A treatment recommendation based on reduced prostate-specific antigen (PSA) failure observed from early results of randomized controlled trials is not likely to prolong survival in men with moderate-to-severe comorbidities, according to a recently published report in the 

Although PSA failure was more common in men with no or minimal comorbidity, PSA failure was shown to be associated with an increased all-cause mortality (ACM) among men with no or minimal comorbidity (adjusted HR, 1.59; 95% CI, 1.03 to 2.46; 

 = .04), but not among those with moderate or severe comorbidity (adjusted HR, 1.75; 95% CI, 0.76-3.99;

“The reason why this is important is because right now, today, there are several large, randomized prostate cancer trials that have reported preliminary results demonstrating a reduction in relapse-free survival (primarily driven by a reduction in PSA failure), but no difference in overall survival,” said lead author Nicholas J. Giacalone, MD, a senior resident in Radiation Oncology at Brigham and Women’s Hospital.

The study examined 206 men with localized intermediate- and high-risk prostate cancer, who were randomly assigned to receive radiation therapy or radiation therapy plus 6 months of androgen deprivation therapy (ADT).

The current standard of care in this space calls for a combination of external-beam radiation therapy (EBRT) and ADT; however, a recent post-random assignment analysis stratified by comorbidity status found that the addition of 6 months of ADT to EBRT was associated with a survival benefit, but only in men with no or minimal comorbidity. The same analysis demonstrated a shortened survival in men with moderate-to-severe comorbidity. Therefore, the current study aimed to answer the question of whether PSA failure—an endpoint that often occurs many years before metastasis and death from prostate cancer&mdash;is a clinically relevant endpoint only in men who have no or minimal comorbidity.

A comorbidity score was assigned at the time of random assignment using the ACE-27, a 27-item comorbidity index validated in patients with cancer. For the current study, patients were separated into 2 different subgroups: men with no or minimal comorbidity and men with moderate-to-severe comorbidity.

Follow-up began on the day of random assignment and concluded on the date the patient was last observed or on the date of death, whichever came first. Lifelong ADT administration for PSA failure was recommended when the PSA level reached 10 ng/mL. The decision to administer salvage ADT was left to the discretion of the treating physician and was dependent on how quickly the PSA was rising, as well as whether it exceeded 10 ng/mL.

Approximately half of men who experienced PSA failure initiated salvage ADT because the remaining patients had slow increases in PSA with long doubling times, and their PSA levels had not yet reached 10 ng/mL at the time of this analysis. Once a patient became refractory to first-line salvage ADT, he was given second- and third-line hormonal treatment, usually followed by cytotoxic chemotherapy.

To record a death as being caused by prostate cancer, there had to be documented castration-resistant metastatic prostate cancer and evidence that the PSA level was increasing at the time of the last follow-up visit despite the use of second-line hormonal maneuvers, and, in most cases, cytotoxic chemotherapy before death.

After a median follow-up of 16.62 years, 156 men (76%) died, of whom 29 (19%) died as a result of prostate cancer. Among men with moderate to severe comorbidity, 46 of 49 (94%) died, compared with 110 of 157 men (70%) with no or minimal comorbidity.

The results of the study showed that men with no or minimal—as compared with moderate-to-severe&mdash;comorbidity were significantly less likely (

 = .006) to have died overall, or to have died as a result of cardiovascular disease (11.5% vs 42.9%). However, men with no or minimal comorbidity were more likely to have died as a result of prostate cancer (15.9% vs 8.2%).

Among men with no or minimal comorbidity at random assignment, the risk of ACM was significantly increased in men who were observed to have PSA failure compared with those who were not. There was no significant increase in risk of ACM in men with moderate-to-severe comorbidity, irrespective of PSA failure status.

Although PSA failure was more common in men with no or minimal comorbidity compared with men with moderate-to-severe comorbidity, the occurrence of PSA failure was associated with a significantly increased risk of ACM only in men with no or minimal, but not moderate-to-severe, comorbidity.

The discordance in association between the occurrence of PSA failure and the subsequent risk of ACM provides evidence to support the possibility that competing risks—and not prostate cancer death&mdash;are the reason for a lack of translation of PSA failure into an increased risk of ACM in men with moderate-to-severe comorbidity.

