S. Marcié

Dose escalation with 3D-CRT in prostate cancer: French study of dose escalation with conformal 3D radiotherapy in prostate cancer—preliminary results

PURPOSEnTo evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients.nnnMETHODS AND MATERIALSnBetween October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy.nnnRESULTSnResults were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of </=1 ng/mL in the 120 patients who did not receive neoadjuvant androgen-deprivation therapy was significantly higher in the dose-escalation group and was directly related to the dose of radiation given.nnnCONCLUSIONnThis multi-institutional study demonstrated the feasibility of escalating the dose of radiation to 80 Gy in prostate cancer patients.

Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis.

The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pHi)-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX) and LS174Tr cells (inducible knock-down for ca9/ca12) were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pHo manipulations and hypoxia (1% O2) exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pHi-regulating capacity of fibroblasts through inhibition of Na+/H+ exchanger 1 sensitize cells to radiation-induced cell death. Secondly, the pHi-regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50 and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pHi regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pHi-regulating CAs as an anti-cancer strategy.

Oxaliplatin-5-fluorouracil and ionizing radiation: Importance of the sequence and influence of p53 status

Objectives and Methods: The association oxaliplatin (OXA)–5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rγ) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. Results: Both cell lines exhibited similar dose response curves to Rγ alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rγ-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rγ. The results from both calculation methods concurred: the combination of OXA-FUFA with Rγ led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rγ occurring when applied before or at mid-drug application. Conclusions: These results could be taken into consideration for an optimal design of clinical protocols associating Rγ and OXA-FUFA.

CyberKnife stereotactic radiotherapy for spinal tumors: value of computed tomographic myelography in spinal cord delineation.

OBJECTIVEnFor para- and intraspinal tumors, precise spinal cord delineation is critical for CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiotherapy. We evaluated whether computed tomographic (CT) myelography is superior to magnetic resonance imaging (MRI) for accurate spinal cord delineation. Treatment parameters and short-term outcome and toxicity are also presented.nnnMETHODSnThe planning CT scan, the gadolinium-enhanced, T1-weighted, 3-dimensional (3D) fast imaging employing steady-state acquisition MRI scan, and the CT myelogram were fused before volume-of-interest delineation. The planning target volume margin was less than 1 mm using the Xsight Spine tracking system (Accuray). We present data from 11 heavily pretreated patients who underwent CyberKnife stereotactic radiosurgery between November 2006 and January 2008.nnnRESULTSnSpatial resolution was 0.46 and 0.93 mm/pixel for CT myelography and 3D-fast imaging employing steady-state acquisition MRI, respectively. The contrast between cerebrospinal fluid and spinal cord was excellent with CT myelography. A transient postmyelography headache occurred in 1 patient. The mean gross tumor volume was 51.1 mL. The mean prescribed dose was 34 Gy in 4 fractions (range, 2-7 fractions) with 147 beams (range, 79-232 beams) to the 75% reference isodose line (range, 68-80%), covering 95% (range, 86-99%) of the gross tumor volume with a mean conformity index of 1.4 (range, 1.1-1.8). No short-term toxicity on the spinal cord was noted at 1- to 6-months of follow-up.nnnCONCLUSIONnCT myelography was more accurate for spinal cord delineation than 3D-fast imaging employing steady-state acquisition MRI (used for its myelographic effect), particularly in the presence of ferromagnetic artifacts in heavily pretreated patients or in patients with severe spinal compression. Because other MRI sequences (T2 and gadolinium-enhanced T1) provide excellent tumor characterization, we suggest trimodality imaging for spinal tumor treatment to yield submillimetric delineation accuracy. Combined with CyberKnife technology, CT myelography can improve the feasibility of dose escalation or reirradiation of spinal tumors in selected patients, thereby increasing local control while avoiding myelopathy. Further follow-up and prospective studies are warranted.OBJECTIVEFor para- and intraspinal tumors, precise spinal cord delineation is critical for CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiotherapy. We evaluated whether computed tomographic (CT) myelography is superior to magnetic resonance imaging (MRI) for accurate spinal cord delineation. Treatment parameters and short-term outcome and toxicity are also presented. METHODSThe planning CT scan, the gadolinium-enhanced, T1-weighted, 3-dimensional (3D) fast imaging employing steady-state acquisition MRI scan, and the CT myelogram were fused before volume-of-interest delineation. The planning target volume margin was less than 1 mm using the Xsight Spine tracking system (Accuray). We present data from 11 heavily pretreated patients who underwent CyberKnife stereotactic radiosurgery between November 2006 and January 2008. RESULTSSpatial resolution was 0.46 and 0.93 mm/pixel for CT myelography and 3D-fast imaging employing steady-state acquisition MRI, respectively. The contrast between cerebrospinal fluid and spinal cord was excellent with CT myelography. A transient postmyelography headache occurred in 1 patient. The mean gross tumor volume was 51.1 mL. The mean prescribed dose was 34 Gy in 4 fractions (range, 2–7 fractions) with 147 beams (range, 79–232 beams) to the 75% reference isodose line (range, 68–80%), covering 95% (range, 86–99%) of the gross tumor volume with a mean conformity index of 1.4 (range, 1.1–1.8). No short-term toxicity on the spinal cord was noted at 1- to 6-months of follow-up. CONCLUSIONCT myelography was more accurate for spinal cord delineation than 3D-fast imaging employing steady-state acquisition MRI (used for its myelographic effect), particularly in the presence of ferromagnetic artifacts in heavily pretreated patients or in patients with severe spinal compression. Because other MRI sequences (T2 and gadolinium-enhanced T1) provide excellent tumor characterization, we suggest trimodality imaging for spinal tumor treatment to yield submillimetric delineation accuracy. Combined with CyberKnife technology, CT myelography can improve the feasibility of dose escalation or reirradiation of spinal tumors in selected patients, thereby increasing local control while avoiding myelopathy. Further follow-up and prospective studies are warranted.

