Jean-Philippe Pignol

Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer

BACKGROUND The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

The Quest for Evidence for Proton Therapy: Model-Based Approach and Precision Medicine

PURPOSE Reducing dose to normal tissues is the advantage of protons versus photons. We aimed to describe a method for translating this reduction into a clinically relevant benefit. METHODS AND MATERIALS Dutch scientific and health care governance bodies have recently issued landmark reports regarding generation of relevant evidence for new technologies in health care including proton therapy. An approach based on normal tissue complication probability (NTCP) models has been adopted to select patients who are most likely to experience fewer (serious) adverse events achievable by state-of-the-art proton treatment. RESULTS By analogy with biologically targeted therapies, the technology needs to be tested in enriched cohorts of patients exhibiting the decisive predictive marker: difference in normal tissue dosimetric signatures between proton and photon treatment plans. Expected clinical benefit is then estimated by virtue of multifactorial NTCP models. In this sense, high-tech radiation therapy falls under precision medicine. As a consequence, randomizing nonenriched populations between photons and protons is predictably inefficient and likely to produce confusing results. CONCLUSIONS Validating NTCP models in appropriately composed cohorts treated with protons should be the primary research agenda leading to urgently needed evidence for proton therapy.

Intratumorally Injected 177Lu-Labeled Gold Nanoparticles: Gold Nanoseed Brachytherapy with Application for Neoadjuvant Treatment of Locally Advanced Breast Cancer

Improvements in the treatment of locally advanced breast cancer (LABC) are needed. Our objective was to study a radiation nanomedicine (gold nanoseeds) composed of 30-nm gold nanoparticles (AuNP) modified with polyethyleneglycol (PEG) chains linked to DOTA for complexing the β-particle emitter 177Lu and to panitumumab for targeting epidermal growth factor receptors (EGFR) (177Lu-T-AuNP) as a novel neoadjuvant brachytherapy for LABC. Nontargeted gold nanoseeds (177Lu-NT-AuNP) were constructed without panitumumab for comparison. Methods: 177Lu-T-AuNP or 177Lu-NT-AuNP was injected intratumorally in CD-1 athymic mice bearing subcutaneous EGFR-positive MDA-MB-468 human breast cancer tumors. Biodistribution and small-animal SPECT/CT imaging studies were performed to evaluate tumor and normal organ localization. A short-term (15 d) study was conducted to select the most effective amount of 177Lu-T-AuNP or 177Lu-NT-AuNP for treatment with long-term observation (90–120 d). Normal organ toxicities were assessed by monitoring body weight, blood cell counts, and serum alanine aminotransferase and creatinine. Radiation-absorbed doses in the tumor and normal organs were estimated by Monte Carlo N-Particle version 5.0 modeling. Results: Tumor radioactivity concentrations were high at 1 h after injection (>300–400 percentage injected dose per gram [%ID/g]) but decreased by 2–3-fold at 48 h after injection. Normal organ uptake was low (<0.5 %ID/g) except for the liver and spleen (<3 %ID/g), increasing by 2–5-fold at 48 h after injection. Treatment with 4.5 MBq (6 × 1011 AuNP) of 177Lu-T-AuNP or 177Lu-NT-AuNP arrested tumor growth over 90 d without normal organ toxicity, whereas tumors continued to grow in mice treated with unlabeled T-AuNP or 177Lu-labeled PEG polymer not linked to AuNP. Survival was prolonged up to 120 d in mice treated with 177Lu-T-AuNP or 177Lu-NT-AuNP. Radiation-absorbed doses to the tumor were 30 and 22 Gy for 177Lu-T-AuNP and 177Lu-NT-AuNP, respectively. Some tumor regions received high radiation doses (250–1,300 Gy). Normal organ doses were low (0.04–0.6 Gy). Conclusion: Gold nanoseeds injected intratumorally were highly effective for inhibiting the growth of breast cancer tumors in CD-1 athymic mice and caused no normal organ toxicity. These results are promising for their application for neoadjuvant brachytherapy of LABC. Because EGFR targeting was not required, the approach is broadly applicable to LABC with different phenotypes.

Report on the Clinical Outcomes of Permanent Breast Seed Implant for Early-Stage Breast Cancers.

