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Journal of Clinical Oncology 03/2013; · 18.37 Impact Factor
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Yves A Lussier,
Nikolai N Khodarev,
Kelly Regan,
Kimberly Corbin,
Haiquan Li,
Sabha Ganai,
Sajid A Khan,
Jennifer Gnerlich,
Thomas E Darga,
Hanli Fan,
Oleksiy Karpenko,
Philip B Paty,
Mitchell C Posner,
Steven J Chmura, Samuel Hellman,
Mark K Ferguson,
Ralph R Weichselbaum
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ABSTRACT: RATIONALE: Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy. METHODS: We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤5 initial metastases resected with curative intent. RESULTS: Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset. CONCLUSION: Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.
PLoS ONE 01/2012; 7(12):e50141. · 4.09 Impact Factor
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Joseph K Salama,
Michael D Hasselle,
Steven J Chmura,
Renuka Malik,
Neil Mehta,
Kamil M Yenice,
Victoria M Villaflor,
Walter M Stadler,
Philip C Hoffman,
Ezra E W Cohen,
Philip P Connell,
Daniel J Haraf,
Everett E Vokes, Samuel Hellman,
Ralph R Weichselbaum
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ABSTRACT: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy.
Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites. Patients were followed radiographically with CT scans of the chest, abdomen, and pelvis and metabolically with fluorodeoxyglucose-positron emission tomography, 1 month after treatment, and then every 3 months. Acute toxicities were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0, and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system.
Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 on a prospective radiation dose escalation study. Median follow-up was 20.9 months. Patients tolerated treatment well; the maximal tolerated dose was not reached in any cohort. Eleven patients (18.3%) have not progressed. One and 2-year progression-free survival are 33.3% (95% confidence interval [CI], 22.8-46.1) and 22.0% (95% CI, 12.8-34.4); 1-year and 2-year overall survival are 81.5% (95% CI, 71.1-91.1) and 56.7% (95% CI, 43.9-68.9). Seventy-two percent of patients whose tumors progressed did so in limited (1-3) metastatic sites.
Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT. Further investigation should focus on patient selection.
Cancer 10/2011; 118(11):2962-70. · 4.77 Impact Factor
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ABSTRACT: We previously proposed a clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases. Here we review clinical and laboratory data that support the hypothesis that oligometastasis is a distinct clinical entity. Investigations of the prevalence, mechanism of occurrence, and position in the metastatic cascade, as well as the determination of molecular markers to distinguish oligometastatic from polymetastatic disease, are ongoing.
Nature Reviews Clinical Oncology 03/2011; 8(6):378-82. · 11.96 Impact Factor
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Yves A Lussier,
H Rosie Xing,
Joseph K Salama,
Nikolai N Khodarev,
Yong Huang,
Qingbei Zhang,
Sajid A Khan,
Xinan Yang,
Michael D Hasselle,
Thomas E Darga,
Renuka Malik,
Hanli Fan,
Samantha Perakis,
Matthew Filippo,
Kimberly Corbin,
Younghee Lee,
Mitchell C Posner,
Steven J Chmura, Samuel Hellman,
Ralph R Weichselbaum
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ABSTRACT: Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤ 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy.
Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy.
Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression.
These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.
PLoS ONE 01/2011; 6(12):e28650. · 4.09 Impact Factor
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Samuel Hellman
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ABSTRACT: Contested Medicine examines the experiments done at the University of Cincinnati by Eugene Saenger and his colleagues during the 1960s, a time of great fear that the Cold War between the United States and the Soviet Union would become a hot war using nuclear weapons. These studies were to provide the Department of Defense information relevant to the consequences of exposure of military personnel to ionizing radiation in such circumstances. Kutcher, a radiation physicist turned historian of science, is especially well prepared to put these studies into the context of the evolving bioethics of the time. He reviews the essential ethical reviews, beginning with the Nuremberg Code and extending to those of the Advisory Committee on Human Radiation Experiments appointed by President Clinton. These evolving ethical standards provide a cautionary note to today's methods of clinical experimentation in search of proper evidence-based medicine. There has been an ascendance of the priority of patient rights over societal good except in increasingly limited special circumstances. Some of what was considered good and necessary science in the 1960s and 1970s is no longer considered proper. Similarly, future ethical norms may well find current trial methodology to be flawed.
