Christina T. Loguidice

by researchers from China indicates panurothelial carcinoma (panUCC) has a high risk of recurring, progressing, and disseminating after conservative surgery, leading to poor outcomes. Therefore, the study&rsquo;s authors recommend standardizing more aggressive surgical treatment for these patients, and they advocate complete urinary tract exenteration (CUTE) in carefully selected patients with panUCC, but especially in those with end-stage renal disease.

&ldquo;The elevated risk of recurrence, progression, and tumor dissemination following conservative surgery reflect potential disadvantages of organ-conserving strategies,&rdquo; the study authors wrote.

PanUCC, which includes the presence of bilateral upper tract urothelial carcinoma (UTUC) and a concomitant bladder tumor (BT), is a rare disease entity. To better understand the clinicopathologic characteristics and treatment outcomes of panUCC in the Asian population, the authors reviewed the medical records of patients treated for UTUC or BT at Peking University First Hospital, Beijing, China, between 1999 and 2012.

&ldquo;Considering the heterogeneity and differences in incidence of urothelial carcinoma between Asian and Western patients, profiling the disease in an Asian cohort may facilitate management and elucidation of the underlying mechanisms,&rdquo; the study authors wrote. &ldquo;Elucidating the features of this uncommon disease entity, our data may contribute to optimal and personalized risk-based therapy while supporting future investigations into the biological mechanisms underlying multiple urothelial tumors,&rdquo; they noted.

Overall, 45 patients (mean age, 64.5 years; 15 men and 30 women) met the authors&rsquo; study criteria (ie, diagnosis of urothelial carcinoma in the bilateral upper tracts and in the bladder either synchronously or metachronously) and were included in the study. Of these patients, 14 initially presented with unilateral UTUC and 11 with BT. The remainder had multiple tumors, including 10 with bilateral UTUC, 6 with unilateral UTUC and concomitant BT, and 4 with synchronous panUCC.

&ldquo;In panUCC, regardless of synchronous or metachronous involvement, tumors in different locations still manifest the biological characteristics of primary UTUC and primary BT. In our cohort, BT demonstrated higher rates of multiple foci, while upper tract tumors were frequently muscle-invasive and larger,&rdquo; the authors wrote.

The median time from patients&rsquo; initial presentation to their tumor disseminating to second and third sites was 8 months (range, 0-84 months) and 21 months (range, 0-141 months), respectively. Tumor dissemination took a little longer in those with tumors initially restricted to one site, with a median time of 24 months for tumor dissemination to second and third sites (range, 3-84 months and 3-141 months, respectively). Location of the initial tumor did not affect the time to development of metachronous disease or affect final tumor stage or grade. In addition, no differences in tumor stage or grade were observed between tumors at the first and third tumor sites; however, tumors at the third site were more likely to have sessile architecture and multiple foci.

Most of the study patients (73.3%) received combined management with conservative and radical surgery. Only 5 patients were treated with CUTE. After a median follow-up of 77 months (range, 16-156 months), 18 patients (40%) died, with 15 deaths (33.3%) directly related to urothelial cancer. The 2- and 5-year cancer-specific survival (CSS) rates were 95.6% and 81.2%, respectively. Univariate analysis found only higher tumor stage to be predictive of worse CSS. No patient demographics or tumor characteristics were found to have an impact on overall survival.

Approximately 60% of patients with UTUC received radical surgery initially or after a recurrence, while fewer than 25% of those with BT received radical surgery for either indication. Of those receiving conservative surgery, 19 experienced local recurrences. After undergoing surgical treatment for recurrence, 10 proceeded to receive CUTE.

Postoperatively, a total of 19 patients required permanent dialysis. None of these patients were renal transplant recipients and 6 had at least one kidney.

The authors reported several limitations with their study, including its retrospective design, which they note &ldquo;precluded evaluation of potentially useful variables such as cytology and lymph node status in all patients.&rdquo;

They also reported potential recall bias, lack of complete pathological results for some patients, and lack of standardization of the surgical approaches used and of the indications for a second surgery, both of which were based on the clinical judgment of the treating physician and on patients&rsquo; preferences and expectations. Furthermore, although not noted by the authors, the small study population and heterogeneity of urothelial carcinoma in different populations might limit the applicability of the findings to other populations, including Western populations and other Asian populations.

Fang D, Liu P, Li X, et al. Characteristics and treatment outcomes of pan-urothelial cell carcinoma: a descriptive analysis of 45 patients. Sci Rep. 2015;5:18014. doi:10.1038/srep18014.

