Project Title: Extranodal extension as an indicator of contralateral neck involvement in squamous cell carcinoma of the oropharynx
Faculty Mentor: Kathryn Hitchcock
Student: Aaron (AJ) Winer
Research Project Description:
In patients with squamous cell carcinoma of the oropharynx, the lymphatics of the neck are so commonly involved that they are treated even when there is no radiographic evidence of early tumor metastasis to the cervical lymph nodes. If the primary tumor is well lateralized, it is known that movement of cancer cells to the contralateral neck is uncommon. Experienced radiation oncologists and surgeons therefore often dissect or irradiate only the ipsilateral neck, sparing the patient considerable morbidity.
In recent months there has been discussion in radiation oncology forums of a new indication for contralateral neck treatment in these patients: extranodal extension (ENE). This is a common phenomenon in which a tumor deposit in a cervical lymph node grows beyond the lymph node capsule and into the surrounding soft tissue. ENE is known to be a strong risk factor for recurrence at the site of that lymph node, and therefore prompts use of a higher dose of radiation in that volume as well as radiation-sensitizing systemic therapy. What has gone unexplained in the ongoing discussions is why the opposite side of the neck would be at greater risk in the presence of ENE. Nevertheless, some well-respected radiation oncologists are recommending bilateral neck irradiation when ENE is present.
The goal of this project is to determine whether recurrence is more common in the untreated contralateral neck in patients with well-lateralized SCCa of the oropharynx when the ipsilateral neck has nodes with ENE. Our hypothesis is that the current practice of treating the ipsilateral neck alone is safe and consistent with good long-term tumor control, even when ENE is present.
Specific Aim #1: Determine the rate of contralateral neck failure in patients with lateralized oropharynx SCCa. We will review our database of patients to determine how often those treated with ipsilateral-only radiotherapy experienced recurrences of the cancer in their contralateral neck. The presence or absence of recurrence at the primary site in this sub-group will also be tabulated.
Specific Aim #2: Compare the rate of recurrence in those with ENE to those lacking ENE.
We will identify those with ENE in the ipsilateral, treated neck in order to determine whether these individuals were more likely to experience recurrence than those without ENE. This determination will drive a recommendation that has the potential to change the way these patients are treated throughout the world
- Chin R, Rao YJ, Hwang MY, et al. Comparison of unilateral versus bilateral intensity‐modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil. Cancer. 2017;123(23):4594-4607.
- Yeung AR, Garg MK, Lawson J, et al. ACR appropriateness criteria® ipsilateral radiation for squamous cell carcinoma of the tonsil. Head Neck. 2012;34(5):613-616.
- Kennedy WR, Herman MP, Deraniyagala RL, et al. Ipsilateral radiotherapy for squamous cell carcinoma of the tonsil. European Archives of Oto-Rhino-Laryngology. 2016;273(8):2151-2156.
- Jensen K, Overgaard M, Grau C. Morbidity after ipsilateral radiotherapy for oropharyngeal cancer. Radiotherapy and Oncology. 2007;85(1):90-97.
- Cerezo L, Martín M, López M, Marín A, Gómez A. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: Results on tumor control and xerostomia. Radiation Oncology. 2009;4(1):33.
- Lynch J, Lal P, Schick U, et al. Multiple cervical lymph node involvement and extra-capsular extension predict for contralateral nodal recurrence after ipsilateral radiotherapy for squamous cell carcinoma of the tonsil. Oral Oncol. 2014;50(9):901-906.
- Sanguineti G, Califano J, Stafford E, et al. Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma. International Journal of Radiation Oncology* Biology* Physics. 2009;74(5):1356-1364.
- Wirtz MM, Temming S, Kocher M, Kunze S, Semrau R. Low risk of contralateral lymph node recurrence in lateralized head and neck carcinoma after postoperative ipsilateral radiotherapy. Strahlentherapie und Onkologie. 2019:1-11.
