number of c-kit-mutations, they are currently also treated with imatinib. Imatinib alone is usually well tolerated. Known adverse effects are diarrhea, nausea, vomiting, erythema, edema or the increase of transaminases; leukopenia or thrombopenia usually occur only in leukemic diseases. Grade III-IV toxicity is reported in fewer than 10% of the patients.

Several in vitro experiments showed a putative radio-sensitizing effect of imatinib [102]. Additionally it has been shown, that the proliferation of fibroblasts can be slowed down in vitro by imatinib [103]. This leads to speculations about a potential protective effect of imatinib with regard to radiation-induced fibrosis. Three in vivo experiments support this hypothesis [104-106].

Regarding the clinical use of radiotherapy and imatinib only limited data is available. Imatinib has been used in recurrent glioma after radiotherapy (one 112-patient-trial with imatinib alone after radiotherapy and three 30-40-patient trials in combination with hydroxyurea). Unexpected adverse effects pointing to an increased toxic profile for the sequential use have not been reported [107-110]. In another trial, 27 patients have been treated with imatinib after radiotherapy in prostate cancer without unexpected side effects [111].

There is only one clinical phase I study regarding the simultaneous application of imatinib to radiotherapy (55.8 Gy in 21 fx) in children with brainstem-tumours. Retrospectively compared to a similar collective, subclinical bleeding seemed increased, but no other unexpected toxicities have been reported [112]. Additionally, there are two case reports for the combinational approach [113,114]. Again, in both cases no unexpected side effects have been reported.

Altogether, sequential application of imatinib with radiotherapy might not bear an increased risk for adverse effects. For the simultaneous application the limited amount of data does not allow a valid judgement about potentially increased side effects.

Discussion

Radiotherapy combined with molecular targeted agents may be associated with unforeseen yet specific toxicities. Based on putative interactions of radiotherapy and the given agent with the targeted signalling cascade, any interactions may not only interfere with any anti-tumour efficacy but may also increase side effects. On the other hand, also radio-protective effects for the tumour are possible if new combined treatment schedules are used. Examples are cetuximab in multimodal radio-chemotherapy regimens for rectal cancer [115-119] or erythropoietin, which was thought to increase the haemoglobin level in head-and-neck cancer patients, but decreased survival most likely due to EPO-receptors on the cancer cells which were not known as a proliferative factor for tumours before [120,121].

However, there are still clinical situations where patients may benefit from the application of a targeted drug in combination with radiotherapy outside approved treatment schedules or clinical trials. The best example is a palliative systemic treatment for disseminated metastases and at the same time an indication for palliative or symptomatic radiotherapy of a single region. In this case, interruption of the systemic treatment may lead to systemic progression under radiotherapy. The present work aims to provide a helpful tool for clinical treatment decisions in such situations.

At present, only limited data is available on the interactions of targeted agents and radiotherapy. Data on toxicity are mostly derived from small case series, retrospective analyses or at best cohort and few randomized studies. For most substances, mild complications are reported-however, rarely exceptional fatal complications have been documented.

Overall, for any of the drugs mentioned here indications for a combination with radiotherapy have to be made cautiously (is a sequential treatment possible?). Furthermore, patients have to be questioned very specifically regarding the intake of targeted drugs. Frequently patients have been advised that these drugs are not "classical cytostatic drugs". Thus patients often do not self-report intake of targeted drugs when counselled for radiotherapy.

Simultaneous applications of targeted drugs during radiotherapy in non-established schedules should be an exception and reserved for those patients where the systemic tumour situation mandates rapid treatment. Whenever possible, large volume radiotherapy plus targeted drugs should be avoided. These remarks are especially important for hypo-fractionated regimens where high toxicities have been observed (in part with fatal consequences).

In conclusion, molecular targeted agents should only very cautiously in combination with radiotherapy. A meticulous and careful balancing of benefits and risks of increased toxicity is advised.

Abbreviation

CNS: central nervous system; CT: chemotherapy; DFS: disease-free survival; EBRT: external beam radiotherapy; EGFRi: epidermal growth factor receptor inhibitor; IGRT: image-guided radiotherapy; KPS: Karnofsky Performance Status; mo: months; mPFS: median progression-free survival; MST: median survival time; MTD: maximum tolerated dose; mTOR: mammalian target of rapamycin.; mTTP: median time to progression; NTD: normalized total dose; OS: overall survival; PFS-6/-12: progression-free survival rate at 6/12 months; pt(s): patient(s); PTEN: phosphatase and tensin homolog deleted on Chromosome 10; QOL: quality of life; RCHT: radio-chemotherapy; RT: radiotherapy; VEGF-R: vascular endothelial growth factor receptor; WBRT: whole brain radiotherapy; wk: week.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MN and CM performed the literature search and wrote the manuscript. MK, CMR and WB performed critical revision. CB participated in the conception as well as the preparation of the manuscript. All authors read and approved the final manuscript.

Articles from Radiation Oncology (London, England) are provided here courtesy of BioMed Central

PMC Copyright Notice

The articles available from the PMC site are protected by copyright, even though access is free. Copyright is held by the respective authors or publishers who provide these articles to PMC. Users of PMC are responsible for complying with the terms and conditions defined by the copyright holder.

Users should assume that standard copyright protection applies to articles in PMC, unless an article contains an explicit license statement that gives a user additional reuse or redistribution rights. PMC does not allow automated/bulk downloading of articles that have standard copyright protection.

See the copyright notice on the PMC site, https://www.ncbi.nlm.nih.gov/pmc/about/copyright/, for further details and specific exceptions.

References

Streffer C. Strong association between cancer and genomic instability. Radiat Environ Biophys. 2010;49(2):125–131

Brahme A, Lind BK. A systems biology approach to radiation therapy optimization. Radiat Environ Biophys. 2010;49(2):111–124

Hille A, Gruger S, Christiansen H, Wolff HA, Volkmer B, Lehmann J, Dorr W, Rave-Frank M. Effect of tumour-cell-derived or recombinant keratinocyte growth factor (KGF) on proliferation and radioresponse of human epithelial tumour cells (HNSCC) and normal keratinocytes in vitro. Radiat Environ Biophys. 2010;49(2):261–270

Jacob P, Ron E. Late health effects of ionizing radiation: bridging the experimental and epidemiological divide. Radiat Environ Biophys. 2010;49(2):109–110

Miller AC, Cohen S, Stewart M, Rivas R, Lison P. Radioprotection by the histone deacetylase inhibitor phenylbutyrate. Radiat Environ Biophys. 2011;50(4):585–596

Soucy KG, Attarzadeh DO, Ramachandran R, Soucy PA, Romer LH, Shoukas AA, Berkowitz DE. Single exposure to radiation produces early anti-angiogenic effects in mouse aorta. Radiat Environ Biophys. 2010;49(3):397–404

Wolff HA, Rolke D, Rave-Frank M, Schirmer M, Eicheler W, Doerfler A, Hille A, Hess CF, Matthias C, Rodel RM, et al. Analysis of chemokine and chemokine receptor expression in squamous cell carcinoma of the head and neck (SCCHN) cell lines. Radiat Environ Biophys. 2011;50(1):145–154

Amir E, Seruga B, Martinez-Lopez J, Kwong R, Pandiella A, Tannock IF, Ocana A. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29(18):2543–2549

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–345

Bonner Ja, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England journal of medicine. 2006;354:567–578

Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–1127

Harari PM, Huang SM. Modulation of molecular targets to enhance radiation. Clin Cancer Res. 2000;6(2):323–325

Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Raju U, Milas L, Chen DJ, Kehlbach R, Rodemann HP. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem. 2005;280(35):31182–31189

Bonner Ja, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer Sa, Zhu J. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. The Lancet Oncology. 2010;11:21–28

Gurtner K, Deuse Y, Butof R, Schaal K, Eicheler W, Oertel R, Grenman R, Thames H, Yaromina A, Baumann M, et al. Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression. Radiother Oncol. 2011;99(3):323–330

Krause M, Gurtner K, Deuse Y, Baumann M. Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: differences between antibodies and TK inhibitors. Int J Radiat Biol. 2009;85(11):943–954

Toulany M, Dittmann K, Kruger M, Baumann M, Rodemann HP. Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol. 2005;76(2):143–150

Budach W, Bolke E, Homey B. Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med. 2007;357(5):514–515

Berger B, Belka C. Severe skin reaction secondary to concomitant radiotherapy plus cetuximab. Radiation oncology (London, England). 2008;3:5

Bölke E, Gerber PA, Lammering G, Peiper M, Müller-Homey A, Pape H, Giro C, Matuschek C, Bruch-Gerharz D, Hoffmann TK, et al. Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab. Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft [et al]. 2008;184:105–110

Billan S, Abdah-Bortnyak R, Kuten A. Severe desquamation with skin necrosis: a distinct pattern of skin toxicity secondary to head and neck irradiation with concomitant cetuximab. Isr Med Assoc J. 2008;10(3):247

Pryor DI, Porceddu SV, Burmeister BH, Guminski A, Thomson DB, Shepherdson K, Poulsen M. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2009;90:172–176

Giro C, Berger B, Bölke E, Ciernik IF, Duprez F, Locati L, Maillard S, Ozsahin M, Pfeffer R, Robertson aG, et al. High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2009;90:166–171