Articles

A study published in Scientific Reports by researchers from China indicates panurothelial carcinoma (panUCC) has a high risk of recurring, progressing, and disseminating after conservative surgery, leading to poor outcomes.

Study Suggests Panurothelial Carcinoma Warrants More Aggressive Surgical Treatment

Vitamin C, often used to fight colds and other pathogens, may also be a powerful weapon against colorectal cancer (CRC), according to a study published in

In the study, cultured CRC cells that harbored

mutations were selectively killed when exposed to high levels of vitamin C. These mutations are present in more than half of patients with CRCs and are often refractory to approved targeted therapies

; thus, there is an urgent need for novel treatments.

The study investigators, led by Lewis Cantley, PhD, Department of Medicine, Weill Cornell Medical College, New York, NY, first observed the cancer-killing effect in cell culture studies. The

-mutated cells were found to have an increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter, a protein that facilitates the transport of glucose across the plasma membranes of cells. Natural antioxidants inside the cancer cells converted the DHA back to vitamin C, but this process consumed all the available antioxidants, and the cells ultimately died from oxidative stress.

-mutant cancer cells could take up DHA at such a high rate that the DHA consumed all the cells&rsquo; antioxidants, which are needed for cancer cell survival,&rdquo; said Cantley in an interview with

. &ldquo;Most cancer cellsand normal cells&mdash;do not have enough glucose transporters to allow DHA to enter at such a rapid rate.&rdquo;

-mutant CRC cells in their cell culture studies, Cantley et al explored whether or not vitamin C could alter the growth of

-mutant CRC in mice. They found that high-dose vitamin C impaired the growth of CRC in mice with

The Cantley et al study is not the first to look at vitamin C as a potential treatment for cancer. &ldquo;Numerous clinical trials have been conducted with vitamin C over the past 49 years, with conflicting results, but these trials have not focused on the mutational background that would predict which patients are likely to respond,&rdquo; Cantley said. Armed with this new knowledge, he and his colleagues have started conferring with other clinicians about the design of clinical trials that would test the idea that

-mutant cancers are more effectively treated by vitamin C than other cancers. Although Cantley does not rule out the possibility that other cancers might benefit from vitamin C treatments, especially if they share the characteristics of

mutant CRCs, research has yet to identify such tumors.

While patients might be tempted to load up on vitamin C based on the recent study results, Cantley warns that it is extremely unlikely that one could consume enough vitamin C orally to achieve the concentration of vitamin C and DHA in the bloodstream that is needed to kill tumors. In fact, Cantley et al suggest that there have been a growing number of phase I/II clinical trials reevaluating intravenous (IV) infusion of vitamin C to treat various cancers because this route of administration was recently linked to superior efficacy over the oral route.

For patients receiving IV vitamin C as part of a cancer treatment regimen, Cantley warns that they should not take antioxidants concomitantly because these agents will prevent the formation of DHA, which was shown to be the effective agent in Cantley et al study.

&ldquo;I think that most oncologists would agree that we are entering an era in which precision medicine will be increasingly important for choosing therapies; however, for most patients, the mutations revealed by sequencing genes in the tumor do not suggest an effective therapy,&rdquo; said Cantley. &ldquo;Although

is one of the most frequently mutated genes, we do not yet have a drug that directly targets it, and even if vitamin C ultimately shows good results in humans with this or the

mutation, it is likely that we will need to combine it with other agents that enhance the formation of reactive oxygen species in the tumor to achieve tumor shrinkage,&rdquo; he said.

Yun J, Mullarky E, Lu C, et al. Vitamin C selectively kills

mutant colorectal cancer cells by targeting GAPDH.

. http://www.sciencemag.org/content/early/2015/11/04/science.aaa5004.full. Published November 5, 2015. Accessed November 12, 2015. doi: 10.1126/science.aaa5004.

Basu GD, Xiu J, Arguello D, et al. Prevalence of

alterations in colorectal cancer: analysis of a large international cohort of 5,900 patients. Poster presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA. Abstract 399.

Vitamin C, often used to fight colds and other pathogens, may also be a powerful weapon against colorectal cancer (CRC), according to a study published in Science.