- Al-Mamgani A, van Werkhoven E, Navran A, et al. Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review. Cancer Treat Rev. 2017;59:102-108.
- Gottumukkala S, Pham N, Sumer B, et al. Risk of contralateral nodal failure following ipsilateral IMRT for node-positive tonsillar cancer. Oral Oncol. 2017;75:35-38.
- Lin CH, Chang J, Lin CY, Fan KH, Huang BS. Ipsilateral neck irradiation for postoperative lateralized buccal mucosa squamous carcinoma with extranodal extension: Propensity analysis. International Journal of Radiation Oncology• Biology• Physics. 2019;105(1):E404.
- Huang SH, Waldron J, Bratman SV, et al. Re-evaluation of ipsilateral radiation for T1-T2N0-N2b tonsil carcinoma at the princess margaret hospital in the human papillomavirus era, 25 years later. International Journal of Radiation Oncology* Biology* Physics. 2017;98(1):159-169.
- Kim Y, Cho KH, Moon SH, et al. Comparison of the clinical outcomes of patients with squamous cell carcinoma of the tonsil receiving postoperative ipsilateral versus bilateral neck radiotherapy: A propensity score matching analysis (KROG 11-07). Cancer research and treatment: official journal of Korean Cancer Association. 2017;49(4):1097.
- Maskell D, Buckley H, Sission K, Roques T, Geropantas K. Ipsilateral neck radiotherapy in N2b well‐lateralized tonsil cancer–Approach with caution. Head Neck. 2019;41(9):2937-2946.
- McDowell L, Casswell G, Bressel M, et al. Patient-reported quality of life and toxicity in unilateral and bilateral radiotherapy for early-stage human papillomavirus associated tonsillar carcinoma. Clinical and Translational Radiation Oncology. 2020;21:85-90.
Project Title: Comparison of myocardial perfusion changes following radiation therapy in breast cancer patients
Faculty Mentor: Walter O’Dell
Student: Rohan Patel
Research Project Description:
Breast cancer affects over 200,000 people annually in the United States. Radiotherapy (RT) is a critical component of breast cancer management, yielding a substantial survival benefit.1-4 These survival benefits have occurred despite technical limitations that result in inadvertent exposure of large volumes of normal tissues to low and moderate doses of radiation. Numerous reports document increased cardiac mortality after RT to the left breast. A meta-analysis of 42,000 women found 1,106 deaths due to cardiac disease, resulting in a 1.27 increase in relative risk (RR) of cardiac death after breast cancer RT.3 Recent data show that cardiac injury is a no-threshold phenomenon, with a 7% increase in RR of cardiac disease with each 1-Gy increase in mean heart dose.5 Although RT techniques have improved over the past few decades including defining anatomy on CT, prone positioning, and breath-hold techniques, portions of the heart remain in the irradiated volume due to proximity to breast tissue. Because cardiac injury is a late effect of radiation, early markers could be used to identify new techniques that would improve the therapeutic ratio of treatment within years rather than decades.
Radiation causes chronic vascular damage and fibrosing inflammation that leads to microvascular changes in the heart, which manifest as reduced cardiac motion. Reduction or elimination of radiation-induced cardiac injury and mortality will improve survival and quality of life for patients treated for breast cancer. This late symptom presentation makes it difficult to quantify the true incidence of RT-related toxicity. It has only been in the past decade that 3-dimensional imaging and mapping of radiation dose distributions have permitted detailed
Knowledge of the actual radiation doses received by critical cardiac structures. The importance of low-dose radiation injury to the heart in breast cancer patients has only been recently recognized, but knowledge of actual dose distributions from these past patients with cardiac injuries is not possible. Thus, prospective studies employing precise radiation dose mapping techniques and new cardiac imaging studies are necessary to define the dose-response relationship for radiation induced cardiac injury. The first step toward improving the therapeutic ratio of breast cancer RT is identifying early markers of cardiac injury that can then be used to evaluate new RT techniques in a timely fashion.
