Prospective randomized clinical studies involving reirradiation: update of a systematic review.

BACKGROUND: Reirradiation is a potentially useful option for many patients with recurrent cancer, aiming at cure or symptom palliation, depending on disease/recurrence type and stage. The purpose of this follow-up study to a previous review from 2016 was to summarize all recently published randomized trials. Points of interest again included identifcation of methodological strengths and weaknesses, practice-changing results, and open questions. MATERIAL AND METHODS: Systematic review of trials published between 2015 and February 2023. RESULTS: We reviewed 7 additional trials, most of which addressed reirradiation of head and neck or brain tumours. The median number of patients was 60. Mirroring the previous review, trial design, primary endpoints and statistical hypotheses varied widely. The updated results only impact on decision making for reirradiation of nasopharynx cancer and glioma. Patients with one of these diseases, as well as other head and neck cancers, may benefit from reirradiation-induced local control, e.g. in terms of progression-free survival. For the first time, hyperfractionated radiotherapy emerged as preferred option for recurrent, inoperable nasopharynx cancer. Despite better therapeutic ratio with hyperfractionation, serious toxicity remains a concern after high cumulative total doses. Randomized trials are still lacking for prostate cancer and other sites. CONCLUSION: Multicentric randomized trials on reirradiation are feasible and continue to refine the current standard of care for recurrent disease after previous radiotherapy. Ongoing prospective studies such as the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer (ESTRO-EORTC) observational cohort ReCare (NCT: NCT03818503) will further shape the clinical practice of reirradiation.

Critical impact of radiotherapy protocol compliance and quality in the treatment of retroperitoneal sarcomas: Results from the EORTC 62092-22092 STRASS trial.

BACKGROUND: The European Organization for Research and Treatment of Cancer 22092-62092 STRASS trial failed to demonstrate the superiority of neoadjuvant radiotherapy (RT) over surgery alone in patients with retroperitoneal sarcoma. Therefore, an RT quality-assurance program was added to the study protocol to detect and correct RT deviations. The authors report results from the trial RT quality-assurance program and its potential effect on patient outcomes. METHODS: To evaluate the effect of RT compliance on survival outcomes, a composite end point was created. It combined the information related to planning target volume coverage, target delineation, total dose received, and overall treatment time into 2 groups: non-RT-compliant (NRC) for patients who had unacceptable deviation(s) in any of the previous categories and RT-compliant (RC) otherwise. Abdominal recurrence-free survival (ARFS) and overall survival were compared between the 2 groups using a Cox proportional hazard model adjusted for known prognostic factors. RESULTS: Thirty-six of 125 patients (28.8%) were classified as NRC, and the remaining 89 patients (71.2%) were classified as RC. The 3-year ARFS rate was 66.8% (95% confidence interval [CI], 55.8%-75.7%) and 49.8% (95% CI, 32.7%-64.8%) for the RC and NRC groups, respectively (adjusted hazard ratio, 2.32; 95% CI, 1.25-4.32; P = .008). Local recurrence after macroscopic complete resection occurred in 13 of 89 patients (14.6%) versus 2 of 36 patients (5.6%) in the RC and NRC groups, respectively. CONCLUSIONS: The current analysis suggests a significant benefit in terms of ARFS in favor of the RC group. This association did not translate into less local relapses after complete resection in the RC group. Multidisciplinary collaboration and review of cases are critical to avoid geographic misses, especially for rare tumors like retroperitoneal sarcoma.

Primary Meningeal Melanocytic Tumors of the Central Nervous System: A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN).

BACKGROUND: Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. METHODS: The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. RESULTS: Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor's aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. CONCLUSIONS: As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities.

Brain Metastases: Is There Still a Role for Whole-Brain Radiation Therapy?

