Advance of the Year: Cancer Immunotherapy

Although all research achievements highlighted in this report are remarkable, one area clearly stands out from the rest: cancer immunotherapy, ASCO’s Advance of the Year. In just a few short years, researchers and regulators have moved several different immunotherapy strategies from bench to bedside.

From the first astounding successes in advanced melanoma, there is now evidence that immunotherapy works against a range of cancers. Even for patients who have exhausted all traditional treatments, immunotherapy is able to halt cancer growth, often with only mild adverse effects.

Scientists first conceived the idea of manipulating the body’s immune system to attack cancer more than a century ago. However, the task proved to be fraught with challenges and setbacks. It would take a deeper understanding of both cancer biology and the immune system before safe and effective immunotherapy could be delivered to patients.

As fundamental research on cancer immunotherapy intensified, clinical trials of promising approaches followed in quick succession. Two main strategies are now being explored, both achieving major success over the past year. The first involves unleashing the body’s natural immune response to cancer, and the second helps the immune system find and destroy cancer cells.

Immune Checkpoint Inhibitors: Enhancing the Immune Response to Cancer



An overactive immune system can lead to excessive inflammation and development of autoimmune disorders. The body uses molecules known as immune checkpoints to control the strength and duration of immune responses, minimizing damage to healthy tissue. Some tumors produce these same molecules and thereby suppress the immune response to the tumor.

Immune checkpoint inhibitors release these tumor-induced brakes on the immune system, unleashing it to attack malignant tumors and stop their growth. These treatments are showing promising results in many types of cancer, including melanoma and lung cancer.

The first FDA-approved immune checkpoint inhibitor, ipilimumab, blocks the CTLA-4 molecule on T cells, which leads to a broad enhancement of immune responses, including attacks on cancer cells. A range of newer drugs targets a different immune checkpoint protein known as PD-1. The treatments work by preventing cancer cells from attaching to the PD-1 protein on immune cells, which leads to an increased antitumor immune response and generally fewer adverse effects.

Melanoma Immunotherapy Moves Ahead: Comparing and Combining Treatments

By the end of 2014, three life-extending checkpoint inhibitor immunotherapies were FDA approved for the treatment of advanced melanoma: ipilimumab, nivolumab, and pembrolizumab. Overall, these new drugs have surpassed the efficacy of traditional melanoma treatments. Nevertheless, advanced melanoma remains incurable, although prolonged remissions induced by these immunotherapies extend life for multiple years for certain patients. In 2015, new studies explored how these three treatments stack up against one another and how to maximize their overall benefit—as stand-alone therapies and as combination regimens.

Ipilimumab, a CTLA-4 immune checkpoint inhibitor, was the first treatment to extend the lives of patients with advanced melanoma. Yet, recent evidence suggests that nivolumab and pembrolizumab, both PD-1 checkpoint inhibitors, may be more effective than ipilimumab. For example, in a recent phase III study, the 1-year survival rates were 68% and 74% for patients treated with pembrolizumab (depending on treatment schedule), compared with 58% for those who received ipilimumab.1 In addition, pembrolizumab was associated with a lower rate of severe adverse effects, such as fatigue, diarrhea, rash, and colon inflammation (colitis).

Patients with advanced melanoma that worsens after ipilimumab or ipilimumab and a BRAF inhibitor (for patients with BRAF-mutated melanoma) gained a new treatment option in 2014.2 The FDA granted accelerated approval to the PD-1 checkpoint inhibitor nivolumab on the basis of preliminary findings from a phase III trial.3 In this clinical trial, tumors shrunk in 32% of patients treated with nivolumab and only in 11% of those who received standard chemotherapy. Longer follow-up will be needed to determine if nivolumab extends survival of patients with advanced melanoma.


Accelerated Approval

The US Food and Drug Administration Accelerated Approval Program allows for earlier approval of drugs that treat serious conditions and that fill an unmet medical need on the basis of a surrogate or intermediate end point that is reasonably likely to predict clinical benefit. After receiving early approval, clinical trials must still be performed to confirm the anticipated clinical benefit of the treatment. Approval of a drug may be withdrawn or the labeled indication of the drug may be changed if trials fail to confirm clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug.


Severe adverse effects of nivolumab included increased pancreatic and liver enzymes (lipase, ALT, AST), anemia, and fatigue, whereas chemotherapy was associated with more hematologic toxicity, including lower white blood cell counts (neutropenia, thrombocytopenia) and anemia. Severe treatment-related adverse effects occurred less frequently with nivolumab than with chemotherapy.

More broadly, these findings imply that patients whose tumors stopped responding to one type of immune checkpoint inhibitor may still benefit from a different checkpoint inhibitor. In fact, some experts believe that combining immunotherapies may be the most promising strategy for patients with advanced melanoma.

An early-stage clinical trial of an immune checkpoint inhibitor combination showed encouraging results.4 Tumor shrinkage rates were nearly six-fold higher (61% v 11%) among patients with untreated advanced melanoma who received ipilimumab and nivolumab than among those who received ipilimumab and placebo.

The combination treatment controlled tumor growth longer than ipilimumab alone, but the rates of severe adverse effects, colitis, diarrhea, and elevated liver enzyme (ALT) levels were higher with the immunotherapy combination (54% v 24%). On the basis of these findings, the FDA granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with advanced melanoma without the BRAF V600 genetic mutation.5

Meanwhile, results from a larger phase III trial of the same immunotherapy combination were also reported in 2015.6 The trial included nearly 1,000 patients with advanced melanoma who had not previously received cancer treatment. The median time before the disease worsened was 11.5 months with ipilimumab and nivolumab, 7 months with nivolumab alone, and 3 months with ipilimumab alone.

The rates of adverse effects were consistent with prior studies and were the highest among patients who received the immunotherapy combination. Given that the combination treatment was associated with the highest rate of severe adverse effects, the researchers also sought to determine whether there would be a particular group of patients who could benefit from this treatment.

They found that patients with higher levels of the PD-L1 protein in their tumors seemed to do as well with nivolumab alone as with the combination, with a median period of 14 months before the disease became worse. In contrast, patients with low PD-L1 levels in their tumors benefited much more from the combination than from nivolumab alone. If validated, these findings would provide clinically relevant information for appropriate selection of patients who are most likely to benefit, while sparing patients in whom toxicities would not be justified.

New Treatment Paradigm For Lung Cancer

The role of immunotherapy reached beyond melanoma to include patients with lung cancer in 2015. Highly promising clinical trials explored the role of immunotherapy using agents directed toward the PD-1 or PD-L1 immune checkpoint proteins. In addition, physicians gained new insight into which patients may benefit most from these drugs.

Lung cancer is the most common malignancy worldwide and the leading cause of cancer-related death, taking 1.6 million lives each year (according to WHO 2012 estimates). Although advanced lung cancer remains incurable, targeted therapies, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors, may help control tumor growth. However, only a small proportion of patients with tumors that harbor specific genetic abnormalities can benefit from targeted therapies at this time.

Non–small-cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85% of all cases. With modern platinum-based chemotherapy, the median life expectancy is only approximately 10 months. For patients whose disease worsens after initial treatment, docetaxel chemotherapy offers only a modest improvement in survival.

Moreover, the adverse effects of chemotherapy are too difficult for many patients to bear. Growing research evidence suggests that immunotherapy may be able to control advanced lung cancer longer, with fewer adverse effects.

In March 2015, the FDA approved nivolumab for the treatment of squamous NSCLC that worsens after platinum-based doublet chemotherapy.7 The approval was given on the basis of findings from a randomized clinical trial of patients with advanced, squamous NSCLC.8 The clinical trial reported that compared with standard second-line chemotherapy, nivolumab significantly improved the median overall survival (9 months v 6 months), nearly doubling the 1-year survival rate (42% v 24%).

Another randomized trial showed that nivolumab can provide a similar benefit to patients with advanced nonsquamous NSCLC, the predominant form of the disease.9 Compared with standard chemotherapy, the median survival was prolonged with nivolumab (12.2 months v 9.4 months). This clinical trial also suggested that patients who had tumors with high PD-L1 levels experienced more benefit from nivolumab.

Generally, nivolumab was easier for patients to tolerate than docetaxel, causing fewer adverse effects. No new toxicities were reported with nivolumab in the treatment of NSCLC. However, rare but serious inflammation involving the lungs (pneumonitis), colon (colitis), and kidneys (nephritis) was also reported in this trial. In October 2015, the FDA expanded the approved use of nivolumab to treat patients with nonsquamous NSCLC whose disease worsened during or after platinum-based chemotherapy.10

Perhaps even more promising than the finding that immune checkpoint inhibitors are active for patients with lung cancer are the early results showing that these responses are quite durable. For example, in one early clinical trial that included patients with advanced, squamous, or nonsquamous NSCLC, the 2- and 3-year survival rates were 42% and 27%, respectively, at the dose chosen for further development.11

Treatment with the PD-1 blocking immunotherapy pembrolizumab was associated with a median survival of 12 months in another early study of patients with advanced, previously treated NSCLC. Overall, tumors shrank in approximately one in five patients, but the rate was again much greater in those with high PD-L1 levels, of whom nearly half experienced tumor shrinkage.12 This group of patients also lived longer before the cancer worsened. No new safety concerns were reported.