Renaissance of contact x-ray therapy for treating rectal cancer

Contact x-ray therapy (CXRT) with 50 kV has proven to be an efficient radiation therapy technique to achieve local control and rectal preservation for early rectal adenocarcinoma. Despite these results, CXRT has not been used due to the shortage of the no longer manufactured Philips RT 50™ unit. Recently, a new CXRT machine (Papillon 50™) became available on the market. This machine delivers a beam of 50 kV with a dose rate close to 15 Gy/min and has a percentage depth dose of 50% at 6–7 mm. The applicator size varies from 2–3 cm in diameter. Due to the original design of the main tube, treatment delivery is quick and more comfortable for the patients. An online viewing system incorporated in the tube allows a good visualization of the tumor with improved accuracy of radiation delivery. An international collaborative trial (Contact Endoscopic Microsurgery [CONTEM]) was set up to accrue approximately 300 cases of rectal adenocarcinoma staged T1, T2 or early T3 tumors in the UK, France, Denmark and Sweden. This trial should confirm the role of CXRT in curative treatment with organ preservation for early rectal cancers.

Organ preservation in rectal adenocarcinoma (T1) T2-T3 Nx M0. Historical overview of the Lyon Sud - nice experience using contact x-ray brachytherapy and external beam radiotherapy for 120 patients.

In most institutions, standard treatment of T2-T3 rectal adenocarcinoma is radical surgery using total mesorectal excision (TME) with or without neoadjuvant treatment [radiotherapy or chemoradiotherapy (CRT)]. Abdomino-perineal excision (APE) is considered by most patients as a severe mutilation but even with low anterior resection (LAR) morbidity is not negligible [1]. Further, postoperative mortality, especially in elderly patients is of great concern [2]. To improve quality of life and individualize treatment, an increasing number of experienced colorectal surgeons are advocating organ preservation using CRT followed either by local excision (LE) [3,4] or only close surveillance after clinical complete response (cCR) usually in T2 or ‘ early T3 ’ tumors [5,6]. In Sao Paulo, Habr-Gama has since many years been the pioneer of such an approach recommending careful evaluation of the clinical tumor response [7] using a long interval after the end of CRT. In case of cCR, her strategy is to adopt a ‘ watch and wait ’ (W-W) policy [8]. In Lyon, Papillon using contact x-ray brachytherapy (CXB) alone was able in the 1970s to achieve close to 90% cCR in more than 300 T1 N0 lesions and gave his name to this technique [9]. Since the mid-1980s, CXB was combined with external beam radiation therapy (EBRT) in order to treat, mainly in inoperable patients, T2-3 tumors at higher risk of perirectal nodal extension [10,11]. Similar approaches were used in various French, British and American institutions [12 – 15]. Since the mid-1990s, CXB was progressively abandoned for four reasons: the Philips RT 50 TM Contact machine was not manufactured anymore, technological innovations drove the interest of radiation oncologists towards three-dimensional (3D) image-guided radiotherapy, they progressively lost the clinical expertise of rigid rectoscopy and LE became the primary treatment of malignant polyps or T1N0 tumors. In 2009 a new Contact machine named Papillon 50 TM , producing a similar 50 kV x-ray beam was introduced in UK and France and initiated a renaissance of this technique [16]. We report here an overview of the use of CXB during a time period of 35 years by a homogeneous team of radiation oncologists working successively in CHU Lyon Sud and Centre Antoine Lacassagne in Nice. The report will focus exclusively on the combined treatment using CXB with EBRT to achieve organ preservation in T2 to early T3 rectal adenocarcinomas.