Koutcher LD, Wolden S, Lee N. Severe Radiation Dermatitis in Patients With Locally Advanced Head and Neck Cancer Treated With Concurrent Radiation and Cetuximab. American journal of clinical oncology. 2009;32:472–476

Studer G, Brown M, Salgueiro EB, Schmückle H, Romancuk N, Winkler G, Lee SJ, Sträuli A, Kissling B, Dummer R, et al. Grade 3/4 Dermatitis in Head and Neck Cancer Patients Treated with Concurrent Cetuximab and IMRT. International journal of radiation oncology, biology, physics. 2011;81(1):110–117

Walsh L, Gillham C, Dunne M, Fraser I, Hollywood D, Armstrong J, Thirion P. Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC). Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2011;98:38–41

Kanakamedala MR, Packianathan S, Vijayakumar S. Lack of Cetuximab induced skin toxicity in a previously irradiated field: case report and review of the literature. Radiat Oncol. 2010;5:38

Hallqvist a, Wagenius G, Rylander H, Brodin O, Holmberg E, Lödén B, Ewers S-B, Bergström S, Wichardt-Johansson G, Nilsson K, et al. Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite--a phase II study from the Swedish Lung Cancer Study Group. Lung cancer (Amsterdam, Netherlands). 2010;71:166–172

Hughes S, Liong J, Miah A, Ahmad S, Leslie M, Harper P, Prendiville J, Shamash J, Subramaniam R, Gaya A, et al. A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2008;3:648–651

Horisberger K, Treschl A, Mai S, Barreto-Miranda M, Kienle P, Ströbel P, Erben P, Woernle C, Dinter D, Kähler G, et al. Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a Phase II MARGIT trial. International journal of radiation oncology, biology, physics. 2009;74:1487–1493

Safran H, Suntharalingam M, Dipetrillo T, Ng T, Doyle LA, Krasna M, Plette A, Evans D, Wanebo H, Akerman P, et al. Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. International journal of radiation oncology, biology, physics. 2008;70:391–395

Hasselbalch B, Lassen U, Hansen S, Holmberg M, Sorensen M, Kosteljanetz M, Broholm H, Stockhausen MT, Poulsen HS. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 12(5):p. 508–516

Giusti RM, Shastri K, Pilaro AM, Fuchs C, Cordoba-Rodriguez R, Koti K, Rothmann M, Men AY, Zhao H, Hughes M, et al. U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res. 2008;14(5):1296–1302

Wirth LJ, Allen aM, Posner MR, Haddad RI, Li Y, Clark JR, Busse PM, Chan aW, Goguen La, Norris CM, et al. Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2010;21:342–347

Pinto C, Di Fabio F, Maiello E, Pini S, Latiano T, Aschele C, Garufi C, Bochicchio A, Rosati G, Aprile G, et al. Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study). Ann Oncol. 2011;22(11):2424–2430

Kruser TJ, Armstrong EA, Ghia AJ, Huang S, Wheeler DL, Radinsky R, Freeman DJ, Harari PM. Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer. Int J Radiat Oncol Biol Phys. 2008;72(2):534–542

Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–1740

Rodríguez MO, Rivero TC, del Castillo Bahi R, Muchuli CR, Bilbao MA, Vinageras EN, Alert J, Galainena JJ, Rodríguez E, Gracias E, et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer biology & therapy. 2010;9:343–349

Bebb G, Smith C, Rorke S, Boland W, Nicacio L, Sukhoo R, Brade A. Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIb, III or IV non-small cell lung cancer unsuitable for radical therapy. Cancer chemotherapy and pharmacology. 2011;67(4):837–45

Choi HJ, Sohn JH, Lee CG, Shim HS, Lee I-J, Yang WI, Kwon JE, Kim SK, Park M-S, Lee JH, et al. A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung cancer (Amsterdam, Netherlands). 2010;71:55–59

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–1672

Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–697

Bourgier C, Ozsahin M, Azria D. Multidisciplinary approach of early breast cancer: the biology applied to radiation oncology. Radiat Oncol. 2010;5:2

Chien AJ, Rugo HS. The cardiac safety of trastuzumab in the treatment of breast cancer. Expert Opin Drug Saf. 2010;9(2):335–346

de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol. 2009;4(2):77–88

Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010;7(10):564–575

Halyard MY, Pisansky TM, Dueck AC, Suman V, Pierce L, Solin L, Marks L, Davidson N, Martino S, Kaufman P, et al. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol. 2009;27(16):2638–2644

Belkacémi Y, Gligorov J, Ozsahin M, Marsiglia H, De Lafontan B, Laharie-Mineur H, Aimard L, Antoine E-C, Cutuli B, Namer M, et al. Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2008;19:1110–1116

Shaffer R, Tyldesley S, Rolles M, Chia S, Mohamed I. Acute cardiotoxicity with concurrent trastuzumab and radiotherapy including internal mammary chain nodes: a retrospective single-institution study. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2009;90:122–126

Magné N, Védrine L, Chargari C. Impact on cardiac toxicity with trastuzumab and radiotherapy: the question is still ongoing. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27:e239 . author reply e240-231.

Lordick F, Geinitz H, Theisen J, Sendler A, Sarbia M. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. International journal of radiation oncology, biology, physics. 2006;64:1295–1298

Crane CH, Eng C, Feig BW, Das P, Skibber JM, Chang GJ, Wolff Ra, Krishnan S, Hamilton S, Janjan Na, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. International journal of radiation oncology, biology, physics. 2010;76:824–830

Velenik V, Oblak I, Anderluh F. Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer. Radiat Oncol. 2010;5:88

Dipetrillo T, Pricolo V, Lagares-Garcia J, Vrees M, Klipfel A, Cataldo T, Sikov W, McNulty B, Shipley J, Anderson E, et al. Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer. International journal of radiation oncology, biology, physics. 2012;82(1):124–129

Bege T, Lelong B, Viret F, Turrini O, Guiramand J, Topart D, Moureau-Zabotto L, Giovannini M, Goncalves A, Delpero JR. Bevacizumab-related surgical site complication despite primary tumor resection in colorectal cancer patients. Ann Surg Oncol. 2009;16(4):856–860

Velenik V, Ocvirk J, Music M, Bracko M, Anderluh F, Oblak I, Edhemovic I, Brecelj E, Kropivnik M, Omejc M. Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study. Radiat Oncol. 2011;6:105

Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27:3020–3026

Koukourakis MI, Giatromanolaki A, Sheldon H, Buffa FM, Kouklakis G, Ragoussis I, Sivridis E, Harris AL. Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: vasculature-independent radiosensitizing effect of bevacizumab. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009;15:7069–7076

Koukourakis MI, Tsoutsou PG, Karpouzis A, Tsiarkatsi M, Karapantzos I, Daniilidis V, Kouskoukis C. Radiochemotherapy with cetuximab, cisplatin, and amifostine for locally advanced head and neck cancer: a feasibility study. International journal of radiation oncology, biology, physics. 2010;77:9–15

Czito BG, Bendell JC, Willett CG, Morse Ma, Blobe GC, Tyler DS, Thomas J, Ludwig Ka, Mantyh CR, Ashton J, et al. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results. International journal of radiation oncology, biology, physics. 2007;68:472–478

Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, Evans DB, Tamm EP, Ng C, Pisters PWT, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2006;24:1145–1151

Crane CH, Winter K, Regine WF, Safran H, Rich Ta, Curran W, Wolff Ra, Willett CG. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27:4096–4102

Small W Jr, Mulcahy MF, Rademaker A, Bentrem DJ, Benson AB, Weitner BB, Talamonti MS. Phase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;80(2):476–482

Goyal S, Rao MS, Khan A, Huzzy L, Green C, Haffty BG. Evaluation of Acute Locoregional Toxicity in Patients with Breast Cancer Treated with Adjuvant Radiotherapy in Combination with Bevacizumab. International journal of radiation oncology, biology, physics. 2010;79:408–413

Spigel DR, Hainsworth JD, Yardley Da, Raefsky E, Patton J, Peacock N, Farley C, Burris Ha, Greco FA. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:43–48

Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: analysis of single-agent and combined modality approaches. Radiat Oncol. 2011;6:2

Gutin PH, Iwamoto FM, Beal K, Mohile Na, Karimi S, Hou BL, Lymberis S, Yamada Y, Chang J, Abrey LE. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. International journal of radiation oncology, biology, physics. 2009;75:156–163

Niyazi M, Ganswindt U, Schwarz SB, Kreth F-W, Tonn J-C, Geisler J, la Fougère C, Ertl L, Linn J, Siefert A, et al. Irradiation and Bevacizumab in High-Grade Glioma Retreatment Settings. International journal of radiation oncology, biology, physics. 2010. p. 1–10

Lai A, Filka E, McGibbon B, Nghiemphu PL, Graham C, Yong WH, Mischel P, Liau LM, Bergsneider M, Pope W, et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys. 2008;71(5):1372–1380

Kelly PJ, Dinkin MJ, Drappatz J, O'Regan KN, Weiss SE. Unexpected late radiation neurotoxicity following bevacizumab use: a case series. J Neurooncol. 2010;102(3):485–490

Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, et al. Phase II Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients With Newly Diagnosed Glioblastoma Multiforme. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;29:

Wirth A. The rationale and role of radiation therapy in the treatment of patients with diffuse large B-cell lymphoma in the Rituximab era. Leuk Lymphoma. 2007;48(11):2121–2136

Yahalom J. Radiation therapy after R-CHOP for diffuse large B-cell lymphoma: the gain remains. J Clin Oncol. 2010;28(27):4105–4107

Phan J, Mazloom A, Jeffrey Medeiros L, Zreik TG, Wogan C, Shihadeh F, Rodriguez MA, Fayad L, Fowler N, Reed V, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:4170–4176

Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–391

Peters NaJB, Richel DJ, Verhoeff JJC, Stalpers LJa. Bowel perforation after radiotherapy in a patient receiving sorafenib. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26:2405–2406

Basille D, Andrejak M, Bentayeb H, Kanaan M, Fournier C, Lecuyer E, Boutemy M, Garidi R, Douadi Y, Dayen C. Bronchial fistula associated with sunitinib in a patient previously treated with radiation therapy. Ann Pharmacother. 44(2):p. 383–386

Hur H, Park AR, Jee SB, Jung SE, Kim W, Jeon HM. Perforation of the colon by invading recurrent gastrointestinal stromal tumors during sunitinib treatment. World J Gastroenterol. 2008;14(39):6096–6099

Kao J, Packer S, Vu HL, Schwartz ME, Sung MW, Stock RG, Lo Y-C, Huang D, Chen S-H, Cesaretti Ja. Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response. Cancer. 2009;115:3571–3580

Pouessel D, Culine S. High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol. 2008;53(2):376–381

Silvano G, Lazzari G, Lovecchio M, Palazzo C. Acute and fatal diarrhoea after erlotinib plus abdominal palliative hypofractionated radiotherapy in a metastatic non-small cell lung cancer patient: a case report. Lung cancer (Amsterdam, Netherlands). 2008;61:270–273

Yan DF, Yan SX, Yang JS, Wang YX, Sun XL, Liao XB, Liu JQ. Hemorrhage of brain metastasis from non-small cell lung cancer post gefitinib therapy: two case reports and review of the literature. BMC cancer. 2010;10:49

Weppler SA, Krause M, Zyromska A, Lambin P, Baumann M, Wouters BG. Response of U87 glioma xenografts treated with concurrent rapamycin and fractionated radiotherapy: possible role for thrombosis. Radiother Oncol. 2007;82(1):96–104

Shinohara E, Cao C, Niermann K, Mu Y, Zeng F, Hallahan D, Lu B. mTOR Inhibitors Are Safe and Effective Radiosensitizers in Glioblastoma Multiforme Pre-Clinical Models. International Journal of Radiation Oncology Biology Physics. 2005;63:172

Manegold C. New options for integrating antiangiogenic therapy and platinum-based first-line chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer. 2008;9(Suppl 3):S100–108

Chen H, Ma Z, Vanderwaal RP, Feng Z, Gonzalez-Suarez I, Wang S, Zhang J, Roti Roti JL, Gonzalo S. The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. Radiat Res. 2010;175(2):214–224

Temkin SM, Yamada SD, Fleming GF. A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies. Gynecologic oncology. 2010;117:473–476

Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–1571

Epperly MW, Greenberger EE, Franicola D, Jacobs S, Greenberger JS. Thalidomide radiosensitization of normal murine hematopoietic but not squamous cell carcinoma or multiple myeloma tumor cell lines. In Vivo. 2006;20(3):333–339

Ansiaux R, Baudelet C, Jordan BF, Beghein N, Sonveaux P, De Wever J, Martinive P, Grégoire V, Feron O, Gallez B. Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clinical cancer research: an official journal of the American Association for Cancer Research. 2005;11:743–750

Kim KT, Chae HS, Kim JS, Kim HK, Cho YS, Choi W, Choi KY, Rho SY, Kang SJ. Thalidomide effect in endothelial cell of acute radiation proctitis. World J Gastroenterol. 2008;14(30):4779–4783

Knisely JPS, Berkey B, Chakravarti A, Yung AWK, Curran WJ, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). International journal of radiation oncology, biology, physics. 2008;71:79–86

Niyazi M, Siefert A, Schwarz SB, Ganswindt U, Kreth F-W, Tonn J-C, Belka C. Therapeutic options for recurrent malignant glioma. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2011;98:1–14

Chang SM, Lamborn KR, Malec M, Larson D, Wara W, Sneed P, Rabbitt J, Page M, Nicholas MK, Prados MD. Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. International journal of radiation oncology, biology, physics. 2004;60:353–357

Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF, et al. A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol. 2007;81(3):271–277

Turner CD, Chi S, Marcus KJ, MacDonald T, Packer RJ, Poussaint TY, Vajapeyam S, Ullrich N, Goumnerova LC, Scott RM, et al. Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme. Journal of neuro-oncology. 2007;82:95–101

Kim SY, Hong YS, Kim DY, Kim TW, Kim JH, Im SA, Lee KS, Yun T, Jeong S-Y, Choi HS, et al. Preoperative Chemoradiation with Cetuximab, Irinotecan, and Capecitabine in Patients with Locally Advanced Resectable Rectal Cancer: A Multicenter Phase II Study. International journal of radiation oncology, biology, physics. 2011;81(3):677–683

Kerst JM, Bex A, Mallo H, Dewit L, Haanen JB, Boogerd W, Teertstra HJ, de Gast GC. Prolonged low dose IL-2 and thalidomide in progressive metastatic renal cell carcinoma with concurrent radiotherapy to bone and/or soft tissue metastasis: a phase II study. Cancer Immunol Immunother. 2005;54(9):926–931

Anscher MS, Garst J, Marks LB, Larrier N, Dunphy F, Herndon JE, Clough R, Marino C, Vujaskovic Z, Zhou S, et al. Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury. Int J Radiat Oncol Biol Phys. 2006;66(2):477–482

Drappatz J, Wong ET, Schiff D, Kesari S, Batchelor TT, Doherty L, Lafrankie DC, Ramakrishna N, Weiss S, Smith ST, et al. A pilot safety study of lenalidomide and radiotherapy for patients with newly diagnosed glioblastoma multiforme. International journal of radiation oncology, biology, physics. 2009;73:222–227

Topaly J, Fruehauf S, Ho AD, Zeller WJ. Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning. Br J Cancer. 2002;86(9):1487–1493

Li M, Ping G, Plathow C, Trinh T, Lipson KE, Hauser K, Krempien R, Debus J, Abdollahi A, Huber PE. Small molecule receptor tyrosine kinase inhibitor of platelet-derived growth factor signaling (SU9518) modifies radiation response in fibroblasts and endothelial cells. BMC cancer. 2006;6:79

Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F, Lee LB, McMahon G, Grone HJ, Lipson KE, et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med. 2005;201(6):925–935

Thomas DM, Fox J, Haston CK. Imatinib therapy reduces radiation-induced pulmonary mast cell influx and delays lung disease in the mouse. Int J Radiat Biol. 86(6):p. 436–444

Li M, Abdollahi A, Grone HJ, Lipson KE, Belka C, Huber PE. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat Oncol. 2009;4:66

Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM, Frenay M, Rampling R, Stupp R, Kros JM, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol. 2008;26(28):4659–4665

Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE, et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol. 2005;23(36):9359–9368

Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005;16(10):1702–1708

Desjardins A, Quinn JA, Vredenburgh JJ, Sathornsumetee S, Friedman AH, Herndon JE, McLendon RE, Provenzale JM, Rich JN, Sampson JH, et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol. 2007;83(1):53–60

Bajaj GK, Zhang Z, Garrett-Mayer E, Drew R, Sinibaldi V, Pili R, Denmeade SR, Carducci MA, Eisenberger MA, DeWeese TL. Phase II study of imatinib mesylate in patients with prostate cancer with evidence of biochemical relapse after definitive radical retropubic prostatectomy or radiotherapy. Urology. 2007;69(3):526–531

Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, Kun LE, Friedman H, Packer R, Banerjee A, et al. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol. 2007;9(2):145–160

Ciresa M, D'Angelillo RM, Ramella S, Cellini F, Gaudino D, Stimato G, Fiore M, Greco C, Nudo R, Trodella L. Molecularly targeted therapy and radiotherapy in the management of localized gastrointestinal stromal tumor (GIST) of the rectum: a case report. Tumori. 2009;95(2):236–239

Boruban C, Sencan O, Akmansu M, Atik ET, Ozbek S. Metastatic gastrointestinal stromal tumor with long-term response after treatment with concomitant radiotherapy and imatinib mesylate. Anti-cancer drugs. 2007;18:969–972

Rödel C, Arnold D, Hipp M, Liersch T, Dellas K, Iesalnieks I, Hermann RM, Lordick F, Hinke A, Hohenberger W, et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. International journal of radiation oncology, biology, physics. 2008;70:1081–1086

Weiss C, Arnold D, Dellas K, Liersch T, Hipp M, Fietkau R, Sauer R, Hinke A, Rodel C. Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: A pooled analysis of three prospective phase I-II trials. Int J Radiat Oncol Biol Phys. 2010;78(2):472–478

Bertolini F, Chiara S, Bengala C, Antognoni P, Dealis C, Zironi S, Malavasi N, Scolaro T, Depenni R, Jovic G, et al. Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. International journal of radiation oncology, biology, physics. 2009;73:466–472

Velenik V, Ocvirk J, Oblak I, Anderluh F. A phase II study of cetuximab, capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2010;36:244–250