These results also provide evidence to support an ongoing discussion of treatment approaches that have been shown in early results of randomized controlled trials to provide a PSA failure-free survival benefit in men who have unfavorable-risk prostate cancer and no or minimal comorbidity.

“Men with minimal or no comorbidities should have the preliminary results of these studies discussed with them, as a reduction in PSA failure may translate into improved overall survival,” said Giacalone.

However, because of the low likelihood that a PSA failure-free survival benefit will translate into a reduction in the risk of death from ACM in men with moderate-to-severe comorbidity, such a discussion may not be appropriate for this subgroup of patients.

“Our study suggests that men with more significant comorbidities—such as a history of coronary artery disease or stroke&mdash;are unlikely to benefit from such treatment shown only to reduce PSA failure, because our study suggests that this is unlikely to transfer into improved overall survival in these men,” explained Giacalone.

The authors of this study emphasize that the current evidence suggests that PSA failure in men with no or minimal comorbidity is a prognostic factor and not a surrogate for prostate cancer death. Therefore, having a negative prognostic factor (PSA failure, in this case) does not necessarily dictate that a patient will subsequently die as a result of prostate cancer.

In order to validate that PSA failure is a surrogate for prostate cancer death in men with no or minimal comorbidity, a randomized trial would have to be conducted, in which men are stratified by comorbidity status before random assignment, and in whom results documented a prostate cancer-specific survival benefit in the experimental arm. RTOG 0815 (NCT00936390) is an ongoing trial in which men were stratified before random assignment using the ACE-27 index, and were then randomly assigned to receive high-dose radiation with or without 6 months of ADT.

If this study shows both a prostate cancer—specific survival and an overall survival benefit in the subgroup of men with no or minimal comorbidity with the addition of ADT to high-dose radiation, then formal testing of PSA failure as a surrogate for prostate cancer–specific mortality and ACM could be performed. Until then, practice-changing measures should only be carried out on the basis of improved overall survival results.

Giacalone NJ, Wu J, Chen MH, et al. Prostate-specific antigen failure and risk of death within comorbidity subgroups among men with unfavorable-risk prostate cancer treated in a randomized trial [published online September 6, 2016]. 

Articles

A treatment recommendation based on reduced prostate-specific antigen failure observed from early results of randomized controlled trials is not likely to prolong survival in men with moderate-to-severe comorbidities.

Study Addresses Appropriate Clinical Use of PSA Trial Data in Prostate Cancer

Evidence has demonstrated that obesity is a risk factor for clear cell renal cell carcinoma (RCC); however, a new report suggests that a high body mass index (BMI) is a prognostic factor for improved survival in patients with metastatic RCC who have received targeted therapy.

The first cohort comprised 1975 patients with metastatic RCC from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), which is a consecutive patient series from institutions in North America, Europe, and Asia. The patients had received targeted therapies, such as VEGF/VEGFR and mTOR inhibitors.

In the IMDC cohort, the median overall survival (OS) was 25.6 months (95% CI, 23.2-28.6) for patients with a high BMI compared with 17.1 months (95% CI, 15.5-18.5) for patients with a low BMI (adjusted HR, 0.84; 95% CI, 0.73-0.95). The association found between BMI and OS was present in the intermediate and poor risk groups (HR, 0.73 and 0.80, respectively), but not in the favorable group (HR, 1.05).

Patients with high BMI had improved time to treatment failure compared with low BMI in both first- and second-line therapy after adjustment for the IMDC prognostic factors.

Similar results were found in the second cohort, which was an external validation cohort. The validation cohort was a pooled analysis of prospective data from 4657 patients with metastatic RCC treated in phase II and III trials sponsored by Pfizer involving sunitinib (Sutent), temsirolimus (Torisel), and axitinib (Inlyta).

The adjusted hazard ratio for OS in this cohort was 0.83 in favor of the group of patients with a high BMI. The overall response rate was 25.3% in patients with a high BMI compared with 17.6% in patients with a low BMI (adjusted odds ratio, 1.53). Both the overweight (BMI, 25 to <30 kg/m

) groups tended to have prolonged progression-free survival and OS in the first- and second line settings.