PURPOSE Permanent breast seed implant is an accelerated partial breast irradiation technique realizing the insertion of (103)Pd seeds in the seroma after lumpectomy. We report the 5-year efficacy and tolerance for a cohort, pooling patients from 3 clinical trials. METHODS AND MATERIALS The trials accrued postmenopausal patients with infiltrating ductal carcinoma or ductal carcinoma in situ ≤3 cm and clear surgical margins, who were node negative, and had a planning target volume <120 cm(3). The outcomes included overall and disease-free survival and local and contralateral recurrence at 5 years. The true local recurrence rate was compared using 2-tailed paired t tests for estimates calculated using the Tufts University ipsilateral breast tumor recurrence and Memorial Sloan Kettering ductal carcinoma in situ nomograms. RESULTS The cohort included 134 patients, and the observed local recurrence rate at a median follow-up period of 63 months was 1.2% ± 1.2%, similar to the estimate for whole breast irradiation (P=.23), significantly better than for surgery alone (relative risk 0.27; P<.001), and significantly lower than contralateral recurrence (relative risk 0.33; P<.001). The 5-year overall survival rate was 97.4% ± 1.9%, and the disease-free survival rate was 96.4% ± 2.1%. At 2 months, 42% of the patients had erythema, 20% induration, and 16% moist desquamation. The rate of mainly grade 1 telangiectasia was 22.4% at 2 years and 24% at 5 years. The rate of asymptomatic induration was 23% at 2 years and 40% at 5 years. CONCLUSIONS The 5-year data suggest that permanent breast seed implantation is a safe accelerated partial breast irradiation option after lumpectomy for early-stage breast cancer with a tolerance profile similar to that of whole breast irradiation.

Prospective Evaluation of Severe Skin Toxicity and Pain During Postmastectomy Radiation Therapy

PURPOSE To prospectively capture acute toxicities and pain associated with postmastectomy radiation therapy (PMRT), to analyze patient and treatment risk factors for severe side effects. METHODS AND MATERIALS Women referred for PMRT were prospectively enrolled and assessed weekly during and after radiation therapy. The endpoint included severe National Cancer Institute Common Terminology Criteria for Adverse Effects grade 3 moist desquamation, other skin symptoms, and pain. RESULTS Of 257 patients, 73 (28.4%) experienced extensive moist desquamation, 84 (32.7%) Common Terminology Criteria for Adverse Effects skin toxicity grade 3, and 57 (22.2%) a pain impacting on daily life activities. Among symptoms only grade 3 moist desquamation was significantly associated with severe pain (P<.001). On multivariate analysis, smoking, high-energy photons, and skin bolus were significantly associated with severe moist desquamation. Skin toxicity doubled for smokers, with 40% severe pain, 48% grade 3 moist desquamation, and 64% grade 3 skin toxicity. Without skin bolus 4.2% had severe pain, none moist desquamation, and 2.1% grade 3 skin toxicity. When skin bolus was used on alternate days, the frequency increased to 15% for pain, 22% for moist desquamation, and 26% for grade 3 skin toxicity. When bolus was used daily, 32% had pain, 41% moist desquamation, and 47% grade 3 skin toxicity. Symptoms peaked 1 to 2 weeks after the end of PMRT. CONCLUSIONS The present cohort study suggests excessive radiation toxicity after PMRT. Among factors associated with an increase of toxicity are smoking habits and the use of skin bolus.

Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial

BACKGROUND AND PURPOSE We report the long-term outcomes in patients enrolled in a multicenter randomized controlled trial comparing Intensity Modulated Radiation Therapy (IMRT) with standard wedge radiotherapy. MATERIALS AND METHODS Trial participants were assessed to compare long-term side effects between treatment arms. The primary endpoint was chronic breast pain assessed by trained observers blinded to treatment allocation. Secondary endpoints included cosmesis and quality of life measures. RESULTS Median follow-up time was 9.8years and 241 patients were available for assessment. There was no significant difference in chronic pain between treatment arms (OR=0.74, range 0.432-1.271). There were also no differences for the secondary endpoints. Univariate and multivariate analyses identified young age (p=0.013) and pain during RT (p<0.001) to be associated with chronic pain. Acute moist desquamation was associated with late subcutaneous fibrosis (p=0.003) and telangiectasia (p=0.039). Pain during RT was associated with a long-term poorer self-assessed cosmetic outcome (p<0.001) and quality of life (p<0.001). CONCLUSIONS Breast IMRT cannot be recommended for all patients to reduce long-term side effects. However, late toxicities were significantly correlated with acute side effects, which are increased in patients having poor dose distribution. Breast IMRT may hence be useful for selected patients.

