Radiotherapy & Oncology

Editorial Board

2010-01-01

Editorial Board

2010-01-01

Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implications

2010-01-14

Abstract: Purpose: To analyze the patterns of failure, the toxicity profile, and the factors influencing efficacy of stereotactic body radiation (SBRT) for early-stage non-small-cell lung cancer (NSCLC).Methods and materials: A search was based on PubMed electronic databases. All searches were conducted in May, 2009.Results: The local control ranged from 80% to 100% in most studies with adequate isocentric or peripheral biologically effective dose (BED). Recurrences were associated with increased tumor size. The main pattern of failure after SBRT was distant metastasis. Grades 3–5 toxicity occurred mostly in centrally located tumors, and adjuvant chemotherapy may further decrease all recurrences; possibly translating to a survival benefit in large or centrally located tumors where high BED cannot be safely reached.Conclusion: SBRT is an excellent treatment option for early-stage, and mostly medically inoperable, NSCLC. BED at both the isocenter and the tumor periphery is very important for optimal tumor control; higher doses are required for large (⩾T2) lesions; SBRT for centrally located tumors can be feasible with a much less aggressive dose regimen than 60–66Gy/3 fractions and adjacent critical structures excluded from the target volume; chemotherapy may optimize the clinical outcome in large or centrally located lesions.

Review of intraoperative imaging and planning techniques in permanent seed prostate brachytherapy

2010-01-14

Abstract: Techniques for permanent low dose rate seed brachytherapy for prostate cancer have evolved in the recent years with increasing use of interactive planning in the operating room (OR) during seed placement. This overcomes one of the main sources of error in the original two-stage technique in which a planning study performed at a time distant from the implant is used to define seed positions and then an attempt to reproduce this at the time of implant is required. This review addresses the various ways in which real-time dosimetry may be used. Three basic approaches are described; intraoperative planning when a plan is produced as a separate stage prior to the implant during a single OR procedure, interactive planning which incorporates stepwise modification of the treatment plan based on feedback from real-time tracking of the actual needle positions and dynamic dose calculation in which there is a continuous updating of the dosimetry using continuous feedback of the seed positions as they are implanted. The impact of these changes on dosimetric and biochemical outcome endpoints is considered demonstrating the superior results which can be obtained by closer integration of the planning processes with actual implantation and seed deposition.

I-125 seed planning: An alternative method of urethra definition

2009-12-14

Abstract: Background and purpose: To investigate the use of aerated aqueous gel rather than a catheter to define the urethra during permanent I-125 seed implant planning.Materials and methods: Twenty patients were treated between September 2007 and March 2008, each having two sequential volume studies: one visualizing the urethra with a catheter and the other using aerated gel. Two individually optimised plans were produced for each patient: one from the gel and the other from the catheter image set, and the plans were analysed dosimetrically. The plans were also interchanged (putting gel plan onto catheter image set and vice versa), and dose homogeneity within a slice was investigated. Three patients had MRI post-implant to check urethral position and dosimetry.Results: The urethra appears larger when defined with gel rather than when defined with a catheter, with volumes of 0.9±0.3 [range: 0.6–1.6]cc and 0.7±0.2 [range: 0.4–1.0]cc, respectively. Catheter plans appear dosimetrically slightly preferable to gel plans with V100 prostate being 99.7±0.2 [range: 99.3–100.0]% and 99.5±0.5 [range: 98.12–99.9]% for catheter and gel, respectively (p=0.048). The urethra appears to receive a higher dose when defined with gel with V150 being 0.5±0.7 [range: 0–2.8]% and 0.2±0.2 [range: 0–2.6]% for gel- and catheter-defined urethras. Seed density, COIN and number of seeds were almost equivalent. Statistically, only V100 prostate and D90 prostate are significantly different. Putting the catheter plan on the gel image set shows a significant increase in urethral dose with V150 urethra increasing significantly from 0.2±0.2 [range: 0–0.6]% from the catheter plan to 15.3±11.9 [range: 0.8–47.0]% for the catheter plan on gel image set (p<0.001). D90 for the inner core of gel and catheter plans was 193.9±6.7 [range: 180.3–202.3]Gy and 198.7±4.7 [range: 190.7–211.5]Gy (p=0.023). Gel plans are cooler centrally and less homogeneous, which could be counteracted by increasing seed activity and/or prescription dose, though the clinical significance of this should be investigated before implementation.Conclusions: This investigation has shown that the urethral position is distorted by the presence of a urinary catheter. The dosimetry may be different from that planned if this is not taken into account.

HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer

2009-11-12

Abstract: Background: HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC.Materials and methods: Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5years after radiotherapy.Results: Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52–0.93]. Positive expression of p16 also significantly improved outcome after radiotherapy (0.41 [0.28–0.61]). In the subgroup of patients with p16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50–0.95]). However, in the p16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45–1.91]).Conclusions: HPV/p16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/p16-negative tumours but was of no significant benefit in HPV/p16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours.

A prospective observational trial on emesis in radiotherapy: Analysis of 1020 patients recruited in 45 Italian radiation oncology centres

2009-12-07

Abstract: Purpose: A prospective observational multicentre trial was carried out to assess the incidence, pattern, and prognostic factors of radiation-induced emesis (RIE), and to evaluate the use of antiemetic drugs in patients treated with radiotherapy or concomitant radio-chemotherapy. The application in clinical practice of the Multinational Association of Supportive Care in Cancer guidelines was also studied.Materials and methods: Forty-five Italian radiation oncology centres took part in this trial. The accrual lasted for 3 consecutive weeks and only patients starting radiotherapy or concomitant radio-chemotherapy in this period were enrolled. Evaluation was based on diary card filled in daily by patients during treatment and one week after stopping it. Diary card recorded the intensity of nausea/vomiting and prophylactic/symptomatic antiemetic drug prescriptions.Results: A total of 1020 patients entered into the trial, and 1004 were evaluable. Vomiting and nausea occurred in 11.0% and 27.1% of patients, respectively, and 27.9% patients had both vomiting and nausea. In multifactorial analysis, the only statistically significant patient-related risk factors were concomitant chemotherapy and previous experience of vomiting induced by chemotherapy. Moreover, two radiotherapy-related factors were significant risk factors for RIE, the irradiated site (upper abdomen) and field size (>400cm2). An antiemetic drug was given only to a minority (17%) of patients receiving RT, and the prescriptions were prophylactic in 12.4% and symptomatic in 4.6%. Different compounds and a wide range of doses and schedules were used.Conclusions: These data were similar to those registered in our previous observational trial, and the radiation oncologists’ attitude in underestimating RIE and under prescribing antiemetics was confirmed.

Optimizing dose prescription in stereotactic body radiotherapy for lung tumours using Monte Carlo dose calculation

2009-12-21

Abstract: Purpose: To define a method of dose prescription employing Monte Carlo (MC) dose calculation in stereotactic body radiotherapy (SBRT) for lung tumours aiming at a dose as low as possible outside of the PTV.Methods and materials: Six typical T1 lung tumours – three small, three large – were constructed centrally, peripherally in the lung, and nearby the thoracic wall, respectively. For each of these, five treatment plans employing dynamic conformal arc technique were made in which the dose was prescribed to encompass the PTV with the prescription isodose level (PIL) set in a range between 50% and 80% of the isocenter dose. Three shells of respectively 10mm thickness around the PTV were constructed to assess the dose in the tissues directly adjacent to the PTV.Results: The PTV was nicely covered (mean 98.8%±0.9%) with favourable conformity indices (mean 1.09±0.1). Mean doses around the PTVs were 73% (±1.3%), 76% (±3.5%), and 85% (±5.1%) of the prescribed dose in shell 1 for PIL50%, PIL65%, and PIL80%, respectively; 40% (±2.6%), 44% (±5.1%), 54% (±9.3%) in shell 2; and 24% (±1.9%), 26% (±3.6%), 33% (±6.8%) in shell 3. All normal tissue doses including the integral dose were also consistently worst for PIL80%. Monitor units were 30% higher for PIL65%, and 70% higher for PIL50%, compared with PIL80%.Conclusions: To improve normal tissue sparing the dose should be prescribed at an isodose lower than 80% of the isocenter dose in SBRT when using conformal arc technique with MC dose calculation.