In order to investigate the underlying biologic differences associated with different BMI groups, the authors focused on the role of the fatty acid synthase (FASN) pathway in patients with metastatic RCC. FASN expression is considered a metabolic oncogene in multiple tumor models, and it has previously been reported to be associated with poor prognosis in several tumor types, including RCC.

The researchers used available genomic data of mRNA expression from patients who were part of the Kidney Renal Clear Cell Carcinoma clinical TCGA consortium. A total of 61 patients with metastatic RCC were identified in this cohort. Patients in the high BMI group (n = 39) had lower FASN expression compared with the low BMI group (n = 22; 

 = .03), and high FASN was associated with worse OS (median, 15 vs 36.8 months for high FASN vs low FASN, respectively).

In a final analysis, the researchers used samples from the IMDC cohort to assess the relationship between BMI and FASN IHC expression. Tissue mircroarrays were used from 146 patients with metastatic RCC who had received targeted therapy.

FASN staining positivity, which was recorded in 45 (31%) cases overall, was more frequently detected in poor (11/23; 48%) and intermediate (20/59; 34%) risk groups compared with the favorable risk group (5/30; 17%; 

-trend = .02). When stratified by FASN IHC expression, OS was 27.5 months (95% CI, 19.3-36.7) in FASN-negative patients versus 14.5 months (95% CI, 10.4-20.5) in FASN-positive patients (HR, 1.71; 95% CI, 1.17-2.51; P = .005). However, the authors noted that, “The adjusted HR of FASN was reduced to 1.28 (95% CI, 0.84-1.95) in the multivariable model, with adjustment of IMDC risk group and BMI.”

In contrast, when adjusted for IMDC risk groups and FASN, BMI remained associated with OS (adjusted HR, 0.44; 95% CI, 0.29-0.66), and this correlation was observed in both FASN-negative (HR, 0.39; 95% CI, 0.24-0.64) and FASN-positive groups (HR, 0.55; 95% CI, 0.27-1.13; 

Several hypotheses have been proposed to explain the association between a high BMI and improved survival outcomes. Nishihara et al2 suggested that the correlation can be reconciled by disease heterogeneity, such that the longer survival among obese patients compared with normal-weight patients is due to a less aggressive disease subtype. The current findings support this theory because FASN gene expression was found to be downregulated in obese patients compared with patients who had a normal BMI. Moreover, higher FASN expression was associated with worse survival.

“This data seems more specific to RCC, where obesity seems to portend a favorable prognosis in metastatic disease,” Toni K. Choueiri, MD, senior author of the study and clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, said in an interview with 

The results of the study pave the way for further exploration of the biology of this association as well as therapeutic approaches that may come of it.

“We plan to take our findings back to the laboratory to discover any therapeutic implications around the FASN pathway,” said Choueiri.

Albiges L, Hakimi AA, Xie W, et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations [published online September 6, 2016]. 

Nishihara R, VanderWeele TJ, Shibuya K, et al. Molecular pathological epidemiology gives clues to paradoxical findings. 

The authors of the study, which was published in the 

, investigated both the clinical and biologic effects of BMI on treatment outcomes in 2 distinct cohorts of patients with metastatic RCC. A high BMI was defined as >25 kg/m

Evidence has demonstrated that obesity is a risk factor for clear cell renal cell carcinoma; however, a new report suggests that a high body mass index is a prognostic factor for improved survival in patients with metastatic RCC who have received targeted therapy.

Obesity Paradox in RCC: Improved OS for Patients With High BMI

Neoadjuvant chemotherapy (NACT) is likely the optimal treatment choice for some women with newly diagnosed advanced ovarian cancer, while other patients should receive primary cytoreductive surgery (PCS), according to a recently published report in the 

This observational study found that patients with stage IIIC disease who NACT had significantly decreased overall survival (OS) compared with those treated with PCS (median, 33 vs 43 months; HR, 1.40; 95% CI, 1.11-1.77). Among patients with stage IV disease, however, there was no significant difference in OS (median, 31 vs 36 months; HR, 1.16; 95% CI, 0.89-1.52).

