Raphaël Moeckli

CYR61 and αVβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.

Objective comparison of image quality and dose between conventional and synchrotron radiation mammography

The shape of the energy spectrum produced by an x-ray tube has a great importance in mammography. Many anode-filtration combinations have been proposed to obtain the most effective spectrum shape for the image quality-dose relationship. On the other hand, third generation synchrotrons such as the European Synchrotron Radiation Facility in Grenoble are able to produce a high flux of monoenergetic radiation. It is thus a powerful tool to study the effect of beam energy on image quality and dose in mammography. An objective method was used to evaluate image quality and dose in mammography with synchrotron radiation and to compare them to standard conventional units. It was performed systematically in the energy range of interest for mammography through the evaluation of a global image quality index and through the measurement of the mean glandular dose. Compared to conventional mammography units, synchrotron radiation shows a great improvement of the image quality-dose relationship, which is due to the beam monochromaticity and to the high intrinsic collimation of the beam, which allows the use of a slit instead of an anti-scatter grid for scatter rejection.

The reasons for discrepancies in target volume delineation : A SASRO study on head-and-neck and prostate cancers

Purpose:To understand the reasons for differences in the delineation of target volumes between physicians.Material and Methods:18 Swiss radiooncology centers were invited to delineate volumes for one prostate and one head-and-neck case. In addition, a questionnaire was sent to evaluate the differences in the volume definition (GTV [gross tumor volume], CTV [clinical target volume], PTV [planning target volume]), the various estimated margins, and the nodes at risk. Coherence between drawn and stated margins by centers was calculated. The questionnaire also included a nonspecific series of questions regarding planning methods in each institution.Results:Fairly large differences in the drawn volumes were seen between the centers in both cases and also in the definition of volumes. Correlation between drawn and stated margins was fair in the prostate case and poor in the head-and-neck case. The questionnaire revealed important differences in the planning methods between centers.Conclusion:These large differences could be explained by (1) a variable knowledge/interpretation of ICRU definitions, (2) variable interpretations of the potential microscopic extent, (3) difficulties in GTV identification, (4) differences in the concept, and (5) incoherence between theory (i.e., stated margins) and practice (i.e., drawn margins).Ziel:Die Ursachen für die unterschiedliche Markierung der Zielvolumina zwischen Ärzten sollten aufgeklärt werden.Material und Methodik:18 schweizerische onkologische Bestrahlungszentren wurden aufgefordert, die Zielvolumina eines Prostata- und eines HNO-Karzinoms einzuzeichnen. Ein Fragebogen wurde zusätzlich beigefügt, um die Unterschiede in der Definition der Volumina (GTV [„gross tumor volume“], CTV [klinisches Zielvolumen], PTV [Planungszielvolumen]) sowie in der Bestimmung der Sicherheitssäume und der Risiko-Lymphknotenstationen abzuschätzen. Die Kohärenz zwischen gezeichneten und geplanten Sicherheitssäumen wurde berechnet. Der Fragebogen umfasste auch eine Reihe unspezifischer Fragen bezüglich Planungsmethoden in der jeweiligen Klinik.Ergebnisse:Es wurden ziemlich große Unterschiede zwischen gezeichneten und geplanten Sicherheitssäumen festgestellt. Die Korrelation war beim Prostatakarzinom mäßig, beim HNO-Fall schwach. Der Fragebogen offenbarte erhebliche Unterschiede in den Planungsmethoden zwischen den verschiedenen Kliniken.Schlussfolgerung:Diese großen Unterschiede ließen sich durch unterschiedliche Kenntnis/Interpretation 1. der ICRU-Definitionen und 2. der möglichen mikroskopischen Tumorausdehnung, 3. Schwierigkeiten bei der GTV-Erfassung, 4. Unterschiede bezüglich des Konzepts und 5. Inkohärenz zwischen Theorie (d.h. geplante Sicherheitssäume) und Praxis (d.h. gezeichnete Sicherheitssäume) erklären.