Machiels J-P, Sempoux C, Scalliet P, Coche J-C, Humblet Y, Van Cutsem E, Kerger J, Canon J-L, Peeters M, Aydin S, et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2007;18:738–744

Henke M, Laszig R, Rübe C, Schäfer U, Haase K-D, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–1260

Henke M, Mattern D, Pepe M, Bézay C, Weissenberger C, Werner M, Pajonk F. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2006;24:4708–4713

Jensen AD, Bergmann ZP, Garcia-Huttenlocher H, Freier K, Debus J, Münter MW. Cetuximab and radiation for primary and recurrent squamous cell carcinoma of the head and neck (SCCHN) in the elderly and multi-morbid patient: a single-centre experience. Head & neck oncology. 2010;2:34

Garcia-Huttenlocher HI, Timke C, Dinkel J, Huber PE, Debus J, Muenter MW. Acute Toxicity of Skin and Mucosa in Patients with Head and Neck Cancer Receiving Radiotherapy Alone or in Combination with Chemotherapy or Cetuximab. International Journal of Radiation OncologyBiologyPhysics. 2009;75:S385–S386

Jatoi a, Schild SE, Foster N, Henning GT, Dornfeld KJ, Flynn PJ, Fitch TR, Dakhil SR, Rowland KM, Stella PJ, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2010;21:2040–2044

Koutcher L, Sherman E, Fury M, Wolden S, Zhang Z, Mo Q, Stewart L, Schupak K, Gelblum D, Wong R, et al. Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer. International journal of radiation oncology, biology, physics. 2011;81(4):915–922

Buiret G, Combe C, Favrel V, Pommier P, Martin L, Ecochard R, Fayette J, Tartas S, Ramade A, Céruse P. A retrospective, multicenter study of the tolerance of induction chemotherapy with docetaxel, Cisplatin, and 5-Fluorouracil followed by radiotherapy with concomitant cetuximab in 46 cases of squamous cell carcinoma of the head and neck. International journal of radiation oncology, biology, physics. 2010;77:430–437

Garcia-Huttenlocher H, Stoiber E, Timke C, Debus J, Münter M. Skin Toxicity under Combined Radio-Immune-Therapy with Cetuximab in Head and Neck Cancer. International Journal of Radiation Oncology • Biology • Physics. 2008;72:S417–S418

Merlano M, Russi E, Benasso M, Corvò R, Colantonio I, Vigna-Taglianti R, Vigo V, Bacigalupo a, Numico G, Crosetto N, et al. Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2010. p. 1–6

Suntharalingam M, Kwok Y, Goloubeva O, Parekh A, Taylor R, Wolf J, Zimrin A, Strome S, Ord R, Cullen KJ. Phase II Study Evaluating the Addition of Cetuximab to the Concurrent Delivery of Weekly Carboplatin, Paclitaxel, and Daily Radiotherapy for Patients With Locally Advanced Squamous Cell Carcinomas of the Head and Neck. Int J Radiat Oncol Biol Phys. . in press .

De Vita F, Orditura M, Martinelli E, Vecchione L, Innocenti R, Sileni VC, Pinto C, Di Maio M, Farella A, Troiani T, et al. A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer. British journal of cancer. 2011;104:427–432

Argiris A, Heron DE, Smith RP, Kim S, Gibson MK, Lai SY, Branstetter BF, Posluszny DM, Wang L, Seethala RR, et al. Induction docetaxel, cisplatin, and cetuximab followed by concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locally advanced head and neck cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:5294–5300

Heron DE, Rwigema J-CM, Gibson MK, Burton SA, Quinn AE, Ferris RL. Concurrent Cetuximab With Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: A Single Institution Matched Case-Control Study. American journal of clinical oncology. 2011;34(2):165–72

Birnbaum A, Dipetrillo T, Rathore R, Anderson E, Wanebo H, Puthwala Y, Joyce D, Safran H, Henderson D, Kennedy T, et al. Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis. American journal of clinical oncology. 2010;33:144–147

Jensen AD, Münter MW, Bischoff HG, Haselmann R, Haberkorn U, Huber PE, Thomas M, Debus J, Herfarth KK. Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: The NEAR trial. Cancer. 2011. p. 1–9

Ruhstaller T, Pless M, Dietrich D, Kranzbuehler H, von Moos R, Moosmann P, Montemurro M, Schneider PM, Rauch D, Gautschi O, et al. Cetuximab in Combination With Chemoradiotherapy Before Surgery in Patients With Resectable, Locally Advanced Esophageal Carcinoma: A Prospective, Multicenter Phase IB/II Trial (SAKK 75/06). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2011. p. 1–6

Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, Zahalsky AJ, Lake S, Needle MN, Shaha AR, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2006;24:1072–1078

Hofheinz R-D, Horisberger K, Woernle C, Wenz F, Kraus-Tiefenbacher U, Kähler G, Dinter D, Grobholz R, Heeger S, Post S, et al. Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. International journal of radiation oncology, biology, physics. 2006;66:1384–1390

Kuhnt T, Sandner a, Wendt T, Engenhart-Cabillic R, Lammering G, Flentje M, Grabenbauer G, Schreiber a, Pirnasch a, Dunst J. Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2010;21:2284–2289

Zwicker F, Roeder F, Thieke C, Timke C, Münter MW, Huber PE, Debus J. IMRT Reirradiation with Concurrent Cetuximab Immunotherapy in Recurrent Head and Neck Cancer. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al]. 2011. p. 32–38

Jensen AD, Krauss J, Weichert W, Debus J, Münter MW. RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab. Radiation oncology (London, England). 2010;5:102

Balermpas P, Hambek M, Seitz O, Rödel C, Weiss C. Combined cetuximab and reirradiation for locoregional recurrent and inoperable squamous cell carcinoma of the head and neck. Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft [et al]. 2009;185:775–781

Caussa L, Kirova YM, Gault N, Pierga J-Y, Savignoni A, Campana F, Dendale R, Fourquet A, Bollet Ma. The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study. European journal of cancer (Oxford, England: 1990). 2011;47:65–73

Anderson PR, Freedman G, Li T, Nicolaou N, Denlinger C. Concurrent Trastuzumab and Breast Radiotherapy in the Adjuvant Setting: Analysis of Acute Toxicity. International Journal of Radiation OncologyBiologyPhysics. 2009;75:S202–S203

Chargari C, Idrissi HR, Pierga J-Y, Bollet Ma, Diéras V, Campana F, Cottu P, Fourquet A, Kirova YM. Preliminary Results of Whole Brain Radiotherapy with Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients. International journal of radiation oncology, biology, physics. 2011;81(3):631–636

Horton JK, Halle J, Ferraro M, Carey L, Moore DT, Ollila D, Sartor CI. Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial. International journal of radiation oncology, biology, physics. 2010;76:998–1004

Crombet T, Osorio M, Cruz T, Roca C, del Castillo R, Mon R, Iznaga-Escobar N, Figueredo R, Koropatnick J, Renginfo E, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22:1646–1654

Vredenburgh JJ, Desjardins A, Kirkpatrick JP, Reardon Da, Peters KB, Herndon JE, Marcello J, Bailey L, Threatt S, Sampson J, et al. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated with Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme. International journal of radiation oncology, biology, physics. 2012;82(1):58–66

Seiwert TY, Haraf DJ, Cohen EEW, Stenson K, Witt ME, Dekker A, Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26:1732–1741

Spigel DR, Hainsworth JD, Yardley DA, Raefsky E, Patton J, Peacock N, Farley C, Burris HA, Greco FA. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol. 2009;28(1):43–48

Koukourakis MI, Giatromanolaki A, Tsoutsou P, Lyratzopoulos N, Pitiakoudis M, Kouklakis G, Chloropoulou PA, Manolas K, Sivridis E. Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a Phase II study. Int J Radiat Oncol Biol Phys. 2010;80(2):492–498

Resch G, De Vries A, Ofner D, Eisterer W, Rabl H, Jagoditsch M, Gnant M, Thaler J. Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer-A two stage phase II clinical trial. Radiother Oncol. . in press .

Vargo JA, Snelling BM, Ghareeb ER, John K, Frame JN, Schmidt JH, Peters KB. Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab. J Neurooncol. 2011;104(2):595–598

Chi K-H, Liao C-S, Chang C-C, Ko H-L, Tsang Y-W, Yang K-C, Mehta MP. Angiogenic blockade and radiotherapy in hepatocellular carcinoma. International journal of radiation oncology, biology, physics. 2010;78:188–193

Staehler M, Haseke N, Stadler T, Nuhn P, Roosen A, Stief CG, Wilkowski R. Feasibility and effects of high-dose hypofractionated radiation therapy and simultaneous multi-kinase inhibition with sunitinib in progressive metastatic renal cell cancer. Urologic oncology. . in press .