“Our results suggest that primary cytoreductive surgery may improve survival for patients with stage IIIC ovarian cancer who are likely to achieve an optimal cytoreduction, while neoadjuvant chemotherapy may be the preferred option for many women with stage IV ovarian cancer,” Larissa A. Meyer, MD, assistant professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, said in an interview with 

These results are consistent with a subset analysis in the EORTC study, which demonstrated improved survival in patients with stage IIIC disease and <45 mm of disease who received PCS versus NACT.

The current study examined the use of NACT, as well as outcomes associated with it, at 6 National Cancer Institute—designated cancer centers between 2003 and 2012. Patients were assigned to a treatment arm (NACT or PCS) on the basis of whether they initially received chemotherapy or surgery.

In the first cohort of patients, the authors examined NACT use over time among 1538 patients diagnosed between 2003 and 2012 and treated within 12 weeks of diagnosis. In the second cohort, the goal was to examine factors and outcomes associated with NACT versus PCS within a subset of 1158 patients from the first cohort. This subset excluded patients who had received intraperitoneal and intravenous (IP/IV) chemotherapy, as few patients treated with NACT receive IP/IV chemotherapy, and it is associated with its own independent survival benefit.

The results of the study showed that, between 2003 and 2011, the use of NACT increased steadily over time from 16% to 34% among patients with stage IIIC ovarian cancer, and from 41% to 62% among patients with stage IV disease.

The authors noted that the degree of variation in the use of NACT between such similar academic institutions suggests that uptake of NACT is influenced by local culture, clinical practice leaders within institutions, and maybe even patients’ preferences.

PCS was found to be associated with significantly improved survival in women with stage IIIC, but not stage IV disease, compared with NACT.

Patients with stage IIIC and IV disease treated with NACT were more likely to achieve <1 cm or microscopic residual disease after interval cytoreductive surgery (ICS) compared with PCS. However, few differences were found in complexity, aggressiveness, or complications of surgery.

The authors wrote that it was important to note that, although patients with stage IIIC disease who received NACT were significantly more likely to have <1 cm or R0 microscopic residual disease after ICS, this finding was not associated with a survival benefit.

In contrast, patients who achieved <1 cm of residual disease after PCS, rather than NACT and ICS, had significantly longer survival. Future research should prospectively compare the survival outcomes of patients treated with PCS versus NACT stratified by residual disease after surgery, according to the authors.

These results come shortly after the publication of ASCO’s new NACT ovarian cancer guideline, which recommends NACT as the optimal first-line treatment for some women with newly diagnosed, advanced ovarian cancer.

“The findings in our study are aligned with the recently issued ASCO/SGO guideline for neoadjuvant chemotherapy,” said Meyer.

One of the guideline recommendations states that NACT is favored over PCS for women who are fit for PCS, but are also deemed unlikely to achieve cytoreduction to <1 cm (ideally to no visible disease) by a gynecologic oncologist. Meyer says the findings of the current study support that recommendation.

The choice between PCS and NACT remains highly controversial, as the optimal treatment of advanced ovarian cancer includes both surgical cytoreduction and platinum-based chemotherapy.

“The bottom line is a one-size-fits-all strategy no longer works for treatment of ovarian cancer,” said Meyer.

Meyer LA, Cronin AM, Sun CC, et al. Use and effectiveness of neoadjuvant chemotherapy for treatment of ovarian cancer (published online September 6, 2015).

Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer: Society of Gynecological Oncology and American Society of Clinical Oncology clinical practice guideline [published online August 8, 2016].

Neoadjuvant chemotherapy is likely the optimal treatment choice for some women with newly diagnosed advanced ovarian cancer, while other patients should receive primary cytoreductive surgery.

Neoadjuvant Chemo Optimal Choice for Some Women With Ovarian Cancer

Vaginal brachytherapy (VB) has been linked to improved survival in women with stage I endometrioid adenocarcinoma of the uterus, according to a large database analysis published in 

“Using the [National Cancer Data Base (NCDB)], we found that vaginal brachytherapy after hysterectomy for stage I endometrial cancer was underused as compared to modern consensus guidelines,” Jonathan Strauss, MD, senior author of the study, said in an interview with 

. “We also found, that, after controlling for other factors, the use of vaginal brachytherapy was associated with a survival advantage. This suggests that greater adherence to current guidelines may improve patient outcomes.”

