Biomedical subjects
Publications and source records attributed to Silvia C Formenti.
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PURPOSE: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. EXPERIMENTAL DESIGN: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival. RESULTS: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the beta2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors. CONCLUSION: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas.
PURPOSE: The development of adverse effects resulting from the radiotherapy of cancer limits the use of this treatment modality. The validation of a test capable of predicting which patients would be most likely to develop adverse responses to radiation treatment, based on the possession of specific genetic variants, would therefore be of value. The purpose of the Genetic Predictors of Adverse Radiotherapy Effects (Gene-PARE) project is to help achieve this goal. METHODS AND MATERIALS: A continuously expanding biorepository has been created consisting of frozen lymphocytes and DNA isolated from patients treated with radiotherapy. In conjunction with this biorepository, a database is maintained with detailed clinical information pertaining to diagnosis, treatment, and outcome. The DNA samples are screened using denaturing high performance liquid chromatography (DHPLC) and the Surveyor nuclease assay for variants in ATM, TGFB1, XRCC1, XRCC3, SOD2, and hHR21. It is anticipated that additional genes that control the biologic response to radiation will be screened in future work. RESULTS: Evidence has been obtained that possession of variants in genes, the products of which play a role in radiation response, is predictive for the development of adverse effects after radiotherapy. CONCLUSIONS: It is anticipated that the Gene-PARE project will yield information that will allow radiation oncologists to use genetic data to optimize treatment on an individual basis.
PURPOSE: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. METHODS AND MATERIALS: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21CIP1 and CDC25A levels. RESULTS: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21CIP1. CONCLUSIONS: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest.
Response of a solid tumor to radiation treatment depends, in part, on the intrinsic radiosensitivity of tumor cells, the proliferation rate of tumor cells between radiation treatments and the hypoxic state of the tumor cells. A successful radiosensitizing agent would target S-phase cells and hypoxia. Recently, we demonstrated the anti-tumor effects of flavopiridol in the GL261 murine glioma model might involve 1) recruitment of tumor cells to S-phase (Newcomb et al Cell Cycle 2004; 3:230-234) and 2) an anti-angiogenic effect on the tumor vasculature by downregulation of hypoxia-inducible factor -1alpha (HIF-1alpha) (Newcomb et al Neuro-Oncology 2005; 7:225-235). Given that flavopiridol has demonstrated radiosensitizing activity in several murine tumor models, we tested whether it would enhance the response of GL261 tumors to radiation. In the present study, we evaluated the intrinsic radiation sensitivity of the GL261 glioma model using the tumor control/cure dose of radiation assay (TCD(50)). We found that a single dose of 65 Gy (CI 57.1-73.1) was required to cure 50% of the tumors locally. Using the tumor growth delay assay, fractionated radiation (5 fractions of 5 Gy over 10 days) combined with flavopiridol (5 mg/kg) given three times weekly for 3 cycles produced a significant growth delay. Our results indicate that the GL261 murine glioma model mimics the radioresistance encountered in human gliomas, and thus should prove useful in identifying promising new investigational radiosensitizers for use in the treatment of glioma patients.
OBJECTIVE: To determine treatment outcome after surgical resection for progressive brain metastases after gamma knife radiosurgery (GKR) and to explore the role of dynamic contrast agent-enhanced perfusion magnetic resonance imaging (MRI) and proton spectroscopic MRI studies (MRS/P) in predicting pathological findings. METHODS: Between 1997 and 2002, 32 patients underwent surgical resection for suspected progression of brain metastases from a cohort of 245 patients with brain metastases treated with GKR. Postradiosurgery MRI surveillance was performed at 6 and 12 weeks, and then every 12 weeks after GKR. In some cases, additional MRI scanning with spectroscopy or perfusion (MRS/P) was used to aid differentiation of radiation change from tumor progression. The decision to perform neurosurgical resection was based on MRI or clinical evidence of lesion progression among patients with a Karnofsky performance score of 60 or more and absent or stable systemic disease. RESULTS: Thirteen percent (32 out of 245) of patients and 6% (38 out of 611) of lesions required surgical resection after GKR. The median time from GKR to surgical resection was 8.6 months (range, 1.7-27.1 mo). The 6-, 12-, and 24-month actuarial survival from time of GKR was 97, 78, and 47% for the resected patients and 65, 40, and 19% for the nonresected patients (P < 0.0001). The two-year survival rate of patients requiring two resections after GKR was 100% compared with 39% for patients undergoing one resection (P = 0.02). The median survival of resected patients was 27.2 months (range, 7.0-72.5 mo) from the diagnosis of brain metastases, 19.9 months (range, 5.0-60.7 mo) from GKR, and 8.9 months (range, 0.2-53.1 mo) from surgical resection. Tumor was found in 90% of resected specimens and necrosis alone in 10%. MRS/P studies were performed in 15 resected patients. Overall, MRS/P predicted tumor in 11 lesions, confirmed pathologically in nine lesions, and necrosis alone was found in two. The MRS/P predicted necrosis alone in three, whereas pathology revealed viable tumor in two and necrosis in one lesion. CONCLUSION: Surgical intervention of progressive brain metastases after GKR in selected patients leads to a meaningful improvement in survival rates. Further studies are necessary to determine the role of MRS/P in the postradiosurgery surveillance of brain metastases.
PURPOSE: To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene. METHODS AND MATERIALS: DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED50). RESULTS: A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED50 of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED50 values) of 1.13 (1.05-1.22), which was significantly greater than unity. CONCLUSION: The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy.
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Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.
PURPOSE: Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases. EXPERIMENTAL DESIGN: The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT. RESULTS: Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells. CONCLUSIONS: The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.