Functional imaging will provide quantitative metrics of physiologic response at tissue levels using 3D medical imaging and post-acquisition engineering. CMR provides traditional metrics of cardiac function and also allows pixel-by-pixel assessment of myocardial strain. These detailed measurements of anatomical and physiologic responses to RT along with organ-specific dosimetry will fuel the modeling of dose-related degenerative tissue response following RT.
Our hypothesis is that radiation exposure of the heart wall will result in a measurable change in regional myocardial perfusion that scales with regional radiation exposure. A secondary hypothesis is that patients receiving proton therapy will have less dysfunction that patients receiving standard X-ray based treatment in according with expected reduction in heart dose.
- Process cardiac MRI perfusion datasets in 12 breast cancer patients acquired pre-RT and 6-13 months post-RT.
- Compute regional metrics of perfusion (time-to-peak contrast uptake, and maximal uptake slope).
- Spatially correlate regional perfusion changes with regional radiation dose.
- Mathematically model the relationship between perfusion deficit and radiation dose.
- Overgaard M, Hansen PS, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337: 949-55.
- Overgaard M, Jensen MB, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999; 353: 1641-8.
- Clarke M, Collins R, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087-106.
- Hwang ES, Lichtensztajn DY, et al. Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. Cancer 2013; 119: 1402-11.
- Darby SC, Ewertz M, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368: 987-98.
- Lightfoot JC, D’Agostino RB, Jr., et al. Novel approach to early detection of doxorubicin cardiotoxicity by gadolinium-enhanced cardiovascular magnetic resonance imaging in an experimental model. Circ Cardiovasc Imaging 2010; 3: 550-8.
- Machann W, Beer M, et al. Cardiac magnetic resonance imaging findings in 20-year survivors of mediastinal radiotherapy for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 2011; 79: 1117-23.
- O’Dell WG, McCulloch AD. Imaging three-dimensional cardiac function. Annu Rev Biomed Eng 2000; 2: 431-56.
- O’Dell WG, Moore CC, et al. Three-dimensional myocardial deformations: calculation with displacement field fitting to tagged MR images. Radiology 1995; 195: 829-35.
- Declerck J, Denney TS, et al. Left ventricular motion reconstruction from planar tagged MR images: a comparison. Phys Med Biol 2000; 45: 1611-32.
Project Title: Upstaging After Surgical Excision in Biopsy Proven Flat Epithelial Atypia
Faculty Mentor: Mariam Hanna
Student: Zereen Sarwar
Research Project Description:
Flat epithelial atypia (FEA) is a benign neoplasm of the breast duct characterized by the replacement of the normal luminal epithelium of the terminal ductal lobular unit by one or more layers of columnar cells with cytologic atypia and no architectural changes (2,4). It is currently considered “high risk” due to possible association with malignancy. It may be a precursor to invasive ductal carcinoma, or it may be a precursor to ductal carcinoma in situ or atypical ductal hyperplasia, both of which have risk of developing into invasive ductal carcinoma (4). However, these associations are not made clear in the literature, and the exact malignant potential of FEA is unknown.
Because of this uncertainty, whether biopsy proven FEA should be surgically excised or followed with subsequent mammography is a subject of considerable debate (1,3,5). At UF, all FEA proven lesions are surgically excised. However, some studies suggest that FEA alone does not pose a considerable risk for malignancy and may be better managed by close monitoring with mammography rather than surgery (1). Breast surgery comes with numerous risks, including cosmetic changes, nerve damage, infection, etc (6). If FEA is shown to have low enough malignant potential that it can be followed with mammography rather than be surgically excised, patients may be able to avoid surgery and the risks that come with it.
We hypothesize that there will be no significant upstaging risk to malignancy of biopsy proven FEA lesions post-surgical excision. Prior research has suggested that FEA alone may not pose as much of a risk for malignancy as previously thought (1).