There has been a significant absence of survival benefit associated with reduction in locoregional recurrence (LRR) in this patient population. Prior to the current study, a wealth of data generally supported the role of pelvic RT after total abdominal hysterectomy bilateral salpingo oophorectomy in early-stage endometrial cancer. Reductions in cumulative incidence of LRR were seen across many of these studies, but these results did not translate into statistically significant advantages in overall survival (OS).

The current study hypothesized that the dearth of significantly advantageous OS results in this space may be attributed to limited sample sizes in the currently available randomized trials and their corresponding lack of statistical power.

Therefore, in this trial, the NCDB was used to evaluate the effect of postoperative RT on morbidity in a large population of women with stage IA or IB endometrioid adenocarcinoma of the endometrium.

A total of 44,309 patients were divided into 4 treatment groups: those who received no RT, those who received pelvis RT, those who received VB, and those who received both pelvis RT and VB.

Among 33,380 women with stage IA disease, 8.9% received adjuvant VB alone, 1.8% received adjuvant pelvic RT alone, and 0.9% received a combination of the 2 therapies. The remaining 88.4% of women with stage IA disease did not receive any form of adjuvant RT.

Among 10,929 women with stage IB disease, 27.7% received adjuvant VB, 13.1% received adjuvant pelvic RT, and 7.5% received a combination of pelvic RT and VB. Approximately 52% of women with stage IB disease did not receive any adjuvant RT.

A multivariate regression analysis assessed demographic and clinical predictors of treatment. For both women with stage IA and IB endometrial cancer, comorbid disease, living farther from the hospital, and lower grade histology were significantly associated with the omission of RT.

Among only women with stage IA disease, age <50 years and smaller tumor size were associated with the omission of RT. Receipt of care at a community hospital and age >70 years were associated with the omission of RT in women with stage IB disease.

These data on patient and tumor factors of prognostic significance are consistent with findings from smaller clinical cohorts.

Survival was compared among treatment groups with the log-rank test and Cox proportional hazards regression, which controlled for demographic and clinical covariates.

The Cox regression analysis indicated that older age, higher grade, larger tumor size, and comorbid disease were all significantly associated with poorer survival in both women with stage IA and IB disease.

For women with stage IA endometrial cancer, lower education level, Medicaid or uninsured status, and living farther from the hospital were associated with poorer survival.

In patients with stage IA disease, adjuvant VB was significantly associated with improved survival (HR, 0.81; 95% CI, 0.67-0.97; P = .021). In women with stage IB disease, adjuvant VB was also found to be significantly associated with improved survival (HR, 0.62; 95% CI, 0.51-0.74; 

These results are quite similar to data found in an earlier and much smaller analysis of the Surveillance, Epidemiology, and End Results Program database, which demonstrated a survival advantage associated with the use of postoperative RT in women with stage IB disease.

The recent national consensus guidelines from the American Society of Radiation Oncology and ASCO have attempted to optimize the selection of postoperative therapy by balancing the benefits seen with a reduction in LRR and the treatment-associated toxicities. For women with low-risk stage IA endometrial cancer, the guidelines currently support observation without RT. On the other hand, VB is recommended for women with higher-risk stage IA or any stage IB disease, and pelvic RT is recommended for women at highest risk (stage IB with high-grade histology).

Across both groups of women with stage IA and IB disease, 88% and 52%, respectively, did not receive RT. Moreover, an examination of a subset of women with stage IB grade 2 and grade 3/4 endometrial cancer—a group of patients that all guidelines say should receive RT&mdash;50% and 41%, respectively, received no RT. These results point to a clear disparity between what national guidelines recommend and what is actually happening in common clinical practice in the United States.

This disparity could potentially be explained by the excessive toxicities associated with RT, which some may feel outweigh the oncologic benefits. For example, in PORTEC-1, a study that evaluated long-term outcomes and quality of life of in patients with endometrial carcinoma, a questionnaire-based analysis of the treatment-associated toxicity showed that the receipt of pelvic RT was associated with increased rates of urinary incontinence, diarrhea, and fecal leakage, as well as reduced scores on an index of physical functioning.