Stereotactic body radiotherapy for unresectable cholangiocarcinoma

Neil Kopek, Marianne Ingerslev Holt, Anders Traberg Hansen, Morten Høyer — 2009-12-07

Abstract: Purpose: To report outcomes of a single institution study of stereotactic body radiotherapy (SBRT) for unresectable cholangiocarcinoma. The dose–volume dependency of the observed gastrointestinal toxicity is explored.Methods and materials: Twenty-seven patients with unresectable cholangiocarcinoma (n=26 Klatskin tumours and one intrahepatic cholangiocarcinoma (IHCC)) were treated by linac-based SBRT. The dose schedule was 45Gy in three fractions prescribed to the isocenter.Results: The median progression-free survival and overall survival were 6.7 and 10.6months, respectively. With a median follow-up of 5.4years, 6 patients had severe duodenal/pyloric ulceration and 3 patients developed duodenal stenosis. Duodenal radiation exposure was higher in patients developing moderate to high-grade gastrointestinal toxicity with the difference in mean maximum dose to 1cm3 of duodenum reaching statistical significance. A statistically significant association between grade⩾2 ulceration and volume of duodenum exposed to selected dose levels was not established.Conclusion: The outcomes of SBRT for unresectable cholangiocarcinoma appear comparable to conventionally fractionated chemoradiotherapy with or without brachytherapy boost. The practical advantages of SBRT are of particular interest for such poor prognosis patients. Patient selection, however, is key in order to avoid compromising such practical gains with excessive gastrointestinal toxicity.

Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer

2010-01-15

Abstract: Purpose: To evaluate outcome of radiotherapy for locally recurrent cervical and endometrial cancer.Materials and methods: Nineteen patients were treated for a locally recurrent cervical (n=12) or endometrial (n=7) cancer median 26months after initial surgery (n=18) or radiotherapy (n=1). The whole pelvis was irradiated with 50Gy conventionally fractionated radiotherapy (n=16). Because of large size of the recurrent cancer (median 4.5cm) and peripheral location (n=12), stereotactic body radiotherapy (SBRT; median 3 fractions of 5Gy to 65%) was used for local dose escalation instead of (n=16) or combined with (n=3) vaginal brachytherapy.Results: After median follow-up of 22months, 3-year overall survival was 34% with systemic progression the leading cause of death (7/10). Median time to systemic progression was 16months. Three local recurrences resulted in a local control rate of 81% at 3years. No correlation between survival, systemic or local control and any patient or treatment characteristic was observed. The rate of late toxicity>grade II was 25% at 3years: two patients developed a grade IV intestino-vaginal fistula and one patient suffered from a grade IV small bowel ileus.Conclusion: Image-guided SBRT for local dose escalation resulted in high rates of local control but was associated with significant late toxicity.