This study aims to determine whether there was upstaging with final diagnosis in UF patients with biopsy proven FEA lesions and to produce a paper from the results of the study. This study also aims to help guide decision making on whether FEA lesions should be surgically excised or followed with mammography.
- Acott AA, Mancino AT, Flat epithelial atypia on core needle biopsy, must be surgically excise? The American Journal of Surgery. 2016;212(6):1211-1213. doi:10.1016/j.amjsurg.2016.09.019
- Lerwill MF. Flat Epithelial Atypia of the Breast. Archives of Pathology & Laboratory Medicine. 2008;132(4):615-621
- Neal L, Sandhu NP, Hieken TJ, Glazebrook KN, Mac Bride MB, Dilaveri CA, et al. Diagnosis and Management of Benign, Atypical, and Indeterminate Breast Lesions Detected on Core Needle Biopsy. Mayo Clinic Proceedings. 2014;89(4):536-547. doi:10.1016/j.mayocp.2014.02.002
- Schiaffino S, Gristina L, Villa A, Tosto S, Monetti F, Carli F, Calabrese M. Flat epithelial atypia: conservative management of patients without residual microcalcifications post-vacuum-assisted breast biopsy. British Institute of Radiology. 2018;92:1081. doi:10.1259/bjr.20170484
- Solorzano S, Mesurolle B, Omeroglu A, El Khoury M, Kao E, Aldis A, Meterissian S. Flat Epithelial Atypia of the Breast: Pathological-Radiological Correlation. American Journal of Roentgenology. 2011;197:740-746. doi:10.2214/AJR.105265
- Vitug AF, Newman LA. Complications in Breast Surgery. Surgical Clinics of North America. 2007;87(2):431-451. doi:10.1016/j.suc.2007.01.005
Project Title: The influence of surgical era on the time to post-operative radiotherapy in squamous cell carcinoma of the head and neck
Faculty Mentor: Joshua Yarrow
Student: Russell Wnek
Research Project Description:
For many cancers of the head and neck, at least two of the three major cancer therapies (surgery, radiotherapy, chemotherapy) must be employed to obtain the best available outcomes including overall survival. For squamous cell carcinoma of the oral cavity or larynx, it is common to perform surgery followed by radiotherapy (RT). The existing literature proves that in these cases, the duration between surgery and RT is critical, with longer intervals associated with significantly worse outcomes. Modern surgeries for this disease, particularly in the oral cavity, tend to be more complex than in the past, transplanting free flaps from the extremities in order to attempt to restore optimal function. It is possible that this trend affects times to RT in these patients.
The goal of this project is to determine whether the time to post-operative radiotherapy in patients whose surgery involved a free flap are different from the time in patients treated with less complex surgeries. We hypothesize that modern free-flap surgeries result in longer delays to post-operative radiotherapy.
Specific Aim #1: To determine the time between surgery and post-operative RT in patients treated with and without free-flaps. We will review patients treated for squamous cell carcinoma with surgery followed by radiotherapy and measure their intervals from surgery to RT. We will tabulate the type of surgery (free flap, no free flap), the surgeon, and potential confounding factors such as co-morbidities. Since free-flaps are often used in SCCa of the oral cavity and rarely for laryngeal cancer, patients with the latter disease will be used to identify factors that influence the duration of this period.
Specific Aim #2: To determine how the time to post-operative RT in patients treated with and without free flaps compares to the ideal period delineated in the literature. We will compare our results to those of other investigators to determine whether surgical technique influences the achievement of post-operative RT within the limited interval that results in the best known outcomes.
- Ang KK, Trotti A, Garden AS, et al. 108Overall time factor in postoperative radiation: Results of a prospective randomized trial. Radiotherapy and Oncology. 1996;40:S30.
- Trotti A, Klotch D, Endicott J, Ridley M, Cantor A. Postoperative accelerated radiotherapy in high‐risk squamous cell carcinoma of the head and neck: Long‐term results of a prospective trial. Head & Neck: Journal for the Sciences and Specialties of the Head and Neck. 1998;20(2):119-123.