Whole-brain radiation therapy (WBRT) has commonly been prescribed to palliate symptoms from brain metastases, to reduce the risk of local relapse after surgical resection, and to improve distant brain control after resection or radiosurgery. While targeting micrometastases throughout the brain can be considered advantageous, the simultaneous exposure of healthy brain tissue might cause adverse events. Attempts to mitigate the risk of neurocognitive decline after WBRT include the selective avoidance of the hippocampi, among others. Besides selective dose reduction, dose escalation to boost volumes, for example, simultaneous integrated boost, aiming at increased tumor control probability is technically feasible. While up-front radiotherapy for newly diagnosed brain metastases often employs radiosurgery or other techniques targeting visible lesions only, sequential (delayed) salvage treatment with WBRT might still become necessary. In addition, the presence of leptomeningeal tumors or very widespread parenchymatous brain metastases might prompt clinicians to prescribe early WBRT.

Personalized radiotherapy of brain metastases: survival prediction by means of dichotomized or differentiated blood test results?

Background and objectives: The validated LabBM score (laboratory parameters in patients with brain metastases) represents a widely applicable survival prediction model, which incorporates 5 blood test results (serum lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin, platelets and hemoglobin). All tests are classified as normal or abnormal, without accounting for the wide range of abnormality observed in practice. We tested the hypothesis that improved stratification might be possible, if more granular test results are employed. Methods: Retrospective analysis of 198 patients managed with primary whole-brain radiotherapy in one of the institutions who validated the original LabBM score. Results: For two blood tests (albumin, CRP), discrimination was best for the original dichotomized version (normal/abnormal). For two others (LDH, hemoglobin), a three-tiered classification was best. The number of patients with low platelet count was not large enough for detailed analyses. A modified LabBM score was developed, which separates the intermediate of originally 3 prognostic groups into 2 statistically significantly different strata, resulting in a 4-tiered score. Conclusion: This initial proof-of-principle study suggests that granular blood test results might contribute to further improvement of the score, or alternatively development of a nomogram, if additional large-scale studies confirm the encouraging results of the present analysis.

How we treat octogenarians with brain metastases.

Biologically younger, fully independent octogenarians are able to tolerate most oncological treatments. Increasing frailty results in decreasing eligibility for certain treatments, e.g., chemotherapy and surgery. Most brain metastases are not an isolated problem, but part of widespread cancer dissemination, often in combination with compromised performance status. Multidisciplinary assessment is key in this vulnerable patient population where age, frailty, comorbidity and even moderate additional deficits from brain metastases or their treatment may result in immobilization, hospitalization, need for nursing home care, termination of systemic anticancer treatment etc. Here, we provide examples of successful treatment (surgery, radiosurgery, systemic therapy) and best supportive care, and comment on the limitations of prognostic scores, which often were developed in all-comers rather than octogenarians. Despite selection bias in retrospective studies, survival after radiosurgery was more encouraging than after whole-brain radiotherapy. Prospective research with focus on octogenarians is warranted to optimize outcomes.

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.

The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

Diagnosis-specific graded prognostic assessment score is valid in patients with brain metastases treated in routine clinical practice in two European countries.

BACKGROUND: Assessment of cancer- and host-related prognostic factors has a long tradition in patients with brain metastases. In continuation of large-scale studies performed by the Radiation Therapy Oncology Group (RTOG) in the United States, the 4-tiered diagnosis-specific graded prognostic assessment (DS-GPA) score has been developed. It stratifies patients with common primary tumours metastasizing to the brain (malignant melanoma, lung, breast, kidney and gastrointestinal cancers) into subgroups with different prognoses. However, many patients in the DS-GPA study were treated with surgical resection or radiosurgery (SRS). The present multi-institutional analysis examined for the first time whether DS-GPA is a valid score in European patients managed in routine clinical practice. MATERIAL/METHODS: This was a retrospective analysis of 412 patients with primary malignant melanoma, lung, breast, kidney or gastrointestinal cancers. Survival was evaluated in uni- and multivariate tests. RESULTS: DS-GPA significantly predicted survival and outperformed initial GPA, a score that is not diagnosis-specific. Median survival by DS-GPA strata (all 412 patients) was 2.7, 3.6, 7.0 and 11.3 months in the 4 groups with 0-1, 1.5-2, 2.5-3 and 3.5-4 points, respectively. The previously published survival data (median 7.2 months for all patients) could not be replicated in this cohort (median 3.6 months). CONCLUSIONS: DS-GPA is a valid prognostic score that might improve shared decision making as well as patient stratification in prospective clinical trials.