Organ or sphincter preservation for rectal cancer. The role of contact X-ray brachytherapy in a monocentric series of 112 patients

BACKGROUNDnContact X-ray brachytherapy (CXB) has been used at Centre Antoine Lacassagne since 2002 to increase the chance of conservative treatment (organ or sphincter preservation) in rectal cancer. A consecutive series of 112 patients (pts) is reported.nnnMETHODSnThree protocols were used in selected rectal adenocarcinomas. Group 1: T1 N0 treated with local excision (LE) followed by adjuvant CXB. Group 2: T2 or early T3 N0 treated with CXB combined with chemoradiotherapy (CRT) followed by surveillance or LE. Group 3: distal locally advanced T3 N0-2 treated with CXB and CRT before total proctectomy.nnnRESULTSnGroup 1: 27xa0pt (pTis: 3; pT1: 21; pT2: 3). After LE with CXB alone (20xa0pt) or CXBxa0+xa0CRT (7xa0pt) one local recurrence occurred. Organ preservation was achieved in 26xa0pt (96%). Group 2: 45xa0pt (T1: 2; T2: 23; T3: 20) treated with CXB alone (4xa0pt) or CXBxa0+xa0CRT or external beam radiotherapy (EBRT) (41xa0pt). A clinical complete response (cCR) was observed in 43/45 (96%) and 3xa0pt developed a local recurrence (11% at 5 years). The specific survival was 76% at 5 years and the rate of organ preservation was 89% (40/45xa0pt) with good bowel function in 36xa0pt. Group 3: 40xa0pt, anterior resection (with sphincter preservation) was possible in 35xa0pt (86%) with a 3-year local recurrence of 6%.nnnCONCLUSIONnCXB usually combined as a boost with CRT or EBRT may safely increase the chance of a conservative treatment (organ or sphincter preservation) for selected rectal cancers.

Irradiation insterstitielle partielle et accélérée du sein de haut débit de dose : résultats préliminaires cliniques et dosimétriques sur 61 patientes

PURPOSEnAmong all the accelerated and partial breast irradiation (APBI) techniques, low then high dose rate, interstitial brachytherapy (HDIB) was the first to be used in this field. This study presents the preliminary clinical and dosimetric results of the APBI using HDIB, performed in Antoine Lacassagne Cancer Center of Nice.nnnPATIENTS AND METHODSnFrom June 2004 to March 2008, 61 patients (37 primary tumors and 24 second conservative treatments after local recurrence) presenting with T1-2 pN0 non-lobular invasive breast carcinoma, underwent lumpectomy with sentinel lymph node dissection and intraoperative tube placement for HDIB. Dose distribution analysis, using dose-volume histograms, was achieved based on a postoperative CT scan. A comparative dosimetric study was performed between optimized (O) and non-optimized (NO) dose distribution. Then, based on conformal index calculation, a novel index was proposed taking into account not only the conformity but also the homogeneity of HDIB implant. An analysis of dose gradient impact on HDIB biological equivalence dose was also conducted. Statistical analysis used T test confirmed by Wilcoxon test for cohort including less than 30 patients.nnnRESULTSnThe comparative dosimetric analysis between O and NO dose distributions shown that conformity indexes (conformal index, conformal number, and D90%) were significantly increased after optimization. Improving conformity leads to increasing hyperdosage volumes (V150% and V200%). A new index named conformity and homogeneity index (CHI) including V150% values, modified the conformal index. A total dose of 34 Gy, delivered through HDIB in 10 fractions over five days was biologically equivalent to 41.93 Gy assuming alpha/beta = 4 Gy and 75.76 Gy if the dose gradient was considered in the calculation.nnnCONCLUSIONSnHDIB is considered as one of the best IPAS technique. HDIB allows dose distribution optimization, skin spearing and accurate clinical target volume definition. Furthermore, HDIB dose gradient could play a key role for breast cancer local control.

Micronucleus induction in 10 human tumour cells after high- and low-dose radiation

A number of data measuring survival of animal or human cells to low LET ionizing radiation have demonstrated that these cells may be hypersensitive to doses below 1 Gy, possibly due to the absence of an inducible repair mechanism, which is observed at higher doses. The production of micronuclei (MN) in cells exposed to ionizing radiation reflects genotoxic damage. Moreover, the micronucleus assay is sensitive to low radiation doses. We have exposed 10 human tumour cell lines to doses ranging between 0.12 and 4 Gy. Using cytochalasin B to block the cells in a binucleate phase, we have scored the fraction of binucleate cells (BNC) expressing MN, as well as the number of MN per BNC, as a function of gamma-ray dose. Experimental points were fitted with a binomial equation. Doses from 1 to 4 Gy were fitted separately from those below 1 Gy, and the initial slopes after both fits were compared. Taken together, the initial slopes of MN induction after low-dose (LD) irradiation were not different from those after high-dose (HD) irradiation. Only in one cell line was a significant increase in MN production detected after LD irradiation. This cell line had the shallowest linear term after HD irradiation. It appeared that the likeliness of expressing hypersensitivity at LD was correlated with the quadratic term of MN induction at HD, which does not contradict an inducible repair hypothesis. However, the failure of observation of a significant hypersensitivity at LD for nine cell lines, and the high variability of response at LD suggests that this occasional effect may be influenced by other factors as well.

Combination of phosphotidylinositol‐3‐kinase targeting with cetuximab and irradiation: A preclinical study on an orthotopic xenograft model of head and neck cancer

The purpose of this study was to investigate the effects of combining the phosphotidylinositol‐3‐kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti‐epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC).