With Optune, a noninvasive device that delivers tumor-treating fields (TTFields) to the brain, oncologists have a rare opportunity to incorporate cutting-edge technology into their standard treatment regimen. “Traditionally, technology and devices are within the domain of neurosurgeons and radiation oncologists,” said Eric Wong, MD.

Wong, associate professor of neurology at Harvard Medical School and co-director, Brain Tumor Center, Beth Israel Deaconess Medical Center, delivered a talk on the topic of TTFields and how the technology can be applied within glioblastoma multiforme (GBM) and beyond at the recent Chemotherapy Foundation Symposium.

“This device has proven, improved efficacy when compared to chemotherapy, it does not have serious adverse events like chemotherapy, and the patient’s quality of life is good,” said Wong.

TTFields, administered by the Optune device, was first approved in 2011 as a monotherapy for adult patients with GBM that recurred or progressed after chemotherapy. That approval was based on a prospective, randomized, open-label, active parallel control trial which compared the effectiveness and safety outcomes of recurrent GBM patients treated with Optune to those treated with an effective best standard of care chemotherapy. Wong was 1 of 3 physicians to present the data to the FDA.

In the study, the median survival was 6.6 months in the Optune arm versus 6.0 months with standard chemotherapy (HR 0.86 [95% CI 0.66-1.12]; 

 = 0.27) and the progression-free survival rate (PFS) at 6 months was 21.4% with Optune compared with 15.1% in the control arm (

= 0.13). Responses were more common in the Optune arm with 14% of patients responding versus 9.6% in the control arm (

In October 2015, the FDA approved Optune in combination with adjuvant temozolomide as a treatment for patients with newly diagnosed GBM following surgery, chemotherapy, and radiation therapy, based on an improvement in survival seen in the phase III EF-14 trial.

“In this phase III study in which patients received adjuvant temozolomide plus tumor treating field or adjuvant temozolomide alone, tumor treating field was clearly superior in terms of patients having a longer overall survival and also a longer progression-free survival,” said Wong.

The trial included 695 patients who were randomized in a 2:1 ratio to receive adjuvant therapy with Optune plus temozolomide or temozolomide alone. After a minimum follow-up of 18 months, the risk of progression or death was reduced by 37% with the addition of Optune to temozolomide. The median PFS was 7.1 months with the combination compared with 4.0 months with temozolomide alone (HR, 0.63; 

 = .001). The median OS was 19.4 months with Optune compared with 16.6 months with temozolomide alone.  

In both trials, Optune proved to be well tolerated, said Wong.

Toxicities are primarily dermatologic and include scalp irritation and scalp burn. In more extreme cases, ulcerations or skin breakdown can occur, he said. Minor skin toxicities are typically treated with a topical high potency corticosteroid cream, while more severe toxicities may require temporary suspension of treatment.

Optune works by attaching directly to the patient’s head to deliver electromagnetic field therapy using low-intensity electrical fields to the brain. The device is portable and battery-operated. The FDA approved a smaller and lighter version of Optune in July 2016.

“It is basically an alternating electric field that is at a frequency of 200 kilohertz,” said Wong. “To give some perspective, this is within the borderline between radio waves and microwave range.”

This technique is thought to slow or reverse tumor growth by inhibiting mitosis during metaphase, anaphase, and telophase, explained Wong.

There are additional trials looking at Optune within the neuro-oncology space, said Wong. The treatment is being investigated in combination with bevacizumab (Avastin) in recurrent GBM as well as with stereotactic radiosurgery. A phase III randomized trial is also currently accruing patients, which will look at the efficacy of tumor treating fields in non-small cell lung (NSCLC) cancer brain metastasis.

In addition, the treatment is being investigated outside of the brain cancer space. There are trials in pancreatic, ovarian, mesothelioma, and NSCLC looking at Optune in combination with several different treatments.  

It is exciting to see something that originated in brain cancer expand outside of it, said Wong.

“It is very interesting that traditionally most of the treatments against malignant gliomas come from outside of this disease site. For example, a drug is approved in breast cancer, lymphoma, lung cancer, and then gets adopted into clinical trials for glioblastoma,” said Wong. “This is happening in the reverse order and it is quite interesting and is really exciting to see a therapy that is showing efficacy in glioblastoma be applied outside of this disease site in other malignancies.”

Stupp, R., Wong E, Kanner A, et al “NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment .modality.” Eur J Cancer 48(14): 2192-202

Articles

Optune, a noninvasive device that delivers tumor-treating fields to the brain, had been found to improve efficacy compared to chemotherapy and is well-tolerated by patients with glioblastoma multiforme (GBM).

Tumor Treating Fields Improve Survival in Glioblastoma

A new study by researchers at the Harvard T.H. Chan School of Public Health has found that women who received the HPV vaccine series as adolescents may have less intensive cervical cancer screening, including starting Pap tests at a later age and extending the time between them.

“The current guidelines, which don’t differentiate based on vaccine status, really don’t make sense for women who have been vaccinated,” said study investigator Jane J. Kim, PhD, professor of Health Decision Science, Department of Health Policy and Management and Center for Health Decision Science, at the Harvard T.H. Chan School of Public Health. “It is overkill in these women. Hopefully, these guidelines will be revisited to look at the heterogeneity and changes in risk that have been introduced by vaccination.”

