Do Cellphones Cause Cancer?

The question of whether cellphones can cause cancer became a popular one after the dramatic increase in cell phone use since the 1990s. Scientists’ main concern is that cell phones can increase the risk of brain tumors or other tumors in the head and neck area – and as of now, there doesn’t seem to be a clear answer.

Cell phones give off a form of energy known as radiofrequency (RF) waves. They are at the low-energy end of the electromagnetic spectrum – as opposed to the higher-energy end where X-rays exist – and they emit a type of non-ionizing radiation. In contrast to ionizing radiation, this type does not cause cancer by damaging DNA in cells, but there is still a concern that it could cause biological effects that result in some cancers.

However, the only consistently recognizable biological effect of RF energy is heat. The closer the phone is to the head, the greater the expected exposure is. If RF radiation is absorbed in large enough amounts by materials containing water, such as food, fluids, and body tissues, it produces this heat that can lead to burns and tissue damage. Still, it is unclear whether RF waves could result in cancer in some circumstances.

An iPhone.

Many factors affect the amount of RF energy a person is exposed to, such as the amount of time spent on the phone, the model of the phone, and if a hands-free device or speaker is being used. The distance and path to the nearest cell phone tower also play a role. The farther a way a person is from the tower, the more energy is required to get a good signal on the phone. The same is true of areas where many people are using their phones and excess energy is required to get a good signal.

RF radiation is so common in the environment that there is no way to completely avoid it. Most phone manufacturers post information about the amount of RF energy absorbed from the phone into the user’s body, called the specific absorption rate (SAR), on their website or user manual. Different phones have different SARs, so customers can reduce RF energy exposure by researching different models when shopping for a phone. The highest SAR in the U.S. is 1.6 watts/kg, but actual SAR values may vary based on certain factors.

Studies have been conducted to find a possible link between cell phone use and the development of tumors. They are fairly limited, however, due to low numbers of study participants and risk of recall bias. Recall bias can occur when individuals who develop brain tumors are more predisposed to recall heavier cell phone use than those who do not, despite lack of true difference. Also, tumors can take decades to develop, and given that cell phones have only been in use for about 20 years, these studies are unable to follow people for very long periods of time. Additionally, cell phone use is constantly changing.

Outside of direct studies on cell phone use, brain cancer incidence and death rates have changed little in the past decade, making it even more difficult to pinpoint if cell phone use plays a role in tumor development.



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Ten Things to Know About Young Women with Breast Cancer

Women who develop breast cancer when they’re relatively young – under age 45 – face a variety of issues unique to their stage of life. Questions about how the disease may affect their careers, relationships, sexual functioning, and ability to have and raise children often become pressing in the aftermath of a diagnosis.

Because breast cancer is relatively rare in young women – the average age at which the disease is diagnosed in the United States is 61 – there has been little research focused on young women, and such research is needed, ranging from the biology of the disease in younger patients to the particular challenges they encounter. To begin to fill in that gap, we launched the Young Women’s Breast Cancer Study in 2006, the first multi-institutional effort to track the medical and psychosocial issues faced by a large group of young women with breast cancer in the U.S.

The study enrolled more than 1,300 women across the country. Participants were surveyed at the time of their diagnosis and treatment, and continue to be surveyed post-treatment about issues such as fertility concerns, sexual functioning, body image, genetic testing, treatment decisions, and family planning. Participants were also asked to provide blood and tissue samples for analyses to better understand the biology of breast cancer in young women.

Meredith Faggen, MD, delivers care to Joyce White, a young woman with breast cancer.

Data collected by the study have significantly increased our understanding of the nature of the disease in younger women and how it impacts their lives. Research based on the data may help change not only the way breast cancer is treated in these patients, but also the support services they receive.

Here are some of the most intriguing findings to date from studies using the Young Women’s Breast Cancer Study data.*