Decreased Local Control Following Radiation Therapy Alone in Early-Stage Glottic Carcinoma with Anterior Commissure Extension*

Purpose:To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx.Patients and Methods:Between 1983–2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35–92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60–74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21–79 days). Median follow-up period was 85 months.Results:The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5–58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control.Conclusion:For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.Ziel:Ergründung der Versagensmechanismen bei der Therapie des Larynxkarzinoms im Frühstadium.Patienten und Methodik:Zwischen 1983 und 2000 wurden 122 konsekutive Patienten, die wegen eines Larynxkarzinoms (UICC T1N0 und T2N0) eine Strahlentherapie erhielten, retrospektiv untersucht. Das Verhältnis von Frauen zu Männern betrug 106 : 16, das mittlere Alter lag bei 62 Jahren. Es handelte sich um 68 Patienten mit T1a-, 18 mit T1b- und 36 mit T2-Tumoren. Die Diagnose wurde bei 104 Patienten mit Hilfe einer Biopsie und bei 18 Patienten mit Laservaporisation oder Stripping gestellt. Bei 49 Patienten (40%) bestand die Behandlungsplanung aus einer dreidimensionalen konformalen Strahlentherapie, einschließlich neun Patienten, die unter Arytänoidprotektion bestrahlt wurden. Die mittlere Dosis von 70 Gy (60–74 GT) wurde über einen mittleren Zeitraum von 46 Tagen verabreicht. Die mittlere Nachbehandlungszeit erstreckte sich über 85 Monate.Ergebnisse:Das 5-Jahres-Überleben betrug 80%. Das tumorspezifische 5-Jahres-Überleben lag bei 94%, und 70% der Patienten blieben während dieses Zeitraums erkrankungsfrei. 83% wiesen nach 5 Jahren kein Lokalrezidiv auf. Der mittlere Zeitraum bis zum Auftreten eines lokalen Rückfalls belief sich bei 19 Patienten auf 13 Monate (5–58 Monate). Die Rezidivbehandlung bestand bei 17 Patienten aus einem chirurgischen Eingriff (ein Patient lehnte die Rezidivbehandlung ab, ein anderer war inoperabel; totale Laryngektomie bei elf und partielle Laryngektomie bzw. Kordektomie bei sechs Patienten). Sechs Patienten starben an ihrem Larynxkarzinom. Eine einseitige Varianzanalyse zeigte, dass die Ausbreitung auf die vordere Kommissur, die Arytänoidprotektion oder eine Strahlendosis < 66 Gy die Prognose der Lokalrezidive verschlechterte. Eine Multivarianzanalyse (Cox-Modell) belegte, dass unter den berücksichtigten Faktoren die Ausbreitung auf die vordere Kommissur, die Protektion des Aryknorpels und männliches Geschlecht die schlechtesten unabhängigen Prognosefaktoren im Hinblick auf Lokalrezidive sind.Schlussfolgerung:Beim Larynxkarzinom im Frühstadium erbringt die Strahlentherapie hervorragende Ergebnisse. Im Fall einer Ausbreitung auf die vordere Kommissur ist ein chirurgischer Eingriff oder eine höhere Strahlendosis erforderlich. Wegen des hohen Rezidivrisikos sollte keine Protektion des Aryknorpels vorgenommen werden.

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: Implications for secondary cancer risk assessment

BACKGROUND AND PURPOSE To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). MATERIALS AND METHODS Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. RESULTS Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. CONCLUSIONS In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