The study evaluated women who received the HPV-vaccine at the recommended age of 11 or 12 years old and are now in their early 20s, which is the recommended cervical screening age. The quadrivalent/4vHPV vaccine (Gardasil) was approved for women aged 11 to 26 in 2006, followed by the bivalent/2vHPV (Cervarix) vaccine for the same age group of women in 2009. Both vaccines target 2 of the cancer-causing HPV viruses that contribute to 70% of cervical cancers. The newer 9-valent/9vHPV vaccine (Gardasil 9), approved in 2014, targets 7 types of HPV that contribute to 90% of cervical cancers.

Current cervical cancer screening guidelines recommend all women receive a cytology or Pap test every 3 years starting at age 21, with the option of switching to Pap/HPV co-testing every 5 years beginning at age 30.

“We are talking about a pretty dramatic reduction in baseline risk if women have been vaccinated by either of these baseline vaccines,” said Kim. “We wanted to look at if, based on this, we should be continuing with what is recommended for average-risk women in these vaccinated women.”

Researchers found that for women who received the recommended dose of the quadrivalent or bivalent HPV vaccine, screening can be initiated later (age 25 to 30), and frequency of screening can be extended to every 5 years.

Women who were vaccinated with the 9-valent vaccine require screening even less frequently, beginning at age 30 to 35 with a frequency of once every 10 years.

Screening should also shift from Pap test screening, to primary HPV testing, said Kim. In 2015, the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology issued joint guidance stating that the HPV test alone for cervical cancer screening is an effective alternative to the current recommendation for screening with the Pap test alone or co-testing with Pap and HPV testing.

“We can move away from Pap testing all together, and actually move to primary HPV testing—to only test for the high-risk type that cause cancer,” said Kim.

There are several benefits to less intensive cervical cancer screening. A Pap test can lack sensitivity and specificity, leading to overtreatment and unnecessary cost. Overtreatment of precancerous lesions identified by a Pap test has been linked to adverse pregnancy outcomes for women of reproductive age, including preterm birth, according to Kim.

“The more that you test, you are inviting some unnecessary procedures and what some might consider harms,” said Kim. “To be able to moderate the screening schedule to basically generate the same amount of benefits that we are observing, if not more, and at a reduced rate of harm, including unnecessary diagnostic procedures and unnecessary costs, is a win—win.”

Several questions remain unanswered regarding the impact that HPV vaccines have had on risk and what the optimal screening method for women who have been vaccinated should be going forward. This will continue to evolve as more women receive the vaccine.

Investigators at Harvard T.H. Chan School of Public Health plan to continue investigation of this topic, said Kim.

“I am definitely interested to see how this plays out in clinical practice in the United States,” she said. “We will be continuing to study this area.”

Due to a dramatic reduction of risk for cervical cancer in women who have received the HBV vaccine, there may be a reduction of screening for those women.

Revisiting Current Cervical Cancer Screening Guidelines for HPV-Vaccinated Women

Even with advancements in antiviral therapies, the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B is still on the rise. According to Robert Wong, MD, this trend indicates the importance of screening and surveillance in this population.

“It is a very interesting phenomenon and there are a lot of different explanations for why this is occurring,” said Wong, an assistant clinical professor of medicine, director of research and education, Division of Gastroenterology and Hepatology at Alameda Health System, Highland Hospital. “I think one of our major hypotheses is that the current effect antiviral therapies are really suppressing disease progression. However, patients with hepatitis B and those with hepatitis B cirrhosis, still have a high risk of liver cancer. It is important to remember that these patients still need routine screening and surveillance for liver cancer.”

 while at the 2016 Annual Meeting of the American Association for the Study of Liver Diseases, Wong discussed why certain patients are at a higher risk for hepatitis B-associated HCC, common risk factors for the disease, and the role healthcare providers need to play in improving outcomes for these patients.

: What are you hoping clinicians take away from these findings?    

: The biggest takeaway is really the importance of screening and surveillance for liver cancer. Early detection is really important; it allows improved access to potentially curative therapies. Even though the current antiviral therapies are good at suppressing the virus, they do not cure hepatitis B in the majority of people. The resistance of chronic hepatitis B in these patients still carries a risk for liver cancer. There is really a need for improved screening and surveillance because we are not doing a good job right now.

In addition, at least in our study in the United States, there is a changing demographic for patients listed for liver transplant secondary to hepatitis B. We sort of expected that in the United States and in other countries because there is higher prevalence in hepatitis B for individuals from high-risk regions, including Africa and Asia.

Our studies show a shift from the early time period to the later time period that, in the most recent time period we studied, over 50% of patients with hepatitis B on the transplant list were Asian. Understanding high-risk populations, and therefore identifying who should be screened for hepatitis B, is key. These patients should always be screened for liver cancer.

Is there an understanding as to why the Asian and African populations are at a higher risk of hepatitis B and liver cancer?

There are several hypotheses that have been proposed to explain that. The first hypothesis is based on the mechanism of infection. In Asia and Africa hepatitis B is usually acquired vertically. The duration of infection is directly correlated with the risk of disease progression and HCC. That is why these patients with hepatitis B from Africa and Asia have higher risk of HCC, because they are probably infected with the virus longer.