  • A substantial portion of young women with hormone receptor-positive breast cancer had high grade, more aggressive tumors.
  • A higher percentage of breast tumors in young women were HER2-positive versus those in older women. The HER2 protein spurs cancer cell growth and is a target for some drugs.
  • There was no association between the age at which participants were last pregnant, or were ever pregnant, and the molecular subtype of cancer they developed.
  • Participants sought care in a timely fashion. The median period between detecting a suspicious breast lump, or other symptom, and seeking care from a physician was only two weeks.
  • Genetic testing rates are increasing. Seventy-seven percent of participants diagnosed with breast cancer in 2006 agreed to be tested for mutations in the BRCA genes, which increase the risk of future breast and/or ovarian cancer. By 2013, that figure had risen to 95 percent.
  • An increasing percentage of young women with cancer in one breast are choosing to have the unaffected breast removed. The vast majority of study participants who chose this option said they did so to decrease the chance of developing cancer in the second breast, but many believe it will improve their survival. Research has shown that for women with breast cancer on one side, having the other breast removed does not improve survival.
  • Thirty-eight percent of participants said that, prior to their diagnosis, they’d been interested in having children. At the time of diagnosis, twenty-six percent indicated such an interest. Although the percentage declined in succeeding years, it remained in the 25 percent range for the first three or four years after diagnosis.
  • 11 percent of participants had taken steps to preserve their fertility by freezing embryos, freezing eggs, or other techniques.
  • Other studies have sought to gauge young women’s fertility following breast cancer treatment, using menstrual periods as a marker of their ability to have children. Among patients under 30, 87 percent continued to have periods, as did 64 percent of those aged 36-40. All patients not treated with chemotherapy continued to have periods in the initial years after diagnosis, as did 60 percent of those who did receive chemotherapy.
  • Of the participants who tried to get pregnant following treatment, the vast majority succeeded.



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Brother’s Stem Cells Make Remission Possible for Pediatric Leukemia Patient

How do you repay someone who has given you the gift of life? Eight-year-old Emma Duffin of Enfield, Connecticut, started by giving a kiss and cuddle to her brother, Alexander, who donated his bone marrow stem cells to Emma to reboot her immune system and send her rare form of leukemia into remission.

Emma’s journey to a stem cell transplant began in April 2014, when her usual energetic demeanor began to change. “Emma was very vibrant, very active, and she did not like to rest,” says her father, Brian Duffin. But suddenly his go-go daughter was exhausted all the time. She was diagnosed with strep throat, then foot-and-mouth disease, but neither medication nor time brought any improvement.

During yet another trip to the emergency room, a blood draw revealed Emma had an alarmingly low level of hemoglobin – a 3 instead of the normal range for a juvenile of 11 or higher.

“For an adult, such low levels would have been fatal,” Brian says. Emma was rushed to Connecticut Children’s Medical Center (CCMC), where she was diagnosed a few days later with acute undifferentiated leukemia.

Most leukemias fall into two types: acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML). Each type is treated with a distinct protocol. Acute undifferentiated leukemia is a subset of the disease that shows markers of both types.

“As a result, part of the leukemia is often resistant to one protocol or the other,” explains Steven Margossian, MD, PhD, a senior physician of pediatric hematology and oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In this circumstance, the best approach is often a bone marrow stem cell transplant. The bone marrow is the factory where leukemia cells are made. By using strong chemotherapy to destroy the existing bone marrow cells, you can then replace those with normal, healthy cells from a donor as closely matched to the patient as possible.”

In Emma’s case, Alexander ended up being her perfect match.

Emma’s oncologist at CCMC trained under Dr. Margossian and referred the family to her mentor.

“When your doctor tells you the number one pediatric stem cell transplant hospital in the world is only 90 minutes from your house, you don’t question it,” says Allyson Duffin, Emma’s mom.

After Emma completed three rounds of chemotherapy at CCMC, the Duffin family traveled to Boston to prepare for “zero day”: the day Dr. Margossian would perform the stem cell transplant. Prior to the transplant, Emma had one last round of high-dose chemotherapy and radiation – a typical pre-transplant treatment called conditioning therapy – to wipe out any remaining malignant stem cells. Then, on zero day, Margossian’s team harvested and processed Alexander’s stem cells and prepared Emma for the infusion. Brian had the privilege of pushing the button that began the infusion, transferring this gift of life from his son to his daughter.

Emma remained at Boston Children’s Hospital for about a month until engraftment, or the point at which the new stem cells produce enough neutrophils, a specific kind of white blood cell, to provide protection against bacterial infection.

“She was still energetic during that time; she has a zest for life that is unquestionable,” Brian says.

On Halloween, Emma dressed as Elsa and enjoyed “reverse trick-or-treating,” as doctors and nurses brought candy to her on their rounds.

Still, the month of recovery had its challenges. The conditioning therapy often causes the onset of mucositis, an extremely painful inflammation of the mucous membranes that line the digestive tract. Emma’s case was especially severe; she had to be fed through a nasal tube.

“For 95 percent of stem cell patients, the pain of mucositis is what they remember the most about their transplant,” Margossian says.