The Reasons for Discrepancies in TargetVolume Delineation

Purpose:To understand the reasons for differences in the delineation of target volumes between physicians.Material and Methods:18 Swiss radiooncology centers were invited to delineate volumes for one prostate and one head-and-neck case. In addition, a questionnaire was sent to evaluate the differences in the volume definition (GTV [gross tumor volume], CTV [clinical target volume], PTV [planning target volume]), the various estimated margins, and the nodes at risk. Coherence between drawn and stated margins by centers was calculated. The questionnaire also included a nonspecific series of questions regarding planning methods in each institution.Results:Fairly large differences in the drawn volumes were seen between the centers in both cases and also in the definition of volumes. Correlation between drawn and stated margins was fair in the prostate case and poor in the head-and-neck case. The questionnaire revealed important differences in the planning methods between centers.Conclusion:These large differences could be explained by (1) a variable knowledge/interpretation of ICRU definitions, (2) variable interpretations of the potential microscopic extent, (3) difficulties in GTV identification, (4) differences in the concept, and (5) incoherence between theory (i.e., stated margins) and practice (i.e., drawn margins).Ziel:Die Ursachen für die unterschiedliche Markierung der Zielvolumina zwischen Ärzten sollten aufgeklärt werden.Material und Methodik:18 schweizerische onkologische Bestrahlungszentren wurden aufgefordert, die Zielvolumina eines Prostata- und eines HNO-Karzinoms einzuzeichnen. Ein Fragebogen wurde zusätzlich beigefügt, um die Unterschiede in der Definition der Volumina (GTV [„gross tumor volume“], CTV [klinisches Zielvolumen], PTV [Planungszielvolumen]) sowie in der Bestimmung der Sicherheitssäume und der Risiko-Lymphknotenstationen abzuschätzen. Die Kohärenz zwischen gezeichneten und geplanten Sicherheitssäumen wurde berechnet. Der Fragebogen umfasste auch eine Reihe unspezifischer Fragen bezüglich Planungsmethoden in der jeweiligen Klinik.Ergebnisse:Es wurden ziemlich große Unterschiede zwischen gezeichneten und geplanten Sicherheitssäumen festgestellt. Die Korrelation war beim Prostatakarzinom mäßig, beim HNO-Fall schwach. Der Fragebogen offenbarte erhebliche Unterschiede in den Planungsmethoden zwischen den verschiedenen Kliniken.Schlussfolgerung:Diese großen Unterschiede ließen sich durch unterschiedliche Kenntnis/Interpretation 1. der ICRU-Definitionen und 2. der möglichen mikroskopischen Tumorausdehnung, 3. Schwierigkeiten bei der GTV-Erfassung, 4. Unterschiede bezüglich des Konzepts und 5. Inkohärenz zwischen Theorie (d.h. geplante Sicherheitssäume) und Praxis (d.h. gezeichnete Sicherheitssäume) erklären.

Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension.

Purpose:To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx.Patients and Methods:Between 1983–2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35–92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60–74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21–79 days). Median follow-up period was 85 months.Results:The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5–58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control.Conclusion:For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.Ziel:Ergründung der Versagensmechanismen bei der Therapie des Larynxkarzinoms im Frühstadium.Patienten und Methodik:Zwischen 1983 und 2000 wurden 122 konsekutive Patienten, die wegen eines Larynxkarzinoms (UICC T1N0 und T2N0) eine Strahlentherapie erhielten, retrospektiv untersucht. Das Verhältnis von Frauen zu Männern betrug 106 : 16, das mittlere Alter lag bei 62 Jahren. Es handelte sich um 68 Patienten mit T1a-, 18 mit T1b- und 36 mit T2-Tumoren. Die Diagnose wurde bei 104 Patienten mit Hilfe einer Biopsie und bei 18 Patienten mit Laservaporisation oder Stripping gestellt. Bei 49 Patienten (40%) bestand die Behandlungsplanung aus einer dreidimensionalen konformalen Strahlentherapie, einschließlich neun Patienten, die unter Arytänoidprotektion bestrahlt wurden. Die mittlere Dosis von 70 Gy (60–74 GT) wurde über einen mittleren Zeitraum von 46 Tagen verabreicht. Die mittlere Nachbehandlungszeit erstreckte sich über 85 Monate.Ergebnisse:Das 5-Jahres-Überleben betrug 80%. Das tumorspezifische 5-Jahres-Überleben lag bei 94%, und 70% der Patienten blieben während dieses Zeitraums erkrankungsfrei. 83% wiesen nach 5 Jahren kein Lokalrezidiv auf. Der mittlere Zeitraum bis zum Auftreten eines lokalen Rückfalls belief sich bei 19 Patienten auf 13 Monate (5–58 Monate). Die Rezidivbehandlung bestand bei 17 Patienten aus einem chirurgischen Eingriff (ein Patient lehnte die Rezidivbehandlung ab, ein anderer war inoperabel; totale Laryngektomie bei elf und partielle Laryngektomie bzw. Kordektomie bei sechs Patienten). Sechs Patienten starben an ihrem Larynxkarzinom. Eine einseitige Varianzanalyse zeigte, dass die Ausbreitung auf die vordere Kommissur, die Arytänoidprotektion oder eine Strahlendosis < 66 Gy die Prognose der Lokalrezidive verschlechterte. Eine Multivarianzanalyse (Cox-Modell) belegte, dass unter den berücksichtigten Faktoren die Ausbreitung auf die vordere Kommissur, die Protektion des Aryknorpels und männliches Geschlecht die schlechtesten unabhängigen Prognosefaktoren im Hinblick auf Lokalrezidive sind.Schlussfolgerung:Beim Larynxkarzinom im Frühstadium erbringt die Strahlentherapie hervorragende Ergebnisse. Im Fall einer Ausbreitung auf die vordere Kommissur ist ein chirurgischer Eingriff oder eine höhere Strahlendosis erforderlich. Wegen des hohen Rezidivrisikos sollte keine Protektion des Aryknorpels vorgenommen werden.