The other very interesting hypothesis is that there are different genotypes of hepatitis B, and the genotypes found in the Asia Pacific regions have been shown to have higher risk of disease progression and higher risk of liver cancer. We don’t routinely in clinical practice check genotypes in the United States, because the different genotypes don’t generally impact treatment management decisions. But that might be something that will change in the future as we try and better identify risk factors for disease progression and also risk factors for HCC.

What are the most common risk factors for HCC?

One of the main risk factors that we know about currently is the duration of infection. The longer the person has chronic hepatitis B there is cumulative risk of developing HCC. Age is also a risk factor, but that is also a surrogate of duration of infection. The presence of advance disease, such as advanced fibrosis or cirrhosis, definitely carries a higher risk of HCC. One of the big risk factors, which was outlined in a 2008 JAMA Oncology article, is a higher hepatitis B viral load, which directly correlates with a higher risk of HCC. That is really why screening these patients, identifying who should be treated, and early treatment to suppress the virus, is so important.

Are there factors that are preventing screening from becoming more widely implemented?

There are several studies in the United States, but also in Europe and Asia, that show the missed opportunities for screening for hepatitis B. I think it is multifactorial. There are patient-related factors, patient awareness and patient education, but provider awareness and education is also important. We need to make sure that the primary physicians, or gastroenterologists, or other types of providers are aware who these high-risk populations are, who they need to screen, how to implement screening and diagnosis, and then refer them to the appropriate treatments.

Another important area where I don’t think we are doing a good job is screening for liver cancer itself. That is not just hepatitis B patients, it’s all patients who are at risk including those with cirrhosis. Hepatitis B is a very different diagnosis in that you can still develop liver cancer without cirrhosis. I think more awareness and education and helping people understand what the guidelines say about both screening for hepatitis B and liver cancer is going to be key to detection.

The most important thing to emphasize, especially for the oncology community, is that it is really important to educate those referring providers, primarily the primary care physicians, about the importance of screening their patients. Screening and early detection vastly improve curative options for these patients.

 Young K, Liu, B, Bhuket T. Despite plateauing of chronic hepatitis b virus (hbv) patients listed for liver transplantation, the proportion of patients with hbv-related hepatocellular carcinoma continues to rise. Presented at the 2016 AASLD Liver Meeting; November 11-15, 2016; Boston, MA. Abstract 21.

The incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B is still on the rise, making screening and surveillance in this population all the more important.

Early Detection Vital as HCC Rates Rise Among Hepatitis B Patients

Fewer than half of women with advanced cervical cancer are receiving all 3 of the treatments that are standard of care (SOC) for the disease: external beam radiation therapy (EBRT), brachytherapy, and chemotherapy, and the presence or absence of brachytherapy was the major difference between patients who did and did not receive SOC, a new study has found.

The research showed that patients who did not receive brachytherapy had a lower chance of survival than those who received all 3 SOC treatments, explained Christine Fisher, MD, a radiation oncologist at the University of Colorado Cancer Center and an investigator on the study.

“Brachytherapy, or internal radiation, is a very, very critical component of the treatment,” said Fisher. “It allows a very high dose of radiation to the tumor, and it is really what allows us to cure these patients, even those who have very large cervical cancers.”

Investigators utilized the National Cancer Database to identify women with locally advanced cervical cancer treated with definitive radiation or chemoradiation therapy, and stratified these patients by treatment received. Of the 15,194 patients included in the study, only 44.3% received SOC treatment, and this group had significantly improved overall survival (OS).

Some patients did receive alternatives to brachytherapy, including 23.8% who received an EBRT boost by itself. Nearly 50% of patients received EBRT with brachytherapy and 26.8% of patients received no radiation boost.

Although an EBRT boost was advantageous over no boost at all (HR, 0.72; 

<.001), OS was superior in patients who received brachytherapy (HR, 0.55; 

“Not having that additional radiation, the brachytherapy, leads to a survival detriment that can not be made up in other ways,” said Fisher. “We really find that some people either get no additional treatment or external beam treatment, and none of those are equivalent to using the internal beam radiation.”

“With image-guided brachytherapy we now have good data, primarily from Europe, telling us that we can improve survival and also reduce complications for these women with brachytherapy,” she added.

The study found that patients were more likely to receive no radiotherapy boost if they had lower incomes or Medicaid. African-American patients were also less likely to receive SOC.

Unfortunately, this is the same group of women who have very poor access to care and are less likely to receive preventive services for cervical cancer in the first place, said Fisher.

A lack of expertise in brachytherapy at non—comprehensive community cancer centers or centers that don’t regularly see many patients with cervical cancer may also be contributing to the problem, said Fisher.

“In terms of thinking about what might be causing this issue, part of it is the comfort level and expertise with brachytherapy as a technique,” said Fisher. “It’s been around for a very long time, but it does require procedural skills and comfort with dosing high levels of radiation. It is very time consuming for physicians, it requires a large team of experts, the correct type of machine, and many smaller radiation centers do not have that available.”

Fisher recommends that physicians who did not feel comfortable or are unable to offer patients brachytherapy should refer their patients to a higher-volume center, preferably a comprehensive cancer center, instead of doing alternative treatment or skipping the treatment entirely. For some patients, it may be easier to receive chemotherapy and external beam radiation closer to home, and then travel to a larger center for brachytherapy.

While improving access to SOC treatment for all patients with cervical cancer is essential, the bigger message is to improve and promote cervical cancer screening and prevention, said Fisher.