Emma also endured graft-versus-host disease (GVHD), another expected side effect of a stem cell transplant in which the donor’s white blood cells (the “graft”) attack the host’s cells, which can cause skin rashes and irritate the digestive system and liver.

“Emma’s nurses were very proactive about it,” Allyson says. “They gave her Benadryl and used every lotion known to man to soothe her skin.”

After Emma was released from the hospital, she remained in quarantine at home for nine months, allowing her fragile immune system to gradually rebuild itself without unnecessary exposure to germs in indoor public places. She entertained plenty of visitors on her front porch, relished rides around town with her family, and enjoyed the occasional meal on the outside patio at her favorite restaurant.

When Emma’s quarantine restrictions were lifted on June 1, 2015, “she celebrated by doing anything and everything,” Brian says with a laugh. “She shopped, she visited friends, she ate inside at her favorite restaurant – and she was excited to go back to school.”

Today, Emma remains healthy. “You would never know she had been so sick,” Allyson says. Now 11, Emma is in a dance troupe and involved in acting. She plays trumpet in her school band. And yes, she and Alexander are back to the usual sibling antics.

“Kids often bounce back more easily, physically and psychologically, because they are more resilient,” Margossian said. “Emma is spunky, and her energetic attitude went a long way in positively influencing her recovery.”



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The Truth About Melanoma and Skin Cancer: Facts and Common Myths

Often caused by excessive exposure to ultraviolet (UV) rays in sunlight, melanoma accounts for only 4 to 5 percent of skin cancer cases, but is responsible for most skin cancer-related deaths. As with many forms of cancer, melanoma is often misunderstood, and myths persist.

When detected and treated in its earliest stages, however, melanoma is often curable. The key is to avoid overexposure to UV rays – by limiting time outdoors during the peak hours of sunlight and wearing sun-protective clothing and sunscreen – and to be on the lookout for changes in moles and other blemishes that can be an early sign of the disease.

Jennifer Y. Lin, MD, of Dana-Farber Cancer Institute’s Melanoma Treatment Program, sets the record straight on five of the most common myths about melanoma.

Myth 1: A diagnosis of melanoma means that I have months to live.

There are four stages of melanoma — five if you include a form known as melanoma in situ, an early form of the disease that affects only the top layer of skin. Stage 1 melanomas, which are less than one millimeter thick and almost always have not spread beyond their original site, have an excellent prognosis and are generally cured by surgery. The depth of the original melanoma is critical to determining how it will be treated and how people with it are likely to fare. Although more melanomas are being diagnosed, the largest portion are made up of Stage 1 melanomas. Before worrying about the worst outcomes, speak with your doctor about what stage melanoma you have.

Myth 2: There is no difference between SPF 30 and SPF 100 sunscreen.

Although the baseline protection from SPF 30 and SPF 100 is not vastly different, the higher number provides longer coverage. (SPF stands for sun protection factor, or the amount of ultraviolet radiation the skin can absorb without burning while the sunscreen is on.)

If it normally takes you 10 minutes in the sun to burn, an SPF 30 sunscreen protects you for 300 minutes. An SPF 100 should, in theory, provide 1,000 minutes of coverage. If you are sweating and active, the sunscreen can rub off and should therefore be reapplied every two hours. When you are using a high SPF, there is a smaller likelihood of having a “missed spot.” A good way to know that you are applying enough sunscreen is to use the measurement of a shot glass of sunscreen for exposed sites.

Myth 3: If it is a cloudy day, I do not need to wear sunscreen.

About 80 percent of ultraviolet radiation reaches the earth even through clouds. Use a moisturizer with sunscreen daily, especially for areas that have high exposure, such as your face.

Myth 4: If I am low in vitamin D levels, I must get some sun exposure.

Although the skin is the most efficient site of vitamin D production, adequate amounts can be obtained from your diet and from supplements. Vitamin D helps you absorb calcium and build strong bones, so we frequently recommend supplements that include vitamin D and calcium.

Myth 5: If I have dark skin, I can’t burn and won’t get melanoma.

Even people with dark skin can burn if they’re exposed to the sun long enough. Although melanoma is much more rare in individuals of darker skin, it can occur. We recommend that darker-skinned individuals inspect their hands and feet once a month.

Source: Dana-Farber Cancer Institute.

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Study reveals that many oncologists recommend medical marijuana clinically despite not feeling sufficiently knowledgeable to do so

  • Researchers identified a discrepancy between oncologists’ self-reported knowledge base and their clinical practices and beliefs regarding medical marijuana.
  • They conclude that critical gaps exist in research, education, and policy regarding medical marijuana.

