Madelon Pijls-Johannesma

Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer.

PURPOSE To identify time factors for combined chemotherapy and radiotherapy predictive for long-term survival of patients with limited-disease small-cell lung cancer (LD-SCLC). METHODS A systematic overview identified suitable phase III trials. Using meta-analysis methodology to compare results within trials, the influence of the timing of chest radiation and the start of any treatment until the end of radiotherapy (SER) on local tumor control, survival, and esophagitis was analyzed. For comparison between studies, the equivalent radiation dose in 2-Gy fractions, corrected for the overall treatment time of chest radiotherapy, was analyzed. RESULTS The SER was the most important predictor of outcome. There was a significantly higher 5-year survival rate in the shorter SER arms (relative risk [RR] = 0.62; 95% CI, 0.49 to 0.80; P = .0003), which was more than 20% when the SER was less than 30 days (upper bound of 95% CI, 90 days). A low SER was associated with a higher incidence of severe esophagitis (RR = 0.55; 95% CI, 0.42 to 073; P < .0001). Each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an overall absolute decrease in the 5-year survival rate of 1.83% +/- 0.18% (95% CI). CONCLUSION A low time between the first day of chemotherapy and the last day of chest radiotherapy is associated with improved survival in LD-SCLC patients. The novel parameter SER, which takes into account accelerated proliferation of tumor clonogens during both radiotherapy and chemotherapy, may facilitate a more rational design of combined-modality treatment in rapidly proliferating tumors.

Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: A meta-analysis

PURPOSE To provide a comparison between radiotherapy with photons, protons and carbon-ions in the treatment of Non-Small-Cell Lung Cancer (NSCLC), performing a meta-analysis of observational studies. METHODS Eligible studies on conventional radiotherapy (CRT), stereotactic radiotherapy (SBRT), concurrent chemoradiation (CCR), proton therapy and carbon-ion therapy were searched through a systematic review. To obtain pooled estimates of 2- and 5-year disease-specific and overall survival and the occurrence of severe adverse events for each treatment modality, a random effects meta-analysis was carried out. Pooled estimates were corrected for effect modifiers. RESULTS Corrected pooled estimates for 2-year overall survival in stage I inoperable NSCLC ranged from 53% for CRT to 74% for carbon-ion therapy. Five-year overall survival for CRT (20%) was statistically significantly lower than that for SBRT (42%), proton therapy (40%) and carbon-ion therapy (42%). However, caution is warranted due to the limited number of patients and limited length of follow-up of the particle studies. CONCLUSION Survival rates for particle therapy were higher than those for CRT, but similar to SBRT in stage I inoperable NSCLC. Particle therapy may be more beneficial in stage III NSCLC, especially in reducing adverse events.

Proton Therapy in Clinical Practice: Current Clinical Evidence

Radiation therapy (RT), as primarily a localized form of treatment, strives for improved local tumor control and cure with few adverse effects. The physical characteristics of protons offer the theoretical benefit of more localized delivery of RT than can be achieved with photons produced by a linear accelerator. The improved dose distribution can potentially be exploited either by allowing higher RT doses to the tumor without increased RT-induced normal tissue toxicity or by reducing adverse effects at equally effective doses. Either of the two approaches is appealing, particularly when a critical normal structure is in close proximity to the tumor. Proton therapy has been in clinical use since the 1970s. It was initially used in two US centers (Boston, MA, and Loma Linda, CA) and subsequently in Europe (d’Orsay, France) and Japan (Tsukuba, Japan); these centers reported most of the initial clinical results. The principal sites chosen for the evaluation of protons were uveal melanomas and tumors at the skull base. Other disease sites were subsequently treated including head and neck and liver tumors; tumors in the brain, upper abdomen, and pelvis; lung cancer; and tumors in the vicinity of the spinal cord. The main rationale had been poor local disease control with conventional therapy, and the proximity of critical dose-limiting normal tissue, which is a bar to safe dose escalation using conventional photon RT. The introduction had frequently been underpinned by planning studies demonstrating, in selected cases, improved dose distribution of protons compared with photons. The perception of physical and clinical advantage has led to the establishment of new clinical facilities, and some tens of thousands of patients are claimed to have been treated to date. The necessary prerequisite for introduction of such technologically complex treatment into the clinical arena is enthusiasm for particle therapy, a belief in its benefit, and considerable financial outlay. The investment in clinical facilities offering proton therapy should not simply follow enthusiasm and belief in the new technology but should be firmly based on objective outcome data demonstrating the real additional value of protons over photons using the criteria of evidence-based medicine. This article attempts to review the currently available clinical evidence.

Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study

BACKGROUND Patients with stage III non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer are excluded from concurrent chemoradiation mostly on the basis of comorbidity and age. The purpose of this prospective study was to get insight in what proportion of patients with locally advanced lung cancer would be suitable for concurrent chemoradiation. PATIENTS AND METHODS From 2002 to 2005, all patients with a pathological diagnosis of lung cancer and with locally advanced disease in the Maastricht Cancer Registry, the Netherlands, comorbidity were prospectively assessed. Patients were regarded as noneligible for concurrent chemoradiation if they had one or more important comorbidity or were 75 years or older. RESULTS In all, 711 patients were included, 577 with NSCLC and 134 with SCLC. Overall, 166 patients (23.3%) were 75 years or older. Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. In all, 408/686 (59%) of the whole patient group were considered as ineligible for concurrent chemoradiation. CONCLUSIONS More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.