In September 2015, the FDA granted accelerated approval to pembrolizumab as a treatment for patients with advanced, PD-L1-positive NSCLC that worsens after other treatments.13 Early reports from ongoing studies have suggested that nivolumab and pembrolizumab may also be effective as initial therapies for patients with advanced NSCLC.14,15

A new immune checkpoint inhibitor, atezolizumab, has also shown promising results in the treatment of advanced NSCLC. Atezolizumab unleashes the immune response to cancer by blocking the PD-L1 protein on tumor cells. In an early study, the median survival among patients who received atezolizumab was 12.6 months, compared with 9.7 months among those treated with docetaxel chemotherapy.16

As in the other studies, patients with the highest levels of PD-L1 in their tumors and immune cells benefited even more. In this group, the median survival was 15.5 months with immunotherapy, compared with 11.1 months with docetaxel. In contrast, among patients with low PD-L1 levels, atezolizumab did not extend survival compared with docetaxel.

Fewer patients experienced severe treatment-related adverse effects in the atezolizumab group compared with the docetaxel group. The most common severe adverse effects related to atezolizumab were pneumonia and increased AST levels.

In February 2015, the FDA granted atezolizumab a breakthrough therapy designation for the treatment of PD-L1–positive NSCLC that worsens after platinum chemotherapy, and a randomized phase III trial for this indication is under way ( identifier: NCT02486718). Other ongoing phase III clinical trials are exploring atezolizumab in combination with chemotherapy.


Breakthrough Therapy Designation

The US Food and Drug Administration (FDA) Breakthrough Therapy Designation serves to expedite the development and review of drugs for treating serious or life-threatening illnesses where preliminary clinical data suggest the drug may provide a substantial improvement in patient outcomes. The designation helps ensure patients gain faster access to promising new treatments through FDA approval.


The therapeutic mechanism of immune checkpoint inhibitors—unleashing immune response to cancer—is profoundly different from that of standard treatments for NSCLC. This may explain the longer duration of benefit some patients experience from immunotherapy compared with chemotherapy or targeted therapy. Unlike other therapies, the effects of immunotherapy can persist long after the patient stops treatment. Future research directions for lung cancer immunotherapy include evaluating combinations of PD-1 or PD-L1 inhibitors with chemotherapy, targeted therapy, and other types of immunotherapy.

Broadening The Possibilities For Checkpoint Inhibitors

The past year brought early reports suggesting that immune checkpoint inhibitors targeting PD-1 and PD-L1 are effective across a range of different cancer types, beyond melanoma and lung cancer. A particularly encouraging finding was that immunotherapy was effective against many tumors that were resistant to traditional treatments.

Bladder Cancer

x-ray view of human body

In the last three decades, there has been little progress in the treatment of advanced bladder cancer. Most patients with advanced bladder cancer are older (the median age of diagnosis is 73 years), and many suffer from kidney impairment. As a result, many patients forgo chemotherapy to avoid its difficult adverse effects. Outcomes are poor for patients who cannot tolerate chemotherapy or whose cancer worsens after initial chemotherapy.

Findings from an early clinical trial of patients with advanced urothelial bladder cancer bring new hope.17 The PD-L1 immune checkpoint inhibitor atezolizumab shrank tumors rapidly—within weeks of starting treatment in many study participants. Again, atezolizumab was particularly effective for patients who had high PD-L1 levels in their tumors and immune cells, with approximately half of these patients experiencing tumor shrinkage. The median duration of response was much longer than that typical for chemotherapy.

The most commonly reported treatment-related adverse effects were decreased appetite and fatigue. Severe adverse effects, such as weakness (asthenia) and hematologic abnormalities (thrombocytopenia and decreased blood phosphorus), occurred in 4% of patients. On the basis of these findings, the FDA granted atezolizumab a breakthrough therapy designation for the treatment of PD-L1–positive, advanced bladder cancer in 2014. An ongoing phase III trial seeks to compare atezolizumab with standard chemotherapy in patients with advanced bladder cancer ( identifier: NCT02302807).

Kidney Cancer

illustration of kidneys

Advanced kidney cancer is another malignancy in dire need of better treatments. The most common type of kidney cancer in adults is called renal cell carcinoma (RCC). At the time of diagnosis, nearly one third of patients with RCC already have metastatic disease, which is difficult to treat.

The last major advance in kidney cancer care occurred a decade ago, with the introduction of targeted therapies for metastatic RCC. Vascular endothelial growth factor (VEGF)–directed therapies and inhibitors of the mammalian target of rapamycin (mTOR) extended the median survival of patients with this disease from 1 year to nearly 3 years.

Yet, new drugs are needed to further extend survival when kidney cancers worsen despite VEGF- and mTOR-targeted therapies. Recent research has suggested that PD-1–directed immunotherapy may improve the outlook for at least some of these patients.

In a randomized phase II trial, nivolumab shrank tumors in approximately 20% of patients with metastatic clear cell RCC who were previously treated with a VEGF inhibitor.18 One striking result was related to the durability of these responses, which lasted more than 22 months in some patients. The median overall survival extended up to 25 months, roughly 1 year longer than is typically achieved with targeted therapies, as reported in prior clinical trials of patients with advanced RCC. Fatigue was the most common treatment-related adverse effect.

Meanwhile, larger ongoing trials are exploring additional uses of PD-1–directed therapies for metastatic RCC. In a phase III study of patients with advanced RCC who were previously treated with VEGF inhibitors, nivolumab improved outcomes compared with the mTOR inhibitor everolimus.19 The median survival was 25 months with nivolumab versus 19.6 months with everolimus. The toxicity profile of nivolumab was consistent with prior reports. However, compared with everolimus, there were fewer severe treatment-related adverse events reported.

Furthermore, although tumors shrank in 25% of patients treated with nivolumab, only 5% of those treated with everolimus experienced tumor shrinkage. Interestingly, however, everolimus delayed tumor growth for a similar length of time as nivolumab, approximately 4 months.

Another ongoing phase III trial is investigating the combination of nivolumab and ipilimumab as an initial treatment for advanced kidney cancer ( identifier: NCT02231749). The FDA approved nivolumab for the treatment of advanced RCC in November 2015.20

Liver Cancer

illustration of liver

Liver cancer is the second most common cause of death resulting from cancer worldwide, claiming approximately 750,000 lives each year.21 The most common type of liver cancer is hepatocellular carcinoma (HCC). The only FDA approved treatment for advanced HCC, sorafenib, extends survival by merely 3 months.

Last year, researchers reported preliminary findings showing a promising role for nivolumab in the treatment of metastatic HCC.22 In the small study, nearly 20% of patients had marked tumor shrinkage in response to nivolumab. Tumors completely disappeared in two patients.

The responses were durable, lasting 9 months or longer in nearly all patients who responded. At 1 year, 62% of patients treated with nivolumab were still alive. This is a dramatic improvement when compared with the historical tumor response rate for sorafenib of only 2% to 3% and 1-year survival rate of 30%. Again, no new safety signals were reported. Of note, severe adverse effects of nivolumab included elevated ALT, AST, and lipase levels.

These early findings suggest that immunotherapy may be an effective treatment for some patients with advanced liver cancer. An expansion phase of this study, which seeks to recruit 400 patients, is projected to be completed in 2018 ( identifier: NCT01658878).

Head and Neck Cancer (HNC)

doctor checking neck of patient

People with recurrent or metastatic HNC have a poor prognosis. With existing treatments—chemotherapy and the targeted drug cetuximab— survival ranges from 10 to 12 months, on average. Overall, few patients respond to these treatments, and adverse effects are significant.

Early findings suggest PD-1 immune checkpoint inhibitors are active in patients with HNC. In one small trial, approximately 25% of patients who received the PD-1 immune checkpoint inhibitor pembrolizumab experienced tumor shrinkage.23 In contrast, the reported response rate to cetuximab was less than 13% in prior clinical trials. Although the toxicity profile of pembrolizumab in this population was similar to that in other trials, only 10% of patients experienced severe adverse effects, such as swelling of the face and lung inflammation (pneumonitis).

Perhaps as important, these agents might be active regardless of whether HNC is associated with human papillomavirus (HPV). It is well known that a subgroup of HNCs is HPV-positive disease, and that these tumors respond better to standard treatment than those that are HPV negative. Yet, in the clinical trial discussed here,23 pembrolizumab was active across a wide range of patients, including those with HPV-positive and HPV-negative tumors.

Although these early data are encouraging, larger studies are needed to determine if pembrolizumab can prolong patient survival. Two phase III trials evaluating pembrolizumab versus standard treatment in patients with recurrent or metastatic HNC are already under way ( identifiers: NCT02358031 and NCT02252042).

