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: € 138.6 million, € 94.9 million, € 23.4 million. Total costs per year are: € 36.7 million, € 24.9 million, € 9.6 million. Cost per fraction is: € 1128 (€ 877-1974), € 743 (€ 578-1300), € 233 (€ 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 € 10,030 (c-ion: lung cancer) to € 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.     

The impact of postmastectomy radiotherapy on local control in patients with invasive lobular breast cancer

Purpose

The aim of this population-based study was to examine the impact of postmastectomy radiotherapy on the risk of local recurrence in patients with invasive lobular breast cancer (ILC).

Methods

The population-based Eindhoven Cancer Registry was used to select all patients with ILC, who underwent mastectomy in five general hospitals in the southern part of the Netherlands between 1995 and 2002. Of the 499 patients 383 patients fulfilled the eligibility criteria. Of these patients, 170 (44.4%) had received postmastectomy radiotherapy. The median follow-up was 7.2 years. Fourteen patients (3.7%) were lost to follow-up.

Results

During follow-up 22 patients developed a local recurrence, of whom 4 had received postmastectomy radiotherapy. The 5-year actuarial risk of local recurrence was 2.1% for the patients with and 8.7% for the patients without postmastectomy radiotherapy. After adjustment for age at diagnosis, tumour stage and adjuvant systemic treatment, the patients who underwent postmastectomy radiotherapy were found to have a more than 3 times lower risk of local recurrence compared to the patients without (Hazard Ratio 0.30; 95% Confidence Interval: 0.10-0.89).

Conclusion

Local control is excellent for patients with ILC who undergo postmastectomy radiotherapy and significantly better than for patients not receiving radiotherapy.     

Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: A critical re-evaluation including uniform pathologic review

Background and purpose

Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates interpretation of published data. One standard treatment option for locoregionally advanced disease is weekly low-dose doxorubicin with concurrent radiation therapy, and was previously developed at our institution. We evaluated our more recent experience with this approach, which included pathologic confirmation of all cases.

Materials and methods

A retrospective review was performed on patients identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Cancer Database. Inclusion criteria: pathologically confirmed ATC; locoregional disease encompassable within a radiation portal; treatment with curative intent at MSKCC with planned weekly doxorubicin (10 mg/m²) and concurrent radiation. Principle outcomes assessed were locoregional progression-free survival (LR-PFS) and overall survival (OS).

Results

Thirty-seven patients were included. Median radiotherapy dose was 57.6 Gy, and was ?50 Gy in 29 (78%), administered through hyperfractionated or once-daily schedules. One-year outcomes were LR-PFS, 45%; OS, 28%.

Conclusion

The prognosis of patients with ATC remains grim and our current results appear inferior to those reported previously by our institution. More accurate histologic diagnoses and patient selection in the present series compared to the prior one may be responsible in part. Better therapy is desperately needed for this aggressive disease.     

Chromosomal aberrations in peripheral blood lymphocytes of prostate cancer patients treated with IMRT and carbon ions

Background and purpose

To investigate the cytogenetic damage in blood lymphocytes of patients treated for prostate cancer with different radiation qualities and target volumes.

Materials and methods

Twenty patients receiving carbon-ion boost irradiation followed by IMRT or IMRT alone for the treatment of prostate cancer entered the study. Cytogenetic damage induced in peripheral blood lymphocytes of these patients was investigated at different times during the radiotherapy course using Giemsa staining and mFISH. A blood sample from each patient was taken before initiation of radiation therapy and irradiated in vitro to test for individual radiosensitivity. In addition, in vitro dose-effect curves for the induction of chromosomal exchanges by X-rays and carbon ions of different energies were measured.

Results

The yield of chromosome aberrations increased during the therapy course, and the frequency was lower in patients irradiated with carbon ions as compared to patients treated with IMRT with similar target volumes. A higher frequency of aberrations was measured by increasing the target volume. In vitro, high-LET carbon ions were more effective than X-rays in inducing aberrations and yielded a higher fraction of complex exchanges. The yield of complex aberrations observed in vivo was very low.

Conclusion

The investigation showed no higher aberration yield induced by treatment with a carbon-ion boost. In contrast, the reduced integral dose to the normal tissue is reflected in a lower chromosomal aberration yield when a carbon-ion boost is used instead of IMRT alone. No cytogenetic “signature” of exposure to densely ionizing carbon ions could be detected in vivo.     