Although most studies treating patients with partial-breast irradiation have used brachytherapy, giving such treatment with external-beam techniques has many potential advantages. However, there is only limited published experience using this approach. These include a randomized trial of partial-breast and whole-breast irradiation performed at the Christie Hospital in Manchester, England, and pilot studies (using much more rigorous selection criteria and sophisticated treatment planning) from groups at the University of Southern California, New York University (using prone positioning of patients), and the William Beaumont Hospital (using the supine position). A multi-institutional pilot trial based on the latter technique has been completed, which was designed to test the feasibility of using this approach in the cooperative oncology group setting. The unprecedented rapidity with which the study completed its target accrual indicates the degree of interest in this approach. This review focuses on the rationale and the reported studies of external-beam partial-breast radiation and identifies some specific issues and remaining problems associated with this approach.
PURPOSE: To analyze the dose/fractionation schedules currently used in ongoing clinical trials of partial breast irradiation (PBI) by comparing their biologically effective dose (BED) values to those of three standard whole breast protocols commonly used after segmental mastectomy in the treatment of breast cancer. METHODS AND MATERIALS: The BED equation derived from the linear-quadratic model for radiation-induced cell killing was used to calculate the BEDs for three commonly used whole breast radiotherapy regimens, in addition to a variety of external beam radiotherapy, as well as high-dose-rate and low-dose-rate brachytherapy, PBI protocols. RESULTS: The BED values of most PBI protocols resulted in tumor control BEDs roughly equivalent to a 50-Gy standard treatment, but consistently lower than the BEDs for regimens in which the tumor bed receives a total dose of either 60 Gy or 66 Gy. The BED values calculated for the acute radiation responses of erythema and desquamation were nearly all lower for the PBI schedules, and the late-response BEDs for most PBI regimens were in a similar range to the BEDs for the standard treatments. CONCLUSION: Biologically effective dose modeling raises the concern that inadequate doses might be delivered by PBI to ensure optimal in-field tumor control.
Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies.
PURPOSE: To report the clinical and dose-volume histogram results of the first 47 patients accrued to a protocol of accelerated partial breast irradiation. Patients were treated in the prone position with three-dimensional conformal radiotherapy after breast-conserving surgery. METHODS AND MATERIALS: Postmenopausal women with Stage T1N0 breast cancer were eligible only after they had first refused to undergo 6 weeks of standard radiotherapy. Planning CT in the prone position was performed on a dedicated table. The postoperative cavity was defined as the clinical target volume, with a 1.5-cm margin added to determine the planning target volume. A total dose of 30 Gy at 6 Gy/fraction was delivered in five fractions within 10 days. RESULTS: The median age of the patients was 67.5 years (range, 51-88 years). The median tumor diameter was 9 mm (range, 1.3-19 mm). In all patients, the prescribed dose encompassed the planning target volume. The mean volume of the ipsilateral breast receiving 100% of the prescription dose was 26% (range, 10-45%), and the mean volume contained within the 50% isodose surface was 47% (range, 23-75%). The lung and heart were spared by treating in the prone position. Acute toxicity was modest, limited mainly to Grade 1-2 erythema. With a median follow-up of 18 months, only Grade 1 late toxicity occurred, and no patient developed local recurrence. CONCLUSION: These data suggest that this approach is well tolerated, with only mild acute side effects and sparing of the heart and lung.
PURPOSE: Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumor-specific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L). METHODS AND MATERIALS: Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression. RESULTS: RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L. CONCLUSIONS: These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation.
Germline variants can be used to study breast cancer susceptibility as well as the variable response to both drug and radiation therapy used in the treatment of breast cancer. In addition to germline high-penetrance mutations important in familial and hereditary breast cancer, a substantial component of breast cancer risk can be attributed to the combined effect of many low-risk germline polymorphisms involved in relevant pathways like those of DNA repair, adhesion, carcinogen and estrogen metabolism. Additionally, the identification of sequence variants in genes involved in response to chemotherapy and radiation treatment, has created the opportunity to apply genomics to individualized treatment. The continued insight into the molecular pathways involved in drug and radiation response has enabled progress in tailoring therapies in such a way as to both maximize efficacy and minimize toxicity. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets can be used to predict toxicity and response to pharmacologic agents used in breast cancer treatment. Similarly, germline variants in genes involved in DNA repair, radiation-induced fibrosis and reactive oxygen species may be used to predict response to radiation therapy. As a result, pharmacogenomics is rapidly evolving to affect the entire spectrum of breast cancer management, influencing both prevention and treatment choices.
PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.
Breast-conserving therapy (BCT) consists of segmental mastectomy followed by postoperative radiation therapy (RT) to the whole breast. At least 6 prospective randomized trials have proven the equivalence of BCT to mastectomy. However, BCT remains underused and, most importantly, a sizable proportion of patients with invasive breast cancer fail to complete the recommended protocol of breast preservation by omitting postoperative RT. The inconvenience of complying with the standard 6-week radiation regimen, which includes approximately 30 daily visits, at least partially explains this lack of adherence. New clinical studies have generated preliminary evidence that more convenient, shorter radiation regimens might reveal equivalence to the current standard. Moreover, the availability of modern technology to deliver and target ionizing radiation by improving homogeneity of radiation dose has made it possible to safely explore the use of greater radiation doses per fraction. Finally, currently ongoing research trials will enable the identification of specific subsets of patients who are likely to be safely treated by partial-breast radiation (instead of radiation to the whole breast) with more accelerated regimens. This article reviews the available data and the current ongoing research on novel RT techniques and fractionation schedules in BCT for early-stage breast cancer.