Blood Cancer: Hodgkin Lymphoma

x-ray view of human body

Hodgkin lymphoma is a cancer of the lymphatic system, and it is most common in two age groups: age 15 to 40 years (particularly young adults in their 20s) and older than age 55 years. With existing initial treatments, four of five patients survive 5 years after a Hodgkin lymphoma diagnosis. People with the disease seldom experience recurrence if a complete response is achieved with initial treatment. When Hodgkin lymphoma does come back, however, it is more difficult to treat. At that time, patients are typically offered additional chemotherapy, radiation therapy, or stem-cell transplantation.

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Emerging research data suggest that immunotherapy, specifically PD-1 blockade, may play a role in the treatment of recurrent Hodgkin lymphoma. Moreover, it has been speculated that a certain genetic abnormality makes Hodgkin lymphoma particularly vulnerable to PD-1 blockade. Findings from a small clinical trial of adult patients with recurrent Hodgkin lymphoma support this hypothesis (this study was funded in part by a grant from the NIH).24

Nearly all the patients in the trial had previously received three or more treatments, including stem-cell transplantation and a targeted drug. Remarkably, the great majority (20 of 23 patients) responded to nivolumab, with cancer completely disappearing in 17%. By 6 months, only 14% of patients experienced disease progression.

The most common treatment-related adverse effects were rash and decreased platelet count (thrombocytopenia). Severe treatment-related adverse effects were rare.

Genetic Abnormality Tied To Better Response To PD-1 Immunotherapy

Tumors with a high number of genetic mutations are likely to trigger a strong immune response, because they make more proteins (antigens) that the immune system recognizes as foreign. Melanoma, bladder cancer, and lung cancer are among the cancers with the most mutations.

In some patients with other types of cancers, the tumors have large numbers of mutations as a result of a genetic abnormality called mismatch repair deficiency, which undermines the ability of a cell to repair DNA damage. Scientists have speculated that tumors with this abnormality may be susceptible to immune checkpoint blockade.

Mismatch repair deficiency occurs in approximately 15% of colorectal cancers. It is also found less frequently in other types of cancer, such as stomach, small bowel, endometrial, prostate, and ovarian cancers. The abnormality is sometimes inherited from parents, as is the case for patients with Lynch syndrome, but more often, mismatch repair deficiency develops at random during a person’s life.

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One small trial reported last year provided the first evidence that mismatch repair–deficient tumors are susceptible to PD-1 blockade (this study was funded in part by a grant from the NIH).25 Four of 10 patients with mismatch repair–deficient colorectal cancer responded to treatment with the immune checkpoint inhibitor pembrolizumab (the median progression-free and overall survival were not reached). In contrast, none of the eight patients with colorectal cancers that were not mismatch repair deficient experienced tumor shrinkage; the median progression-free survival was 2.2 months.

Furthermore, the researchers found that pembrolizumab was active against other types of cancer with mismatch repair deficiency, such as endometrial, ampullary, duodenal, and stomach cancers. Five of seven patients responded to pembrolizumab, and the median time to disease progression was 5.4 months.

The toxicity profile of pembrolizumab was similar to that in other trial reports. Severe adverse effects, such as low serum protein levels (hypoalbuminemia), low blood cell counts (anemia and lymphopenia), and bowel obstruction, occurred in 41% of patients.

Although this study was small, it opens the possibility of a new treatment option for patients with advanced cancer who have tumors with mismatch repair deficiency. More broadly, it shows that evaluation of the tumor genome can help identify patients who benefit from immunotherapy, regardless of the type of tumor they have. It is already suspected that cancers with other DNA repair deficiencies might also be sensitive to PD-1 blockade.

Mismatch Repair Deficiency: A New Understanding of Cancer Genetics Proves Life Changing for Mike Chettle

couple smiling

“It’s shocking to see your name on a diagnosis like that,” said Mike Chettle, four years after he first learned that he had duodenal and colon cancer.

Mike had known that he had a family history of Lynch syndrome, an inherited condition that increases the risk for certain types of cancer, particularly colorectal. Because of this, he took precautions and underwent regular screening. In 2011, however, he developed a bleeding ulcer that turned out to be cancer.

With his diagnosis began a litany of treatments–“It was a long, long road,” said Mike. His first treatments included a complex surgery involving the colon and several organs, followed by chemotherapy.

A year later, the cancer had spread to Mike’s liver. He underwent another surgery, and it was then that doctors discovered 26 tumors throughout his abdomen. Subsequent treatment included various chemotherapy regimens, which caused Mike numerous side effects, including nausea, vomiting, neuropathy and “chemo brain.” Today, nearly four years later, he still experiences many of chemotherapy’s lingering effects.

All the treatments proved unsuccessful, however. Two years ago, Mike was told that the cancer had spread to his bones. Cancerous spots were also still present on his liver.

“It was spreading fast,” he recalled. “I was limping. I couldn’t turn my neck. I was in a lot of pain.” He had exhausted all treatment options and was at the point of considering comfort care.

The turning point came when his oncologist, Steven M. Duffy, MD, of the Bon Secours Cancer Institute Medical Oncology at St. Mary’s in Richmond, Virginia, referred Mike to Luis Diaz, MD, an attending physician at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “I probably wouldn’t be alive if he hadn’t sent me there,” reflects Mike.

Dr. Diaz suggested Mike enroll in a phase II clinical trial he was conducting that studied a genetic abnormality called mismatch repair (MMR) deficiency. Dr. Diaz, together with Dung T. Le, MD, sought to determine whether this abnormality makes tumors more susceptible to treatment with a drug called pembrolizumab, an immunotherapy that targets an immune checkpoint known as the PD-1 checkpoint.

“Opening the door to this effective new therapy is a breakthrough for this subset of patients with metastatic colon cancer and other hard-to-treat cancers,” said Dr. Le.

Within two or three months of enrolling in the trial, Mike’s symptoms began to subside. “I was able to turn my neck again,” Mike said. By the time his daughter’s wedding took place a few months later, he was experiencing noticeable improvement. Mike walked her down the aisle.

The new treatment comes with minimal side effects compared to what Mike experienced with chemotherapy, and it is also more convenient. He receives a half-hour infusion every two weeks, as opposed to four- or five-hour infusions for chemo. “Half an hour treatment, and then I’m on my way home,” he said.

Mike has been on the trial for almost two years and has experienced a complete response to the treatment, meaning nearly all tumors have disappeared. “I feel like I’ve been blessed to have good doctors who led me to where I am, to be in that trial,” he said.


Dung T. Le, MD
Photo: Flynn Larsen

“It’s satisfying to see patients like Mike respond and do well,” said Dr. Le. “While he still has to come see us every couple of weeks, we hope soon that he can transition into the stage of care called surveillance, a time when we actively monitor him after treatment is no longer needed. He may only need scans every few months.”

The researchers anticipate that other patients with MMR deficiency will benefit from these findings for years to come and that the study will have broad implications for patients with a wide range of cancers going forward. “This study is really about bridging immunotherapy and genomics for the benefit of patients,” said Dr. Le, reiterating the importance of clinical trials in advancing cancer care. Mike feels that by participating in a clinical trial, he became one of the lucky ones.

Mike is pictured above with his wife. See "Genetic Abnormality Tied to Better Response to PD-1 Immunotherapy" above to learn more about the trial that saved Mike’s life, featured as one of the year’s top cancer advances.

Novel Immunotherapy Approaches Boost The Immune System

T-Cell Therapies Promising For Blood Cancers

In addition to immune checkpoint inhibitors, researchers are exploring other immunotherapy approaches, all of which are centered on T cells. A unique new immunotherapy, the antibody blinatumomab, attaches to two different proteins on white blood cells: CD19 on B cells and CD3 on T cells. By doing so, the antibody brings the cancer-killing T cells into contact with the malignant B-cell leukemia cells.

In an early-stage trial, nearly one third of patients with relapsed or treatment-resistant ALL had no evidence of cancer (complete remission) after receiving blinatumomab.26 The responses were durable, lasting more than 6 months in many patients.

The study participants had an uncommon but aggressive type of ALL known as Philadelphia chromosome–negative precursor B-cell ALL, a rapidly growing cancer in which the bone marrow makes too many immature white blood cells. On the basis of these results, in December 2014, the FDA approved blinatumomab to treat this difficult disease.27


graphic showing how an immunotherapy works

CAR T-cell therapy: this promising new treatment involves
collecting T cells from a patient, genetically reprogramming them in the lab, and infusing them into the patient to find and attack cancer cells.

Although more research is needed to determine whether blinatumomab can improve survival compared with standard chemotherapy, it seems that immunotherapy will play a role in the treatment of ALL. Future directions include exploring use of blinatumomab earlier in the course of the disease and in combination with other therapies.

Another unique new strategy is the so-called chimeric antigen receptor (CAR) T-cell therapy. This approach involves collecting T cells from a patient, genetically reprogramming them in the laboratory, and infusing them back into the patient. The reprogrammed T cells make specific proteins that enable them to find and attack cancer cells throughout the body.

Early reports have suggested that patients with various difficult-to-treat blood cancers might benefit from CAR T-cell therapy. For example, CD19-directed CAR T cells are programmed to attack malignant B cells that have the CD19 molecule on their surface.