“Cervical cancer is nearly 100% preventable,” said Fisher. “The ideal goal would be that we wouldn’t have to put patients through this treatment at all anymore, and that we could really prevent this cancer perfectly through vaccination or—next-best option&mdash;through routine screening with pap testing, as well as testing for high-risk HPV DNA. Those are always preferred options to having an invasive cancer, which either requires major surgery or radiation.

 Robin TP, Amini A, Schefter TE, et al. Disparities in standard of care treatment and associated survival decrement in patients with locally advanced cervical cancer. 

Brachytherapy is one of three treatments considered standard of care for women with advanced cervical cancer, and it significantly increases the chance of survival. However, less than half of patients with this disease receive standard of care.

Many Women With Cervical Cancer Not Receiving Recommended Therapy

For patients with multiple myeloma, newly approved therapies have led to impressive gains in terms of both remission and improved quality of life, according to Sundar Jagannath, MD.

“Every time one of these novel agents comes into the treatment of multiple myeloma—if we follow the SEER data&mdash;we can actually see that it has an impact on the survival of the patient,” says Jagannath, a professor of Medicine, Hematology and Medical Oncology at Mount Sinai Hospital.

“Moreover, the progression-free survival (PFS) rates are improving. That means a lot of patients are responding to treatment, and they are in remission. When patients are in remission, their quality of life is good, they are more productive, and more patients go to work. These changes are all important, dramatic, and have really changed how patients with multiple myeloma are treated and how they enjoy their lives,” added Jagannath.

The triplet regimen of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone has made a significant impact, says Jagannath, especially since it became a standard of care for patients with previously untreated multiple myeloma following the phase III randomized SWOG S0777 trial, results of which were presented at the 2015 Annual Meeting of the American Society of Hematology (ASH).

The study showed that bortezomib, lenalidomide, and dexamethasone resulted in a statistically significant and clinically meaningful improvement in PFS and also an increased overall survival (OS) compared with lenalidomide and dexamethasone alone in previously untreated patients with multiple myeloma without intent for immediate autologous stem cell transplantation.

Daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro), all approved by the FDA in November 2015 for previously treated multiple myeloma, are also poised to make an impact in the frontline setting. Checkpoint inhibitors have potential in this space as well, says Jagannath.

In a recent interview, Jagannath discussed the importance of the standardization of a 3-drug regimen for newly diagnosed multiple myeloma, how the regimen may evolve going forward, and other novel agents on the horizon.

What advances in newly diagnosed multiple myeloma have made the most impact on the field thus far?

: The treatment of multiple myeloma is changing very rapidly. There are many new drugs coming into the field. There was a pivotal trial reported at the last ASH meeting, which, once and for all, said that 3 drugs were better than 2 drugs for all patients. Typically, we recommend a proteasome inhibitor, such as bortezomib or carfilzomib (Kyprolis), lenalidomide, and dexamethasone. This has become the standard of care for newly diagnosed patients.

This standard makes it easier for physicians, because they no longer have to go through a complicated algorithm of a good-risk/poor-risk patient, looking at cytogenetics, FISH (fluorescence in situ hybridization), and so on. What is also important is that the 3-drug regimen not only increased the response rate and depth of response, but there was improvement in the PFS. Surprisingly, it even had an impact on OS. Therefore, choosing the best treatment upfront becomes very important.

Is this standard 3-drug regimen here to stay, or will that evolve also?

The pipeline is very robust, so I am sure that, in a year or so, we may even include different drugs in the frontline combination—especially monoclonal antibodies&mdash;such as the anti-CD38 agents daratumumab and elotuzumab.

All of these are being investigated in frontline in randomized trials. We will be eagerly awaiting these results. We will have the findings regarding the combinations of elotuzumab/lenalidomide/dexamethasone, as well as the oral proteasome inhibitor ixazomib with lenalidomide and dexamethasone. Over the next few years, the treatment of the patient with newly diagnosed myeloma will be evolving. One thing that is certain is that 3 drugs will be better than 2.

At this time, are there any patients who should not receive a 3-drug regimen in the upfront setting?

In clinical trials, evidence-based medicine will say that 3 drugs are better than 2. However, there are certain mitigating circumstances in which the choice of therapy will depend on how the patient presents. For patients presenting with renal impairment, there are challenges in using lenalidomide. It may be better to use thalidomide instead.

Likewise, with frail patients, you may not want to use all 3 drugs; you may use a 2-drug approach and dose adjustments may be required. There are circumstances where a 3-drug combination with the same 3 drugs we are recommending now—bortezomib, lenalidomide, and dexamethasone&mdash;may not be ideal.

What novel agents or approaches do you see on the horizon?

It is an exciting time. I am especially excited about the use of monoclonal antibodies and immunotherapy in patients with newly diagnosed multiple myeloma. Monoclonal antibodies and novel immunotherapy approaches may overcome mutational burden in the cancer cells, or drug resistance in the cancer cells.

Patients we have traditionally considered as high risk and difficult to treat could potentially have improved outcomes. In this regard, daratumumab and elotuzumab have a lot of potential. Checkpoint inhibitors are always being investigated in the advanced setting. If those trials are positive, they may move into the upfront setting. My feeling is that immunology is poised to play a major role in the treatment of multiple myeloma. The impact is not only going to be in relapsed myeloma; the impact will be felt in patients newly diagnosed with multiple myeloma.