Small cell carcinoma of the upper urinary tract (UUT-SCC): report of a rare entity and systematic review of the literature

Background

Primary small cell carcinoma of the upper urinary tract (UUT-SCC) is an extremely uncommon disease. The current knowledge of these rare tumors is mainly based on case reports or small series.

Methods

We reported two cases and performed a systematic literature search from 1970 to 2010 for articles on UUT-SCC. Overall, 40 patients with UUT-SCC were reviewed, a database was generated to analyze clinical characteristics, pathological features and therapy outcomes and to attempt in identifying prognostic factors.

Results

For the 39 cases with available data, median age was 66.5 years and male-female ratio was 2:1. An Asian ethnic background was more common (59%). Surgery was the standard treatment given to all patients. In 67% of cases, SCC coexisted with another malignant component, including urothelial carcinoma in 62% of patients. Overall median survival was 15 months and the 1-, 2- and 3-year survival rates were 58.4%, 38.1% and 23.8%, respectively. Of all cases, 53.8% developed detectable metastasis in a median delay of 13 months. Pathological stage was the only significant prognostic factor found (p = 0.01). Patients who received adjuvant chemotherapy seem to have a higher median survival comparatively to those who did not receive chemotherapy but this was not statistically significant (24 vs. 12 months, p = 0.56).

Conclusions

UUT-SCC is an extremely rare tumor characterized by an aggressive clinical course. Local or distant metastases are frequent and survival is poor. Pathological stage appeared to be a prognostic factor for overall survival.     

Residual postoperative tumour volume predicts outcome after high-dose radiotherapy for chordoma and chondrosarcoma of the skull base and spine

Aims

High-dose radiotherapy after surgical debulking is the treatment of choice for chordomas and chondrosarcomas. This study reviewed our outcomes, in relation to residual tumour volume and radiation dose, in order to inform our future practice.

Patients and methods

Nineteen patients referred to the Neuro-Oncology Unit at Addenbrooke’s Hospital (Cambridge, UK) between 1996 and 2009 and treated with photon radiotherapy were reviewed. Seventeen of the 19 were treated with curative intent. The median follow-up was 53 months. The tumours in the study had a mean gross tumour volume (GTV) of 17.2 cm³ (median 10.5 cm³) and a range of 0-76.3 cm³. The median dose was 65 Gy in 39 fractions.

Results

The 5 year cause-specific survival for radically treated patients with chordomas was 92% and the 5 year local control rate was 83%. The 5 year cause-specific survival and local control rates with chondrosarcomas were both 100%. A planning target volume (PTV) below 90 cm³ is predictive of local control, but volumes above this are not. The GTV seems to be a better predictor of outcome: among the 17 of 19 patients treated curatively, a GTV threshold of 30 cm³ distinguished local failures from the 15 patients with local control, with sensitivity to detect local control of 100% (95% confidence interval 78-100%), specificity 100% (95% confidence interval 16-100%) and positive predictive value 100% (95% confidence interval 78-100%).

Conclusions

Our results show a high level of efficacy for fractionated photon radiotherapy after surgery, in keeping with other series. In addition, we found that although surgical debulking is essential, a small residual tumour volume may still be controlled with high-dose photon radiotherapy. This information may be relevant during neurosurgical planning, possibly allowing a reduction in risk of serious neurological deficits. This should encourage the further development of sophisticated photon radiotherapy, for patients unsuitable for proton therapy.     

Concepts and terms for dose/volume parameters in carbon-ion radiotherapy: Conclusions of the ULICE taskforce

Purpose

The Union of Light Ion Centers in Europe (ULICE) program addressed the need for uniting scientific results for carbon-ion radiation therapy obtained by several institutions worldwide in different fields of excellence, and translating them into a real benefit to the community. Particularly, the concepts for dose/volume parameters developed in photon radiotherapy cannot be extrapolated to high linear energy transfer particles.

Can we optimize chemo-radiation and surgery in locally advanced stage III non-small cell lung cancer based on evidence from randomized clinical trials? A hypothesis-generating study

Purpose

Improved local tumor control (LC) improves survival of patients with non-small cell lung cancer (NSCLC). We estimated the capability of surgical and non-surgical options to improve LC further in this disease.

Methods

Eligible studies were phase III trials reporting 2-year survival data as well as the incidence of LC and/or distant metastases. Effect estimates, as well as the statistical uncertainty of these, were combined in order to estimate the benefit in terms of LC from combining multiple modalities.