How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons

PURPOSE Particle therapy has potentially a better therapeutic ratio than photon therapy. However, investment costs are much higher. This study provides an estimation and comparison of the costs of these therapies. METHODS Within an extensive analytical framework capital and operational costs, cost per fraction, and four tumor specific treatment costs are calculated for three facilities: combined carbon-ion/proton, proton-only, and photon. RESULTS Capital costs for the combined, proton-only and photon facilities are: euro 138.6 million, euro 94.9 million, euro 23.4 million. Total costs per year are: euro 36.7 million, euro 24.9 million, euro 9.6 million. Cost per fraction is: euro 1128 (euro 877-1974), euro 743 (euro 578-1300), euro 233 (euro 190-407). Cost ratio particle/photon therapy is 4.8 for the combined and 3.2 for the proton-only facility. Particle treatment costs vary from euro 10,030 (c-ion: lung cancer) to euro 39,610 (proton: head & neck tumors). Cost difference between particle and photon therapies is relatively small for lung and prostate cancer, larger for skull-base chordoma and head & neck tumors. CONCLUSION Investment costs are highest for the combined carbon-ion/proton facility and lowest for the photon facility. Cost differences become smaller when total costs per year and specific treatment costs are compared. Lower fractionation schedule of particle therapy might further reduce its costs.

Charged particles in radiotherapy: A 5-year update of a systematic review

Although proton therapy has been used for many decades because of their superior dose distribution over photons and reduced integral dose, their clinical implementation is still controversial. We updated a systematic review of charged particle therapy. Although still no randomised trials were identified, the field is moving quickly and we therefore also formulated ways to move forward. In our view, the aim should be to build enough proton therapy facilities with interest in research to further improve the treatment and to run the needed clinical trials.

The Potential Benefit of Radiotherapy with Protons in Head and Neck Cancer with Respect to Normal Tissue Sparing: A Systematic Review of Literature

PURPOSE Clinical studies concerning head and neck cancer patients treated with protons reporting on radiation-induced side effects are scarce. Therefore, we reviewed the literature regarding the potential benefits of protons compared with the currently used photons in terms of lower doses to normal tissue and the potential for fewer subsequent radiation-induced side effects, with the main focus on in silico planning comparative (ISPC) studies. MATERIALS AND METHODS A literature search was performed by two independent researchers on ISPC studies that included proton-based and photon-based irradiation techniques. RESULTS Initially, 877 papers were retrieved and 14 relevant and eligible ISPC studies were identified and included in this review. Four studies included paranasal sinus cancer cases, three included nasopharyngeal cancer cases, and seven included oropharyngeal, hypopharyngeal, and/or laryngeal cancer cases. Seven studies compared the most sophisticated photon and proton techniques: intensity-modulated photon therapy versus intensity-modulated proton therapy (IMPT). Four studies compared different proton techniques. All studies showed that protons had a lower normal tissue dose, while keeping similar or better target coverage. Two studies found that these lower doses theoretically translated into a significantly lower incidence of salivary dysfunction. CONCLUSION The results of ISPC studies indicate that protons have the potential for a significantly lower normal tissue dose, while keeping similar or better target coverage. Scanned IMPT probably offers the most advantage and will allow for a substantially lower probability of radiation-induced side effects. The results of these ISPC studies should be confirmed in properly designed clinical trials.

Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer

Introduction: This multicentric in silico trial compares photon and proton radiotherapy for non-small cell lung cancer patients. The hypothesis is that proton radiotherapy decreases the dose and the volume of irradiated normal tissues even when escalating to the maximum tolerable dose of one or more of the organs at risk (OAR). Methods: Twenty-five patients, stage IA-IIIB, were prospectively included. On 4D F18-labeled fluorodeoxyglucose-positron emission tomography-computed tomography scans, the gross tumor, clinical and planning target volumes, and OAR were delineated. Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) photon and passive scattered conformal proton therapy (PSPT) plans were created to give 70 Gy to the tumor in 35 fractions. Dose (de-)escalation was performed by rescaling to the maximum tolerable dose. Results: Protons resulted in the lowest dose to the OAR, while keeping the dose to the target at 70 Gy. The integral dose (ID) was higher for 3DCRT (59%) and IMRT (43%) than for PSPT. The mean lung dose reduced from 18.9 Gy for 3DCRT and 16.4 Gy for IMRT to 13.5 Gy for PSPT. For 10 patients, escalation to 87 Gy was possible for all 3 modalities. The mean lung dose and ID were 40 and 65% higher for photons than for protons, respectively. Conclusions: The treatment planning results of the Radiation Oncology Collaborative Comparison trial show a reduction of ID and the dose to the OAR when treating with protons instead of photons, even with dose escalation. This shows that PSPT is able to give a high tumor dose, while keeping the OAR dose lower than with the photon modalities.

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons

PURPOSE To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer. METHODS A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy. RESULTS In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site. CONCLUSIONS For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.

Current Clinical Evidence for Proton Therapy

Proton beam therapy provides the opportunity for more localized delivery of ionizing radiation with the potential for improved normal tissue avoidance to reduce treatment related morbidity and to allow for dose escalation to improve disease control and survival without increased toxicity. However, a systematic review of published peer-reviewed literature reported previously and updated here is devoid of any clinical data demonstrating benefit in terms of survival, tumor control, or toxicity in comparison with best conventional treatment for any of the tumors so far treated including skull base and ocular tumors, prostate cancer and childhood malignancies. The current lack of evidence for benefit of protons should provide a stimulus for continued research. Well designed in silico clinical trials using validated normal tissue complication probability-models are important to predict the magnitude of benefit for individual tumor sites but the future use of protons should be guided by clear evidence of benefit demonstrated in well-designed prospective studies, away from commercial influence, and this is likely to require international collaboration. Any complex and expensive technology, including proton therapy, should not be employed on the basis of belief alone and requires testing to avoid inappropriate use of potential detriment to future patients.