Dr. Sundar Jagannath discusses the benefits in progression-free survival and quality of life from newly-approved therapies for patients with multiple myeloma.

New Standard Myeloma Therapies Making a Big Difference for Patients

The field of breast cancer has evolved from the days of defaulting to chemotherapy for every patient, yet much work remains to individualize treatment. Though more promising novel regimens have become available, an expert urges clinicians to carefully weigh whether a particular new agent will provide a significant enough benefit to offset its associated toxicities, cost, and the time and commitment by the patient it requires.

“We have built very successful treatments that have improved survival in patients with breast cancer. The challenge we have now is to not keep adding more and more treatments as we look for better therapies to cure that group of patients who will have a recurrence,” explained Hope S. Rugo, MD, in a presentation at the recent 2016 International Congress on the Future of Breast Cancer.

“At the same time, we also need to understand that, for the majority of patients, we are doing a pretty good job. We don’t need to add more toxicities and costs by giving them additional therapies.”

Thus, when it comes to breast cancer treatments, sometimes less is more, said Rugo, professor of Medicine and director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center. With advances in the understanding of the heterogeneity of breast cancer, she said that tumor biology and genomic testing should guide systemic therapy selection tailored to each individual patient’s tumor.

“What we are focusing on is the idea of looking at the patient and not just looking at whether they have a bigger tumor or a smaller tumor, node-positive or node-negative disease, or high- or low-grade disease, but actually taking all of those pieces and putting them together. We need to take this, along with the patient’s age and medical issues, and try to balance it to get the best therapeutic efficacy with the least toxicity, time and effort, cost, etc.,” said Rugo.

Current research still focuses on adding new therapies to standard regimens, rather than determining if the standard-of-care approach is enough for patients with low-risk disease. This approach is especially detrimental in the design of clinical trials, said Rugo.

“Clinical trials that include patients who have low-risk disease right now have a higher chance of failure,” she added. “Unless you have something that makes a massive impact on that high-risk population, you are going to lose the impact because of patients with low-risk disease who you have inadvertently included in your population. You have low benefit and low power to see the benefit in the highest-risk population, which means that you lose, and the patient loses. Then, we don’t go forward with drugs that probably would have changed the outcome.”

This challenge was observed in the phase III ALTTO trial,

 which looked at the dual HER2-blockade lapatinib (Tykerb) and trastuzumab (Herceptin) versus trastuzumab alone in patients with early HER2-positive breast cancer.

The findings indicated that treatment with lapatinib plus trastuzumab, either sequentially or concurrently, was associated with a high rate of disease-free survival (DFS). However, the combination did not produce a statistically significant advantage over trastuzumab alone.

“There are obvious issues with drug tolerance that complicate this analysis, but the most important factor was that this low-risk group of patients was going to do really well with just chemotherapy and trastuzumab,” said Rugo.

 also demonstrated that additional treatment isn’t always necessary for low-risk patients. The randomized trial was designed to prospectively determine whether chemotherapy improved clinical outcomes in patients with a mid-range risk score (RS). It also aimed to confirm that patients with a low RS had excellent outcomes with hormonal therapy alone.

All patients in the trial had estrogen receptor (ER)-positive, HER2-negative, node-negative breast cancer. Low risk was defined as less than 11 using Oncotype Dx. Patients with a mid-range RS of 11 to 25 were randomized to chemohormonal therapy, the standard treatment arm in accordance with NCCN guidelines at the time versus hormone therapy. Patients with a RS less than 25 were assigned to chemoendocrine therapy; patients with a RS of less than 11 were assigned to hormone therapy alone.

In patients with a RS less than 11 who received hormone therapy alone there was a 7.3% distant recurrence rate at 10 years. In patients with an RS greater than 25 who received chemotherapy plus hormone therapy, there was 16.1% distant recurrence rate at 10 years. In the trial overall, there was a 5-year invasive DFS rate of 93.8% and a 5-year overall survival rate of 98%.

“This is a group of patients who really don’t need most treatments,” said Rugo. “These patients clearly don’t need more than hormone therapy, but I think we are still really learning what to do with that intermediate-risk group of patients. Right now, this is not a group of patients who necessarily needs chemotherapy; this is a group where we have to use clinical pathologic information to try and tweak the information or, potentially, send out an additional genomic test.”

Numerous other trials have demonstrated that, for certain low-risk patients, adding novel treatments isn’t necessary. However, while the less-is-more approach should be considered for low-risk patients, there are still high-risk patients who will benefit from more novel treatments, said Rugo.

The focus should be on identifying which patients will have good responses or have high-risk disease using intrinsic subtyping and immune signatures, she added.

“We must always ask if all patients need all therapies,” said Rugo. “This is what personalized medicine is all about.”

Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). 

Sparano J, Gray R, Makower D, et al. Prospective validation of a 21-gene expression assay in breast cancer. 

In Low-Risk Breast Cancer, Less Treatment May Be Better

An analysis of over 28,000 patients younger than 65 with incurable cancers found that approximately three-fourths of them received aggressive care within the last 30 days of life and one-third died in the hospital, according to findings presented at the 2016 ASCO Annual Meeting.