Results

It was estimated that the highest rates of LC can be obtained with high-dose concurrent chemo-radiation followed by surgery. In this situation, escalating the pre-operative radiation dose from 45 to 66 Gy, delivered concurrently with chemotherapy, could increase LC from 58% to 76%. Toxicity may also be higher, but could not be estimated. Without surgery, the gain in LC from concurrent chemo-radiation versus sequential, corresponds to a radiation dose increase from 65 to 72 Gy.

Conclusions

We hypothesize that high-dose concurrent chemo-radiation followed by surgery could be superior to other current treatment approaches for selected patients with stage III NSCLC, provided toxicity would be low. At present, high-dose concurrent chemo-radiation followed by surgery should be considered experimental.     

Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys

Background and purpose

Endoglin is a transforming growth factor beta (TGF-β) co-receptor mainly expressed in dividing endothelial cells. It regulates cell proliferation and survival and is upregulated at sites of vessel repair. Mutations in endoglin have been linked to the vascular disease hereditary hemorrhagic telangiectasia (HHT). HHT patients display dilated capillaries (telangiectasia) that are prone to rupture. Cancer patients receiving radiotherapy develop similar vascular damage in normal tissues lying in the irradiation field. If located in the mucosa, irradiation-induced telangiectasia can lead to severe bleeding. Therefore, this study was aimed at investigating the role of endoglin in radiation-induced telangiectasia formation.

Materials and methods

Kidneys of endoglin heterozygous (Eng^+/−) or wild type mice were irradiated with 16 Gy. Mice were sacrificed after 20 weeks and changes in gene expression and protein levels were analysed.

Results

Expression of TGF-β target genes involved in radiation-induced fibrosis and fibrosis development in the kidney decreased in Eng^+/− compared to wild type mice. Unexpectedly, Eng^+/− mice also displayed reduced telangiectasia formation in the irradiated kidney.

Conclusions

Endoglin plays an important role in the development of irradiation-induced normal tissue damage. Future studies will show whether interfering with endoglin functions protects tissues from late radiation toxicity.     

Treatment with curative intent of stage III non-small cell lung cancer patients of 75 years: a prospective population-based study

Background

There is little data on the survival of elderly patients with stage III non-small cell lung cancer (NSCLC).

Methods

Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included.

Findings

One thousand and two patients with stage III were diagnosed, of which 237 were 75 years or older. From 228 patients, co-morbidity scores were available. Only 33/237 patients (14.5%) had no co-morbidities, 195 (85.5%) had one or more important co-morbidities, 60 (26.3%) two or more co-morbidities, 18 (7.9%) three or more co-morbidities and 2 patients (0.9%) suffered from four co-morbidities. Forty-eight percent were treated with curative intent. No significant difference in Charlson co-morbidity, age or gender was found between patients receiving curative or palliative intent treatment. Treatment with curative intent was associated with increased overall survival (OS) compared to palliative treatment: median OS 14.2 months (9.6-18.7) versus 5.2 months (4.3-6.0), 2-year OS 35.5% versus 12.1%, for curative versus palliative treatment.Patients who received only radiotherapy with curative intent had a median OS of 11.1 months (95% confidence interval [95% CI] 6.4-15.8) and a 5-year OS of 20.3%; for sequential chemotherapy and radiotherapy, the median OS was 18.0 months (95% CI 12.2-23.7), with a 5-year OS of 14.9%. Only four patients received concurrent chemo-radiation.

Interpretation

In this prospective series treating elderly patients with stage III NSCLC with curative intent was associated with significant 5-year survival rates.     

Continuous EGFR-TKI administration following radiotherapy for non-small cell lung cancer patients with isolated CNS failure

Introduction

Based on previous reports, patients who experience isolated central nervous system (CNS) failure may not have systemic acquired resistance to EGFR-TKI therapy. However, because there are few articles that have reported on the clinical efficacy of continuous EGFR-TKI administration following progressive disease (PD) in isolated CNS metastasis, we retrospectively investigated the possibility of using the treatment.

Patients and methods

From July 2002 to December 2009, 17 non-small cell lung cancer patients showed isolated CNS failure after clinical benefit (partial response or stable disease longer than 6 months) from EGFR-TKIs and continuously received EGFR-TKIs following radiotherapy (whole brain radiotherapy or stereotactic radiotherapy) to the CNS metastases.

Results

The response rate and the disease control rate of CNS lesions were 41% and 76%, respectively. The median progression free survival, extracranial progression free survival and the median overall survival time were 80 days, 171 days and 403 days, respectively. The toxicities which were observed during the first EGFR-TKI treatments were sustained, but did not worsen during this study period. The acute toxicities caused by radiotherapy to the CNS were controllable. There were no remarkable late toxicities related to the treatment.

Conclusions

Continuous administration of EGFR-TKI following radiotherapy after PD in isolated CNS metastasis appears to be a valid treatment option.     

A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer

Background and purpose

We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC).

Materials and methods

A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival.

Results

Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively.

Conclusions

Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.     

Three-year results after radiotherapy for locally advanced sinonasal adenoid cystic carcinoma,using highly conformational radiotherapy techniques proton therapy and/or Tomotherapy

Purpose

We report the patient outcomes of a treatment combining proton therapy and Tomotherapy in sinonasal adenoid cystic carcinoma involving skull base.

Radiation-induced lipid peroxidation activates src kinase and triggers nuclear EGFR transport

Purpose

Elucidation of the molecular mechanism of radiation-induced activation of src kinase, which initiates EGFR internalization and nuclear transport.

Material and methods

Radiation-induced src activation was investigated in the bronchial carcinoma cell line A549. Proteins were Western blotted and quantified by the help of specific antibodies. Residual DNA-damage was quantified with γH₂AX-foci analysis. Radiation-induced lipid peroxidation was prevented by acetyl-cysteine.

Results

The radiation-induced src activation and EGFR stabilization could be mimicked by addition of hydroxy-nonenal (HNE), one of the major lipid peroxidation products. Radiation-generated HNE is bound to EGFR and src and correlated with complex formation between both following radiation. Treatment with HNE activated src and stimulated radiation-associated EGFR and caveolin 1 phosphorylations resulting in increased nuclear transport of EGFR. Consequently, radiation-induced phosphorylation and activation of DNA-PK were increased. This phosphorylation was associated with improved removal of residual damage 24 h after irradiation. Inhibition of radiation-induced HNE generation by acetyl-cysteine blocked radiation-induced src activation and EGFR phosphorylation.

Conclusions

HNE generated in response to radiation exposure activates src kinase and is involved in regulation of radiation-stimulated DNA-repair processes.     

Effectiveness of surgery and individualized high-dose hyperfractionated accelerated radiotherapy on survival in clinical stage I non-small cell lung cancer. A propensity score matched analysis

Background and purpose

Surgery is considered the treatment of choice for early-stage non-small cell lung cancer (NSCLC). Patients with poor pulmonary function or other comorbidities are treated with radiotherapy. The objective of this investigation is to compare the 3-year survival of two early-stage NSCLC populations treated in two different hospitals, either by surgical resection (lobectomy) or by individualized high-dose accelerated radiotherapy, after matching patients by propensity scoring analysis.

Methods

A retrospective comparative study has been performed on two series of consecutive patients with cytohistological diagnosis of NSCLC, clinically staged IA by means of PET-scan (radiotherapy group) and pathologically staged IA (surgery group).

Results

A total of 157 cases were initially selected for the analysis (110 operated and 47 treated by radiotherapy). Patients in the radiotherapy group were older, with higher comorbidity and lower FEV1% with 3-years probability of survival for operated patients higher than that found for patients treated by radiotherapy. After matching by propensity scoring (using age and FEV1%), differences disappear and 3-years probability of survival had no statistical differences.

Conclusions

Although this is a non-randomized retrospective analysis, we have not found 3-years survival differences after matching cases between surgery and radiotherapy. Nevertheless, data presented here support the continuous investigation for non-surgical alternatives in this disease.     

Carbon ion radiation therapy for high-risk meningiomas

Background

We analyzed outcome after a carbon ion boost in combination with precision photon radiation therapy in patients with meningiomas.

Patients and methods

Ten patients with meningiomas were treated with carbon ion RT as part of a Phase I/II trial. Carbon ion RT was conducted in conjunction with fractionated stereotactic RT (FSRT) or intensity-modulated RT (IMRT). Eight patients were treated as primary RT, in 2 patients carbon ion RT was performed as re-irradiation. Carbon ion RT was applied with a median dose of 18 Gy E, and photon RT was applied with a median dose of 50.4 Gy. Two patients with a history of former irradiation received 18 Gy E of carbon ion RT and a reduced dose of photon treatment.

Results

The median follow-up time was 77 months. Five patients died during follow-up, of which four died of tumor progression. In the group treated in the primary situation, actuarial survival rates after RT were 75% and 63% at 5 and 7 years. After re-irradiation, both patients died at 10 and 67 months, respectively. Actuarial local control rates after primary RT were 86% and 72% at 5 and 7 years. Two patients developed tumor recurrence after re-irradiation, 6 and 67 months after treatment.