A treatment planning study comparing helical tomotherapy with intensity-modulated radiotherapy for the treatment of anal cancer

2009-11-06

Abstract: Purpose: A planning study to compare helical tomotherapy (HT) and intensity-modulated radiotherapy (IMRT) for the treatment of anal canal cancer.Materials and methods: Sixteen (8 males and 8 females) patients with anal cancer previously treated radically were identified. HT and IMRT plans were generated and dosimetric comparisons of the plans were performed. The planning goals were to deliver 54Gy to the tumor (PTV54Gy) and 48Gy to the nodes at risk (PTVNode) in 30 fractions.Results: PTVs: HT plans were more homogeneous for both men and women. Male patients: HT vs. IMRT: Dmax: 55.87±0.58 vs. 59.17±3.24 (p=0.036); Dmin: 52.91±0.36 vs. 44.09±6.84 (p=0.012); female patients: HT vs. IMRT: Dmax: 56.14±0.71 vs. 59.47±0.81 (p=0.012); Dmin: 52.36±0.87 vs. 50.97±1.42 (p=0.028). OARs: In general, HT plans delivered a lower dose to the peritoneal cavity, external genitalia and the bladder and IMRT plans resulted in greater sparing of the pelvic bones (iliac crest/femur) for both men and women. Iliac crest/femur: the difference was significant only for the mean V10Gy of iliac crest in women (p⩽0.012). External genitalia: HT plans achieved better sparing in women compared to men (p⩽0.046). For men, the mean doses were 18.96±3.17 and 15.72±3.21 for the HT and IMRT plan, respectively (p⩽0.017). Skin: both techniques achieved comparable sparing of the non-target skin (p=NS).Conclusions: HT and IMRT techniques achieved comparable target dose coverage and organ sparing, whereas HT plans were more homogeneous for both men and women.

Re-irradiation of metastatic spinal cord compression: A feasibility study by volumetric-modulated arc radiotherapy for in-field recurrence creating a dosimetric hole on the central canal

2009-12-21

Abstract: When local recurrences arise within an irradiated region involving metastatic spinal cord compression, the dose limit to the spinal cord reduces the chance to re-treat the patient by 3D-conformational RT technique. The possibility of using volumetric modulated arc RT by RapidArc was evaluated for dose sparing at spinal cord level and preserving target coverage. A clinically satisfactory PTV coverage and dose sparing to the spinal cord were obtained. An upcoming trial on patients will provide clinical outcomes.

Quantitative evaluation of cone-beam computed tomography in target volume definition for offline image-guided radiation therapy of prostate cancer

Weihu Wang, Qiuwen Wu, Di Yan — 2009-11-09

Abstract: Purpose: To quantitatively evaluate cone-beam CT (CBCT) in target volume definition in an offline image guidance environment.Methods and materials: Fifteen patients each with five helical CTs (HCT) and eight CBCTs were included. A single physician manually delineated prostate and seminal vesicles (SVs) on each CT. The clinical target volume (CTV) was prostate for low risk group (G1), plus SVs for intermediate risk group (G2). The internal target volumes (ITVs) on CBCT (ITVCBCT) were constructed and compared with ITVHCT. The following comparisons were performed: CTV and ITV in HCT and CBCT; similarity of ITVs using overlap index (OI); surface differences between ITVs; quality assurance of ITVCBCT using CTV from weekly CBCT; and dosimetric evaluations of ITVHCT coverage on plans from ITVCBCT.Results: There was no statistical significant difference of CTV or ITV. The ITV OIs were 91%/88% for G1/G2 patients. They improved significantly with 1–2mm margins. Therefore, the ITVs were mostly within 2mm. The CTVs from weekly CBCT had >95% overlap with ITVCBCT. The ITV dose differences (D95, and Dmean) were <0.3%.Conclusions: It is feasible to use CBCT for target definition in offline image guidance, thereby eliminating the separate helical CT scan process.

