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Philip J. Saylor and M. Dror Michaelson

Systemic treatment options for advanced renal cell carcinoma (RCC) have expanded considerably with the development of targeted therapies. Clear cell RCC commonly features mutation or inactivation of the von Hippel-Lindau gene and resultant overexpression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Since then, anti-VEGF receptor therapy with multitargeted kinase inhibitors also has shown substantial efficacy. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Other kinase inhibitors are in development. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival when used in second-line treatment. Non-clear cell and sarcomatoid RCC are both underrepresented in completed trials but are the subject of active research. Ongoing and planned studies will also evaluate the use of combinations of targeted agents, a strategy that is not advisable outside of clinical trials. Finally, postnephrectomy adjuvant treatment with targeted agents is not yet standard but is under investigation in phase III trials.

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Samuel J. Slomowitz and Paul J. Shami

Extramedullary involvement is considered to be an uncommon presentation of acute myeloid leukemia (AML), although some data suggest it may be present in up to 30% of patients. Extra-medullary involvement by AML can present in a variety of clinical manifestations, most notably in the form of myeloid sarcoma, leukemia cutis, and central nervous system involvement. Each presents a unique clinical scenario in terms of symptoms and management. Extramedullary disease in any form presenting without evidence of bone marrow disease is still considered evidence of systemic disease and is usually treated as such. Most commonly, extramedullary disease presents concurrently with bone marrow disease, and although it may require additional local therapy in the form of intrathecal chemotherapy or radiation, the principles of systemic treatment remain unchanged. The prognostic impact of extramedullary disease is unclear. Specifically, whether hematopoietic stem cell transplantation should be considered in first remission irrespective of other prognostic factors has not been established. Patients who undergo transplantation have similar outcomes as patients without extramedullary disease, although they do have a higher rate of extramedullary relapse. More research is needed to define the molecular basis for extramedullary disease, its prognostic impact, and optimal management.

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Andrew H. Ko and Christopher H. Crane

It is well established that the development of distant metastatic disease represents the dominant pattern of tumor recurrence/progression among patients with operable and locally advanced pancreatic cancer. However, the contribution of localized or locoregional tumor burden to pancreatic cancer–associated morbidity and mortality may be underappreciated, and therefore balancing competing considerations of systemic versus local disease control becomes important in therapeutic decision-making. The role of local therapies, particularly radiation therapy, has remained somewhat controversial in this disease context. Several phase II and III trials have sought to address the relative importance and role of radiation in both the localized and locally advanced settings, including the sequencing of this modality relative to systemic therapy and its optimal means of administration. However, differences and limitations in study design have produced mixed results, particularly in terms of the contribution of radiation to overall survival benefit. An emerging paradigm that makes conceptual sense and remains the subject of active investigation is to start with a defined period of systemic treatment, thus limiting radiation to the subset of patients who do not manifest with metastatic disease during initial therapy and are therefore most likely to benefit from local control.

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Vanderbilt-Ingram Cancer Center

Occult primary tumors, or cancers of unknown primary, account for 5% to 10% of all diagnosed cancers, and are manifested by a wide variety of clinical presentations, while conferring a poor prognosis for most patients. Even after postmortem examination, the primary tumor is not identified in 20% to 50% of patients. Multiple sites of involvement are observed in more than 50% of patients. Although certain patterns of metastases suggest possible primaries, occult primaries can metastasize to any site. In most patients, occult primary tumors are refractory to systemic treatments, and chemotherapy is only palliative and does not significantly improve long-term survival. However, special pathologic studies can identify subsets of patients with tumor types that are more responsive. Treatment options should be individualized for this selected group to achieve improved response and survival rates. Important updates for the NCCN guidelines include the additions of tables on tumor-specific markers and their staining pattern as well as analysis of undifferentiated carcinoma.

For the most recent version of the guidelines, please visit NCCN.org

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Andrew G. Robinson, Xuejiao Wei, William J. Mackillop, Yingwei Peng and Christopher M. Booth

Background: Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines. Patterns of care in routine clinical practice have not been well described. This article describes use rates of chemotherapy and referral rates to medical oncology in the last year of life among patients who have died of bladder cancer. Methods: A population-based cohort of patients with bladder cancer was identified from the Ontario Cancer Registry; the study population included patients who died of bladder cancer between 1995 and 2009. Electronic records of treatment and physician billing records were used to identify treatment patterns and referral to medical oncology. Log-binomial and modified Poisson regression were used to examine factors associated with chemotherapy use and medical oncology consultation. Results: A total of 8,005 patients died of bladder cancer, 25% (n=1,964) of whom received chemotherapy in the last year of life. Use was independently associated with patient age, comorbidities, socioeconomic status, sex, time period, and treatment region. A total of 68% (n=5,426) of patients were seen by a medical oncologist. Referral to medical oncology was associated with age, comorbidities, year of death. Geographic variation was seen with chemotherapy use—from 18% to 30%—that persisted on adjusted analysis. Conclusions: The efficacy of palliative chemotherapy demonstrated in clinical trials and recommended in guidelines has not translated into widespread use in practice. Understanding the extent to which patient preferences and health system factors influence use is needed. Access to acceptable palliative systemic treatments remains an unmet need for most patients dying of bladder cancer.

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Dadasaheb Akolkar, Darshana Patil, Anantbhushan Ranade, Revati Patil, Sachin Apurwa, Sanket Patil, Pradip Fulmali, Pradip Devhare, Navin Srivastava, Ajay Srinivasan and Rajan Datar

Background: Post failure of 3 lines of systemic treatments in breast cancers, Standard of Care guidelines recommend palliative care or clinical trials for such patients. We retrospectively evaluated the efficacy of ultra-personalized treatment in a

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Junji Lin, Santosh Gautam, Nan Hu, Debra Wertz, Gboyega Adeboyeje and Sumesh Kachroo

(range 38.5-86.0 years). At diagnosis, 331 (81.5%) pts had extensive stage disease and 225 (55.4%) had brain metastasis. Of 346 pts with systemic treatment (IO-naïve) in 1st line (1L), 43 (12.4%) had impaired performance status. 255 (73.7%) used

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Mohamed Ali Maher, Abdelhamid Mohamed Fouad and Mariam Maged Elhaddad

Context: The systemic treatment of metastatic breast cancer (MBC) prolongs survival and enhances quality of life but is not curative. Therefore, treatments associated with minimal toxicity are preferred. Thus, the use of the minimally toxic

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Thomas W. Flaig

. Flaig acknowledged this news and described the systemic treatment options for first- and second-line metastatic urothelial bladder carcinoma ( Figure 1 ). In addition, Dr. Flaig compared the similarities and differences among new immunotherapy options

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surgical approaches to systemic therapies in the management of kidney cancer, Steven L. Chang, MD, MS, and Toni K. Choueiri, MD, Dana-Farber/Brigham and Women's Cancer Center, summarized the benefits and risks of current surgical and systemic treatment