While a wide majority of oncologists do not feel informed enough about medical marijuana’s utility to make clinical recommendations, most do in fact conduct discussions on medical marijuana in the clinic and nearly half recommend it to their patients, say researchers who surveyed a population-based sample of medical oncologists.

The study, published today in the Journal of ClinicalOncology, is the first nationally-representative survey of medical oncologists to examine attitudes, knowledge and practices regarding the agent since medical marijuana became legal on the state level in the U.S. Medical marijuana refers to the non-pharmaceutical cannabis products that healthcare providers recommend for therapeutic purposes. A significant proportion of medical marijuana products are whole-plant marijuana, which contains hundreds of active ingredients with complicated synergistic and inhibitory interactions. By contrast, cannabinoid pharmaceuticals, which are available with a prescription through a pharmacy, contain no more than a couple of active ingredients. While considerable research has gone into the development of cannabinoid pharmaceuticals, much less has been completed on medical marijuana’s utility in cancer and other diseases. The researchers speculate that the immature scientific evidence base poses challenges for oncologists.

“In this study, we identified a concerning discrepancy: although 80% of the oncologists we surveyed discussed medical marijuana with patients and nearly half recommended use of the agent clinically, less than 30% of the total sample actually consider themselves knowledgeable enough to make such recommendations,” said Ilana Braun, MD, chief of Dana-Farber Cancer Institute’s Division of Adult Psychosocial Oncology. “We can think of few other instances in which physicians would offer clinical advice about a topic on which they do not feel knowledgeable. We suspect that this is at least partly due to the uncomfortable spot in which oncologists find themselves.  Medical marijuana is legal in over half the states, with cancer as a qualifying condition in the vast majority of laws, yet the scientific evidence base supporting use of medical marijuana in oncology remains thin.”

The mailed survey queried medical oncologists’ attitudes toward medical marijuana’s efficacy and safety in comparison with standard treatments; their practices regarding medical marijuana, including holding discussions with patients and recommending medical marijuana clinically; and whether they considered themselves sufficiently informed regarding medical marijuana’s utility in oncology. Responses indicated significant differences in attitudes and practices based on non-clinical factors, for instance regional location in the U.S.

“Ensuring that physicians have a sufficient knowledge on which to base their medical recommendations is essential to providing high quality care, according to Eric G. Campbell, PhD, formerly a professor of medicine at the Massachusetts General Hospital, now a professor at the University of Colorado School of Medicine. “Our study suggests that there is clearly room for improvement when it comes to medical marijuana.”

To date, no randomized clinical trials have examined whole-plant medical marijuana’s effects in cancer patients, so oncologists are limited to relying on lower quality evidence, research on pharmaceutical cannabinoids or research on medical marijuana’s use in treating diseases other than cancer.

Of note, additional findings of the current study suggest that nearly two-thirds of oncologists believe medical marijuana to be an effective adjunct to standard pain treatment, and equally or more effective than the standard therapies for symptoms like nausea or lack of appetite, common side effects of cancer treatments such as chemotherapy.



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Antidepressants for the treatment of depression in people with cancer.

BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have been shown to have a negative impact in terms of quality of life, compliance with anti-cancer treatment, suicide risk and likely even the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results.

OBJECTIVES: To assess the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage).

SEARCH METHODS: We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 6), MEDLINE Ovid (1946 to June week 4 2017), Embase Ovid (1980 to 2017 week 27) and PsycINFO Ovid (1987 to July week 4 2017). We additionally handsearched the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug-approving agencies for published, unpublished and ongoing controlled trials.

SELECTION CRITERIA: We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis).

DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a form specifically designed for the aims of this review. The two authors compared the data extracted and then entered data into Review Manager 5 using a double-entry procedure. Information extracted included study and participant characteristics, intervention details, outcome measures for each time point of interest, cost analysis and sponsorship by a drug company. We used the standard methodological procedures expected by Cochrane.