Hui EP, Lui VW, Wong CS, Ma BB, Lau CP, Cheung CS, Ho K, Cheng SH, Ng MH, Chan AT. Preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma. Invest New Drugs. 2010;29(6):1123–1131

Harrington KJ, El-Hariry Ia, Holford CS, Lusinchi A, Nutting CM, Rosine D, Tanay M, Deutsch E, Matthews J, D'Ambrosio C, et al. Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27:1100–1107

Cohen EEW, Haraf DJ, Kunnavakkam R, Stenson KM, Blair Ea, Brockstein B, Lester EP, Salama JK, Dekker A, Williams R, et al. Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:3336–3343

Pollack IF, Stewart CF, Kocak M, Poussaint TY, Broniscer A, Banerjee A, Douglas JG, Kun LE, Boyett JM, Geyer JR. A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: A report from the Pediatric Brain Tumor Consortium. Neuro-oncology. 2011;13(3):290–297

Valentini V, De Paoli A, Gambacorta MA, Mantini G, Ratto C, Vecchio FM, Barbaro B, Innocente R, Rossi C, Boz G, et al. Infusional 5-fluorouracil and ZD1839 (Gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II Trial (1839IL/0092). International journal of radiation oncology, biology, physics. 2008;72:644–649

Wang J, Xia TY, Wang YJ, Li HQ, Li P, Wang JD, Chang DS, Liu LY, Di YP, Wang X, et al. Prospective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2011;81(3):e59–e65

Zhang G, Xie L, Xu X, Chen J, Fu X, Jiang G, Fan M. Thoracic Radiotherapy and Concurrent Gefitinib in Patients with IIIB/IV Non-small Cell Lung Cancer (NSCLC): Phase I Study. International Journal of Radiation OncologyBiologyPhysics. 2009;75:S455

Chen C, Kane M, Song J, Campana J, Raben A, Hu K, Harrison L, Quon H, Dancey J, Baron A, et al. Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2007;25:4880–4886

Maurel J, Martin-Richard M, Conill C, Sánchez M, Petriz L, Ginès A, Miquel R, Gallego R, Cajal R, Ayuso C, et al. Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer. International journal of radiation oncology, biology, physics. 2006;66:1391–1398

Czito BG, Willett CG, Bendell JC, Morse Ma, Tyler DS, Fernando NH, Mantyh CR, Blobe GC, Honeycutt W, Yu D, et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2006;24:656–662

Center B, Petty WJ, Ayala D, Hinson WH, Lovato J, Capellari J, Oaks T, Miller Aa, Blackstock AW. A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2010;5:69–74

Schwer AL, Damek DM, Kavanagh BD, Gaspar LE, Lillehei K, Stuhr K, Chen C. A phase I dose-escalation study of fractionated stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant gliomas. International journal of radiation oncology, biology, physics. 2008;70:993–1001

Olsen CC, Schefter TE, Chen H, Kane M, Leong S, McCarter MD, Chen Y, Mack P, Eckhardt SG, Stiegmann G, et al. Results of a phase I trial of 12 patients with locally advanced pancreatic carcinoma combining gefitinib, paclitaxel, and 3-dimensional conformal radiation: report of toxicity and evaluation of circulating K-ras as a potential biomarker of response to the. American journal of clinical oncology. 2009;32:115–121

Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle Ka, Uhm JH, Geoffroy FJ, Arusell R, Kitange G, Jenkins RB, et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26:5603–5609

Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27:579–584

Herchenhorn D, Dias FL, Viegas CMP, Federico MH, Araújo CMM, Small I, Bezerra M, Fontão K, Knust RE, Ferreira CG, et al. Phase I/II study of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. International journal of radiation oncology, biology, physics. 2010;78:696–702

Choong NW, Mauer AM, Haraf DJ, Lester E, Hoffman PC, Kozloff M, Lin S, Dancey JE, Szeto L, Grushko T, et al. Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2008;3:1003–1011

Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GHJ, Suh JH, Toms Sa, Vogelbaum Ma, Weil RJ, et al. Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. Journal of neuro-oncology. 2010;98:93–99

Chang C-C, Chi K-H, Kao S-J, Hsu P-S, Tsang Y-W, Chang H-J, Yeh Y-W, Hsieh Y-S, Jiang J-S. Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: A mono-institutional experience. Lung cancer (Amsterdam, Netherlands). 2011;73(2):189–194

Li G, Hu W, Wang J, Deng X, Zhang P, Zhang X, Xie C, Wu S. Phase II Study of Concurrent Chemoradiation in Combination with Erlotinib for Locally Advanced Esophageal Carcinoma. International journal of radiation oncology, biology, physics. 2010;78:1407–1412

Broniscer A, Baker SJ, Stewart CF, Merchant TE, Laningham FH, Schaiquevich P, Kocak M, Morris EB, Endersby R, Ellison DW, et al. Phase I and pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009;15:701–707

Robertson J, Ballouz S, Jaiyesimi I, Jury R, Margolis J. A Phase I Study of Dose Escalating Conformal Radiation Therapy with Concurrent Full-dose Gemcitabine and Erlotinib for Unresected Pancreas Cancer. International Journal of Radiation OncologyBiologyPhysics. 2009;75:S270

Duffy a, Kortmansky J, Schwartz GK, Capanu M, Puleio S, Minsky B, Saltz L, Kelsen DP, O'Reilly EM. A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2008;19:86–91

Krishnan S, Brown PD, Ballman KV, Fiveash JB, Uhm JH, Giannini C, Jaeckle Ka, Geoffroy FJ, Nabors LB, Buckner JC. Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: results of North Central Cancer Treatment Group protocol N0177. International journal of radiation oncology, biology, physics. 2006;65:1192–1199

Iannitti D, Dipetrillo T, Akerman P, Barnett JM, Maia-Acuna C, Cruff D, Miner T, Martel D, Cioffi W, Remis M, et al. Erlotinib and Chemoradiation Followed by Maintenance Erlotinib for Locally Advanced Pancreatic Cancer. American Journal of Clinical Oncology. 2005;28:570–575

Nogueira-Rodrigues A, do Carmo CC, Viegas C, Erlich F, Camisão C, Fontão K, Lima R, Herchenhorn D, Martins RG, Moralez GM, et al. Phase I trial of erlotinib combined with cisplatin and radiotherapy for patients with locally advanced cervical squamous cell cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 2008;14:6324–6329

Arias de la Vega F, Contreras J, de Las Heras M, de la Torre A, Arrazubi V, Herruzo I, Prieto I, Garcia-Saenz JA, Romero J, Calvo FA. Erlotinib and chemoradiation in patients with surgically resected locally advanced squamous cell carcinoma of the head and neck: a GICOR phase I trial. Ann Oncol. 2011. . in press .

Lind JSW, Lagerwaard FJ, Smit EF, Senan S. Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer. International journal of radiation oncology, biology, physics. 2009;74:1391–1396

Dobelbower MC, Russo SM, Raisch KP, Seay LL, Clemons LK, Suter S, Posey J, Bonner Ja. Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and concurrent 5-fluorouracil, cisplatin and radiotherapy for patients with esophageal cancer: a phase I study. Anti-cancer drugs. 2006;17:95–102

Huang Y-J, Liu S-F, Wang C-J, Huang M-Y. Exacerbated radiodermatitis and bilateral subdural hemorrhage after whole brain irradiation combined with epidermal growth factor receptor tyrosine kinase inhibitors for brain metastases in lung cancer. Lung cancer (Amsterdam, Netherlands). 2008;59:407–410

Sarkaria JN, Schwingler P, Schild SE, Grogan PT, Mladek AC, Mandrekar SJ, Tan AD, Kobayashi T, Marks RS, Kita H, et al. Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2007;2:751–757

Bourgier C, Massard C, Moldovan C, Soria JC, Deutsch E. Total recall of radiotherapy with mTOR inhibitors: a novel and potentially frequent side-effect? Ann Oncol. 2011;22(2):485–486

Chang SM, Lamborn KR, Malec M, Larson D, Wara W, Sneed P, Rabbitt J, Page M, Nicholas MK, Prados MD. Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2004;60(2):353–357

Atkins MB, Sosman Ja, Agarwala S, Logan T, Clark JI, Ernstoff MS, Lawson D, Dutcher JP, Weiss G, Curti B, et al. Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. Cancer. 2008;113:2139–2145

Ch'ang H-J, Hsu C, Chen C-H, Chang Y-H, Chang JS, Chen L-T. Phase II Study of Concomitant Thalidomide During Radiotherapy for Hepatocellular Carcinoma. International journal of radiation oncology, biology, physics. 2011. . in press .

[Back]

Table 1.