111 In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection

INTRODUCTION Gold nanoparticles (AuNP; 30nm) were modified with polyethylene glycol (PEG) chains linked to trastuzumab for binding to HER2-positive breast cancer (BC) cells and diethylenetriaminepentaacetic acid (DTPA) for complexing the Auger electron-emitter, 111In (trastuzumab-AuNP-111In). Our objective was to determine the cytotoxicity of trastuzumab-AuNP-111In on HER2-positive BC cells in vitro and evaluate its tumor growth inhibition properties and normal tissue toxicity in vivo following intratumoral (i.t.) injection in mice with s.c. HER2-overexpressing BC xenografts. METHODS Binding and internalization of trastuzumab-AuNP-111In or non-targeted AuNP-111In in SK-BR-3 (1-2×106 HER2/cell) and MDA-MB-361 (5×105 HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP-111In or AuNP-111In was determined. DNA double-strand breaks (DSBs) were assayed by probing for γ-H2AX. Tumor growth was monitored over 70days in CD1 athymic mice with s.c. MDA-MB-361 xenografts after i.t. injection of 10MBq (0.7mg; 2.6×1012 AuNP) of trastuzumab-AuNP-111In and normal tissue toxicity was assessed by monitoring body weight, complete blood cell (CBC) counts and serum alanine aminotransferase (ALT) and creatinine (Cr). RESULTS Trastuzumab-AuNP-111In was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP-111In was more efficiently internalized than AuNP-111In and localized to a peri-nuclear region. The SF fraction of SK-BR-3 cells was reduced by 1.8-fold by treatment with 3nM (7MBq/mL) of trastuzumab-AuNP-111In. The SF of MDA-MB-361 cells was reduced by 3.7-fold at 14.4nM (33.6MBq/mL). In comparison, non-targeted AuNP-111In at these concentrations reduced the SF of SK-BR-3 or MDA-MB-361 cells by 1.2-fold (P=0.03) and 1.7-fold (P<0.0001), respectively. DNA DSBs were greater in SK-BR-3 and MDA-MB-361 cells exposed to trastuzumab-AuNP-111In compared to AuNP-111In, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t. injection of trastuzumab-AuNP-111In in CD1 athymic mice with s.c. MDA-MB-361 tumors arrested tumor growth for 70days. There was no apparent normal tissue toxicity. The radiation absorbed dose deposited in the tumor by trastuzumab-AuNP-111In was 60.5Gy, while normal organs received <0.9Gy. CONCLUSION These results are promising for further development of trastuzumab-AuNP-111In as a novel Auger electron-emitting radiation nanomedicine for local treatment of HER2-positive BC. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE A local radiation treatment for HER2-positive BC based on AuNP modified with trastuzumab and labeled with the Auger electron-emitter, 111In was developed and shown to arrest tumor growth with no normal tissue toxicity.

Dose heterogeneity correction for low-energy brachytherapy sources using dual-energy CT images

Permanent seed implant brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. The current standard for calculation of dose around brachytherapy sources is based on the AAPM TG-43 formalism, which generates the dose in a homogeneous water medium. Recently, AAPM TG-186 emphasized the importance of accounting for tissue heterogeneities. We have previously reported on a methodology where the absorbed dose in tissue can be obtained by multiplying the dose, calculated by the TG-43 formalism, by an inhomogeneity correction factor (ICF). In this work we make use of dual energy CT (DECT) images to extract ICF parameters. The advantage of DECT over conventional CT is that it eliminates the need for tissue segmentation as well as assignment of population based atomic compositions. DECT images of a heterogeneous phantom were acquired and the dose was calculated using both TG-43 and TG-43 [Formula: see text] formalisms. The results were compared to experimental measurements using Gafchromic films in the mid-plane of the phantom. For a seed implant configuration of 8 seeds spaced 1.5 cm apart in a cubic structure, the gamma passing score for 2%/2 mm criteria improved from 40.8% to 90.5% when ICF was applied to TG-43 dose distributions.

Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study

The value of adjuvant radiotherapy in triple‐negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast‐conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23–96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node‐negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline‐based regimes. In 775 women with T1‐2, N0‐1, M0 TNBCs, 5‐year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8–98.8%), followed by BCT (90.8%, 95% CI: 85.0–94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4–88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3‐4, N2‐3, M0 TNBCs, BCT was associated with highest 5‐year RSR (94.1%, 95% CI: 81.3–99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3–70.1%), and mastectomy only (58.6%, 95% CI: 43.5–71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.

The evaluation of innovation in radiation oncology – what can we do and what should we do?

Due to multiple factors including population ageing and generalization of cancer screening, the incidence of cancer is rising in both developed and emerging countries [1]. More patients mean more health care spending, and in a context of economic stagnation this creates serious fi nancial pressure for the society and the individuals. New technologies are almost invariably more expensive than older ones, because of development cost and also incentive cost related to their adoption [2]. However, since the introduction in the 1990s of computed tomography (CT) planning and multileaf collimation leading to intensity-modulated radiotherapy (IMRT), the pace of innovation in radiation oncology has accelerated and the adoption of new technology is rarely based on level 1 clinical evidences [3,4]. Currently two new technologies, namely, the MR-Linac and intensity-modulated proton therapy (IMPT) [5,6], are being introduced, inducing major changes in the radiation oncology practice and may also lead to ballooning costs especially for the later one. There have been repeated press releases questioning the need for expensive techniques like proton therapy, pointing out at the limited amount of evidences to justify their implementation, and recommending abandoning their development [7]. In this commentary we review three different strategies to demonstrate measurable, reproducible and meaningful patient benefi ts for new technologies to better justify their adoption and to be able to produce cost effectiveness measures.