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy

2009-11-13

Abstract: Background and purpose: KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established.Materials and methods: DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1–3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters.Results: Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p=0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p=0.012).Conclusion: We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

Endogenous and radiation-induced expression of γH2AX in biopsies from patients treated for carcinoma of the uterine cervix

2009-11-11

Abstract: Background and purpose: The possibility of using γH2AX foci as a marker of DNA damage and as a potential predictor of tumour response to treatment was examined using biopsies from 3 sets of patients with advanced carcinoma of the cervix. The relation between endogenous γH2AX expression and hypoxia was also examined.Materials and methods: Set 1 consisted of 26 biopsies that included pre-treatment and 24h post-radiation treatment samples. Pre-treatment biopsies from 12 patients in Set 2 were used to develop image analysis software while pre-treatment biopsies from 33 patients in Set 3 were examined for the relation between staining for the hypoxia marker pimonidazole and endogenous γH2AX expression. Formalin-fixed paraffin-embedded sections were analyzed after antigen retrieval and fluorescence antibody labeling for the hypoxia markers CAIX or pimonidazole in combination with γH2AX staining.Results: Before treatment, 24±19% of cells contained γH2AX foci, with most positive cells containing fewer than 5 foci per nucleus. Twenty-four hours after exposure to the first fraction of 1.8–2.5Gy, 38±19% contained foci. CAIX positive cells were 1.4 times more likely to exhibit endogenous γH2AX foci, and pimonidazole-positive cells were 2.8 times more likely to contain γH2AX foci. For 18 patients for whom both pre-treatment and 24h post-irradiation biopsies were available, local control was unrelated to the fraction of cells that retained γH2AX foci. However, 24h after irradiation, tumours that had received 2.5Gy showed a significantly higher fraction of cells with residual γH2AX foci than tumours given 1.8Gy.Conclusions: Endogenous γH2AX foci are enriched in hypoxic tumour regions. Small differences in delivered dose can produce quantifiable differences in residual DNA damage that can overshadow inter-tumour differences in response.

A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis

2009-11-23

Abstract: Background and purpose: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive γH2AX response exists in human epidermis. The aim of this study was to investigate the dose–response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions.Materials: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1Gy were biopsied on the same occasion to determine dose–response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and γH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis.Results: The individual dose–response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7weeks of radiotherapy (p<0.01). Growth arrest and cell proliferation assessed at 1week and 6.5weeks showed, in both cases, hypersensitive increase of p21 (p<0.01) and hypersensitive depression of mitosis (p<0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell death was infrequent but increased significantly between 1 and 6.5weeks and displayed a hypersensitive dose–response at the end of the treatment period.Conclusions: A low-dose hypersensitivity in basal skin keratinocyte reduction is present throughout 7weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect.

Glycolytic metabolism and tumour response to fractionated irradiation

2009-12-28

Abstract: Background and purpose: To study whether pre-therapeutic lactate or pyruvate predict for tumour response to fractionated irradiation and to identify possible coherencies between intermediates of glycolysis and expression levels of selected proteins.Materials and methods: Concentrations of lactate, pyruvate, glucose and ATP were quantified via bioluminescence imaging in tumour xenografts derived from 10 human head and neck squamous cell carcinoma (HNSCC) lines. Tumours were irradiated with 30 fractions within 6weeks. Expression levels of the selected proteins in tumours were measured at the mRNA and protein level. Tumour-infiltrating leucocytes were quantified after staining for CD45.Results: Lactate but not pyruvate concentrations were significantly correlated with tumour response to fractionated irradiation. Lactate concentrations in vivo did not reflect lactate production rates in vitro. Metabolite concentrations did not correlate with GLUT1, PFK-L or LDH-A at the transcriptional or protein level. CD45-positive cell infiltration was low in the majority of tumours and did not correlate with lactate concentration.Conclusions: Our data support the hypothesis that the antioxidative capacity of lactate may contribute to radioresistance in malignant tumours. Non-invasive imaging of lactate to monitor radiation response and testing inhibitors of glycolysis to improve outcome after fractionated radiotherapy warrant further investigations.