Variability of a peripheral dose among various linac geometries for second cancer risk assessment

Second cancer risk assessment for radiotherapy is controversial due to the large uncertainties of the dose-response relationship. This could be improved by a better assessment of the peripheral doses to healthy organs in future epidemiological studies. In this framework, we developed a simple Monte Carlo (MC) model of the Siemens Primus 6 MV linac for both open and wedged fields that we then validated with dose profiles measured in a water tank up to 30 cm from the central axis. The differences between the measured and calculated doses were comparable to other more complex MC models and never exceeded 50%. We then compared our simple MC model with the peripheral dose profiles of five different linacs with different collimation systems. We found that the peripheral dose between two linacs could differ up to a factor of 9 for small fields (5 × 5 cm2) and up to a factor of 10 for wedged fields. Considering that an uncertainty of 50% in dose estimation could be acceptable in the context of risk assessment, the MC model can be used as a generic model for large open fields (≥10 × 10 cm2) only. The uncertainties in peripheral doses should be considered in future epidemiological studies when designing the width of the dose bins to stratify the risk as a function of the dose.

A Monte Carlo-based procedure for independent monitor unit calculation in IMRT treatment plans.

Intensity-modulated radiotherapy (IMRT) treatment plan verification by comparison with measured data requires having access to the linear accelerator and is time consuming. In this paper, we propose a method for monitor unit (MU) calculation and plan comparison for step and shoot IMRT based on the Monte Carlo code EGSnrc/BEAMnrc. The beamlets of an IMRT treatment plan are individually simulated using Monte Carlo and converted into absorbed dose to water per MU. The dose of the whole treatment can be expressed through a linear matrix equation of the MU and dose per MU of every beamlet. Due to the positivity of the absorbed dose and MU values, this equation is solved for the MU values using a non-negative least-squares fit optimization algorithm (NNLS). The Monte Carlo plan is formed by multiplying the Monte Carlo absorbed dose to water per MU with the Monte Carlo/NNLS MU. Several treatment plan localizations calculated with a commercial treatment planning system (TPS) are compared with the proposed method for validation. The Monte Carlo/NNLS MUs are close to the ones calculated by the TPS and lead to a treatment dose distribution which is clinically equivalent to the one calculated by the TPS. This procedure can be used as an IMRT QA and further development could allow this technique to be used for other radiotherapy techniques like tomotherapy or volumetric modulated arc therapy.

106Ruthenium Brachytherapy for Retinoblastoma

PURPOSE To evaluate the efficacy of (106)Ru plaque brachytherapy for the treatment of retinoblastoma. METHODS AND MATERIALS We reviewed a retrospective, noncomparative case series of 39 children with retinoblastoma treated with (106)Ru plaques at the Jules-Gonin Eye Hospital between October 1992 and July 2006, with 12 months of follow-up. RESULTS A total of 63 tumors were treated with (106)Ru brachytherapy in 41 eyes. The median patient age was 27 months. (106)Ru brachytherapy was the first-line treatment for 3 tumors (4.8%), second-line treatment for 13 (20.6%), and salvage treatment for 47 tumors (74.6%) resistant to other treatment modalities. Overall tumor control was achieved in 73% at 1 year. Tumor recurrence at 12 months was observed in 2 (12.5%) of 16 tumors for which (106)Ru brachytherapy was used as the first- or second-line treatment and in 15 (31.9%) of 47 tumors for which (106)Ru brachytherapy was used as salvage treatment. Eye retention was achieved in 76% of cases (31 of 41 eyes). Univariate and multivariate analyses revealed no statistically significant risk factors for tumor recurrence. Radiation complications included retinal detachment in 7 (17.1%), proliferative retinopathy in 1 (2.4%), and subcapsular cataract in 4 (9.7%) of 41 eyes. CONCLUSION (106)Ru brachytherapy is an effective treatment for retinoblastoma, with few secondary complications. Local vitreous seeding can be successfully treated with (106)Ru brachytherapy.