Studies on monoclonal EGFR antibodies

Substance
Author(s)
Year
Study type
N
Tumour
RT dose/ChTx/technique
Toxicity

Cetuximab
Bonner et al. [10]
2006
Phase III
211 (cetux-arm)
LA-HNSCC
70-78.8 Gy (hyper-fractionated)
Significant differences or trend in arms: 8% grade III-V acneiform rash, 1% grade III-V voice alteration, 1% grade III-V infusion reaction

Koutcher et al. [24]
2009
Retrospective
115
LA-HNSCC
66 Gy/69.96 Gy
3% grade IV radio-dermatitis, 19% grade III radio-dermatitis

Studer et al. [25]
2011
Prospective
99
HNSCC
66-70 Gy, 30/99 switch from Cis
34% grade II/IV dermatitis

Hallqvist et al. [28]
2010
Phase II
75
NSCLC
68 Gy, Ind. ChTx Doc/Cis + concomitant Cetux
1% grade V pneumonitis, 4% grade III pneumonitis, 5% grade III + IV hypersensitivity, 15% grade III + IV febrile neutropenia, 4% III skin reactions

Jensen et al. [122]
2010
Retrospective
73
HNSCC
22 pts Re-RT (50-60 Gy), 66-70 Gy
5% grade III allergic reaction, 4% grade III acneiform rash

Garcia-Huttenlocher et al. [123]
2009
Retrospective
65
HNSCC
Median 66 Gy (IMRT)
Grade III: skin toxicity 28%, mucositis 25%

Rödel et al. [115]
2008
Phase I/II
12/48
Rectal cancer
50,4 Gy +Capecitabine + Oxaliplatin
Phase II only Grade IV/V: Leukopenia, thrombocytopenia, Diarrhea, Creatinine elevation, e-lyte derivation, infection each 2%

Safran et al. [31]
2008
Phase II
60
Esophago-gastric-cancer
Cetux/Carbo/Tax + 50.4 Gy
23% grade III rash, 15% grade III/IV esophagitis, 5% III + IV hypersensitivity, 3% grade IV neutropenia (10% grade III), 2% IV anemia (8% grade III)

Jatoi et al. [124]
2010
Phase II
57
NSCLC
60 Gy
2% grade IV each: dysphagia/hypomagnesemia/dyspnea/headache/thrombosis/GI hemorrhage, 7% grade III rash

Horisberger et al. [30]
2009
Phase II
50
Rectal cancer
50,4 Gy + Capecitabine + Irinotecan
Leukopenia 4% grade III and IV each
Grade III: Diarrhea 60%, abdominal pain 8%, ALAT/ASAT elevation 20%, Acneiform skin rash 12%, anemia, nausea/vomiting, bilirubin elevation, proctitis each 4%

Koutcher et al. [125]
2011
Retrospective
49
LA-HNSCC
69.96 Gy (IMRT) (comparison vs. concomitant Cis)
20% late grade III + IV toxicity

Walsh et al. [26]
2011
Retrospective
48 (14 excluded because of SIB)
HNSCC
Cis vs. Cetux (66-70 Gy)
44% ≥ grade III skin toxicity, 52% ≥ grade III mucositis, 6% ≥ grade III acneiform rash

Buiret et al. [126]
2010
Retrospective multicenter
46
HNSCC
Ind. ChTx Doc/Cis/5-FU, RIT (70 Gy)
No grade IV toxicity

Garcia-Huttenlocher et al. [127]
2008
Retrospective
46
HNSCC
Median 66 Gy (IMRT)
20% grade III skin toxicity, 4% grade III mucositis

Merlano et al. [128]
2010
Phase II
45
HNSCC
Up to 70 Gy, three cycles Cis/5-FU, split course RT, RT + cetux
2% grade IV leukopenia (38% grade III), 7% grade IV neutropenia (33% grade III), 2% grade IV thrombopenia (13% grade III), 36% grade IV stomatitis (29% grade III), 73% grade III radiodermatitis, 7% grade III rash

Koukourakis et al. [60]
2010
Phase I
43
LA-HNSCC
21 × 2.7 Gy (56.7 Gy) + amifostine + Cis
16% grade III + IV mucositis, 2% grade III + IV skin toxicity

Suntharalingam et al. [129]
2011
Phase II
43
LA-HNSCC
70,2 Gy (3D/IMRT) + Paclitaxel, Carboplatin,
Grade 3 mucositis (79%), rash (9%), leukopenia (19%), neutropenia (19%), and RT dermatitis (16%)

De Vita et al. [130]
2011
Phase II
41
Esophageal cancer
Ind. FOLFOX4 + 50.4 Gy/Cetux
30% grade II/IV skin toxicity/neutropenia

Bertolini et al. [117]
2009
Phase II
40
LA rectal cancer
50-50.4 Gy + neoadj. Cetux/Cetux + 5-FU concomitant
8% grade III/IV skin rash, 8% grade III/IV hypersensitivity, 13% grade III/IV GI toxicity, 3% grade III/IV febrile neutropenia

Kim et al. [98]
2011
Phase II
40
Rectal cancer
Capecitabine + Cetux + Irinotecan + 50.4 Gy
3% grade IV leukopenia, 3% grade III rash

Machiels et al. [119]
2007
Phase I/II
40
Rectal cancer
45 Gy + Capecitabine
3% grade III/IV allergic reaction, 3% grade III/IV dermatitis

Argiris et al. [131]
2010
Prospective
39
LA-HNC
Induction Docetaxel/Cis/Cetux + concurrent Cisplatin/Cetux/70-74 Gy-RT
Grade III/IV: oral mucositis 46%, Anemia 21%, in-field dermatitis 23%, Dysphagia 41%, Thrombocytopenia 10%, Neutropenia 31%, febrile neutropenia 5%, infection 18%, fatigue 13%, nausea 10%, vomiting 3%, renal failure 3%, DVT 5%, bleeding 5%.

Velenik et al. [118]
2010
Phase II
37
Rectal cancer
45 Gy RT + capecitabine (neoadjuvant)
Grade III: diarrhea 11%, anorexia 3%, hepatotoxicity 3%, in-field-dermatitis 16%, infection 3%, hypersensitivity 5%.

Heron et al. [132]
2011
Matched pair retrospective
35
HNSCC
SBRT Re-RT
No significant increase grade III + IV

Birnbaum et al. [133]
2010
Phase I
32
LA-HNSCC
66-72 Gy, Ind. Cetux + Carbo/Tax/Cetux concomitant
3% grade III allergic reaction, 3% grade IV metabolic symptom, 69% grade III + IV mucositis, 3% grade IV dysphagia, 59% pts grade III + IV skin toxicity

Jensen et al. [134]
2011
Phase II
30
NSCLC
66 Gy (IMRT)
Pulmonary embolism 3% grade III + 3% grade V endocarditis and myocardial infarction grade V each 3%, 13% grade III/IV pneumonia esophagitis, diarrhea, DVT, exacerbation of COPD, urosepsis, pericardial effusion, pneumonitis grade III each 3%

Ruhstaller et al. [135]
2011
Phase IB/II
28
Esophageal cancer
Induction ChTx Cis/docetaxel + neoadjuvant RCh-immunotherapy
25% grade III/IV esophagitis, 4% grade III/IV rash

Pfister et al. [136]
2006
Phase I
22
LA-HNSCC
70 Gy RT + Cisplatin
Study closed due to significant AEs.
Grade V pneumonia and one death of unknown cause,
Grade IV: MI 5%, arrhythmia 5%, metabolic 5%, infection 5%

Hofheinz et al. [137]
2006
Phase I
20
Rectal cancer
Capecitabine + Irinotecan + 50.4 Gy
No grade IV, no rash, 20% grade III diarrhea

Kuhnt et al. [138]
2010
Phase I
18 (16 eligible)
LA-HNSCC
HART (70.6 Gy) + Cis
56% grade III mucositis, 38% ≥ grade III radiodermatitis, 25% ≥ grade III neutropenia, 6% grade III rash

Pryor et al. [22]
2009
Prospective
13
HNSCC
70 Gy
46% ≥ grade III acneiform rash, 77% ≥ grade III dermatitis

Hughes et al. [29]
2008
Phase I
12
NSCLC
64 Gy
Grade III fatigue, pneumonitis each 8%
Grade V Infection 8%

Zwicker et al. [139]
2011
Phase II
10
HNSCC
IMRT 50.4 Gy Re-RT + Cetux
10% grade V mucositis, 10% grade III mucositis, 10% grade IV erythema (20% grade III), 20% grade III acneiform rash

Jensen et al. [140]
2010
prospective
9
Adenoid cystic carcinoma of HN
5/9: re-RT: median 50,4 Gy, median 65 Gy otherwise (IMRT or C-12 boost)
Grade III Mucositis and Grade III Dysphagia

Balermpas et al. [141]
2009
Prospective
7
HNSCC
Re-irradiation 50,4 Gy-54,0 Gy
New acute side effects:
Grade III: pain 14%, mucositis 71%. Dysphagia 57%. Xerostomia 14%. Fibrosis 14%, acneiform rash 29%.

Berger et al. [19]
2008
Case report
1
HNSCC
72 Gy., regimen change to cetuximab from 5-FU/MMC
Grade IV Dermatitis

Trastuzumab
Halyard et al. [48]
2009
Phase III
1503
Breast cancer
Median 50,4 Gy, previous OP + ChTx
Skin toxicity grade III: 4% (simultaneous) -6% (adjuvant), cardiac events 2% (simultaneous)-3% (adjuvant)

Belkacemi et al. [49]
2008
Multicentric study
146
Breast cancer
Median 50 Gy
> grade II esophagitis (12%), 1 pt grade III esophagitis, 5% grade III dermatitis, ≥ grade II LVEF (10%)

Caussa et al. [142]
2011
Prospective
106
Breast cancer
50 Gy (2 Gy) + 16 Gy boost
2% grade III skin reaction, 1% grade III esophagitis

Anderson [143]
2009
Matched case control study
85
Breast cancer
n. r.
Grade III dermatotoxicity 2%, 1% ≥ grade II LVEF decrease (reversible)

Shaffer et al. [50]
2009
retrospective
44
Breast cancer
40-50.4 Gy
In 14% stopped because of cardiac toxicity

Chargari et al. [144]
2011
Phase I
31
Brain mets breast cancer
30 Gy (3 Gy) WBRT
No grade > II

Horton et al. [145]
2010
Phase II
12
Locally recurrent breast cancer
50 Gy, ChTx refractory
17% grade III skin toxicity, 8% grade III lymphopenia, no cardiac toxicity

Panitumumab
Pinto et al. [35]
2011
Phase II
60
Rectal cancer
5-fluorouracil-oxaliplatin + RT
Grade 3-4 toxicity: diarrhea (39%, one toxic death), cutaneous reactions (19%), nausea, neutropenia (2%), others.