Perspectives in Biology and Medicine 01/2010; 53(2):304-14. · 1.08 Impact Factor
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Cancer Research 02/2009; 69(2):383-92. · 7.86 Impact Factor
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ABSTRACT: Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy.
Patients with one to five sites of metastatic cancer with a life expectancy of >3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system.
Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade > or =3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients.
Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.
Clinical Cancer Research 08/2008; 14(16):5255-9. · 7.74 Impact Factor
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ABSTRACT: To determine the relative influence of treatment features and treatment availabilities on final treatment decisions in early prostate cancer.
We describe and apply a model, based on hedonic prices, to understand provider-patient interactions in prostate cancer. This model included four treatments (observation, external beam radiotherapy, brachytherapy, and prostatectomy) and five treatment features (one efficacy and four treatment complication features). We performed a literature search to estimate (1) the intersections of the "bid" functions and "offer" functions with the price function along different treatment feature axes, and (2) the treatments actually rendered in different patient subgroups based on age. We performed regressions to determine the relative weight of each feature in the overall interaction and the relative availability of each treatment modality to explain differences between observed vs. predicted use of different modalities in different patient subpopulations.
Treatment efficacy and potency preservation are the major factors influencing decisions for young patients, whereas preservation of urinary and rectal function is much more important for very elderly patients. Referral patterns seem to be responsible for most of the deviations of observed use of different treatments from those predicted by idealized provider-patient interactions. Specifically, prostatectomy is used far more commonly in young patients and radiotherapy and observation used far more commonly in elderly patients than predicted by a uniform referral pattern.
The hedonic prices approach facilitated identifying the relative importance of treatment features and quantification of the impact of the prevailing referral pattern on prostate cancer treatment decisions.
International Journal of Radiation OncologyBiologyPhysics 04/2008; 70(4):1158-68. · 4.11 Impact Factor
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Journal of Clinical Oncology 03/2008; 26(6):821-2. · 18.37 Impact Factor
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Samuel Hellman
Journal of Investigative Dermatology 04/2006; 126(3):525-6. · 6.31 Impact Factor
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Samuel Hellman
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ABSTRACT: The word cancer produces widely differing perceptions between the general public, and the scientific and medical communities. These different ideas lead to very diverse understandings of the disease. The paradigms affect both the focus and design of research and also impact upon patient care. The cultural perception is very pessimistic: a relentless, incurable, extremely painful disease, the treatment of which is conceived as difficult, with little chance of a simple cure. Within the medical and scientific communities, however, there are a number of quite different views of the disease. Both the orderly extension of disease described by Halsted, and the systemic nature of cancer even when it appears to be localized, are perceptions within the professional community. The promise of a 'magic bullet' is in sharp contrast to the incremental advances seen in clinical oncology. What is needed is a clear recognition of how these varying perceptions of cancer affect and limit communication among the cancer-related disciplines as well as between these disciplines and the public. Both professionals and the general public should consider cancer as a group of diseases for which cure is related to tumor type, stage and available treatment.
Nature Clinical Practice Oncology 01/2006; 2(12):618-24. · 8.00 Impact Factor
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ABSTRACT: To quantify, using the number needed to treat (NNT) methodology, the benefit of short-term (< or =6 months) hormone therapy adjuvant to radiotherapy in the group of patients with early (clinical stage T1-T2c) prostate cancer.
The absolute biochemical control benefit for the use of hormones adjuvant to radiotherapy in early-stage disease was determined by literature review. A model was developed to estimate the utility-adjusted survival detriment due to the side effects of hormone therapy. The NNTs before and after the incorporation of hormone sequelae were computed; the sign and magnitude of the NNTs were used to gauge the effect of the hormones.
The absolute NNT analysis, based on summarizing the results of 8 reports including a total of 3652 patients, demonstrated an advantage to the addition of hormones for the general early-stage prostate cancer population as well as for all prognostic groups. After adjustment for hormone-induced functional loss, the advantage of hormones remained considerable in the high- and intermediate-risk groups, with the utility-adjusted NNT becoming weakened in the low-risk group when the utility compromise from complications of hormones was assumed to be considerable.