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In a study of adults and children with relapsed ALL, 27 of 30 patients achieved complete remission after receiving this novel therapy, and for some (19 of 30), the remissions were durable, lasting as long as 2 years (this study was funded in part by a grant from the NIH).28 Overall, 78% of patients were alive 6 months after receiving CAR T cells.


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In another early study, 12 of 15 patients with chemotherapy-resistant DLBCL and other blood cancers responded to CD-19 directed CAR T cells, with cancer completely disappearing in eight of the patients (this study was funded in part by a grant from the NIH).29

Although these findings are promising and support further research, the studies were small and limited to patients with hard-to-treat cancers. It is not yet clear if CAR T-cell therapy will have broader use in the future. In addition, because CAR T-cell therapy can cause considerable toxicities, such as fever (pyrexia), low blood pressure (hypotension), delirium, and neurologic adverse effects, it is administered only in specialized clinical centers at this time.


Representative Michael C. Burgess of Texas


"The 21st Century Cures is the promise of the future. This initiative will provide the next generation of doctors with powerful tools that will alleviate human suffering—and fight cancer—on a scale never before known."

— Rep. Michael C. Burgess, MD (R-TX)

Cancer Vaccines: A Potential New Treatment Option For Brain Cancer


Glioblastoma is an aggressive and incurable form of brain cancer. Most patients are diagnosed when the disease is already at an advanced stage. Although surgery and chemotherapy can be effective initially, the cancer inevitably worsens over time. After a relapse, few treatment options remain, and the average survival duration is only 1.5 years.

Researchers have been exploring several new avenues for treating brain cancer, including immunotherapy strategies, such as vaccines, which deliver substances that trigger a specific immune response. Unlike prevention vaccines such as the HPV vaccine, the goal of therapeutic cancer vaccines is not to prevent cancer but to help the immune system find and attack it.

Preliminary findings from a phase II trial indicate that therapeutic cancer vaccines can improve outcomes for patients with relapsed glioblastoma.30 The rindopepimut vaccine works against glioblastoma tumors with a specific genetic mutation known as EGFRvIII, which contributes to uncontrolled growth of brain tumors. The mutation occurs in approximately one in four glioblastomas. It does not occur in healthy brain tissue.

In the study, patients with recurrent glioblastoma who received the vaccine along with the targeted drug bevacizumab developed an immune response to the cancer. Compared with patients who received bevacizumab alone, those who also received the vaccine experienced greater tumor shrinkage and a longer time before disease worsening. The median survival in the vaccine group was 12 months compared with 8.8 months in the bevacizumabalone group. The most common toxicity of rindopepimut was a mild injection site reaction.

In early 2015, the FDA granted rindopepimut breakthrough therapy designation for EGFRvIII-positive glioblastoma. A phase III trial of rindopepimut in patients newly diagnosed with this type of glioblastoma is under way ( identifier: NCT01480479). Meanwhile, several ongoing, early-stage clinical trials are exploring other vaccines for glioblastoma. Cancer vaccines are also being explored as treatments for a range of other cancers, including breast, lung, bladder, cervical, kidney, pancreatic, prostate, and blood cancers.

Continuing Immunotherapy Research

Altogether, the rapid succession of immunotherapy research advances heralds a new pillar of cancer treatment beyond the traditional staples of chemotherapy, radiation therapy, and surgery. Compared with chemotherapy and targeted therapy, immunotherapy has the potential to control tumor growth much longer and often with fewer adverse effects.

It seems reasonable that harnessing a patient’s own immune system to fight cancer would be universally effective. In many studies thus far, however, only a minority of patients have benefited from immunotherapy approaches. With initial immunotherapies proving effective for some patients, researchers are now exploring ways to improve outcomes for more patients. These include combining different immunotherapies, using immunotherapy in combination with other traditional treatments, and starting immunotherapy earlier in the course of the disease.

Researchers are also studying ways to reliably predict response to immunotherapy, so patients can be spared the adverse effects and costs of treatments that may not help them. In addition, longer follow-up of patients who have received immunotherapies in clinical trials will help assess the true clinical benefit of these approaches.


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  7. US Food and Drug Administration: FDA expands approved use of Opdivo to treat lung cancer.
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  9. Paz-Ares L, Horn L, Borghael H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. J Clin Oncol 33, 2015 (suppl; abstr LBA109)
  10. US Food and Drug Administration: FDA expands approved use of Opdivo in advanced lung cancer.
  11. Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol 33:2004-2012, 2015
  12. Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015
  13. US Food and Drug Administration: FDA approves Keytruda for advanced non-small cell lung cancer.
  14. Rizvi N, Garon E, Patnaik A, et al: Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 32:507s, 2014 (suppl; abstr 800)
  15. Gettinger S, Shepherd F, Antonia S, et al: First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol 32:512s, 2014 (suppl; abstr 8024)
  16. Vansteenkiste J, Fehrenbacher L, Spira AI, et al: Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR). Presented at the European Cancer Congress, Vienna, Austria, September 25-29, 2015 (abstr 14LBA)
  17. Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558-562, 2014
  18. Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol 33:1430-1437, 2015
  19. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015
  20. US Food and Drug Administration: FDA approves Opdivo to treat advanced form of kidney cancer.
  21. GLOBOCAN 2012: Estimated cancer incidence, mortaliy, and prevalence worldwide in 2012.
  22. El-Khoueiry AB, Melero I, Crocenzi TS, et al: Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 33, 2015 (suppl; abstr LBA101)
  23. Seiwert TY, Haddad RI, Gupta S, et al: Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol 33, 2015 (suppl; abstr LBA6008)
  24. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015
  25. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015
  26. Topp MS, Gökbuget N, Stein AS, et al: Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Oncol 16:57-66, 2015
  27. US Food and Drug Administration: FDA approves Blincyto to treat a rare form of acute lymphoblastic leukemia.
  28. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014
  29. Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-549, 2015
  30. Reardon DA, Schuster J, Tran DD, et al: ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol 33, 2015 (suppl; abstr 2009)

Advances in Cancer Prevention

From genes to lifestyle and environment, many different factors can lead to the development of cancer. Worldwide, chronic infections cause approximately 2 million new cancer cases each year.1 Among the four main cancer-causing pathogens is human papillomavirus (HPV), the virus that causes nearly all cervical cancers. The same virus is also associated with other genital cancers in both men and women, as well as a rising number of head and neck cancers.

According to the Centers for Disease Control and Prevention (CDC), genital HPV is the most common sexually transmitted virus in the United States, affecting 79 million people. In most cases, the immune system fights off the virus within a couple of years. However, if HPV persists, it can cause tissue damage that may lead to cervical cancer, as well as other cancers. Although there are more than 150 different types of HPV, only approximately 15 are associated with increased cancer risk.

Preventive vaccines can reduce the risk of HPV infection and development of HPV-related cancers. Two of the high-risk types of HPV (HPV-16 and HPV-18) cause approximately 70% of cervical cancers, and vaccines for these two strains have been available for nearly a decade. In 2015, a new preventive vaccine was introduced that protects against additional cancer-causing HPV strains, and new research confirmed the positive impact widespread HPV vaccination could have on the rates of HPV cancers.

graphic that says HPV vaccines could prevent 29,000 HPV related cancers per year in the united states

Global Opportunity And Challenge

Cervical cancer is the second most common type of cancer in women worldwide. Routine screening through Pap smears and, more recently, HPV DNA tests has dramatically reduced cervical cancer rates in Western countries. In low-resource countries, however, large-scale routine cervical cancer screening is not feasible, and access to treatment is limited. According to the CDC, nine of 10 deaths resulting from cervical cancer occur in less developed regions of the world.

HPV vaccination may be the best strategy for reducing the global burden of cervical cancer. To realize the full potential of HPV vaccines, more eligible persons need to be vaccinated. Cultural, educational, and socioeconomic barriers to vaccination will first need to be overcome. In addition, worldwide implementation will require more costeffective vaccines in the future.

Promise Of HPV Vaccines

To date, the FDA has approved three different HPV vaccines for the prevention of cervical cancer: Gardasil, Cervarix and Gardasil 9. Gardasil, introduced in 2006, protects against high-risk HPV-16 and HPV-18 and two types of low-risk HPV that cause 90% of genital warts. Cervarix, approved in 2009, also protects against HPV-16 and HPV-18. Either vaccine can prevent up to 70% of cervical cancers.

In late 2014, the FDA approved Gardasil 9, which protects against nine high-risk HPV types, including five that are not addressed by Gardasil or Cervarix.2 By covering these additional HPV types, researchers estimate that Gardasil 9 could potentially prevent 90% of cervical cancers worldwide.3

Furthermore, a major study published in 2015 found that widespread HPV vaccination with Gardasil or Cervarix could prevent as many as 25,000 HPV-related cancers per year in the United States alone.4 These include the majority of invasive cervical, anal, oropharyngeal, and vaginal cancers, as well as some other genital cancers. The Gardasil 9 vaccine could prevent an additional 4,000 cancer cases per year. These estimates, made using US cancer registry data and detection rates of HPV types in tumor tissue, will help evaluate the effectiveness of future HPV vaccines.