- Peters LJ, Withers HR. Applying radiobiological principles to combined modality treatment of head and neck cancer—the time factor. International Journal of Radiation Oncology* Biology* Physics. 1997;39(4):831-836.
- Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ, Million RR. An analysis of factors influencing the outcome of postoperative irradiation for squamous cell carcinoma of the oral cavity. International Journal of Radiation Oncology* Biology* Physics. 1997;39(1):137-148.
- Byers RM, Clayman GL, Guillamondequi OM, Peters LJ, Goepfert H. Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract. Head Neck. 1992;14(2):133-138.
- Amdur RJ, Parsons JT, Mendenhall WM, Million RR, Cassisi NJ. Split-course versus continuous-course irradiation in the postoperative setting for squamous cell carcinoma of the head and neck. International Journal of Radiation Oncology* Biology* Physics. 1989;17(2):279-285.
- Robertson C, Robertson AG, Hendry JH, et al. Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers. Int J Radiat Oncol Biol Phys. 1998;40(2):319-329.
- Schiff PB, Harrison LB, Strong EW, et al. Impact of the time interval between surgery and postoperative radiation therapy on locoregional control in advanced head and neck cancer. J Surg Oncol. 1990;43(4):203-208.
- Vikram B. Importance of the time interval between surgery postoperative radiation therapy in the combined management of head & neck cancer. International Journal of Radiation Oncology* Biology* Physics. 1979;5(10):1837-1840.
- Rosenthal DI, Liu L, Lee JH, et al. Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck. Head Neck. 2002;24(2):115-126.
- Evans M, Beasley M. Target delineation for postoperative treatment of head and neck cancer. Oral Oncol. 2018;86:288-295.
- Levy DA, Li H, Sterba KR, et al. Development and validation of nomograms for predicting delayed postoperative radiotherapy initiation in head and neck squamous cell carcinoma. JAMA Otolaryngology–Head & Neck Surgery. 2020.
Project Title: The Efficacy of Standard US-Guided Biopsy versus MRI Fusion Guided Biopsy in Detecting Prostate Cancer
Faculty Mentor: Joseph Grajo
Student: Apara Agarwal
Research Project Description:
Prostate cancer is the most common male cancer in the United States, and among the most common causes of death secondary to cancer. It has a varied clinical presentation prior to diagnosis. The decision for imaging-guided biopsy is typically made due to a mix of suspicious symptoms, abnormal digital rectal examination, and abnormal prostate-specific antigen (1). The gold standard for diagnosing prostate cancer is via biopsy, with the current standard of care being 12 core template ultrasound (US) guided biopsy, also known as transrectal ultrasound (TRUS). Previous studies have validated the use of 12 cores in the biopsy, as increasing the number of cores to 18-24 did not yield higher cancer incidences (2). However, with recent advances and availability of technology, there may be advantages to using magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion biopsy (1).
A significant advancement in MRI technology comes from the multiple parametric technique (mpMRI), which allows clinicians to examine suspicious lesions in a less invasive manner. Lesions that are selected via mpMRI can then be biopsied via a variety of MRI-guided methods, including MRI-TRUS fusion biopsy (1). MRI-TRUS fusion biopsy has several advantages over other MRI-guided methods as it allows clinicians to obtain the biopsy in an outpatient setting, as opposed to the direct-MRI guided biopsy which requires coordination with anesthesiology (3). One study of these techniques was large multicenter randomized control trial of 665 men who received follow-up MRI-TRUS or one of two other MRI-guided biopsies after an initial negative US-guided biopsy (4). This study did not show any significant change in detection rates among the three MRI-guided techniques (4). Several studies have been published comparing MRI-TRUS fusion biopsies with the standard US-only biopsy (2,5). Also for this fusion biopsy there must be someone trained in operating the MRI and the software to link MRI-obtained data with the US-obtained data, leading to significant cost (5,6).