Personalized treatment of brain metastases: Evolving survival prediction models may benefit from evaluation of serum tumor markers (narrative review).

Treatment of a limited number of brain metastases (oligometastases) might include complex and sometimes invasive approaches, e.g. neurosurgical resection followed by post-operative stereotactic radiotherapy, and thus, correct identification of patients who are appropriate candidates is crucial. Both, staging procedures that visualize the true number of metastastic lesions and prognostic assessments that identify patients with limited survival, who should be managed with less complex, palliative approaches, are necessary before proceeding with local treatment that aims at eradication of all oligometastases. Some of the prognostic models, e.g. the LabBM score (laboratory parameters in patients with brain metastases), include blood biomarkers believed to represent surrogate markers of disease extent. In a recent study, patients with oligometastases and a LabBM score of 0 (no abnormal biomarkers) had an actuarial 5-year survival rate of 27% after neurosurgical resection and 39% after stereotactic radiotherapy. Other studies have tied serum tumor markers such as carcinoembryonic antigen (CEA) to survival outcomes. Even if head-to-head comparisons and large-scale definitive analyses are lacking, the available data suggest that attempts to integrate tumor marker levels in blood biomarker-based survival prediction models are warranted.

Evolution of treatment strategies for oligometastatic NSCLC patients - A systematic review of the literature.

BACKGROUND: The concept of oligometastatic disease (OMD) has expanded the scope of potentially curative therapy for metastatic NSCLC. However, large uncertainties remain regarding its definition and optimal management strategies. We therefore conducted a systematic review to investigate the value of various multimodality treatment concepts. METHODS: We searched the available literature in Pubmed, Medline and EMBASE using the terms "oligomet*", "synchron*", "oligorec*", "metachr*" "NSCLC", "lung cancer" and "stage IV" and included studies reporting treatment regimens and outcomes on radically treated patients with either "synchronous", "metachronous" or "mixed" OMD. Only de-novo diagnosis of OMD was considered. The impact of patient and treatment characteristics on overall survival (OS) and time trends in patterns of care were investigated. RESULTS: 54 studies published between 1987 and 2018 were included. Despite a wide range of OMD definitions, 90.1% of patients were treated for a single metastasis. Systemic therapy was used as backbone treatment for most patients. Although surgery was the preferred local treatment in earlier studies, the use of stereotactic radiotherapy increased rapidly after 2011. No OS difference was observed between surgery or radiotherapy as the treatment of primary tumor or metastases, respectively. A time trend towards improved OS after 2011 could be detected. CONCLUSIONS: While evidence in favor of radical treatment is emerging, most studies remain retrospective and mainly evaluate patients with singular metastases. While surgery, stereotactic radiotherapy and chemotherapy are the cornerstones of current treatment strategies, future clinical trials need to address the high risk of distant metastases by integrating targeted or immunotherapy.

Disease presentation and outcome in very young patients with brain metastases from breast cancer.

AIMS AND BACKGROUND: Little information is available on disease presentation and treatment outcome in very young patients with brain metastases from breast cancer. Therefore, we evaluated our results in this group. METHODS: In our database, 7/74 breast cancer patients treated for brain metastases were < 40 years old. All received whole-brain radiation therapy plus individual local or systemic measures. RESULTS: In patients with information available, tumors were poorly differentiated and metastatic to the axillary lymph nodes at primary diagnosis. All patients had extracranial metastases. Two died from their brain disease within 5 months. Five patients died from extracranial progression after 3-84 months (2 long-term survivors beyond 2 years, characterized by single brain lesions and high performance status). CONCLUSIONS: Very young patients did not achieve a better outcome than intermediate age groups. Whole-brain radiation therapy plus surgery or radiosurgery provided durable CNS control in most of the patients. Improved systemic therapy appears to represent the key to a better outcome.