Short-term hormone therapy seems to be beneficial for selected early-stage prostate cancer patients. The advantage seems to be greatest in the intermediate- and high-risk groups; with current follow-up, the side effects of hormones may outweigh their benefit in certain clinical situations in the favorable group. The present investigation demonstrates the significant role of the NNT technique for oncologic and radiotherapeutic management decisions when treatment complications need to be considered and balanced with the beneficial effects of the treatment.
International Journal of Radiation OncologyBiologyPhysics 04/2005; 61(3):687-94. · 4.11 Impact Factor
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Nature Clinical Practice Oncology 03/2005; 2(2):60-1. · 8.00 Impact Factor
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ABSTRACT: To determine whether in the natural history of metastatic non-small cell lung cancer (NSCLC) a time interval exists when metastases are limited in number and/or destination organs. Thirty-eight stage IIIB (pleural effusion)/IV NSCLC patients were treated on a phase II trial of oxaliplatin and paclitaxel. Patients' charts were reviewed and all sites of disease at initial presentation and at subsequent follow-ups were recorded, including the number of organs involved and the number of individual metastatic sites. At presentation, 74% of patients had metastases confined to one or two organs (including the lung primary). Fifty percent had < or =3 metastatic sites in addition to the lung primary. At last follow-up, 17 patients developed new lesions, 14 in a new organ and 3 in a previously involved organ. Nineteen (50%) had stable (n=12) or progressive (n=7) disease in initially involved sites without developing any new metastatic tumors. Among the 17 patients who presented with < or =4 metastatic sites and no pleural effusion, 11 (65%) had stable or progressive disease in initially involved sites without developing new metastases. These results suggest that a subset of patients who present with metastatic NSCLC may not have widely disseminated disease and that some form of local treatment combined with systemic therapy might be beneficial in these patients. Our data support the feasibility of a clinical trial that incorporates local therapies to sterilize metastases in patients with NSCLC.
International Journal of Oncology 12/2004; 25(6):1677-83. · 2.40 Impact Factor
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Carlos A Lopez,
Eric T Kimchi,
Helena J Mauceri,
James O Park,
Neil Mehta,
Kevin T Murphy,
Michael A Beckett, Samuel Hellman,
Mitchell C Posner,
Donald W Kufe,
Ralph R Weichselbaum
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ABSTRACT: A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.
Molecular Cancer Therapeutics 10/2004; 3(9):1167-75. · 5.23 Impact Factor
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ABSTRACT: The authors evaluated the two indicators of metastatic proclivity (namely, virulence [V; the rate of appearance of distant metastases] and metastagenicity [M; the ultimate likelihood of developing distant metastases]) of breast carcinoma in elderly women. The authors then compared these characteristics with the corresponding characteristics in a cohort of younger women to determine whether breast carcinoma was more indolent in women age > 70 years, as is commonly believed in the medical community.
The authors examined 2136 women who underwent mastectomy without adjuvant systemic therapy at The University of Chicago Hospitals (Chicago, IL) between 1927 and 1987. The median follow-up period was 12.3 years. Distant disease-free survival (DDFS) was determined for women who did not receive systemic therapy. V and M were obtained from log-linear plots of DDFS.
No significant difference in tumor size at presentation was observed among women age < 40 years, women ages 40-70 years, and women age > 70 years (P = 0.86), whereas significantly fewer women age > 70 years presented with positive lymph nodes compared with younger women (P = 0.05). In women with negative lymph node status, there was a higher DDFS rate among patients ages 40-70 years (81% at 10 years) compared with patients age > 70 years (65% at 10 years; P = 0.018). There was no significant age-related difference among women with lymph node-positive disease (P = 0.2). For example, the 10-year DDFS rate for women ages 40-70 years was 33%, compared with 38% for women age > 70 years. Among those with lymph node-negative disease, V was 3% per year for women ages 40-70 years as well as women age > 70 years. Among women with lymph node-negative disease, M was 0.20 for patients ages 40-70 years and 0.35 for patients age > 70 years. In women with positive lymph node status, both V (11% per year vs. 10% per year) and M (0.70 vs. 0.65) were similar in both age groups.