The analysis, which included patients with 5 different types of metastatic cancer, also found that providing aggressive care at the end of life was not impacted by ASCO’s Choosing Wisely recommendations, issued in 2012, which strongly advised against cancer-directed therapy in patients with advanced solid tumors who are unlikely to benefit from it. The recommendation instead encouraged a focus on symptom-directed palliative care, but this analysis found no increase in hospice care use since 2012.

“Aggressive medical care for patients with incurable cancers at the end of life is widely recognized to be harmful to patients and their families,” said Ronald C. Chen, MD, MPH, who presented the analysis at an ASCO press conference. “Additional efforts are critically needed to improve end-of-life care for patients with terminal disease to ensure that the care provided meets the goals and preferences of patients and their families.”

The study looked at data from large commercial insurance claims of patients in 14 states. Patients were aged <65 years, had metastatic cancer of the lung, breast, prostate, colon, or pancreas, and died between 2007 and 2014. The study examined 6 indicators of aggressive care at the end of life: chemotherapy, radiation, invasive procedures (eg, biopsy, surgery), emergency department visits/hospitalization, intensive care, and in-hospital death.

The study included 12,764 patients with lung cancer, breast cancer (5855), colorectal (5207), pancreatic (3397), and prostate (1508).

Incidence of each aggressive therapy was remarkably similar across all 5 cancer types, said Chen.

The most common form of aggressive care was hospital admission or emergency department visit, occurring in 65% of patients with lung or pancreatic cancer, 62% of patients with colorectal or prostate cancer, and 64% of patients with breast cancer.

Notably, fewer than that 1 in 5 patients in the study utilized hospice care, said Chen.

Across all 5 cancers investigated during the last 30 days of life, chemotherapy rate ranged from approximately 24% to 33% of patients, invasive procedure rate (25% to 31%), and ICU care (16% to 21%).

Radiotherapy was the least utilized treatment at the end of life, and also the most inconsistently prescribed across cancer types. Rates of use ranged from approximately 6% in pancreatic cancer to 21% in lung cancer.

In addition, the study found that between 30% and 35% of patients across all 5 tumor types investigated, died in the hospital

The overall rate of any aggressive care was 75 % for lung and pancreatic cancer, 74% for breast cancer, 72% for prostate cancer, and 71% for colorectal.

 Study investigators also analyzed treatment trends before 2012 and between the first quarter of 2012 and the fourth quarter of 2014.

“The percentage of patients who received aggressive care over the last 30 days of life really didn’t change over time in these 5 cancers, said Chen. “We also saw little change before 2012, and the use of aggressive care did not seem to decrease after ASCO’s 2012 Choosing Wisely recommendations.”

While it is unclear exactly why the ASCO recommendations did not result in any changes, the bigger issue is why there are not more initiatives to improve end-of-life care overall, said press panel moderator Patricia Ganz, MD, FASCO, ASCO Expert in breast cancer.

“While Dr. Chen focused on Choosing Wisely in 2012, giving chemotherapy in the last 30 days of life has been a coping measure for a very long time, and it has been nationally looked at as one of our failures in giving good end-of-life care,” said Ganz.

“The fact that there wasn’t any dramatic change in 2012 doesn’t really bother me in the sense that we’ve been talking about this for a very long time and we haven’t seen any movement. We have a lot yet to do in terms of delivering high quality end-of-life care.”

It is most likely that end-of-life aggressive treatment is driven both by patients and their doctors, said Chen.

Oncologists are not always aware or accepting that a patient is nearing the end of life, and they may be motivated to continue to treat the patient by a strong desire to help them, despite survival chances, said Chen. However, the study also showed that two-thirds of patients went to the emergency department or were admitted to the hospital at the end of their lives, suggesting that patients may also play an active role in the high rate of aggressive treatment at end of life.

“These younger patients may want to continue to receive aggressive care for their cancers,” said Chen.

While it is ultimately up to a patient if he or she would like to continue receiving aggressive treatment at the end of life, oncologists and oncology nurses need to do a better job of discussing patients’ wishes and educating them on their options, said Andrew Epstein, MD, press briefing panelist and ASCO Expert in palliative care.

“Education for any clinician, whether it is a physician a nurse, or others, is extremely important in order to improve their ability to have these very challenging conversations about the end of life and what is important to patients and their families,” said Epstein. “We need to teach oncology professionals, especially doctors, in order to make these very, very challenging conversations easier. We need to find out what is important to patients and their families and marry the care delivered to what they say is important.”

Next steps for this research could include using this dataset to compare end-of-life aggressive treatment rates in younger patients to those in older patients, said Ganz. Previous studies have shown that elderly patients have similar rates of aggressive treatment in their last 30 days of life, but no side-by-side comparison has been done, she said.

“Looking at the younger patients, we need to know if they are being treated more aggressively than the older population, what the patterns of care are, and if they mimic what is seen in the older population,” said Ganz. “This is a really great opportunity from this database to begin to look at this.”

 Falchook A, Tian F, Basak R et al. Aggressive care at the end-of-life for younger cancer patients: impact of ASCO’s Choosing Wisely Campaign. 

An analysis of over 28,000 patients younger than 65 with incurable cancers found that approximately three-fourths of them received aggressive care within the last 30 days of life and one-third died in the hospital.

Patients Still Getting Aggressive End-of-Life Treatment Though Unlikely to Benefit

Androgen-deprivation therapy, while an effective treatment for prostate cancer, can result in side effects and a reduced quality of life. Allowing low-risk patients to take breaks between treatments—a practice known as intermittent hormonal therapy, or a “hormone holiday”&mdash;may combat these challenges without impacting survival.