A 2014 immunization survey found that 60% of US adolescent girls and 42% of teen boys have started the three-dose HPV vaccine series.5 However, the survey data also indicate that the rates of series completion are poor; only 40% of girls and 22% of boys who began HPV vaccination received the recommended three doses.

The CDC recommends that all boys and girls age 11 to 12 years receive an HPV vaccine. Although the HPV vaccine has been available for a decade, and vaccination coverage is improving, HPV vaccination rates in the United States lag behind those of other developed countries. Furthermore, HPV vaccination rates are significantly lower than the rates of other vaccinations recommended for adolescents (eg, pertussis and meningococcal disease vaccines).5

Remaining Questions

Given that none of the available vaccines protect against all high-risk HPV types, routine cervical cancer screening is still recommended after HPV vaccination. It is not yet known how long the initial series of HPV vaccinations will last or whether booster vaccinations might be necessary to maintain ongoing protection.

Longer follow-up of people who received a vaccine in clinical trials will provide important information about the need for reimmunization. It will likely take several more years to determine the impact of vaccination on overall incidence of and death rates from HPV-related cancers.


  1. de Martel C, Ferlay J, Franceschi S, et al: Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol 13:607-615, 2012
  2. US Food and Drug Administration: FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV.
  3. Joura EA, Giuliano AR, Iversen OE, et al; Broad Spectrum HPV Vaccine Study: A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 372:711-723, 2015
  4. Saraiya M, Unger ER, Thompson TD, et al; HPV Typing of Cancers Workgroup: US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst 107:djv086, 2015
  5. Reagan-Steiner S, Yankey D, Jeyarajah J, et al: National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years: United States, 2014. MMWR Morb Mortal Wkly Rep 64:784-792, 2015

Advances in Cancer Treatment

Research continues to deliver new and improved treatment options for thousands of people living with cancer. Between October 1, 2014, and October 15, 2015, the FDA approved 10 new cancer treatments and a new cancer prevention vaccine. These new approvals include three immunotherapies (blinatumomab, nivolumab, and dinutuximab) and five novel targeted drugs (olaparib, palbociclib, lenvatinib, panobinostat, and sonidegib).

In addition, the FDA expanded the use of 12 previously approved cancer therapies and one device. Altogether, the approvals have broadened treatment options for the most common cancers, including lung, breast, colorectal, and skin cancers, as well as less common but difficult-to-treat illnesses, such as ovarian cancer, multiple myeloma, ALL, and brain cancer.

Besides tremendous success with immunotherapy (as described in Advance of the Year: Cancer Immunotherapy), 2015 marked significant advances in using well-established approaches to treat cancer: hormone therapy, chemotherapy, and surgery. Such advances will help improve outcomes for patients with breast cancer, head and neck cancer, rectal cancer, and stomach cancer, as well as sarcoma. Researchers have also reported encouraging results using a unique new, noninvasive device to treat the most deadly type of brain cancer.

Precision medicine is shaping up to become a mainstream treatment approach for many types of cancer. Our understanding of tumor biology and the molecules that make tumors grow and spread is rapidly expanding. Building on this knowledge, promising new targeted therapies have emerged for several hard-to-treat forms of blood, ovarian, breast, and kidney cancers.







Novel Treatment Device For Brain Cancer

Glioblastoma is one of the most common and deadliest forms of brain cancer in adults. Fewer than 10% of patients survive 5 years after initial diagnosis. Despite initial remission, the tumor often grows back and spreads quickly to other areas of the brain.

Preliminary findings from a large clinical trial point to a new possibility to improve outcomes for glioblastoma.1 The approach is unlike other treatments for brain or other cancers, using so-called tumor-treating fields (TTFs) to stop the growth of rapidly dividing tumor cells. TTFs are low-intensity electrical fields that are delivered through the skin from a device patients wear on their head.

In the trial of patients with newly diagnosed glioblastoma who underwent surgery, adding TTFs to standard radiation therapy and chemotherapy delayed disease progression by a median duration of 3 months. The 2-year survival rate was 43% in the TTF group versus 29% in the standard therapy group (brain surgery followed by radiation therapy and chemotherapy).

The TTF device was previously approved by the FDA for the treatment of recurrent glioblastoma, and in 2015, the FDA expanded its use to treat patients with newly diagnosed glioblastoma.2,3 Yet, it is unclear how well this new therapy that disrupts cell division will be adopted in routine practice. The effect of the device on patient quality of life remains controversial, because some patients have reported that wearing the device was too onerous.

Averting Breast Cancer Recurrence

Ovarian Suppression Helps Younger, High-Risk Patients

Initial treatment of estrogen receptor (ER)–positive breast cancer includes surgery followed by radiation therapy or chemotherapy. For premenopausal women, additional (adjuvant) treatment with the hormone drug tamoxifen is recommended to prevent recurrence—especially in women who are at higher risk. Knowing this type of breast cancer is fueled by estrogen, some experts surmised that blocking ovarian production of estrogen would further slow tumor growth and prolong the time to recurrence of the cancer. Ovarian function can be suppressed chemically, surgically, or by irradiation of the ovaries.

federally funded research logoIn 2015, the researchers’ hypothesis was confirmed when a phase III trial showed that ovarian suppression added to adjuvant hormone therapy improved outcomes for premenopausal women with a high risk of recurrence (this study was funded in part by a grant from the NIH).4 Compared with women with lower risk of recurrence, the study participants with higher risk tended to have larger, higher-grade tumors and cancer that had spread to the lymph nodes. All high-risk women had previously received chemotherapy.

At 5 years, 78% of the high-risk women who received tamoxifen alone were cancer free. By comparison, 82% of those treated with ovarian suppression and tamoxifen and 86% of those treated with ovarian suppression and the aromatase inhibitor exemestane were cancer free at 5 years. As expected, the addition of ovarian suppression contributed to symptoms of menopause.

The added benefit of ovarian suppression was particularly prominent among patients younger than age 35 years, nearly all of whom had previously received chemotherapy. Among these patients, 5-year cancer-free rates improved from 68% with tamoxifen alone to 79% with tamoxifen and ovarian suppression and to 83% with exemestane and ovarian suppression. For women with a lower risk of recurrence who had not previously received chemotherapy, outcomes were similar regardless of the type of adjuvant treatment received, with more than 95% remaining cancer free at 5 years. These findings support the use of adjuvant ovarian suppression with hormone therapy as a standard of care for premenopausal women with hormone receptor–positive breast cancer, particularly those who have high-risk disease and have been treated with chemotherapy. 


In Their Own Words: Wanda Lucas, MBA

Wanda Lucas, MBA

My experience with breast cancer has been full of emotions. Like so many others, I was in shock with the news of my diagnosis. 

During my treatment, I agreed to participate in a couple of epidemiological studies and the Suppression of Ovarian Function Trial (SOFT). I recognized that treatment choices that were available to me in 2006 were the result of someone agreeing to participate in a trial, at another point in time. In my mind, saying “yes” was an opportunity to make a difference in the lives of others who may be facing a similar diagnosis.  

Many patients are simply never asked to participate. Earlier this year, I was in a room with more than 60 African American women who had been diagnosed with breast cancer. When asked how many people had been approached about participating in a clinical trial, only five of us raised our hands. That’s unsettling because we were in Washington, DC, which is home to four cancer centers!

My work in advocacy has led me to believe that a better allocation of research funding coupled with more effective research direction is needed. Far too often, many young researchers are not valued or rewarded for their capabilities or potential impact on the progress of cancer research. As a result, many of these brilliant minds are abandoning academic research centers, leaving us with gaps in necessary research, knowledge and breakthroughs. 

Funding vehicles should require collaborations, provide incentives for groundbreaking research and foster paradigm shifts. We need programs, such as the Department of Defense Breast Cancer Research Program, that recognize and reward innovative research ideas, particularly those that focus on prevention and stopping metastasis. It is time to stop this disease in its tracks!

Wanda is a 10-year breast cancer survivor and is a founding member of Georgetown Breast Cancer Advocates, a member of the Board of Directors of the National Breast Cancer Coalition and Annie Appleseed Project. See "Ovarian Suppression Helps Younger, High-Risk Patients" above to learn about the SOFT study Wanda participated in.   


Aromatase Inhibitors—An Additional Option For DCIS

Women with DCIS are at increased risk of developing invasive breast cancer. To reduce this risk, physicians recommend that women with ER-positive DCIS receive tamoxifen for 5 years after breast-conservation surgery (lumpectomy).

federally funded research logo
A nationwide randomized trial reported that the aromatase inhibitor anastrazole may also yield excellent outcomes for postmenopausal women (this study was funded in part by a grant from the NIH).5 Ten-year breast cancer–free survival rates were higher in the anastrazole group than in the tamoxifen group (93% v 89%). This benefit was primarily seen in postmenopausal patients age younger than 60 years.

Both tamoxifen and aromatase inhibitors are already being used to prevent recurrences of more advanced forms of breast cancer. This is the first study to compare the two treatments in postmenopausal women with DCIS.