Fewer women age > 70 years had lymph node involvement at presentation. However, when this finding was taken into account, the authors found no evidence that breast carcinoma was more indolent in women age > 70 years. These results support the use of similar diagnostic and therapeutic efforts for elderly women and younger women, with modification for elderly women based only on comorbidity.
Cancer 05/2004; 100(9):1807-13. · 4.77 Impact Factor
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ABSTRACT: Hormone therapy commonly is used to treat metastatic, locally advanced, and localized prostate carcinoma. The objective of the current investigation was to determine, using the number-needed-to-treat (NNT) method, the effect of using hormone therapy to treat locally advanced disease, with consideration given to both the complications and the known advantages associated with hormone therapy.
A literature review was performed to determine 1) the absolute benefit, based on available clinical endpoints, associated with the addition of hormone therapy to external beam radiotherapy for locally advanced prostate carcinoma; 2) the incidence of side effects of short-term and long-term hormone therapy; and 3) the stepwise progression from biochemical failure to death. A model was constructed to estimate the complication/utility-adjusted survival detriment resulting from the side effects of short-term (</= 6 months) and long-term (> 6 months) hormone therapy, and the absolute/unadjusted and complication-adjusted NNTs for the addition of short-term and long-term hormone therapy were computed. In all cases, the magnitudes and signs of the NNTs obtained were used to gauge the effect of hormone therapy.
The unadjusted NNTs were positive and in most cases had relatively small magnitudes (the greater the NNT, the smaller the benefit) for both short-term and long-term hormone therapy; these results were expected, and they suggested that there is a strong benefit associated with the use of hormones adjuvant to radiotherapy for locally advanced disease. Adjusted NNTs remained positive and had relatively small magnitudes even after the introduction into the analysis of complications of short-term and long-term hormone therapy. This finding, although weak with respect to the effect of short-term hormone therapy on cause-specific survival, remained robust over the range of values for utility impairment expected from short-term and long-term hormone therapy.
The benefits of short-term and long-term hormone therapy for locally advanced prostate carcinoma appear to be significant and to outweigh the associated side effects. Long-term therapy appears to be better than short-term therapy in terms of virtually all endpoints studied, even when the increased incidence of side effects is considered. The current investigation was successful in the use of the complication-adjusted NNT method for oncologic and radiotherapeutic scenarios in which the results of randomized trials could be summarized, adjusted for treatment toxicity, and individualized to a given patient.
Cancer 12/2003; 98(11):2351-61. · 4.77 Impact Factor
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Harry Bartelink,
Christopher Benz,
Don Cleveland,
Ronald Dorn,
Julie Gralow,
William J Gradishar,
Kathleen Grant,
Ruth Heimann, Samuel Hellman,
Clifford Hudis,
Robert Kerbel,
Marc Lippman,
John Lung,
Mitchell C Posner,
Patricia Steeg,
Robert Vestal,
Ralph R Weichselbaum,
Bruce Zetter
Breast Cancer Research and Treatment 08/2003; 80(2):139-44. · 4.43 Impact Factor
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ABSTRACT: Prostate cancer is one of the most common malignant diseases for which health-care intervention is sought worldwide, and in many developed countries it is the most common. Some patients with early-stage prostate cancer, especially those who are elderly and have comorbidities, can be observed without treatment. Surgery (radical prostatectomy) and radiotherapy (external-beam radiotherapy, brachytherapy, or both) are the most widely accepted curative options for patients with early-stage disease who need intervention. All these local treatments have been refined, resulting in comparable cure rates; however, they all have different side-effect profiles. Adjuvant systemic treatments (hormones or chemotherapy), which are effective for advanced-stage disease, might have a greater role in early-stage disease. Selecting the best option for individuals from the available options is challenging--the decision on whether and how to treat is based on many disease and patient factors. Here, we review the major treatment options, discuss their relative advantages and disadvantages, and provide a general approach to management of patients with early-stage prostate cancer.
The Lancet 04/2003; 361(9362):1045-53. · 38.28 Impact Factor