Update of human spinal cord reirradiation tolerance based on additional data from 38 patients.

PURPOSE: To update a combined analysis of all published clinical data. METHODS AND MATERIALS: We collected data from 38 additional patients treated in our department or published in four different reports and calculated the biologically effective dose (BED) according to the linear-quadratic model using an alpha/beta value of 2 Gy for cervical and thoracic cord and 4 Gy for lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy(2) or 75 Gy(4). RESULTS: The 2005 risk score based on three variables (cumulative BED, highest BED of all treatment series in a particular individual, and interval), which discriminate three different risk groups, does not require modification. The low-risk group now contains 1 case of radiation myelopathy (RM) after hypofractionated stereotactic reirradiation. Therefore, the rate increased from 0% to 3%. Intermediate-risk patients developed RM in 25%, and high-risk patients in 90%. When the interval between the two treatment courses is not shorter than 6 months and the dose of each course is < or =98 Gy(2), the cumulative BED where no case of RM has yet been reported is 120 Gy(2). CONCLUSIONS: Based on these updated results, the risk of RM appears small after < or =135.5 Gy(2) when the interval is not shorter than 6 months and the dose of each course is < or =98 Gy(2). We would recommend limiting the dose to the lowest feasible level. The influence of very steep dose gradients from stereotactic and intensity-modulated approaches (i.e., a more complex volume-effect) requires further evaluation.

Re-irradiation for Recurrent Primary Brain Tumors.

BACKGROUND: Historically, radiation oncologists have been cautious about re-irradiating brain tumors because of concerns about the risks of late central nervous system (CNS) toxicity, especially radionecrosis, that may occur several months to years following treatment. Today there are still limited prospective data addressing this approach. MATERIALS AND METHODS: Systematic review of published trials reporting clinical results after re-irradiation of patients with different types of brain tumors was performed. RESULTS: Data mainly related to glioblastoma, anaplastic glioma, medulloblastoma, ependymoma and meningioma have been published. Randomized studies are scarce. As in first-line scenarios, efficacy of radiotherapy is influenced by histology. Based on the reported outcomes, preliminary recommendations for dose/fractionation regimens can be given. CONCLUSION: Re-irradiation of brain tumors is increasingly considered as our understanding of brain tolerance to radiation evolves and developments in radiation technology and imaging make highly accurate targeting of recurrent tumors possible. With developments in systemic therapy, further exploration of the role of re-irradiation on its own or in combination with novel agents is needed.

Potential role of growth factors in diminishing radiation therapy neural tissue injury.

Human growth factors are firmly established in treatment of cytopenias that are associated with cancer chemotherapy, and have been used successfully to reduce severe mucositis in patients receiving radiation therapy and chemotherapy in the setting of autologous bone marrow transplantation. The ability of growth factors that are involved in differentiation and proliferation of neural tissue cells to prevent or accelerate recovery from radiation injury currently is being evaluated in preclinical studies. Data from these studies indicate that brief therapeutic intervention with platelet-derived growth factor, insulin-like growth factor-1, vascular endothelial growth factor, and the combination of insulin-like growth factor-1 and basic fibroblast growth factor can prevent or delay radiation myelopathy after spinal cord irradiation. Additional investigation is required to define potentially clinically useful growth factor regimens in the clinic.

Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients.