Wirth et al. [34]
2010
Phase I
19
LA-HNSCC
70 Gy + Carbo/Tax (2 Gy) IMRT
1 pt grade III febrile neutropenia, 84% grade III + IV mucositis, 95% grade III dysphagia, 42% grade III dermatitis, 11% grade III rash, 21% grade III nausea

Nimotuzumab (h-R3)
Rodriguez et al. [38]
2010
Prospective randomized
106
HNSCC
n. r.
III/IV not reported

Crombet et al. [146]
2004
Phase I
24
HNSCC
66 Gy (2 Gy)
4% grade III somnolence, 13% grade III dysphagia, 21% grade III mucositis, 13% grade III dermatitis, 4% grade III laryngitis

Bebb et al. [39]
2011
Phase I
18
NSCLC
36/30 Gy (3 Gy)
50% grade III + IV

Choi et al. [40]
2010
Phase I
15
NSCLC
36/30 Gy (3 Gy)
7% grade IV febrile neutropenia/pneumonia, 40% grade III lymphopenia

N-number of patients, pt(s)-patient(s), n. r.-not reported, ChTx-chemotherapy, HCC-hepatocellular carcinoma, RCC-renal cell cancer, GBM-glioblastoma multiforme, DVT-deep vein thrombosis, Fx-fractions, SRS-stereotactic radiosurgery, DLT-dose limiting toxicity, LA-locally advanced, Gem-gemcitabine, Tax-Taxol (paclitaxel), Tx-therapy, TMZ-temozolomide, PCP-Pneumocystis pneumonia, Cis-cisplatin, Eto-etoposide, Doc-docetaxel

[Back]

[Back]

Table 2.

Studies on VEGF antibodies.

Substance
Author(s)
Year
Study type
N
tumour
RT dose/ChTx/technique
Toxicity

Bevacizumab
Vredenburgh et al. [147]
2010

125
Glioblastoma
59,4 Gy/Temozolomide
Grade III Thromboembolic events: 2%

Crane et al. [63]
2009
Phase II
82
Pancreatic Cancer
50,4 Gy/Capecitabine
Toxicities possibly attributable to bevacizumab: GI bleeding: 6%. (d83,127,179, 180, 316); grade III, IV, V GI perforation: 4%. (d195,231,286)
DVT grade III + IV: 4%; grade III hypertension: 2%;

Lai et al. [72]
2010
Phase II
70
Glioblastoma
60 Gy/Temozolomide
Grade IV cerebrovascular ischemia: 9%; Grade III+IV CNS hemorrhage: 3%; Grade III+IV GI bleeding/perforation 6%; grade IIII Optic neuropathy: 1%. Grade III+IV venous Thrombosis/PE: 19%.

Crane et al. [62]
2006
Phase I
48
Pancreatic Cancer
50,4 Gy/Capecitabine
Toxicities possibly attributable to bevacizumab: grade III+V ulceration with bleeding in RT field: 8%. (retrospectively fistulous connection identified in 4%)
Grade III GI perforation: 4%; bleeding outside field): 4%; grade III hypertension: 2%.

Seiwert et al. [148]
2008
Phase I
43
Head & Neck
63-72 Gy/5-FU and Hydroxyurea
Grade V bleeding events: 5%; grade V infection/sepsis: 7%, 2% unknown cause of death; grade III+ Thromboembolic events: 5% DVT, 2% stroke (leading to fatal sepsis, see above); fistula (due to radionecrosis or residual tumour): 12%. Tissue necrosis 9%.

Spigel et al. [149]
2009
Phase II
A 29 B 5
SCLC
61,2 Gy/Carboplatin/Irinotecan (A-limited stage B-locally advanced)
A Grade IV+V tracheoesophageal fistula: 7%. Grade V aerodigestive hemorrhage. B Grade III tracheoesophageal fistula: 40%. Both studies closed due to toxicity.

Willet et al. [58]
2009
Phase II
32
Rectal Cancer
50,4 Gy//5-FU
Grade III toxicities: GI abscess 3%, Hypertension 9%, radiation dermatitis: 6%; wound separation 3%. No grade IV.

Dipetrillo et al. [55]
2012
Phase I
26
Rectal Cancer
50,4 Gy/FOLFOX
Grade III + IV Diarrhea: 42%; Bleeding (g3): 4%; g3 neuropathy: 4%; Radiation dermatitis G3: 8%; postoperative wound complications: 35%-the study was discontinued due to this toxicity.

Crane et al. [53]
2010
Phase II
25
Rectal Cancer
50,4 Gy/Capecitabine
grade III perianal desquamation: 4%; 12% major surgical complications such as anastomotic dehiscence (4%), wound dehiscence (8%)

Gutin et al. [68]
2009
Phase I
25
Glioblastoma/Anaplastic Gliomas
30 Gy/5 × 6 Gy
Grade IV Gastrointestinal bleeding: 4%, bowel perforation: 4%, wound healing complication: 4%. Grade III CNS hemorrhage: 4%.

Koukourakis et al. [59]
2009
Phase I/II
22
Rectal Cancer
15 × 3,4 Gy/amifostine, capecitabine
Fistula: 9%, grade IV skin necrosis 5%.

Niyazi et al. [69]
2010
Retrospective
20
Recurrent Glioblastoma
36 Gy
Grade IV wound healing complication: 5%. grade III DVT: 5%.

Koukourakis et al. [150]
2011
Phase II
19
Rectal cancer
10 × 3, 4 Gy Amifostine/Capecitabine
Grade III diarrhea: 11%.

Goyal et al. [65]
2010
Retrospective
14
Breast cancer
50 Gy + 10 Gy
No Grade III/IV toxicity (only acute toxicity assessed)

Czito et al. [61]
2007
Phase I
11
Rectal Cancer
50,4 Gy/Oxaliplatin + Capecitabine
No grade III + toxicities attributable to bevacizumab: grade III-IV diarrhea: 27%,

Resch et al. [151]
2011
Phase II
8
Rectal cancer
45 Gy/Capecitabine
Discontinued due to tox after 8 Pt., Grade III GI bleeding: 25%, Grade III diarrhea: 25%

Kelly et al. [71]
2010
Case reports
3
Glioblastoma

Optic neuropathy

Vargo et al. [152]
2011
Case report
1
Glioblastoma

Dural venous thrombosis

N-number of patients

[Back]

[Back]

Table 3.

Studies on small molecules.

Substance
Author(s)
Year
Study type
N
tumour
RT dose/ChTx/technique
Toxicity

Sunitinib
Chi et al. [153]
2010
Phase II
23
HCC
52.5 (15 Fx) IMRT/3D-CT
9% grade III upper GI bleeding, 4% hepatitis grade III/4% grade III pancreatitis, 26% grade III + IV thrombopenia, 4% grade III leukopenia

Stähler et al. [154]
2010
Prospective, non-randomized
22
RCC (all sites)
Median 40 Gy (median 8 Fx)
5% grade IV hypertension, 14% grade III + IV nausea

Kao et al. [80]
2009
Phase I
21
Oligometastases
40-50 Gy (10 Fx)
62% grade III + IV lymphopenia, 19% grade III neutropenia, 14% grade III + IV thrombopenia, 5% grade III rectal bleeding

Hui et al. [155]
2010
Phase II
13
Nasopharyngeal carcinoma
Sunitinib after RT (60-70 Gy) and multiple Chx
15% fatal hemorrhages, 31% Grade IV hemorrhages, (among other toxicities)

sorafenib
Peters et al. [77]
2008
Case study
1
RCC
8 Gy single dose
Grade V bowel perforation (stopped two days before, three days later recommenced)

lapatinib
Harrington et al. [156]
2009
Phase I
31
LA-HNSCC
66-70 Gy + CisPt
35% grade III mucositis, 19% grade III dermatitis, 13% grade III + IV lymphopenia, 6% grade III neutropenia

gefitinib
Cohen et al. [157]
2010
Phase I
69
LA-HNSCC
IC Carbo/Tax, hydroxyurea + 5-FU, 2 × 1.5 Gy/d
29% grade III + IV neutropenia, 86% grade III + IV mucositis, 33% grade III + IV dermatitis, 3% grade V infections, 17% grade III + IV infections, 4% grade III rash, 3% grade III neurotoxicity

Pollack et al. [158]
2011
Phase II
43
Brainstem glioma in children
55,8 Gy
Grade III+IV: lymphopenia (21%), neutropenia (2%), GI (12%), infection (7%), n, pulmonary (5%), renal, skin (2%), metabolic (2%), intratumoral hemorrhage: 7%.