In PORTEC-2, a trial in which VB was compared with pelvic RT in patients with endometrial cancer, multiple quality-of-life measures were superior in the VB arm. These results, along with the findings in the current study, suggest that VB is the preferred RT approach.

However, the results of the current study seem to support the notion that the discrepancy between the national guidelines and common clinical practice is actually attributed to the statistical power of the moderately sized randomized trials that may be insufficient to detect an OS benefit.

1. Rydzewski NR, Strohl AE, Donnelly ED, et al. Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: a National Cancer Data Base Study [published online August 10, 2016]. 

Compared with patients who received no form of radiotherapy (RT), adjuvant VB was associated with a 19% and 38% reduction in the risk of death in women with stage IA and stage IB disease, respectively. It was also discovered that use of vaginal brachytherapy was not consistent with guideline recommendations.

Vaginal brachytherapy has been linked to improved survival in women with stage I endometrioid adenocarcinoma of the uterus.

Vaginal Brachytherapy Linked to Improved Survival in Endometrial Cancer

Neoadjuvant chemotherapy (NACT) is the optimal first-line treatment for some women with newly diagnosed, advanced ovarian cancer, according to a new joint clinical practice guideline from ASCO and the Society of Gynecologic Oncology (SGO).

While the standard of care in this setting is primary cytoreductive surgery (PCS) followed by chemotherapy, the new guideline, which was published today in the 

 suggests that some patients may benefit more from NACT and interval cytoreduction.

“This guideline is a big step forward in one of the most contentious areas within gynecologic oncology,” said Alexi A. Wright, MD, co-chair and ASCO’s representative on the Expert Panel that worked on developing the guideline.

The evidence supporting these recommendations comes from four phase III clinical trials, which found that for women with stage IIIC or IV epithelial ovarian cancer, NACT and interval cytoreduction were preferable to adjuvant chemotherapy and primary cytoreduction with respect to overall and progression-free survival.

However, it is important to note that women with suspected stage IIIC or IV invasive epithelial ovarian cancer should seek evaluation by a gynecologic oncologist before beginning either type of therapy, according to one of the new guideline recommendations. Such an evaluation should include a CT of the abdomen and pelvis with oral and intravenous contrast and chest imaging (CT preferred) to determine the extent of disease, as well as whether the patient is a candidate to undergo PCS with acceptable risks and associated morbidity.

Other tools may be used to assess patients as well, such as laparoscopic evaluation or additional radiographic imaging (FDG-PET scan or diffusion-weighted MRI). However, the use of these methods has been found to be inferior to CT findings at this time.

For women who are assessed by a gynecologic oncologist and are determined to be a fit for PCS, with potentially resectable disease, either PCS or NACT can be offered as treatment. With respect to progression-free and overall survival, as well as perioperative morbidity and mortality, NACT has been found to be generally noninferior to PCS. Neoadjuvant chemotherapy is associated with less peri- and postoperative morbidity and mortality and shorter hospitalizations. Primary cytoreductive surgery, on the other hand, may offer superior survival results in patients with newly diagnosed stage IIIC or IV epithelial ovarian cancer.

The benefits of these respective therapies come from the results of 4 randomized clinical trials comparing NACT and interval cytoreduction with primary cytoreduction and chemotherapy among women with advanced ovarian cancer.

In the EORTC 55971 trial, NACT was generally found to be noninferior to PCS in terms of overall survival, though perioperative morbidity and mortality were lower in the neoadjuvant arm. Analyses of subgroups found that patients with stage IIIC cancer and less extensive metastatic tumors had higher survival when treated with PCS rather than NACT, while patients with stage IV disease and larger metastatic tumors had better survival with NACT.

The CHORUS trial also found NACT to be noninferior to PCS with respect to overall survival. However, postoperative mortality and serious (grade 3 or 4) postoperative adverse events were less common in patients enrolled in the NACT arm than in the PCS arm.