PURPOSE: Driven by numerous reports on recovery of occult radiation injury, reirradiation of the spinal cord today is considered a realistic option. In rodents, long-term recovery was observed to start at approximately 8 weeks. However, prospective clinical studies are lacking. Therefore, a combined analysis of all published clinical data might provide a valuable basis for future trials. METHODS AND MATERIALS: We collected data from 40 individual patients published in eight different reports after a comprehensive MEDLINE search. These represent all patients with data available for dose per fraction and total dose of each of both treatment courses. We recalculated the biologically effective dose (BED) according to the linear-quadratic model using an alpha/beta value of 2 Gy for the cervical and thoracic cord and 4 Gy for the lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy(2) or 75 Gy(4). For treatment with two daily fractions, a correction term was introduced to take incomplete repair of sublethal damage into account. RESULTS: The cumulative doses ranged from 108 to 205 Gy(2) (median dose, 135 Gy(2)). The median interval between both series was 20 months. Three patients were treated to the lumbar segments only. The median follow-up was 17 months for patients without myelopathy. Eleven patients developed myelopathy after 4-25 months (median, 11 months). Myelopathy was seen only in patients who had received one course to a dose of > or =102 Gy(2) (n = 9) or were retreated after 2 months (n = 2). In the absence of these two risk factors, no myelopathy developed in 19 patients treated with < or =135.5 Gy(2) or 7 patients treated with 136-150 Gy(2). A risk score based on the cumulative BED, the greatest BED for all treatment series in a particular individual, and interval was developed. Low-risk patients remained free of myelopathy and 33% of intermediate-risk patients and 90% of high-risk patients developed myelopathy. CONCLUSION: On the basis of these literature data (and with due caution), the risk of myelopathy appears small after < or =135.5 Gy(2) when the interval is not shorter than 6 months and the dose of each course is < or =98 Gy(2). We would recommend limiting the dose to this level, whenever technically feasible. However, it appears prudent to propose the collection of prospective data from a greater number of patients receiving doses in the range of 136-150 Gy(2) to assess the safety of higher retreatment doses for those patients in whom limited doses might compromise tumor control.

Scientific impact of studies published in temporarily available radiation oncology journals: a citation analysis.

The purpose of this study was to review all articles published in two temporarily available radiation oncology journals (Radiation Oncology Investigations, Journal of Radiosurgery) in order to evaluate their scientific impact. From several potential measures of impact and relevance of research, we selected article citation rate because landmark or practice-changing research is likely to be cited frequently. The citation database Scopus was used to analyse number of citations. During the time period 1996-1999 the journal Radiation Oncology Investigations published 205 articles, which achieved a median number of 6 citations (range 0-116). However, the most frequently cited article in the first 4 volumes achieved only 23 citations. The Journal of Radiosurgery published only 31 articles, all in the year 1999, which achieved a median number of 1 citation (range 0-11). No prospective randomized studies or phase I-II collaborative group trials were published in these journals. Apparently, the Journal of Radiosurgery acquired relatively few manuscripts that were interesting and important enough to impact clinical practice. Radiation Oncology Investigations' citation pattern was better and closer related to that reported in several previous studies focusing on the field of radiation oncology. The vast majority of articles published in temporarily available radiation oncology journals had limited clinical impact and achieved few citations. Highly influential research was unlikely to be submitted during the initial phase of establishing new radiation oncology journals.

Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy.

PURPOSE: To present an overview of the significance of erbB tyrosine kinase family members as prognostic-predictive factors and as targets of therapeutic intervention in patients with head-and-neck carcinomas (HNCs). METHODS AND MATERIALS: The data of clinical studies addressing the correlation between the expression of erbB family tyrosine kinases, particularly epidermal growth factor receptor (EGFR), and the prognosis and pattern of failure were reviewed, along with the response of HNCs to EGFR antagonists such as a chimeric monoclonal antibody and a couple of small molecule tyrosine kinase inhibitors. RESULTS: Correlative biomarker studies showed that most HNCs express high levels of EGFR and/or other members of the erbB family. Several studies have demonstrated that patients with EGFR-overexpressing tumors had significantly worse overall survival. Compelling evidence has emerged showing that EGFR-overexpressing HNCs respond more poorly to radiotherapy (RT), although data of its impact on the response to chemotherapy are scarce. Clinical studies have so far showed that tyrosine kinase inhibitors have rather limited antitumor activities when given alone. Stimulated by promising preclinical data, the value of EGFR antagonists in the combined modality setting, particularly with RT, is being addressed in clinical trials. CONCLUSION: Members of the erbB receptor tyrosine kinase family, particularly EGFR, were found to be a strong biomarker for poor prognosis and HNC resistance to RT. The available data showed that EGFR antagonists given as single modality therapies yield rather limited antitumor activity. The results of trials testing the efficacy of combining EGFR antagonist with RT or chemotherapy will emerge within the next few years.

Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies.

PURPOSE: Evidence is rapidly mounting that dysregulated epidermal growth factor receptor (EGFR) signaling is one of the underlying mechanisms of more aggressive tumor behavior and increased tumor resistance to cytotoxic agents, including radiotherapy (RT). This has led to extensive preclinical and clinical studies aimed at developing effective treatment strategies that counteract EGFR-mediated signaling. In this article, we review preclinical studies, primarily from our laboratory, addressing the role of EGFR in tumor radioresponse and the use of C225, a human-mouse chimeric anti-EGFR monoclonal antibody, to improve the results of RT. METHODS AND MATERIALS: Mouse carcinomas were used to study the influence of EGFR on tumor radioresponse. EGFR expression was assessed by Western blot analysis, and cDNA transfection experiments were performed to determine a causal relationship between EGFR and tumor cell radioresistance. A431 human tumor xenografts growing in nude mice were used to test whether blockade of EGFR with C225 anti-EGFR antibody enhances tumor radioresponse. RESULTS: Our studies showed that high levels of EGFR were associated with decreased tumor radiocurability of murine carcinomas. The causal role of EGFR in mediating cellular resistance to RT was demonstrated by transfecting the EGFR cDNA into the cells with low levels of EGFR. The EGFR-high expression-transfected clones became more resistant to RT. RT activated EGFR and its downstream signaling pathways in radioresistant, but not in radiosensitive, tumors, which can be regarded as an adaptive response to radiation damage. Additional studies investigated whether blockade of EGFR and inhibition of EGFR-mediated downstream signaling can be exploited for therapeutic purposes. The results described here showed that treatment of human tumor xenografts with C225 can markedly enhance the tumor response to RT, as assessed by both tumor growth delay and the tumor cure rate. CONCLUSION: The findings from our in vivo preclinical studies suggest that overexpression of EGFR could serve as a predictor of tumor treatment outcome by RT and as a therapeutic target to enhance the efficacy of RT. This therapeutic strategy is currently being explored in patients with head-and-neck cancers.

Modulation of rodent spinal cord radiation tolerance by administration of platelet-derived growth factor.

PURPOSE: To examine the role of platelet-derived growth factor (PDGF) for ameliorating radiation myelopathy of the cervical spinal cord in a rodent model. METHODS AND MATERIALS: After developing the technique for cannulation of the basal cistern, initial animal experiments were conducted to test the feasibility of intrathecal continuous infusion of PDGF in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of PDGF. Subsequently, the dose-modification factor was determined in a larger group of rats. Irradiation was given in 2 fractions (16 Gy followed by 14-24 Gy) and animals were examined for the development of paresis. RESULTS: The initial dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (100% in saline-treated control rats, 25% with the most effective dose of PDGF, up to 100% with less effective doses). The most effective dose of PDGF was 0.014 mug per day. Subsequent experiments revealed a median effective dose (ED(50)) of 35.6 Gy (95% confidence interval, 34.7-36.5 Gy) for animals receiving this dose of PDGF in contrast to 33.8 Gy (33.4-34.3 Gy) for the control group (p = 0.003). The dose-modification factor obtained with this dose of PDGF was 1.05. CONCLUSIONS: Intrathecal administration of PDGF concomitant to irradiation of the cervical spinal cord in rats was feasible. Treatment with PDGF significantly increased the tolerance of the spinal cord. The PDGF experiments should be viewed as a proof of principle that brief therapeutic intervention in the earliest phase of damage induction can reduce late effects in the spinal cord. They form the basis for further studies of growth factor administration in this particular model.

Epidermal growth factor receptor as a target to improve treatment of lung cancer.

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.