Importantly, the two hormonal drugs cause different adverse effects. The main adverse effect of anastrazole is hastening of osteoporosis, which increases the risk of bone fracture. Compared with those receiving tamoxifen, women receiving anastrazole are more likely to have joint pain but less likely to have hot flashes or blood clots in the veins. Tamoxifen is associated with slightly increased rates of uterine cancer, although this risk is low overall. Experts agree that both approaches carry their own risks and benefits and that patients should still consider the full range of options, including foregoing adjuvant treatment.

Targeted Therapy

Targeted therapy is designed to target molecules precisely in or on cancer cells or in the tissue surrounding a tumor. Genetic changes can cause cells to make too much of a certain protein or to produce abnormal proteins. Targeted therapy works by blocking or switching off such proteins that cause the cells to keep growing and dividing.

Precision medicine builds on the ever-expanding understanding of tumor biology. Several recent advances illustrate how specific molecular vulnerabilities in cancer can be exploited to develop powerful new treatments.

In 2015, researchers reported remarkable success with targeted therapy, with a range of new treatments that slow the growth of advanced cancers. In addition, early promising results were reported on drugs targeting a number of rare genetic abnormalities in lung tumors.

The FDA approved two first-in-class therapies, olaparib for the treatment of advanced ovarian cancer and palbociclib for the treatment of advanced breast cancer. Each of these drugs blocks a specific molecule that fuels the growth of that cancer.

Scientists also use information on the genetic makeup of different cancers to find new uses for existing drugs. For example, the targeted therapy ibrutinib, previously approved for chronic lymphocytic leukemia, was shown to work well against another type of blood cancer that shares the same genetic mutation, Waldenström’s macroglobulinemia (WM).

Similarly, another study confirmed that sorafenib, a drug used to treat liver, kidney, and thyroid cancers, is effective against acute myeloid leukemia (AML), as predicted by early research on key molecules implicated in this disease. Finally, a drug approved to treat thyroid cancer, cabozantinib, was found to delay worsening of advanced kidney cancer and NSCLC.


In Their Own Words: Debbie Zelman, Esq.

Debbie Zelman and her family

I was diagnosed with stage IV stomach cancer in April 2008. At the time of my diagnosis, I was told that my chance of being alive in five years was 4% because there were very few effective treatment options for advanced stomach cancer because it is not a common cancer in the United States. 

Only 2% of all stomach cancer is a result of an inherited genetic mutation. I have undergone two types of genetic testing, which told me that my cancer was not inherited from my family. However, testing revealed that my tumor included a genetic mutation called HER2 positive. This finding allowed me to receive innovative, targeted treatments, which saved my life. I still receive these targeted treatments both intravenously and orally.

The treatments that I have been on and are currently receiving were all advances made as a result of clinical trials. I have been a beneficiary of the research done in clinical trials, and they have extended my life. I live still from scan to scan, not knowing what the next scan might reveal, but I am still here to celebrate birthdays, anniversaries, attend my children’s recitals, concerts, and competitions, help in the college search for my high school seniors, and anything else that comes along with being a mother, wife, daughter, sister and friend. I am grateful that I am still here to do all of these things and to enjoy life.

Debbie, pictured above with her husband and children, is a 7-year stomach cancer survivor, president and founder of Debbie’s Dream Foundation: Curing Stomach Cancer, a member of the NCI Patient Advocate Steering Committee and the NCI  Esophago-Gastric Task Force, as well as an American Cancer Society Research Stakeholder.


Tumor Biology: Aiming At Rare Targets In Lung Cancer

Genetic mutations that cause cells to make abnormal proteins can lead to cancer. A landmark 2014 study found that two thirds of advanced lung adenocarcinomas harbor at least one such cancer-causing genetic change.6 This finding is important, because it suggests that most such patients may benefit from a targeted treatment that blocks the cancer-fueling protein. Nonetheless, only a minority of patients with lung cancer are candidates for targeted therapies at this time.


pie chart showing genetic mutations in lung tumors

In the study, the most common genetic abnormalities were KRAS mutation (25%), sensitizing EGFR mutations (17%), ALK rearrangements (8%), other EGFR mutations (4%), ERBB2 mutations (3%), and BRAF mutations (2%). Several targeted drugs are already widely used to treat patients with EGFR mutations in the tumor: afatinib, erlotinib, and gefinitib. Crizotinib and ceritinib are recommended for tumors with ALK rearrangements. However, development of new options remains critical, because not all patients with ALK-positive NSCLC respond to these treatments, and some cannot tolerate them. Unfortunately, no treatments are yet available to target the most common genetic change: KRAS mutation.

Findings from a recent phase II trial point to a promising new treatment for patients with advanced ALK-positive NSCLC that is resistant to crizotinib. A novel ALK inhibitor, alectinib, shrank tumors in half of the patients treated in the trial, with a median response duration exceeding 11 months.7 The treatment also shrank brain metastases in close to 60% of patients. Serious treatment-related adverse effects, such as dyspnea and pulmonary embolism, occurred in 27% of patients.

In June 2013, the FDA granted alectinib a breakthrough therapy designation. In 2014, alectinib was approved in Japan for the treatment of advanced or recurrent ALK-positive NSCLC. In December 2015, the FDA granted accelerated approval to alectinib for the treatment of patients with metastatic ALK-positive NSCLC that has worsened after, or who could not tolerate crizotinib.However, larger studies are needed to confirm the efficacy of alectinib. 

Meanwhile, many other ALK inhibitors that seem more potent than crizotinib or are active in crizotinib-resistant tumors are already in clinical trials.9 Emerging research findings suggest that patients with lung cancers driven by uncommon genetic abnormalities can also benefit from targeted therapies.

federally funded research logo

In another early clinical trial, crizotinib shrank tumors of 72% of patients with ROS1 gene rearrangements (this study was funded in part by a grant from the NIH).10 The median duration of response was more than 17 months. ROS1 rearrangement is found in only 1% of tumors of patients with NSCLC. The most common treatment-related toxicities were visual impairment, diarrhea, and nausea. However, nearly all of the reported adverse effects were mild.

Approximately 28% of patients with similarly uncommon RET gene rearrangements responded to the targeted drugs cabozantinib, which was previously approved by the FDA for the treatment of thyroid cancer.11 The median time to progression of advanced NSCLC was 7 months. Toxicities were mostly mild and included fatigue, diarrhea, hand-foot syndrome, and low platelets.

Preliminary results from a small trial suggest that the targeted drug dabrafenib is active against advanced NSCLCs harboring a specific mutation in the BRAF gene, V600E.12 The treatment shrank tumors in 63% of the patients, and treatment-related adverse effects were mostly mild. The most common toxicities were fever, diarrhea, nausea, and vomiting. Dabrafenib is approved for the treatment of melanoma with the same mutation.

Finally, a large genomic profiling study identified a rare new subgroup of patients with NSCLC who could potentially respond to targeted MET inhibitors.13

Although ALKROS1RET, and BRAF mutations are rare in frequency, given the high incidence of NSCLC, thousands of people may be candidates for the new targeted therapies. Further research is needed to determine the best way to screen patients for rare genetic changes. New technologies, such as next-generation sequencing and multiplex testing, may help more patients receive treatments targeting mutations in the tumor.


In Their Own Words: Dusty Donaldson

Dusty Donaldson

Imagine a tragic scenario where a jumbo jet—carrying more than 400 passengers—crashes into the ground. No one survives. In the United States alone, the number of people who die from lung cancer is like a jumbo jet crashing to the ground—each and every day. 

When I was diagnosed with lung cancer 10 years ago, I was overwhelmed less by my diagnosis than by the dismal state of lung cancer research. Lung cancer claims more lives than breast, colon and prostate cancers combined. 

When I was diagnosed a decade ago, I wondered if I would live to see any significant improvement in the state of lung cancer. Frankly, now I cannot keep up with the changes. Every day brings a very real possibility of another breakthrough therapy or discovery. I am so encouraged by what researchers are doing in the realm of lung cancer. I am one of the few lung cancer survivors fortunate to have lived long enough to see this amazing transformation.

Make no mistake. We have not arrived. Lung cancer remains the unparalleled cancer killer and the least funded major cancer. But the tide is changing. There is much more to discover, many more people to help. This is not a time to rest on  our laurels or become complacent. But perhaps this is a good time to look back and be encouraged by just how far we have come.

Dusty is a 10-year lung cancer survivor, founder of the Dusty Joy Foundation, and co-chair of the Lung Cancer Action Network (LungCAN).


Zeroing In On A Blood Cancer's Weak Spot

Waldenström's macroglobulinemia (WM) is a rare, slow-growing type of lymphoma. The disease can start almost anywhere in the body and may spread to almost any organ. In fact, when WM is diagnosed, it usually involves the blood and the bone marrow.

blood cells

Patients with WM sometimes have thickened blood, which may cause symptoms such as headache, blurry vision, dizziness, and shortness of breath. Treatments include watchful waiting, chemotherapy, and monoclonal antibodies. This approach to treatment changed in 2015 with the approval of a new targeted drug that is effective in the vast majority of patients with WM.