MAIN RESULTS: We retrieved a total of 10 studies (885 participants), seven of which contributed to the meta-analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update we included one additional unpublished study. These new data contributed to the secondary analysis, while the results of the primary analysis remained unchanged.For acute-phase treatment response (6 to 12 weeks), we found no difference between antidepressants as a class and placebo on symptoms of depression measured both as a continuous outcome (standardised mean difference (SMD) -0.45, 95% confidence interval (CI) -1.01 to 0.11, five RCTs, 266 participants; very low certainty evidence) and as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants; very low certainty evidence). No trials reported data on follow-up response (more than 12 weeks). In head-to-head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, showing no difference between these two classes (SMD -0.08, 95% CI -0.34 to 0.18, three RCTs, 237 participants; very low certainty evidence). No clear evidence of a beneficial effect of antidepressants versus either placebo or other antidepressants emerged from our analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low certainty evidence). In terms of dropouts due to any cause, we found no difference between antidepressants as a class compared with placebo (RR 0.85, 95% CI 0.52 to 1.38, seven RCTs, 479 participants; very low certainty evidence), and between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the certainty (quality) of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity.

AUTHORS’ CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo. On the basis of these results, clear implications for practice cannot be deduced. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. To better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.


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New Standard of Care in Advanced Renal Cell Carcinoma?

Combination immunotherapy could be a new standard of care for some patients with advanced renal cell carcinoma (RCC), suggest the results of a large randomized phase 3 trial

In the trial, both overall survival and objective response rates were significantly higher with nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) as compared to sunitinib (Sutent, Pfizer) in patients with intermediate- and poor-risk advanced RCC.

The 18-month overall survival rate was 75% with nivolumab plus ipilimumab vs 60% with sunitinib; the objective response rate was 42% vs 27%.

The findings were initially presented at the European Society of Medical Oncology 2017 Congress and were reported by Medscape Medical News at that time. They have now been published online in the New England Journal of Medicine.

“The study showed improvement in response and overall survival compared to sunitinib for patients with intermediate or poor features, comprising about 80% of patients with metastatic RCC,” said lead author Robert Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

“In this group, nivolumab plus ipilimumab should be a new treatment option — pending regulatory approval — and a new standard of care,” he told Medscape Medical News. “The benefit was seen in the entire kidney cancer population as well, but in the small subset of patients with favorable-risk disease, the sunitinib group had higher response rates. So sunitinib will be regarded by most as the option of choice for favorable-risk patients.”

The combination of nivolumab plus ipilimumab has already been investigated in several tumor types, and response rates tend to be better than those of either agent used alone. The combination has been approved for the treatment of advanced melanoma.

The combination has also demonstrated antitumor activity in untreated and previously treated patients with advanced RCC, the authors note.

Significant Improvement in Survival and Response

The cohort included 1082 patients with previously untreated clear-cell advanced RCC who were randomly assigned to receive treatment with nivolumab plus ipilimumab (n = 547) or with sunitinib (n = 535). In the intent-to-treat population, 423 patients had intermediate-risk disease, and 416 patients had poor-risk disease.

The coprimary end points were overall survival, objective response rate, and progression-free survival in the group at intermediate or poor risk.

In the intermediate- and poor-risk group, the 12-month overall survival rate was significantly better in the nivolumab plus ipilimumab arm compared with that in the sunitinib arm: 80% vs 72% (hazard ratio for death, 0.63; 99.8% confidence interval, 0.44 – 0.89; P < .001).

The median overall survival was not reached with nivolumab plus ipilimumab. It was 26.0 months with sunitinib.

A complete response was observed in 40 patients (9%) in the nivolumab plus ipilimumab arm and in 5 patients (1%) in the sunitinib arm. Among the intermediate- and poor-risk patients, 81% in the nivolumab plus ipilimumab arm demonstrated a duration of response of at least 1 year; 70% of patients in the sunitinib arm demonstrated a duration of response of at least 1 year. The median duration of response not reached in the nivolumab plus ipilimumab arm; it was 18.2 months in the sunitinib arm.

For progression-free survival, the median was 11.6 months with nivolumab plus ipilimumab and 8.4 months with sunitinib, but the difference between groups did not meet the prespecified threshold (P = .009) for statistical significance (hazard ratio for disease progression or death, 0.82; P = .03).

The authors assessed outcomes for the entire intent-to-treat population (patients with favorable, intermediate, or poor risk). The 12-month overall survival rate was 83% for immunotherapy vs 77% with sunitinib; the 18-month overall survival rate was 78% vs 68%.

The median overall survival was not reached for the nivolumab plus ipilimumab arm; it was 32.9 months for the sunitinib arm. The rate of independently assessed objective response was 39% with nivolumab plus ipilimumab and 32% with sunitinib (P = .02; not significant per the prespecified 0.001 threshold).

Median progression-free survival rates were similar for both groups: 12.4 with nivolumab plus ipilimumab and 12.3 months with sunitinib (hazard ratio for disease progression or death, 0.98; P = .85).