A recent systematic review and meta-analysis conducted by JAMA Oncology found no significant difference between intermittent and continuous therapy for overall survival (HR, 1.02; 95% CI, 0.93-1.11; 8 trials, 5352 patients), cancer-specific survival (HR, 1.02; 95% CI, 0.87-1.19; 5 trials, 3613 patients), and progression-free survival (HR, 0.94; 95% CI, 0.84-1.05; 4 trials, 1774 patients).

The review was based on 15 trials with 6856 patients who also reported a minimal difference in quality of life between interventions and an improvement in physical and sexual functioning with intermittent therapy.1

To learn more about intermittent hormonal therapy and its benefits and challenges, 

 spoke with Leonard G. Gomella, MD, who presented on the topic at the 26th International Prostate Cancer Update, which took place from January 20 to 23, 2016, in Denver, Colorado.

Gomella is the the Bernard W. Godwin, Jr. Professor of Prostate Cancer and chairman of the Department of Urology at Jefferson Medical College, senior director for Clinical Affairs of Jefferson Kimmel Cancer Center, and president of the Society for Urologic Oncology.

: What are the biggest benefits of intermittent hormonal therapy?

: Intermittent hormonal therapy has been growing in popularity over the years. Patients who receive hormone therapy often have side effects, and giving them so-called “hormone holidays” may improve quality of life. Over the years, there has really been a lot of trials and experimental work that laid the groundwork for this going back 20 years.

Very recently, several big clinical trials have basically shown that, in general, patients who receive intermittent hormonal therapy have the same cancer-specific and overall survival as patients who receive continuous hormonal therapy. Patients can take a “hormone holiday” and perhaps improve their quality of life and, along the way, also save some money.

In addition, there has also always been a theoretical idea that intermittent hormonal therapy could potentially delay the development of castration-resistant prostate cancer.

What is the basis for the theory that intermittent hormonal therapy could delay the development of castration-resistant prostate cancer?

It encourages the prostate cancer to have more dependence on hormonal manipulation. When the testosterone levels are high, it encourages the development and growth of cells, which are androgen-dependent. When the hormone levels are low, it encourages the growth of cells that are androgen-independent.

By theoretically encouraging more cells to be androgen-dependent, you tend to keep them more dependent on the hormones and potentially delay the development of androgen or castration resistance. This has been effectively shown in animal models and in cell cultures, but it remains theoretical in patient use.

Are there any challenges regarding the use of intermittent hormonal therapy?

The one thing that may have negatively impacted intermittent hormonal therapy is the updated CHAARTED and STAMPEDE data. People are now coming in with metastatic disease and receiving both chemotherapy and hormonal therapy.

The use of intermittent hormonal therapy for these patients, who are now getting hormonal therapy and chemotherapy at the presentation of metastatic prostate cancer, may actually start to go down because we don’t yet have any data at this point combining intermittent hormonal therapy with chemotherapy. That is now going to become the standard of care for patients with metastatic disease. We may need to investigate that.

I believe it will become a standard of care for people to use intermittent hormonal therapy after chemotherapy. However, we don’t know if that is going to be better or the same.

How should oncologists determine which patients should receive intermittent hormonal therapy, and when the best times are to start and stop treatment?

The success of intermittent hormonal therapy is based on proper patient stratification. For example, if you have a patient who you are going to start hormonal therapy on who has advanced prostate cancer or recurrent cancer following local radiation or local radiation plus surgery, you put them on hormonal therapy.

After 7 or 8 months, check their PSA. If their PSA has come down to less than 4, hormonal therapy can be stopped. The patient is then followed every 3 months. When their PSA starts to increase again—especially if it goes up to 10 or 20 depending on each individual oncologist’s threshold&mdash;then you restart them on hormonal therapy.

The most important thing is patient stratification. If a patient does not get a very low PSA after 7 or 8 months of hormonal therapy, you should probably not do intermittent hormonal therapy. They should stay on continuous hormonal therapy.

Basically, all of the major organizations now endorse this. The risk is really minimal. The upside is probably greater than the downside.

If you stratify patients properly, it is safe. The patients who do the best have very low PSA levels after you put them on hormone therapy. If a patient does not have a low PSA following therapy, they should not go on intermittent hormonal therapy.

One analysis showed if you have patients with really aggressive cancer, like those who have a high Gleason score, you probably should leave them on continuous hormonal therapy. There is a small risk that you might compromise a patient’s survival if you don’t follow the stratification and correctly identify those who are going to be the best responders but, overall, it is not considered to be that hazardous.

What role does imaging play in intermittent hormonal therapy?

One thing an oncologist should do is try to identify metastatic disease early. That is where imaging may come into play. We have a tendency to image people less often in urology, even though medical oncologists are aggressive about imaging patients. The take-home message is that we should try to image patients more often to identify early metastatic disease, and start them on treatment at the earliest time of metastasis.

Magnan S, Zarychanski R, Pilote L, et al. Intermittent vs continuous androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. 

Androgen-deprivation therapy, while an effective treatment for prostate cancer, can result in side effects and a reduced quality of life. 