Radiocontrast media affect radiation-induced DNA damage repair in vitro and in vivo by affecting Akt signalling

Mahmoud Toulany, Rainer Kehlbach, H. Peter Rodemann, Hossein Mozdarani — 2009-12-14

Abstract: Purpose: The study was performed to investigate cytogenetic effects of ionic and non-ionic radiocontrast media (RCM) meglumine, iohexol alone and in combination with irradiation in mouse bone marrow cells in vivo and in vitro.Materials and methods: Micronuclei assay was performed in bone marrow cells (BMC) of Balb/C mice intraperitoneally injected with RCM in the presence or absence of whole-body irradiation of 50mGy. DNA repair (NHEJ) signalling and efficiency were analyzed by Western blot and γH2AX-foci assay in normal fibroblast HSF-7 and HUVEC cells.Results: Both compounds reduced proliferation of BMC significantly. Concentrations of 0.5, 1 and 2ml/kg meglumine or iohexol significantly enhanced the frequency of micronucleated polychromatic erythrocytes (MnPCEs) at all doses of meglumine (p<0.01) and 2ml/kg of iohexol (p<0.05). Combined with irradiation meglumine at 0.5 and 1ml/kg led to a higher frequency of MnPCEs than iohexol/IR (p<0.05). Meglumine induced DNA-double strand breaks (DNA-DSB) in non-irradiated HSF and strongly increased residual DNA-DSB within 10min to 24h after irradiation with 200 or 400mGy (p<0.001). Iohexol did not induce DNA-DSB but blocked repair of radiation-induced DNA-DSB significantly (p<0.05). Meglumine blocked IR-induced Akt phosphorylation, phosphorylation of DNA-PKcs (S2056, T2609) and ATM (S1981). Iohexol only blocked phosphorylation of Akt and DNA-PKcs at S2056.Conclusion: RCM result in clastogenic effects through interference intracellular signalling cascades involved in the regulation of non-homologous end-joining repair of DNA-DSB.

Establishment of a radiogenomics consortium

Catharine West, Barry S. Rosenstein — 2010-01-14

A Radiogenomics Consortium was established in Manchester, United Kingdom November 17–18th 2009 in conjunction with the 15th LH Gray Workshop with investigators from throughout the world participating in the conference. The unifying interest of these researchers is the identification of genetic variants, primarily single nucleotide polymorphisms (SNPs), associated with the development of normal tissue toxicities resulting from radiation therapy. There are two overall goals for this field of research. The first is to develop an assay capable of predicting which cancer patients are most likely to develop radiation injuries resulting from treatment with a standard radiotherapy protocol. The second aim is to obtain information to assist with the elucidation of the molecular pathways responsible for radiation-induced normal tissue toxicities through identification of genes possessing SNPs associated with the development of radiation-induced adverse effects.

Re the article: “Impact of the boost dose of 10Gy versus 26Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. On behalf of the EORTC Radiation Oncology and Breast Cancer Groups. Radiother Oncol 2009;90:80–5”

Anusheel Munshi — 2009-09-14

Dr. Poortmans and his colleagues need to be complimented for conducting and reporting the EORTC 22881-10882 ‘‘boost” trial . This trial addresses a very relevant issue for the breast radiation oncologists. It investigates the relevance of a boost dose to the primary tumour site after lumpectomy and whole breast irradiation. Intuitively it can be stated that higher doses should lead to significantly better local control rates. In this context, the results of the trial are provocative indeed.

Philip Poortmans, Harry Bartelink, Laurence Collette — 2009-09-27

We appreciate the opportunity to address the items raised by Dr. Anusheel Munshi . First of all we would like to mention that this trial was conducted from 1989 to 1996 and that the obtained results should be seen within that timeframe. When the trial was designed, the attention was focussed on infiltration of the margin by invasive tumour only. Therefore, we randomized patients in two different groups, according to the result supplied by the local pathologist: (1) with a complete excision of the invasive tumour and (2) with a microscopically incomplete excision of the primary tumour. Patients who underwent a re-excision with final tumour-free margins could only be randomized in the first patient category. Probably due to the increased attention to the requirement of obtaining a complete excision before initiating whole breast irradiation, much less patients than we anticipated in our statistical assumptions were randomized in the incomplete excision part of the trial. Therefore, we mentioned in our publication that indeed the number of patients is one of the most important limitations of this report and limited us to firmly conclude that a higher radiation dose is of benefit for patients with an incomplete excision. Moreover, it limited us to further split our patient groups in subgroups.

Concurrent trastuzumab – Internal mammary irradiation for HER2 positive breast cancer: “It hurts to be on the cutting edge”

Yazid Belkacémi, Joseph Gligorov — 2009-05-04

In regard to Richard Shaffer et al. Re: 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. Radiother Oncol 2009; 90: 122–6.

In response to Dr Belkacemi et al.

Scott Tyldesley, Richard Shaffer, Islam Mohamed, Stephen Chia, Martin Rolles — 2009-05-04

We thank Dr Belkacemi et al. for their thoughtful comments and analysis. Their arguments are more in agreement with our own than in contrast to them. We also recommend that T and IMC radiotherapy should be used concurrently with caution until long-term toxicity results are available.

High doses per fraction and the linear-quadratic model

Adel Courdi — 2009-11-05

The paper by Gay et al. is a useful and well documented contribution, aiming at drawing attention to the effects of high doses per fraction on normal tissue response, and provides useful guidelines to minimize late effects by formulating normal tissue isodose constraints . Yet the authors have assumed that the linear-quadratic (LQ) model is valid up to a dose per fraction (d/f) of 28Gy. They cited a previous review and a letter in which the LQ model was considered as the best model «at present» for fitting at high d/f . However, the review was published more than 15years ago and the letter referred to data in the seventies and eighties. Nowadays it can hardly be assumed that the LQ model is appropriate to estimate the effect at a d/f of 28Gy. Experimental data suggest that at high doses the survival curve asymptotically approaches the straight line . An extrapolation beyond a dose as low as 6Gy would lack clinically useful precision. Moreover, a recent report demonstrates that the two-component (TC) model is likely to better fit the effect at high d/f . The TC model predicts higher tolerance doses at high d/f; in other words, the LQ model underestimates normal tissue tolerance at high d/f. Indeed the authors admit that the LQ model would give a conservative estimation, with the resulting selected constraints being more stringent than necessary. However, those values may be far from those expected, and those actually applied. According to the LQ model, a single dose of 28Gy would be equivalent to 210Gy on nervous tissue and to 174Gy on bronchial tissue, if converted to conventional fractionation, a too high equivalent dose. A common fractionation schedule in lung tumours treated with stereotactic radiotherapy using the Cyberknife is 3 fractions of 20Gy, with acceptable toxicity . With an α/β ratio of 3Gy for bronchial stenosis, the LQ model predicts in that case an equivalence of 276Gy given conventionally, much exceeding the 70Gy carrying 5% risk of bronchial stenosis as the authors correctly emphasized. Gay et al. stated: «it is unlikely that there will be any statistically significant definitive dose volume data for these endpoints in the near future». On the contrary, results with very high d/f, hypofractionated schedules using these new modalities will highly contribute refining the dose–effect relationship at these high d/f and high total doses.

Role of the linear-quadratic model in high doses per fraction

H. Gay — 2009-09-22

We thank Dr. Courdi for his comments, and he correctly points that the sentence on page 370 should have said: “…a biologically effective dose of 80Gy…”. The assumption that the linear-quadratic (LQ) model is valid up to 28Gy was arbitrarily chosen for consistency because in Table 2 the largest dose per fraction obtained with the model was “27.79Gy”. Fowler et al. have made similar assumptions for theoretical analyses . Our assumption should not be misinterpreted that we endorse this as fact. Quite the opposite, regarding tumor control we cannot emphasize enough that the clinicians should select hypofractionated regimens based on the published results showing efficacy and safety or as part of a clinical trial. This is because the LQ model could overestimate the effectiveness of the calculated regimen resulting in suboptimal local control.

TNF and oral mucositis: Response to effect of selective inhibitors of inflammation on oral mucositis: Preclinical studies. Radiother Oncol 2009; 92:472–6

Barbara S. Fox, Stephen Sonis — 2010-01-15

To the Editor, We read with interest the article by Haagen et al. in which the authors reported that inhibitors of TNF or COX-2 did not attenuate radiation-induced oral mucositis in a murine model. Based on their findings, the authors concluded that inflammatory processes did not significantly influence the incidence or course of oral mucositis.

In response to Fox and Sonis

J. Haagen, M. Schmidt, K. Wolfram, Wolfgang Dörr — 2010-01-14

To the Editor, We appreciate the interest of Fox and Sonis in our article reporting results on the effect of inhibitors of inflammation on radiation-induced oral mucositis in our mouse model . In this study, neither inhibition of TNF-α (by the antibody infliximab) nor of COX-2 (by the tyrosine kinase inhibitor celecoxib) resulted in modulation of the epithelial response of oral mucosa during fractionated irradiation. The conclusion from these observations was that those inflammatory changes mediated through TNF-α or COX-2 are not relevant for the radiation effects of oral epithelium. In their letter, Fox and Sonis stress that one explanation for the missing effect of infliximab (not of celecoxib) might be a lack of cross-reactivity with murine TNF-α. This possibility was discussed in the original paper , where we explained that infliximab (administered in protocols comparable to those used in our study) was effective in a number of mouse models of various diseases, such as diabetes , aortic transplant arteriosclerosis or bone marrow transplantation . Moreover, infliximab was demonstrated to be effective in further mouse model, e.g. for allergenic asthma , antigen-induced arthritis or aortic aneurisms . We consider it highly unlikely that the observed results in these models are all based on unspecific effects of infliximab. Hence, our conclusion that the TNF-α signaling cascades are of minor or no relevance for the manifestation of epithelial ulcers appears justified.

Important ESTRO dates

2010-01-01

Radiotherapy & Oncology

Editorial Board

Editorial Board

Contents

Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implications

Review of intraoperative imaging and planning techniques in permanent seed prostate brachytherapy

I-125 seed planning: An alternative method of urethra definition

HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer

A prospective observational trial on emesis in radiotherapy: Analysis of 1020 patients recruited in 45 Italian radiation oncology centres

Optimizing dose prescription in stereotactic body radiotherapy for lung tumours using Monte Carlo dose calculation

Stereotactic body radiotherapy for unresectable cholangiocarcinoma

Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer

A treatment planning study comparing helical tomotherapy with intensity-modulated radiotherapy for the treatment of anal cancer

Re-irradiation of metastatic spinal cord compression: A feasibility study by volumetric-modulated arc radiotherapy for in-field recurrence creating a dosimetric hole on the central canal

Quantitative evaluation of cone-beam computed tomography in target volume definition for offline image-guided radiation therapy of prostate cancer

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy

Endogenous and radiation-induced expression of γH2AX in biopsies from patients treated for carcinoma of the uterine cervix

A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis

Glycolytic metabolism and tumour response to fractionated irradiation

Radiocontrast media affect radiation-induced DNA damage repair in vitro and in vivo by affecting Akt signalling

Establishment of a radiogenomics consortium

Concurrent trastuzumab – Internal mammary irradiation for HER2 positive breast cancer: “It hurts to be on the cutting edge”

In response to Dr Belkacemi et al.

High doses per fraction and the linear-quadratic model

Role of the linear-quadratic model in high doses per fraction

TNF and oral mucositis: Response to effect of selective inhibitors of inflammation on oral mucositis: Preclinical studies. Radiother Oncol 2009; 92:472–6

In response to Fox and Sonis

Important ESTRO dates