Similar results were found in the JCOG0602 trial, where patients in the neoadjuvant arm experienced less blood loss and ascites during or after surgery and were less likely to experience grade 3 or 4 nonhematologic adverse events after surgery.

Critics of the EORTC and CHORUS trials (which are, to date, the only published randomized phase III trials comparing NACT and PCS) have noted that both studies had a shorter median overall survival than what has been reported in previous findings. However, these short survival results may actually reflect trial participants rather than differences in treatment. The population of patients was older (≥65 years old), had poorer performance status, and had higher stage tumors compared with other trials. Therefore, it remains to be seen whether these results apply to younger populations with better performance status and/or less bulky disease.

Though many of these findings seem to favor neoadjuvant chemotherapy, it is not the ideal choice of therapy for every woman with advanced ovarian cancer. According to the new guideline, patients with a high likelihood of achieving cytoreduction to <1 cm (ideally to no visible disease) with acceptable morbidity are recommended to receive primary cytoreductive surgery. However, for women with a high preoperative risk profile or a low likelihood of achieving cytoreduction to <1 cm of residual disease (ideally to no visible disease), NACT is preferred instead.

If a patient is set to receive NACT and interval cytoreduction, the new guideline recommends that she should have histologic confirmation (core biopsy preferred) of an invasive ovarian, fallopian tube, or peritoneal cancer. Data on inherited mutations (such as germline 

), cell surface proteins, and the tumor microenvironment are beginning to be evaluated as well when it comes to treatment selection and clinical trial enrollment.

When patients are given NACT, a platinum/taxane doublet is recommended, though alternative regimens may be selected based on individual patient factors, according to the ASCO/SGO guideline. Another recommendation highlights the timing of interval cytoreduction once patients receive NACT. Ideally, interval cytoreductive surgery should be performed after ≤4 cycles of NACT for those with a response to chemotherapy or stable disease.

As for patients with progressive disease on NACT, the new guideline recommends alternative chemotherapy regimens, clinical trials, and/or discontinuation of active cancer therapy and initiation of end-of-life care. There is generally little role for surgery in this context, and it is not advised unless it is used for palliation.

“These evidence-based recommendations will improve the quality of care provided to women with ovarian cancer,” Mitchell I. Edelson, MD, co-chair and SGO’S representative on the Expert Panel, said in a statement.

The Expert Panel has agreed that future studies will focus on a number of areas, including the development and validation of a preoperative risk prediction model to identify patients who may have a risk of morbidity from PCS. Future research will also examine the value of alternative assessments that gynecologic oncologists can use when screening patients, such as perfusion CT, dynamic MRI, or PET-CT.

Future studies will also explore novel agents in the neoadjuvant setting, such as targeted therapies, immunotherapy, vaccines, and cancer stem-cell-directed treatments.

Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline [published online August 8, 2016]. 

Neoadjuvant chemotherapy is the optimal first-line treatment for some women with newly diagnosed, advanced ovarian cancer.

ASCO Issues New Guideline for Neoadjuvant Chemotherapy in Ovarian Cancer

The shockwaves created by the UK’s vote to secede from the European Union (EU) are likely to reverberate for years to come, particularly in the field of oncology.

Because of the lack of precedent for such a significant event, the consequences of Brexit can only be speculated upon for now, but healthcare professionals have good reason to be concerned for the future of their industry.

According to The Lancet Oncology, new clinical trials in cancer research will likely be delayed for some time as sponsors realign their organizations and restructure how funds are allocated to both the EU and the UK. Thus, advancements in treatment for cancer patients are almost certain to remain stagnant in years to come.

If Britain fails to keep up with modern research, the nation will likely lose considerable influence in the world of healthcare. Moreover, while the headquarters for the European Medicines Agency (EMA) are currently located in London, they will presumably move to a different nation in the EU following Britain’s departure.

Many in the field believe that such a shift represents a gradual but inevitable loss of an esteemed reputation that the UK will eventually lose in healthcare.

Even if the EMA does not eventually move out of the UK, Britain’s National Health Service (NHS) is also likely to face difficult times when it comes to maintaining its current roster of elite medical professionals, many of whom were originally trained in the EU.