In 2012, scientists first reported on a genetic mutation that occurs frequently in patients with WM. The abnormality leads to activation of the Bruton’s tyrosine kinase (BTK) protein, which drives tumor growth. Less than 3 years later, a small clinical study showed that blocking BTK with the targeted drug ibrutinib could be a promising new treatment strategy for WM.14

Overall, 90% of patients with previously treated WM responded to ibrutinib, and the 2-year survival rate exceeded 95%. These findings led to the FDA approval of ibrutinib for WM in January 2015.15 Ibrutinib was previously approved for the treatment of other types of blood cancer. 

Sorafenib Targets Acute Myeloid Leukemia (AML)

Sorafenib is a targeted drug that blocks a range of molecules that promote the growth of cancer cells and of the blood vessels to the tumor. It is has been FDA approved for the treatment of people with certain types of liver, kidney, and thyroid cancers.

Early research suggested that sorafenib may work against AML, because it blocks several key molecules implicated in this disease. Preliminary data from the first randomized trial of sorafenib in patients with newly diagnosed AML has now confirmed this.16

At 3 years, 56% of patients who received sorafenib and standard chemotherapy and 38% of those treated with placebo and standard chemotherapy had not relapsed. The 3-year overall survival rates were 63% with sorafenib and chemotherapy and 56% with chemotherapy alone. The most common severe treatment-related toxicities included fever and bleeding events, both of which occurred more often with sorafenib.

The study was limited to adult patients younger than age 60 years. A prior study in older patients with AML showed no benefit of sorafenib. Larger trials are needed to fully assess the role of sorafenib in the treatment of people with AML. 

Homologous DNA Repair: A Novel Therapeutic Target In Ovarian Cancer

In late 2014, the FDA approved olaparib for the treatment of advanced serous ovarian cancer with BRCA gene mutations.17 This approval marked the first major improvement in the treatment of high-grade serous ovarian cancer in 30 years. Serous ovarian cancer is the most common type of ovarian cancer, accounting for two thirds of ovarian cancer diagnoses.

Up to 15% of all ovarian cancers are linked to hereditary mutations in BRCA genes, which encode proteins that repair damaged DNA. Olaparib is the first of a new class of DNA repair-blocking drugs called poly (ADP-ribose) polymerase (PARP) inhibitors. The year 2015 was marked by steady advances in research on PARP inhibitors, including new understanding of the populations they might benefit, as well as the development of other PARP-targeted drugs.

Cancer cells that already have a decreased ability to repair DNA damage because of mutations in BRCA1 or BRCA2 genes are particularly vulnerable to PARP inhibitors. These drugs completely disable the DNA repair mechanisms ofBRCA-mutated cancer cells, leading to cell death. Approximately half of high-grade ovarian cancers have other defects in the DNA repair machinery of the cells, which may also make them susceptible to PARP inhibitors. Healthy cells that do not have an underlying defect in DNA repair are able to survive PARP blockade.

Approval of olaparib was given on the basis of a study of women with platinum-sensitive, recurrent, serous ovarian cancer.18 Preliminary findings showed that maintenance treatment with olaparib delayed disease progression by 7 months compared with placebo. Patients with BRCA mutations experienced the most benefit from olaparib, and longer patient follow-up is needed to determine if olaparib extends overall survival. Serious treatment-related adverse effects, such as fatigue and anemia, were reported in 18% of patients who received olaparib.

The most common adverse effects among patients treated with olaparib were fatigue and anemia. Serious adverse effects, such as small intestinal obstruction, were reported in 18% of patients who received olaparib and 9% of those who received placebo.

Other recent research has suggested that women who have tumors that become resistant to chemotherapy may also benefit from olaparib.19 One study showed that olaparib added to chemotherapy slowed cancer progression by roughly 3 months compared with chemotherapy alone. Again, the greatest clinical benefit was seen in patients with BRCAmutations. Phase III confirmatory trials of olaparib as a maintenance treatment for women with recurrent ovarian cancer are under way ( identifier: NCT01844986).

federally funded research

Ongoing research is also investigating how PARP inhibitors can be used more effectively. One study found that adding cediranib to olaparib delayed disease progression of recurrent serous ovarian cancer for 8 months longer than olaparib alone (this study was funded by a grant from the NIH).20 Women without inherited BRCA mutations particularly benefited from the combination. Cediranib is a targeted drug that blocks the growth of blood vessels to the tumor. In a previous clinical trial, cediranib administered as maintenance therapy improved survival of women with recurrent ovarian cancer.21

Scientists are also working on ways to identify patients who are most likely to benefit from PARP inhibitors. For example, it seems that tumors with a mutation in the RAD51C gene, which is involved in homologous DNA repair, respond well to another PARP inhibitor, rucaparib.22 Like olaparib, rucaparib was active against ovarian tumors with BRCA mutations, with 66% of patients experiencing tumor shrinkage.

Importantly, however, rucaparib was also active against BRCA-negative tumors with homologous DNA repair deficiency leading to tumor genome-wide changes, known as loss of heterozygosity. Among women with recurrent ovarian cancer treated in a phase II study of rucaparib, the population of patients who had loss of heterozygosity also had a treatment response rate of 32%. The most common treatment-related adverse effects included GI symptoms, fatigue, anemia, and increased liver enzyme (ALT and AST) levels.

In 2015, the FDA granted rucaparib a breakthrough therapy designation to treat women with BRCA-positive advanced ovarian cancer. Pivotal studies of rucaparib in women with high-grade ovarian cancer are underway ( identifier: NCT01968213). The studies will also try to define a molecular signature that might be used to predict which patients might benefit from PARP-directed therapies.

Meanwhile, genomic analyses of tumor tissue are revealing additional molecular defects that could serve as therapeutic targets in the future. One such study has recently identified genes implicated in the resistance of ovarian cancer to chemotherapy.23


Representative Gene Green of Texas

"Just about every person in this country has been touched by cancer and we want to make sure that what we do in Congress helps bring better treatments and cures to the people who are fighting life-threatening diseases. Clinical cancer research has yielded tremendous gains and breakthroughs, but we can’t afford to stop this progress. Millions of Americans are counting on us."

 — Rep. Gene Green (D-TX)


Palbociclib Sets A New Standard Of Breast Cancer Care

The year 2015 brought an entirely novel treatment option for women with ER-positive breast cancer. This is the most common type of breast cancer, accounting for two thirds of cases. ER-positive breast tumors need estrogen to grow. Blocking estrogen production or its receptor is the cornerstone of ER-positive breast cancer therapy.

In recent years, scientists discovered that proteins called CDK4 and CDK6 also play a critical role in ER-positive breast cancer growth. Two large clinical studies subsequently showed that blocking CDK4 and CDK6 with the new oral drug palbociclib improved patient outcomes.

The first study compared standard hormone therapy letrozole with the combination of letrozole and palbociclib in postmenopausal women with advanced ER-positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.24 The patients had not previously received any systemic treatment of the advanced disease.

The median time before the cancer worsened (progression-free survival) was 20 months with the palbociclib combination compared to 10 months with letrozole alone. Severe adverse effects, such as low white blood cell levels (neutropenia and leucopenia) and fatigue, were more frequently reported among patients who received palbociclib and letrozole.

Severe adverse effects related to the palbociclib and letrozole combination regimen included low white blood cell levels, fatigue, pulmonary embolism, back pain, and diarrhea. In February 2015, the FDA granted accelerated approval of palbociclib to be used with letrozole as initial therapy for women with ER-positive, HER2–negative breast cancer.25

After initial hormonal therapy stops working for women with advanced breast cancer, the next step is typically chemotherapy. Although chemotherapy can be effective, many women find the adverse effects too debilitating. The second study assessed whether palbociclib could defer the need for chemotherapy.26

Women with advanced, ER-positive breast cancer that relapsed or worsened after prior hormone therapy received palbociclib with the hormone drug fulvestrant or fulvestrant with placebo. The median time before the disease worsened was markedly longer with the combination treatment (9.2 months) compared with fulvestrant alone (3.8 months). Both premenopausal and postmenopausal women benefited from palbociclib. Severe treatment-related adverse effects, such as low blood cell counts (neutropenia, leukopenia, and thrombocytopenia), anemia, and fatigue, were much more common in patients who received the combination of palbociclib and fulvestrant.

Together, the findings support the use of palbociclib as part of the standard therapy for ER-positive advanced breast cancer. More research is needed to determine the impact of palbociclib on overall survival and patient quality of life.

Expanding Treatment Options For Advanced Kidney Cancer 

Patients with advanced kidney cancer that worsens despite standard therapy are in urgent need of better treatment options. Research published in 2015 promises two potential new possibilities: an immunotherapy (see Advance of the Year: Cancer Immunotherapy) and a targeted drug, both of which outperformed the standard second-line treatment, everolimus. The targeted drug everolimus blocks a protein called mTOR .

The targeted therapycabozantinib blocks several different targets in cancer cells, including RET, MET, and VEGF receptor 2. The drug was previously approved for the treatment of advanced thyroid cancer.

In a large clinical trial of patients with previously treated metastaic kidney cancer, the median time before the disease worsened was 7.4 months with cabozantinib versus 3.8 months with everolimus.27 A preliminary analysis also showed a trend for improved overall survival with cabozantinib, but longer patient follow-up is needed to confirm this benefit.