Breaks From Prostate Cancer Hormone Therapy May Improve Quality of Life

Rolapitant (Varubi), which was recently approved by the FDA, has been shown to significantly reduce delayed phase CINV when used in combination with other antiemetic agents.

The approval was based on data from several phase III trials of rolapitant in more than 2500 patients receiving various emetogenic chemotherapy agents, including cisplatin, carboplatin, and anthracycline/cyclophosphamide-based regimens.

The phase III HEC1 trial examined rolapitant in highly emetogenic cisplatin-based chemotherapy regimens. Patients received rolapitant (n = 264) or placebo (n = 262) prior to chemotherapy administration. All patients also received the 5HT3-antagonist granisetron and dexamethasone. The primary endpoint was complete response (CR), defined as no vomiting or use of rescue medication 25 to 120 hours after treatment initiation. The CR rate was 72.7% in the rolapitant arm versus 58.4% in the control arm (P <.001).

In the identically designed HEC2 trial, CR in the rolapitant group (n = 271) versus the control arm (n = 273) was 70.1% versus 61.9% (P = .043), respectively.

A separate, similarly designed phase III trial evaluated rolapitant in 1332 patients receiving moderately emetogenic chemotherapy regimens. In the delayed phase of CINV, CR was 71.3% in the rolapitant arm versus 61.6% in patients receiving granisetron plus dexamethasone alone (P <.001).

We spoke with Marleen Meyers, MD, medical oncologist at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, to discuss the approval of rolapitant, its impact on patient quality of life and effective chemotherapy administration, as well as the advancement of antiemetic drugs in recent years.

Please discuss the pivotal research supporting the approval of rolapitant for CINV.

: The trials randomized patients who were receiving the types of chemotherapy regimens that tend to cause delayed nausea. This occurs about 25 to 120 hours after chemotherapy. It is difficult to control. Patients go home and feel fine, but then after a day or 2, or even 3, they cannot keep food down. This trial randomized patients to receive either standard antinausea medication, which was granisetron as well as dexamethasone, or granisetron, dexamethasone, and rolapitant. There was a significant improvement in terms of lowering the amount of nausea and the extent of nausea in patients who received rolapitant.

What effect do you think this approval will have on patient care?

By adding another drug to the armamentarium, there is a better chance of controlling this part of the toxicity. This is another tool in the toolbox, which works in combination with our current medicines and gives them the best chemotherapy experience possible.

What impact can prolonged nausea and vomiting have on patients’ overall health and quality of life?

Getting through some chemotherapy regimens can take a Herculean effort. Anything that slows the patient down, or makes them feel weak or tired, can really make it difficult. Prolonged nausea and vomiting can cause depression, dehydration, weight loss, malnutrition, and more. It can cause various effects that make it more difficult for a patient to continue chemotherapy. It can delay effective administration of the chemotherapy.

Who are the ideal patients for rolapitant?

It can be used in patients who have a wide variety of cancers, but it is really aimed at the patients who are getting the type of chemotherapy that causes delayed nausea and vomiting. The two most common drugs to cause delayed nausea are doxorubicin and cisplatin. However, any chemotherapy can cause delayed nausea or vomiting, so it can certainly be used in any person with any chemotherapy.

Are there any concerning side effects associated with rolapitant?

The side effects are the same as most other antinausea medications. In the study, researchers found that the most common side effects were poor appetite, dizziness, and lowered blood cell count, particularly white blood cells. In chemotherapy, that is something that must be watched closely. It can also cause hiccups. There are no serious side effects.

How has the control of nausea and vomiting related to chemotherapy changed in recent years?

We have come a long way in the past 25 years with reducing nausea for chemotherapy. In my early days of oncology, when we would give a drug like doxorubicin, which tends to cause a lot of nausea and vomiting, our antinausea medication was so poor that we often had to admit people to the hospital to give them the drug. Often, we had to sedate them and give them intravenous fluids because the vomiting was so severe. Since then, we have made tremendous strides on both early and delayed nausea and vomiting.

There is still a perception by patients that chemotherapy is going to be horrible, which is mostly based on portrayals from the movies. When there is a character with cancer, they are always miserable. They are in the bathroom with their head in the toilet bowl and their eyes are sunken in. Fortunately, that is not something that commonly happens anymore. In the majority of incidences, we can now control the nausea and vomiting to a degree that is very manageable.

In my practice, it is extremely rare that anyone vomits anymore. People feel nauseous and queasy, but they rarely actually vomit because of the medications we now have available. The new agents that have come out over the past 10 years have truly changed the face of oncology.

Rolapitant (Varubi), which was recently approved by the FDA, has been shown to significantly reduce delayed phase CINV when used in combination with other antiemetic agents.


Rolapitant Alleviates CINV: Q & A with Dr. Marleen Meyers

Does drinking a lot of coffee reduce colon cancer recurrence risk? Possibly, according to a study published online in the 

 which found that for patients with stage III colon cancer, drinking four or more cups of coffee per day may reduce risk of recurrence by 42% and death by 34%.

The results are based on data from 953 patients with stage III colon cancer who during, and 6 months following, adjuvant chemotherapy prospectively reported their intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. Patients who consumed four cups or more of total coffee per day experienced an adjusted hazard ratio for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34-0.99), compared with those who did not drink coffee (

For patients with stage III colon cancer, drinking four or more cups of coffee per day may reduce risk of recurrence by 42% and death by 34%.

Laura Panjwani