“My main concern in the big picture is potential damage to the UK’s reputation as a destination for top-flight researchers,” said Myles Allen of the University of Oxford’s Environmental Change Institute.

Allen worries that the UK’s divorce from the EU will negatively affect the nation’s ability to recruit the best of the best in the field—another damaging blow to the UK’s standing in healthcare.

These changes would not only damage Britain’s prominence in the industry, but they would also lead to a long-term dearth of quality treatment options for patients.

For example, following Brexit, British patients will not be able to benefit from important initiatives like the European Cancer Patient’s Bill of Rights, which essentially promises citizens battling cancer the right to the best healthcare available in the EU.

Brexit supporters had also claimed in their campaign that the secession would actually bring more money to the NHS because it would no longer owe the EU £350 million a week as part of its membership in the union. The pledge was even prominently displayed on the campaign’s “battle bus,” promising a bright and hopeful future for the nation.

However, leading Brexit campaigner Iain Duncan Smith quickly backtracked on this promise.

“I never said that during the course of the election,” said Smith. “The £350 million was an extrapolation of the £19.1 billion—that’s the total amount of money we gave across to the European Union. What we actually said was a significant amount of it would go to the NHS…There was talk about it going to the NHS, but there are other bits and pieces like agriculture, which is part of the process. That is the divide up. It was never the total.”

Unfortunately, Smith is right; approximately half of the money that Britain currently gives to the EU is eventually funded back to the country through subsidies for agriculture, research grants, and infrastructure needs. That money is already committed and therefore cannot be reallocated to the NHS.

While the potential consequences of Brexit are already stirring tension, nothing is certain for the future of both Britain and the EU. Even as the news of Britain’s exit begins to sink in and take shape, prospective prime minister Boris Johnson rocked the boat once more when he removed himself from the race to be the next Conservative leader.

Some speculate, perhaps, that Brexit could be cancelled before it even truly happens. Many analysts, including Secretary of State John Kerry, are already speculating that the vote could be reversed.

Regardless of how Brexit ultimately pans out, both Britain and the EU are sure to face uncertain times overall, especially in the field of cancer research, as everyone attempts to rebuild these broken pieces.

Reality check: What might Brexit mean for medicines and clinical trials [news release]? BBC News; June 22, 2016. http://www.bbc.com/news/uk-politics-eu-referendum-36599417. Accessed June 29, 2016.

Why Brexit freaks out so many scientists [news release]. National Geographic; June 24, 2016. http://news.nationalgeographic.com/2016/06/brexit-science-climate-change-environment-policy/. Accessed June 29, 2016.

European Bill of Cancer Patients’ Rights. European Cancer Patient Coalition. http://www.ecpc.org/activities/policy-and-advocacy/policy-initiatives/138-european-bill-of-cancer-patients-rights. Accessed June 29, 2016.

Brexit’s broken promises: Health care, immigration, and the economy [news release]. CNNMoney; June 27, 2016. http://money.cnn.com/2016/06/27/news/economy/brexit-broken-promises/. Accessed June 29, 2016.

Iain Duncan Smith backtracks on leave side’s £350m NHS claim [news release]. The Guardian; June 26, 2016. http://www.theguardian.com/politics/2016/jun/26/eu-referendum-brexit-vote-leave-iain-duncan-smith-nhs. Accessed June 29, 2016.

How much does the EU really cost Britain [news release]? CNNMoney; June 2, 2016. http://money.cnn.com/2016/06/02/news/brexit-eu-budget-cost-uk/?iid=EL. Accessed June 29, 2016.

Boris Johnson rules himself out of Conservative leader race [news release]. BBC News; June 30, 2016. http://www.bbc.com/news/uk-politics-36672591. Accessed June 30, 2016.

Could Brexit be canceled? Here’s how vote might be reversed [news release]. London, UK: NBC News; June 29, 2016. http://www.nbcnews.com/storyline/brexit-referendum/could-brexit-be-canceled-here-s-how-vote-could-be-n600451. Accessed June 29, 2016.

The shockwaves created by the UK's vote to secede from the European Union are likely to reverberate for years to come, particularly in the field of oncology.

Allie Strickler