Conclusion

In conclusion, carbon ion radiation shows promising results in patients with atypical or anaplastic meningiomas. Further evaluation in a larger, prospective study in comparison to proton RT or modern photon RT is needed to corroborate these results.     

Comparison of second cancer risk due to out-of-field doses from 6-MV IMRT and proton therapy based on 6 pediatric patient treatment plans

Background and purpose

This study compared 6-MV IMRT and proton therapy in terms of organ specific second cancer lifetime attributable risks (LARs) caused by scattered and secondary out-of-field radiation.

Materials and methods

Based on simulated organ doses, excess relative and excess absolute risk models were applied to assess organ-specific LARs. Two treatment sites (cranium and central spine) were considered involving six treatment volumes and six patient ages (9-month, 4-year, 8-year, 11-year, 14-year, and adult).

Results

The LARs for thyroid cancer from a 6 cm diameter field treating a brain lesion in a 4-year old patient were estimated to be 1.1% and 0.3% in passive proton therapy and IMRT, respectively. However, estimated LARs for bladder cancer, more than 25 cm from the field edge for the same patient and treatment field, were estimated to be 0.2% and 0.02% from IMRT and proton therapy, respectively. Risks for proton beam scanning was found to be an order of magnitude smaller compared to passive proton therapy.

Conclusion

In terms of out-of-field risks, IMRT offers advantage close to the primary field and an increasing advantage for passive proton therapy is noticed with increasing distance to the field. Scanning proton beam therapy shows the lowest risks.     

Radiographic and metabolic response rates following image-guided stereotactic radiotherapy for lung tumors

Purpose

To evaluate radiographic and metabolic response after stereotactic body radiotherapy (SBRT) for early lung tumors.

Materials and methods

Thirty-nine tumors were treated prospectively with SBRT (dose = 48-60 Gy, 4-5 Fx). Thirty-six cases were primary NSCLC (T1N0 = 67%; T2N0 = 25%); three cases were solitary metastases. Patients were followed using CT and PET at 6, 16, and 52 weeks post-SBRT, with CT follow-up thereafter. RECIST and EORTC criteria were used to evaluate CT and PET responses.

Results

At median follow-up of 9 months (0.4-26), RECIST complete response (CR), partial response (PR), and stable disease (SD) rates were 3%, 43%, 54% at 6 weeks; 15%, 38%, 46% at 16 weeks; 27%, 64%, 9% at 52 weeks. Mean baseline tumor volume was reduced by 46%, 70%, 87%, and 96%, respectively at 6, 16, 52, and 72 weeks. Mean baseline maximum standardized uptake value (SUV) was 8.3 (1.1-20.3) and reduced to 3.4, 3.0, and 3.7 at 6, 16, and 52 weeks after SBRT. EORTC metabolic CR/PR, SD, and progressive disease rates were 67%, 22%, 11% at 6 weeks; 86%, 10%, 3% at 16 weeks; 95%, 5%, 0% at 52 weeks.

Conclusions

SBRT yields excellent RECIST and EORTC based response. Metabolic response is rapid however radiographic response occurs even after 1-year post treatment.     

Survival after radiotherapy in gastric cancer: Systematic review and meta-analysis

Background and purpose

A systematic review and meta-analysis was performed to assess the impact of radiotherapy on both 3- and 5-year survival in patients with resectable gastric cancer.

Methods

Randomized Clinical Trials (RCTs) in which radiotherapy, (preoperative, postoperative and/or intraoperative), was compared with surgery alone or surgery plus chemotherapy in resectable gastric cancer were identified by searching web-based databases and supplemented by manual examination of reference lists. Meta-analysis was performed using Risk Ratios (RRs). Random or fixed effects models were used to combine data. The methodological quality was evaluated by Chalmers’ score.

Results

Radiotherapy had a significant impact on 5-year survival. Using an intent to treat (ITT) and a Per Protocol (PP) analysis, the overall 5-year RR was 1.26 (95% CI: 1.08-1.48; NNT = 17) and 1.31 (95% CI: 1.04-1.66; NNT = 13), respectively. Although the quality of the studies was variable, the data were consistent and no clear publication bias was found.

Conclusion

This meta-analysis showed a statistically significant 5-year survival benefit with the addition of radiotherapy in patients with resectable gastric cancer. Radiotherapy remains a standard component in the treatment of resectable gastric cancer and new RCTs need to address the impact of new conformal radiotherapy technologies.