Valentini et al. [159]
2008
Phase I/II
41
Rectal cancer
45 Gy + 5.4 Gy + 5-FU
20% grade III + IV GI toxicity, 15% grade III + IV skin toxicity, 39% grade III + IV hepatic toxicity, 10% grade III + IV GU toxicity, 7% other toxicities grade III + IV

Wang et al. [160]
2011
Prospective
26
Stage III/IV NSCLC
Median 70 Gy
Grade IV leukopenia 4%, grade IV thrombopenia 8%, grade III esophagitis 4%, grade III pneumonitis 4%

Zhang et al. [161]
2009
Phase I
24
NSCLC
54-60 Gy
4% grade III nausea

Chen et al. [162]
2007
Phase I
23
HNSCC
Up to 72 Gy
13% grade III dermatitis, 57% grade III + IV mucositis, 39% grade III + IV dysphagia, 17% grade III + IV diarrhea, 30% grade III + IV neutropenia, 9% grade III + IV anemia, 4% grade IV tumour hemorrhage, 4% grade III GI bleeding

Maurel et al. [163]
2006
Phase I
18
Pancreatic cancer
45 Gy
No DLT, 11% grade III + IV neutropenia, 6% anemia grade III

Czito et al. [164]
2006
Phase I
16
Pancreatic + rectal cancer
50.4 Gy (1.8 Gy) + capecitabine
31% grade III + IV diarrhea

Center et al. [165]
2010
Phase I
16
NSCLC
70 Gy 3D-CT + docetaxel
27% grade III + IV hematotoxicity, 27% grade III + IV esophagitis, 20% grade III + IV pulmonary toxicity

Schwer et al. [166]
2008
Phase I
15
Malignant glioma
SRS 18-36 Gy
No DLT, no grade > II

Olsen et al. [167]
2009
Phase I
12
Pancreatic cancer
50.4 Gy (1.8 Gy)
45% grade III nausea

erlotinib
Brown et al. [168]
2008
Phase I/II
79
GBM
60 Gy + TMZ
18% grade III/IV rash, 16% grade III/IV fatigue, 24% grade III/IV thrombopenia, 4% grade III nausea, 8% grade III diarrhea, 28% grade III/IV leukopenia, 3% grade III anorexia, 18% grade III/IV neutropenia, 6% grade III anemia, 14% grade III lymphopenia, 1% grade V infection without neutropenia, 5% grade III infection without neutropenia, 6% grade III/IV dyspnea, 1% grade III/IV keratitis, 1% grade V pneumonitis, 6% grade III/IV pneumonitis

Prados et al. [169]
2009
Phase II
65
GBM
59.4 Gy/60 Gy + TMZ
43% grade III lymphopenia, 3% grade IV neutropenia, 2% grade IV thrombopenia, 8% grade III/IV fatigue, 2% grade III diarrhea, 6% grade III rash

Herchenhorn et al. [170]
2010
Phase I/II
37
LA-HNSCC
70 Gy + Cis
No DLT

Choong et al. [171]
2008
Phase I
34
NSCLC Stage III
66 Gy (2 Gy), Arm A: Erlotinib + Cis/Eto, Arm B: Induction Carbo/Tax, Carbo/Tax + Erlotinib
41% grade III + IV WBC, 32% grade III + IV neutropenia, 21% grade III + IV thrombopenia, 26% grade III + IV esophagitis, 3% grade III + IV vomiting, 6% grade III + IV diarrhea, 3% grade III/IV pneumonitis/ototoxicity

Peereboom et al. [172]
2010
Phase II
27
GBM
60 Gy + TMZ
7% grade V febrile neutropenia, 4% grade V sepsis without neutropenia, 4% grade V PCP, a pt grade III neutropenia, 15% grade III neutropenia, 30% grade III + IV thrombopenia, 56% pts grade III lymphopenia, 15% grade III + IV anemia, 7% grade III fatigue

Chang et al. [173]
2011
Retrospective
25
NSCLC
40-50 Gy
4% grade III rash, 4% grade III diarrhea/esophagitis/anemia, 8% grade III neutropenia/thrombopenia, 8% grade V pneumonitis, 4% grade III pneumonitis

Li et al. [174]
2010
Phase II
24
LA esophageal cancer
60 Gy + Carbo/Tax
17% ≥ grade III leukopenia, 8% thrombopenia ≥ grade III

Broniscer et al. [175]
2009
Phase I
23
GBM
54-59.4 Gy
39% grade III + IV lymphopenia, 4% grade III rash, 4% grade III diarrhea

Robertson et al. [176]
2009
Phase I
22
Pancreatic cancer
Gem weekly, 30-38 Gy
5% grade III vomiting/fatigue/nausea, 5% grade III vomiting/diarrhea/nausea, 9% grade IV fatigue

Duffy et al. [177]
2008
Phase I
20
Pancreatic cancer
50.4 Gy + Gem
100% grade III lymphopenia, 25% grade III thrombopenia, 30% grade III neutropenia, 5% grade IV neutropenia, 10% grade III anemia, 5% grade III fatigue, 15% grade III diarrhea, 10% grade III rash

Krishnan et al. [178]
2006
Phase I
20
GBM
60 Gy
15% grade III stomatitis, 5% grade III fatigue/diarrhea

Iannitti et al. [179]
2005
Phase I
17
LA Pancreatic cancer
50.4 Gy + Tax/Gem
6% grade III nausea/fatigue/rash/small bowel stricture/thrombopenia (each), 18% grade III dehydration/thrombosis, 12% grade III diarrhea/hypersensitivity, 6% grade IV neutropenia

Nogueira-Rodrigues et al. [180]
2008
Phase I
15
LA cervical cancer
45 Gy + brachyTx + CisPt
7% grade IV hepatotoxicity, 7% grade III dermatitis, 20% III diarrhea, 13% grade III rash

Arias de la Vega et al. [181]
2011
Phase I
13
LA-HNSCC
63 Gy + Cis adjuvant
Grade III/IV: Mucositis 54%, Asthenia 15%, skin 23%, diarrhea 15%.

Lind et al. [182]
2009
Phase I
11
NSCLC, brain metastases
WBRT (30 Gy)
9% grade III rash/fatigue

Dobelbower et al. [183]
2006
Phase I
11
Esophageal cancer
50.4 Gy + 5-FU
36% pts grade III + IV leukopenia, 9% grade III anemia, 9% grade III thrombopenia, 18% grade III + IV neutropenia, 27% grade III dehydration, 9% grade III nausea, 9% grade III/9% grade IV esophagitis

Silvano et al. [82]
2008
Case report
1
NSCLC
2 × 8 Gy
Death caused by fatal diarrhea

Huang et al. [184]
2008
Case study
1
NSCLC
WBRT 37.5 Gy
Death caused by exacerbated radiodermatitis and subdural hemorrhage

mTOR inhibitors (Sirolimus)
Sarkaria et al. [185]
2007
Phase I
7
NSCLC
60 Gy + CisPt weekly
14% grade III dysphagia, esophagitis, febrile neutropenia, pneumonia

Bourgier et al. [186]
2011
Case reports
3
Breast/prostate/ovary cancer
45 Gy/70 Gy, later
Gastrointestinal radiation recall syndrome with everolimus/temsirolimus

N-number of patients, pt(s)-patient(s), n. r.-not reported, ChTx-chemotherapy, HCC-hepatocellular carcinoma, RCC-renal cell cancer, GBM-glioblastoma multiforme, DVT-deep vein thrombosis, Fx-fractions, SRS-stereotactic radiosurgery, DLT-dose limiting toxicity, LA-locally advanced, Gem-gemcitabine, Tax-Taxol (paclitaxel), Tx-therapy, TMZ-temozolomide, PCP-Pneumocystis pneumonia, Cis-cisplatin, Eto-etoposide,

[Back]

[Back]

Table 4.

Studies on thalidomide and derivatives.

Substance | Author(s) | Year | Study type | N | tumour | RT dose/ChTx/technique | Toxicity
Thalidomide | Knisely et al. [93] | 2008 | Phase III | 332 (90 thalidomide) | Brain metastases | 37,5 Gy (2,5 Gy) | 53% interruptions because of side-effects
| Chang et al. [187] | 2004 | Phase II | 67 | GBM | 60 Gy (2 Gy), TMZ concomitant | 10% grade III + IV neutropenia, 1% grade V; 16% grade III + IV thrombopenia, 9% grade III + IV rash, 1% grade III constipation, 9% grade III fatigue
| Atkins et al. [188] | 2008 | Phase II | 39 | CNS metastases (melanoma) | 30 Gy (3 Gy) WBRT + TMZ concomitant | 10% grade III + IV + V thrombosis, 5% grade III + IV + V myelosuppression, 8% grade III + IV + V cardiac events
| Ch'ang et al. [189] | 2011 | Phase II | 24 | HCC | 50 Gy (2 Gy) | 54% rash, 38% somnolence, 33% constipation
| Turner et al. [97] | 2007 | Phase II | 13 | Brainstem glioma + GBM | 55.8 Gy (1.8 Gy) | 8% grade IV DVT, ≥ 15% grade III leukopenia/motoneuropathy/constipation
Lenalidomide | Drappatz et al. [101] | 2009 | Pilot study | 23 | GBM | 60 Gy (2 Gy) | 4% grade IV pneumonitis/hypoxia, 9% grade III nausea, 4% grade IV pulmonary embolism, 4% grade III pneumonia

N-number of patients, pt(s)-patient(s), n. r.-not reported, ChTx-chemotherapy, LA-HNSCC-locally advanced head-and-neck cancer, GBM-glioblastoma multiforme, DVT-deep vein thrombosis

[Back]