Patients who have an initially negative systematic biopsy may still present with symptoms generating continued clinical concern for prostate cancer. Several studies, including a large multi-institutional cohort, have shown some evidence in these patients having increased sensitivity of clinically significant cancer detection rate via MRI fusion biopsy over repeat standard biopsy because the yield of fusion biopsies did not decrease with increased number of prior negative biopsies, whereas the standard biopsy yield did decrease (5). Our hypothesis is hat fusion biopsy will provide better clinically significant cancer detection rates as a minimally invasive procedure, and outperforms the current gold standard of TRUS biopsy on repeat biopsy.
The specific aims of this project include analyzing patients who received a fusion biopsy guided by MRI and US after an initial negative standard US biopsy to see the differences in biopsy quality in the two methods.
- Streicher J, Meyerson BL, Karivedu V, Sidana A. A review of optimal prostate biopsy: indications and techniques. Ther Adv Urol. 2019;11:1756287219870074. Published 2019 Aug 28. doi:10.1177/1756287219870074
- Eichler K, Hempel S, Wilby J, Myers L, Bachmann LM, Kleijnen J. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol. 2006;175(5):1605-12. Published 2006 May. doi: 10.1016/S0022-5347(05)00957-2
- Woodrum DA, Gorny KR, Greenwood B, Mynderse LA. MRI-Guided Prostate Biopsy of Native and Recurrent Prostate Cancer. Semin Intervent Radiol. 2016;33(3):196‐205. doi:10.1055/s-0036-1586151
- Wezgelin O, Exterkatede L, van der Leest M, Kummer JA, Vreuls W, de Bruin PC, Bosch JLHR, Barentsz JO, Somford DM, van Melick HHE. The FUTURE trial: a multicenter randomised controlled trial on target biopsy techniques based on magnetic resonance imaging in the diagnosis of prostate cancer in patients with prior negative biopsies. Eur Urol. 2019;75(4):582-590. Epublished 2018 Dec 3. doi: 10.1016/j.eururo.2018.11.040
- Sidana A, Watson MJ, George AK, Rastinehad AR, Vourganti S, Rais-Bahrami S, Muthigi A, Maruf M, Gordetsky JB, Nix JW, Merino MJ, Turkbey B, Choyke PL, Wood BJ, Pinto PA. Fusion prostate biopsy outperforms 12-core systematic prostate biopsy in patients with prior negative systematic biopsy: a multi-institutional analysis. J Urol Onc. 2018;36(7):341.e1-341.e7. Published 2018 Jul. https://doi.org/10.1016/j.urolonc.2018.04.002
- Frye TP, Pinto PA, George AK. Optimizing patient population for MP-MRI and fusion biopsy for prostate cancer detection. Curr Urol Rep. 2015;50(16). https://doi.org/10.1007/s11934-015-0521-y
- Moore CM, Kasivisvanathan V, Eggener S, Emberton M, Fütterer JJ, Gill IS, Grubb Iii RL, Hadaschik B, Klotz L, Margolis DJ, Marks LS, Melamed J, Oto A, Palmer SL, Pinto P, Puech P, Punwani S, Rosenkrantz AB, Schoots IG, Simon R, Taneja SS, Turkbey B, Ukimura O, van der Meulen J, Villers A, Watanabe Y. Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an International Working Group. Eur Urol. 2013 Oct;64(4):544-52. doi: 10.1016/j.eururo.2013.03.030. Epub 2013 Mar 20. PubMed PMID: 23537686.
- Mozer, P., Rouprêt, M., Le Cossec, C., Granger, B., Comperat, E., de Gorski, A., Cussenot, O. and Renard‐Penna, R. (2015), MRI/TRUS‐fusion targeted vs standard TRUS‐guided biopsy. BJU Int. 2014;115:50-57. doi:10.1111/bju.12690