Favorable Risk Favors Sunitinib

The subgroup of patients who were considered to be at favorable risk did worse with immunotherapy than with sunitinib. An exploratory analysis found that in this small subgroup (n = 249), response rates were higher and progression-free survival was longer with sunitinib than with the combination of nivolumab and ipilimumab.

The 12-month overall survival rate was 94% with nivolumab plus ipilimumab and 96% with sunitinib. The 18-month overall survival rates were 88% and 93%, respectively (the hazard ratio for death favored sunitinib: 1.45; 99.8% CI, 0.51 – 4.12; P = .27). The objective response rate was 29% with nivolumab plus ipilimumab vs 52% with sunitinib (P < .001). The median progression-free survival was 15.3 months vs 25.1 months (hazard ratio for disease progression or death, 2.18; 99.1% CI, 1.29 – 3.68; P < .001), favoring sunitinib.

The rate of complete response, however, was 11% with nivolumab plus ipilimumab and 6% with sunitinib.

“It is important to evaluate and better understand the underlying tumor biology of each of these groups to better define what is driving response to nivolumab plus ipilimumab and to sunitinib,” said Motzer. “We have not compared the combination to nivolumab alone, although cross-study comparisons favor the nivolumab/ipilimumab combination in producing tumor responses.”

Patients who received the immunotherapy combination had fewer grade 3-4 adverse events than those who received sunitinib (46% vs 63%), but there were more discontinuations (22% with immunotherapy vs 12% with sunitinib) and more treatment-related deaths (8 patients vs 4 patients). Overall, treatment-related adverse events of any grade occurred in 93% of patients in the immunotherapy group vs 97% of those treated with sunitinib.

Curative Treatments Needed

In an accompanying editorial, Brendan Curti, MD, from the Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, writes that it is “notable that tumors with a greater number of mutations appear more likely to have a response to checkpoint immunotherapy.”

This may account for the better response with immunotherapy seen in some patients but not others. There may be a “higher tumor mutational load and a broad, though ineffective, extant adaptive immune response in patients with intermediate- and poor-risk renal-cell carcinoma as compared with patients with favorable-risk disease,” says Curti.

But importantly, the combination of ipilimumab and nivolumab is a step in the right direction when it comes to improving treatment in RCC. He notes that for the past quarter century, treatment has evolved from “infrequently effective cytokine-based immunotherapy to active but rarely curative TKI [tyrosine kinase inhibitor] treatment, and now to more effective immunotherapy that in some clinical settings is superior to TKIs.”

However, with current therapies, there is still only a small probability of complete response or cure. “The goal of future immunotherapy development should be not just transient response or tumor control, but rather cure in a higher proportion of patients,” Curti emphasizes.

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First Trial of Three Aromatase Inhibitors: Similar Efficacy, Safety

The first-ever direct comparison of three adjuvant aromatase inhibitors for the treatment of postmenopausal hormone receptor–positive early breast cancer shows no significant differences in clinical efficacy or safety, according to an Italian research team.

In the randomized, open-label phase 3 FATA-GIM3 trial of almost 3700 women, the 5-year disease-free survival for patients treated with anastrozole (Arimidex, Novartis), exemestane (Aromasin, Pfizer), or letrozole (Femara, Novartis) was 90.0%, 88.0% and 89.4%, respectively.

There were no unexpected serious adverse reactions or treatment-related deaths, say Francesco Perrone, MD, of the Istituto Nazionale per lo Studio e la Cura dei Tumori, in Naples, Italy, and colleagues. No differences were observed between patient subgroups, even though more than 50% of patients were overweight or obese.

The study was published online February 23 in the Lancet Oncology.

This is also the first trial to compare an up-front treatment schedule with a switch schedule using anastrozole, the study authors note. The up-front schedule consisted of 5 years of treatment with aromatase inhibitors; the switch schedule consisted of 2 years of treatment with tamoxifen followed by 3 years of treatment with aromatase inhibitors.

The study shows that both treatment schedules were clinically relevant. There was only a 1.6% difference in disease-free survival after 2 years. After 5 years, the disease-free survival was 88.5% with the switch strategy and 89.8% with the up-front regimen (hazard ratio [HR], 0.89; P = .23).

“FATA-GIM3 is the only trial to compare upfront treatment with a switch strategy using anastrozole, and the first trial to directly compare the three aromatase inhibitors; thus, contributing to the knowledge base, which is currently limited to indirect comparisons of the EBCTCG [Early Breast Cancer Trialists’ Collaborative Group] meta-analysis and two head-to-head trials, one of which was limited to node-positive patients,” Perrone and colleagues write.