Vitamin C Shown to Kill Colorectal Cancer Cells Carrying KRAS and BRAF Mutations

Investigators of a new, prospective, multi-institutional, phase II study reported that favorable-risk oropharyngeal squamous cell carcinoma (OPSCC) positive for human papillomavirus (HPV) or p16 can be treated successfully with fewer side effects using substantially decreased chemoradiotherapy (CRT) doses. The study findings were presented at the 2015 American Society for Radiation Oncology Annual Meeting and published online in the

International Journal of Radiation Oncology, Biology, Physics

The study builds on previous research that showed that patients with HPV- or p16-associated OPSCCs responded much better to radiation and chemotherapy than patients with HPV- or p16-negative disease.

In addition to having favorable-risk OPSCCs, all study patients (n=43) had a minimal smoking history.

Treatment was limited to 60 Gy intensity-modulated radiotherapy with concurrent weekly 30 mg/m

intravenous cisplatinum for 6 weeks. Historically, standard treatment of OPSCCs includes 70 Gy intensity-modulated radiotherapy once weekly for 7 weeks, three high doses of cisplatinum, and, in some cases, post-treatment surgery.

Although this standard regimen has a high cure rate (>90%), it has been associated with numerous side effects and long-term complications.

&ldquo;We decided on the lower dosages based on our experiences with anal cancer,&rdquo; said the study&rsquo;s first author and principal investigator Bhishamjit S. Chera, MD, UNC Lineberger member and associate professor in the Department of Radiation Oncology at the University of North Carolina (UNC) School of Medicine, in an interview with

. &ldquo;Squamous cell carcinoma of the anal canal is also related to HPV and standardly treated with radiation and chemotherapy, with radiation doses ranging from 50 Gy to 60 Gy. We hypothesized that HPV-associated oropharyngeal cancer would be as radiosensitive as HPV-associated anal cancer, leading us to select the 60 Gy dosage.&rdquo;

In the study, the de-intensified CRT regimen achieved an 86% pathologic complete response rate. Of its&nbsp;43&nbsp;patients, 37 (86%) achieved a pathologic complete response with the de-intensified CRT regimen. Disease in the remaining 6 patients was limited to microscopic foci of residual cancer, with one at the primary site and five in the lymph nodes. Pathologic complete response, which was the study&rsquo;s primary endpoint, was assessed for through a biopsy of the primary tumor site and a limited neck surgery to remove any pretreatment cancerous lymph node regions. After a median follow-up of 20.7 months (range, 6-36 months), all patients were alive with no evidence of disease. &ldquo;These results suggest that we are probably over-treating these patients with the standard radiation and chemotherapy regimens,&rdquo; said Chera.

The study also had several secondary endpoint measures, including physician-reported toxicity, patient-reported symptoms, quality of life, and penetration aspiration scale scores for modified barium-swallow studies. Overall, the investigators observed fewer acute side effects with the de-intensified regimen.

&ldquo;Most notably, patients experienced fewer hematological toxicities and less swallowing side effects,&rdquo; said Chera. &ldquo;With standard radiation and chemotherapy, approximately 80% of patients require a feeding tube to make it through treatment and 10% need a permanent feeding tube, whereas in our study of de-intensified radiation and chemotherapy, only 40% needed a feeding tube and none were permanent.&rdquo;

Chera believes the study patients will have excellent long-term cancer control but notes that further follow-up is needed. Although other clinical trials are evaluating different de-intensified regimens, Chera noted that his study is unique because both radiation and chemotherapy were substantially reduced and neither induction chemotherapy nor definitive surgery were performed.

that additional follow-up studies are underway or planned, including one that eliminates chemotherapy altogether for select patients. &ldquo;We are currently conducting a follow-up, second-generation, phase II study at UNC with our colleagues in the University of Florida, which will soon be close to accrual and in which the lowest stage patients are only getting 60 Gy intensity-modulated radiotherapy, without concurrent chemotherapy,&rdquo; he said. &ldquo;In addition, patients with moderate and remote smoking histories are eligible and biopsy with limited neck surgery is not mandated, as all patients are assessed with a posttreatment positron emission tomography/computed tomography scan at 12 weeks to guide biopsy/surgical evaluation.&rdquo;

A third-generation study is also planned. &ldquo;This study will use cancer genomics to help us identify more patients in whom we can safely de-intensify treatment,&rdquo; said Chera.

Chera&rsquo;s current study was funded by the UNC School of Medicine, Department of Radiation Oncology, and the University of Florida School of Medicine, Department of Radiation Oncology.

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Chera BS, Amdur RJ, Tepper JE, et al. A prospective phase II trial of deintensified chemoradiation therapy for low risk HPV associated oropharyngeal squamous cell carcinoma. 2015;93(3):S2. http://www.redjournal.org/article/S0360-3016(15)00742-7/fulltext. Accessed November 3, 2015.