“The number of deaths and other breast-related events was too low to allow reliable conclusions to be drawn on endpoints other than disease-free survival,” the investigators add. The 5-year overall survival was 95.3% with the switch schedule and 96.8% with the up-front schedule (HR, 0.72; P = .052).

Tamoxifen vs AIs: Clear Differences

The researchers suggest that clinicians consider patient preferences, tolerability, and cost when determining the best treatment approach.

“Clinical benefits and tolerability are particularly important in the choice between aromatase inhibitors and tamoxifen,” Perrone told Medscape Medical News. The safety profile is “clearly different,” he added. He noted that musculoskeletal side effects are seen more frequently with aromatase inhibitors.

“We should still consider tamoxifen a good option,” Perrone emphasized.

Findings from the earlier ATAC study suggested that less costly switch therapy might be more effective than up-front therapy, state the investigators, who conducted a literature search through August 30, 2017. ATAC findings also indicated that longer exposure to aromatase inhibitors could be associated with a greater risk for cardiac and musculoskeletal toxicity.

When FATA-GIM3 was designed in 2006, the up-front aromatase inhibitor treatment strategy was about to become standard practice, the study authors say.

In an accompanying comment, Luc Y. Dirix, MD, of the University of Antwerp, Belgium, called the FATA-GIM3 trial “an important confirmatory study.

“These data are the first for the switch approach with anastrozole,” he confirmed. “Patients and clinicians can be confident that any aromatase inhibitor is acceptable in this treatment strategy.”

FATA-GIM3 reinforces results from the EBCTGC meta-analysis, which demonstrated a small absolute benefit with up-front therapy after 5 years of follow-up, Dirix notes. Two large international trials established the clinical relevance of the up-front and switch regimens while the FATA-GIM2 trial was still underway, he points out.

The BIG1-98 trial found that tamoxifen followed by letrozole was more effective then letrozole alone. Similarly, the TEAM trial showed that tamoxifen followed by exemestane was more effective than exemestane alone.

“The duration of adjuvant endocrine therapy is now considered a more crucial factor in treatment outcomes,” Dirix says.

The editorialist also says that “even if the upfront strategy is preferred, FATA-GIM3 confirms the absence of a relevant difference between the aromatase inhibitors (with only small differences in toxicities but not in efficacy), giving clinicians the freedom to exchange one aromatase inhibitor for another.”

For the study, 3697 postsurgical patients with invasive hormone receptor–positive breast cancer were enrolled from 76 Italian public healthcare institutions between March 9, 2007, and July 31, 2012. Participants were randomly assigned to one of six treatment groups.

A total of 1847 participants received up-front treatment. These patients took oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 5 years. A total of 1850 patients were assigned to switch therapy. These patients received oral tamoxifen 20 mg once daily for 2 years followed by oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 3 years.

The median time on tamoxifen was 24 months. The median time on the three aromatase inhibitors was 32 to 35 months in the switch group and 54 to 56 months in the up-front group.

Toxicity was the main reason for early treatment interruption. This was seen more frequently in patients treated with tamoxifen (11%) than in those treated with aromatase inhibitors (5% in the switch group and 7% in the up-front group).

Endometrial side effects were the most frequent reason for tamoxifen interruption (4%). Three percent of patients in the switch group and 4% in the up-front group experienced grade 3-4 musculoskeletal side effects.

A total of 85 patients were diagnosed with a second nonbreast cancer. Five patients were diagnosed after breast cancer recurrence.

There were 138 deaths, including 80 participants treated using the switch schedule and 58 patients treated using the up-front schedule. Breast cancer was the most frequent cause of death in both groups: 55 participants (3%) in the switch group, and 30 (2%) in the up-front group.

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Overlooked Biomarker May Predict Cancer Immunotherapy Response

Hi. I’m David Kerr, professor of cancer medicine from the University of Oxford.

As you know, I’ve believed for some time that ploidy (the number of sets of chromosomes in a cell) measurements have been largely overlooked in terms of the relative importance of prognostic markers for the whole range of different cancer types. One of my friends and colleagues, Prof Håvard Danielsen, from the University of Oslo, has established what I consider one of the best assays in the world for measuring ploidy and DNA content in tumors, and characterizing it from paraffin-embedded tissue. ‘It’s a very available system.

New Data on an Overlooked Biomarker

To this end, a really interesting study was recently reported in Science by Teresa Davoli and colleagues,[1] who looked at ploidy across a whole range of tumor types and tried to relate ploidy measurements to the hallmarks of cancer. A ploidy is also known as somatic copy number alterations (SCNAs), and [the authors] refined the definition of ploidy a little, into [SCNAs] that were predominantly focal or [SCNAs] that mainly correlated with whole-arm ploidy, or changes in DNA content in that way.

This was a fascinating study, in which they found that ploidy was indeed associated with prognosis, but also with signatures associated with proliferation, increased expression of the gene’s enzymes involved in control of proliferation and cell cycle—this was mainly for the focal SCNAs. The larger, long-arm, and chromosomal ploidy tended to be associated with reduced expression of immune signature and immune infiltration.

This is an important first step in showing that ploidy does correlate with drivers or hallmarks of cancer. There are some subtle differences that lead you toward increased proliferation or increased immune invasion, both of which work in terms of establishing the cancer.

The researchers then retrospectively analyzed ploidy levels in melanoma tumor specimens saved from two large trials using immune checkpoint inhibitors. What they showed was that aneuploid tumors (eg, elevated levels of SCNA) were indeed more resistant to immune blockade.

It’s a really fascinating new potential use of ploidy, which has been around for decades and has been much overlooked. Not only is it a prognostic marker and therefore gives us important information about the biological behavior of our patients’ tumors, but it may also be a predictive factor in that aneuploid tumors may be relatively resistant to immune checkpoint blockade.

[Because this study was conducted] retrospectively, there’s much work yet to be done. [However, it offers] a really interesting insight for a marker, which I think could be delivered relatively easily in a sophisticated way in every pathology lab in the world. It surprises me that we don’t measure ploidy more. [It is] another interesting insight—some beautiful basic science uncovering the subtle differences in ploidy, how it links to the different hallmarks of cancer, and how it may aid us in selecting patients who may benefit less from immune checkpoint inhibitors.

Thank you for listening. It will be really keen for you to have a look at the Science paper and post any comments that you may care to talk about. This is an unfinished story but one that must be followed up prospectively.

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Oral Edoxaban May Be an Alternative to Dalteparin for Cancer-Related VTE

Hello. I am David Kerr, professor of cancer medicine from the University of Oxford, in England. I want to talk about a study published in the February 15 edition of the New England Journal of Medicine.[1] This was a beautifully well-designed and conducted randomized trial that compared edoxaban, a novel oral anticoagulant, with dalteparin in patients with cancer who had a venous thromboembolism (VTE).

The trials group calls itself the Hokusai Group. For those of you who don’t know Hokusai, he was an important Japanese painter who created many woodblock prints and was a member of the school of ukiyo-e, painters of passing, or everyday, life. There is something about the ephemerality of their art that has always attracted me. Among the more famous paintings are different views of Mount Fuji. My apologies if I am being a smarty pants, a clever clogs. But some of these paintings, particularly The Great Wave, are absolutely beautiful.

This trials group randomly assigned just over 1000 patients to receive oral edoxaban (after 5 days of low-molecular-weight heparin) or subcutaneous dalteparin. It was a noninferiority trial; treatment was given for a minimum of 6 months and a maximum of 12 months after the initial venothrombotic or embolic event. The composite endpoint, which is being used more and more in these trials of novel oral anticoagulants, was the recurrence rates of VTE and major bleeding incidents. The trial showed that edoxaban is not inferior to subcutaneous dalteparin.

Within the composite endpoint, there were fewer further thromboembolic events in the edoxaban arm but more bleeding events in the edoxaban arm. They evened each other out in terms of the noninferiority.

This was quite a useful study. It is an important first step in being able to show that we can substitute useful oral treatment for daily subcutaneous dalteparin. Patients don’t like dalteparin. We’ve all had patients who self-administer dalteparin during chemotherapy, and they are covered in bruises; they are sore. It’s a nuisance and it’s necessary, but if we find that we can substitute edoxaban, which is given orally and is well tolerated, then this is quite an important landmark study.

The major bleeds were predominantly in the upper gastrointestinal (GI) area. Quite a number of the patients who had GI bleeding had previously undergone GI surgery of some sort. Interpret that as you will.

This is an important study—well designed, well conducted, well reported—that tells us that we have a possible alternative to discuss with patients, offering them edoxaban instead of subcutaneous dalteparin.

Thank you for listening. Thank you for allowing me to segue into stories about Hokusai and the painters of ukiyo-e. Think about the passing life, the ephemerality. W.H. Auden called life the gallop to the grave; there’s some truth in that.

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