Most cancer-free in favorable-risk, HPV-positive head and neck cancer patients after lower intensity chemo and radiation [press release]. Charlottesville, VA: newswise; October 19, 2015. http://www.newswise.com/articles/most-cancer-free-in-favorable-risk-hpv-positive-head-and-neck-cancer-patients-after-lower-intensity-chemo-and-radiation. Accessed November 3, 2015.

ClinicalTrials.gov. De-intensification of radiation and chemotherapy for low-risk human papillomavirus-related oropharyngeal squamous cell carcinoma. NCT01530997. https://clinicaltrials.gov/ct2/show/NCT01530997. Accessed November 3, 2015.

Investigators of a new phase II study reported that favorable-risk oropharyngeal squamous cell carcinoma testing positive for human papillomavirus or p16 can be treated successfully using substantially decreased chemoradiotherapy doses.

A Lessened CRT Regimen Shows Good Results Treating Favorable-Risk Oropharyngeal Squamous Cell Carcinoma

Response rates to standard platinum-based chemotherapy among patients with the clear cell subtype of ovarian cancer are especially low, necessitating new treatment targets. Researchers at The Wistar Institute in Philadelphia, Pennsylvania, have announced that they may have identified one such target, opening the door to the development of the first targeted therapy for patients with ovarian clear cell carcinomas. The study findings were published online in

&ldquo;One of the significant challenges with the treatment of ovarian cancer is finding a suitable target that effectively halts the progression of the disease in a personalized manner based on one&rsquo;s genetic makeup,&rdquo; said Rugang Zhang, PhD, associate professor, Wistar&rsquo;s Gene Expression and Regulation Program, and corresponding author of the study, in a Wistar press release. &ldquo;With this study, we have done just that. For patients with this particular subtype, this newly discovered targeted approach may eventually lead to the first effective targeted therapy they&rsquo;ve ever had.&rdquo;

, a gene that remodels chromatin, a complex of proteins that enables DNA to be tightly packed within cells. Normally functioning

enables chromatin to unfold so that cells receive signals that dictate their behavior, which is important for preventing cells from becoming cancerous. In particular, the researchers examined how

affects EZH2, an enzyme that facilitates compaction of DNA in the chromatin structure.

Although a certain level of EZH2 is important for maintaining a transcriptional balance, an overabundance of this enzyme turns off the genes in the compacted regions, stopping the cells from receiving the DNA instructions necessary for making tumor-fighting proteins. Studies have shown an overabundance of EZH2 to be associated with progression of numerous cancers, including ovarian clear cell carcinoma, a cancer that affects 5% to 10% of US women with ovarian cancer.

and EZH led the researchers to explore EZH2 inhibition as a potential treatment target. Using experimental models, they found that EZH2 inhibition caused regression of ovarian tumors with mutated

. Furthermore, there were minimal effects on the growth of ovarian tumors with normal or unmutated

. Based on these findings, Zhang and colleagues concluded that the response to EZH2 inhibition correlates with

Zhang and colleagues believe their research has the potential to change the care of many patients with ovarian clear cell carcinomas, because 50% of women with these cancers have been found to have

mutations. In fact, Zhang et al note that

has one of the highest mutation rates among all types of human cancer, yet no therapies designed to target this common mutation have been developed to date. However, EZH2 inhibitors are in development for other cancer types, most notably B-cell lymphomas.

&ldquo;With EZH2 inhibitors currently in clinical development, we believe that our findings will have far-reaching implications,&rdquo; said Benjamin Bitler, PhD, an American Cancer Society postdoctoral fellowship recipient and first author of the study, in the press release. &ldquo;Excitingly, this study provides a much-needed therapeutic strategy for clear cell ovarian cancer and can be utilized to aid in the identification of patients that could benefit from EZH2 inhibition therapy.&rdquo;

Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.

Response rates to standard platinum-based chemotherapy among patients with the clear cell subtype of ovarian cancer are especially low, necessitating new treatment targets.

Christina T. Loguidice | Authors

Articles

Study Suggests Panurothelial Carcinoma Warrants More Aggressive Surgical Treatment

Vitamin C Shown to Kill Colorectal Cancer Cells Carrying KRAS and BRAF Mutations

A Lessened CRT Regimen Shows Good Results Treating Favorable-Risk Oropharyngeal Squamous Cell Carcinoma

New Research May Open Door to Personalized Ovarian Cancer Treatment