The rates of adverse effects were similar with either drug, although the incidence of severe adverse effects was higher with cabozantinib. The most common severe adverse events related to cabozantinib were high blood pressure (hypertension), diarrhea, and fatigue, whereas anemia, fatigue, and high blood sugar (hyperglycemia) were most common with everolimus. 


In Their Own Words: Paula Bowen

Paula Bowen

Mine was not your typical cancer diagnosis. How does a healthy, forty-two year old, African-American female present with Stage III kidney cancer? This was back in 1992 when the “typical” kidney cancer patient was described as an “older white male.” At that time, there was only one FDA-approved treatment for clear cell kidney cancer, which ultimately failed me.

Shortly after my initial diagnosis, I became actively involved with the Kidney Cancer Association. It is from this platform where I jumpstarted my cancer advocacy work. I have lobbied on Capitol Hill to get federal funding for cancer research increased. This is vital in the fight against cancer. Using kidney cancer as my gauge, we now have over a dozen drugs that have received FDA approval for the treatment of kidney cancer. Without federal funding, these breakthroughs would never have occurred.

Having the good fortune of continuing to survive metastatic kidney cancer has not been without its challenges. Even after 20+ years, I am still concerned that an ache or pain is not just part of the aging process. However, I am not as fearful as before for my own personal situation. Should the need arise, I too, now have viable options. Would I participate in a clinical trial? Yes, I would. Clinical trials are the litmus test for all drug discovery and development. We know that one size does not fit all. A sound education program, highlighting the success stories of those from underserved populations, could go a long way in helping to increase participation of women and minorities in clinical trials.

I made the decision many years ago to lead and live my best life. I have had the good fortune to surround myself with wonderful family, good friends, good music and good wine. It doesn’t get much better than this!

Paula is a 23-year kidney cancer survivor and member of the Kidney Cancer Association Board of Directors.


Adjuvant Chemotherapy Extends Survival For Patients With Stomach Cancer

Localized stomach cancer can potentially be cured with surgery, but recurrences are common. Approximately four in 10 patients experience a relapse within 2 years of surgery. After a relapse, treatment is much more difficult, and survival is shortened.

Recent research has demonstrated that outcomes can be improved if patients receive chemotherapy after surgery. A large randomized clinical trial compared postsurgery (adjuvant) capecitabine and oxaliplatin chemotherapy with observation.28 The patients had stage II to IIIB stomach cancer and had undergone surgical removal of parts of the stomach and nearby lymph nodes.

Adjuvant chemotherapy decreased the risk of cancer recurrence after surgery by 42%. The estimated 5-year survival rate was 78% in the chemotherapy group compared with 69% in the observation group. 

New Treatment For Soft-Tissue Sarcoma

Patients with advanced soft tissue sarcoma have poor outcomes, typically surviving 1 year or less. If the disease worsens after initial chemotherapy, there are few options available for further treatment. Early clinical trial findings point to promising new treatments for two common types of soft tissue sarcoma, liposarcomas (fatty tissue) and leiomyosarcoma (muscle tissue).

Among patients with treatment-resistant disease, eribulin chemotherapy extended the median survival from 11.5 to 13.5 months compared with the standard treatment dacarbazine.29 This was the first clinical trial in 20 years to show that a new drug improved survival in any type of sarcoma. For a disease where such few treatment options exist, even a 2-month improvement in survival represents progress. Nevertheless, the survival gain must be weighed against the burden of its adverse effects.

Eribulin belongs to a class of anticancer drugs known as microtubule inhibitors, which block cell division. The FDA approved eribulin for the treatment of advanced breast cancer in 2010.

sea sponges

Interesting Fact: Eribulin and trabectedin are 
natural products derived from oceanic organisms -
the sea sponge and the sea squirt, respectively.

Preliminary findings from another study suggest that the chemotherapy drug trabectedin can be effective against treatment-resistant soft tissue sarcoma.30 Compared with dacarbazine, trabectedin slowed liposarcoma and leiomyosarcoma progression by a median duration of 10 weeks. Longer follow-up is needed to determine if there is an improvement in overall survival.

The most common toxicities related to trabectedin were GI symptoms, fatigue, headache, and tissue swelling. Severe treatment-related adverse effects, including decreased white blood cell (neutrophil) levels and increased ALT levels, were more common with trabectedin than with dacarbazine.

The antitumor effects of trabectedin are multipronged: it blocks cell division, transcription of genes, and DNA repair. Recently, scientists discovered that trabectedin may also affect the tumor microenvironment. In October 2015, the FDA approved trabectedin to treat patients with chemotherapy-resistant liposarcoma or leiomyosarcoma that cannot be removed by surgery or is advanced.31

Although these survival gains could be construed as minimal, it is important to understand that improvements in survival of patients with soft tissue sarcoma have not been achieved until now. The hope is that these incremental improvements will provide new opportunities for clinical research in this hard-to-treat cancer. 

Advances In Surgery

For the vast majority of patients today, surgery remains a critical part of cancer care. Although it can be lifesaving, surgery also carries the risk of complications, which can impair a patient’s quality of life.

Research has delivered new insights that will help physicians and patients decide when it is most appropriate to undergo neck lymph node surgery. Until now, research evidence in this area was sorely lacking.

Another large clinical trial provided reassurance to patients with rectal cancer considering laparoscopic surgery. It showed that this less invasive procedure offers the same survival benefit with fewer risks compared with traditional surgery.

Each year, thousands of women with early-stage breast cancer undergo a lumpectomy. For such women, a new surgical technique that involves removing a little more tissue during lumpectomy may significantly reduce the need for additional surgery after an initial lumpectomy.

Neck Lymph Node Removal: When Is It Necessary?

Cancers that begin in the head or neck often spread to lymph nodes in the neck. Physicians commonly recommend preventive (elective or planned) neck lymph node surgery to reduce the risk of cancer recurrence and spread.

In addition to general risks of anesthesia and surgery, neck lymph node surgery may cause damage to the nerves of the lip and tongue, limited neck and shoulder movement, and problems talking and swallowing. To avoid such risks, some patients opt to delay lymph node removal until their cancer returns or worsens. Recent evidence from two large clinical trials will help physicians and patients decide when such surgery is the appropriate choice.

A phase III study conducted in India showed that elective neck lymph node surgery had a clear benefit for patients with early oral cancer.32 According to preliminary results, elective neck surgery halved the risk of relapse and increased 3-year survival rates by 12%. This new evidence will likely encourage greater use of elective lymph node surgery for patients with early oral cancer.

Another large clinical trial explored whether patients with more advanced HNC (stage III or IV) could forgo planned (elective) neck lymph node surgery after chemotherapy and radiation therapy and instead undergo active surveillance with positron emission tomography (PET)/computed tomography (CT).33 One group of patients with squamous cell HNC was assigned to undergo a planned neck surgery before or after chemotherapy and radiation therapy. A second group received chemotherapy and radiation therapy followed by active surveillance with PET/CT imaging. Those patients underwent neck surgery only if the PET/CT scan revealed abnormalities.

There was no difference in survival between the two patient groups, but the PET/CT group underwent fewer neck surgeries and experienced considerably fewer complications than the group that underwent the planned neck surgery. The findings suggest that after chemotherapy and radiation therapy, patients with advanced HNC can be safely observed using PET/CT. The surveillance approach was also more cost effective compared with immediate neck surgery. 

Rectal Cancer: Laparoscopic Surgery Outperforms Traditional Surgery 

Patients with rectal cancer have two surgical options: laparoscopic surgery or traditional (open) surgery. Laparoscopic surgery is performed through several small incisions instead of one large incision. A video camera and thin instruments are placed through the incisions to allow access to the inside of the body. Laparoscopic procedures are as safe as traditional surgery, and recovery time is shorter.

A large clinical trial comparing traditional and laparoscopic rectal cancer surgery concluded that the laparoscopic procedure may improve outcomes for some patients.34 The rates of local recurrence did not differ between laparoscopy and traditional surgery. However, among patients with distal rectal cancer, local recurrences were less frequent after laparoscopy than after traditional surgery.

At 3 years, the rate of disease-free survival was 75% in the laparoscopy group and 71% in the traditional surgery group. For patients with stage III rectal cancer, however, laparoscopy provided a larger improvement in 3-year disease-free survival: the rates were 52% with traditional surgery and 65% with laparoscopy. Across disease stages, the two types of surgery resulted in similar overall survival rates at 3 years. These findings suggest that laparoscopic surgery, when performed by a highly trained colorectal surgeon, is not inferior to traditional surgery, at least for some types of rectal cancer. 

Lumpectomy: Getting It Right The First Time

Many women diagnosed with early-stage breast cancer undergo a lumpectomy. During a lumpectomy, the surgeon removes the tumor and a small area of surrounding healthy tissue, which is known as a surgical margin. Specimens of the removed tissue are examined under a microscope. If cancer cells are seen at or close to the edge of the specimen, it is said to have positive margins. Margins that are free of cancer cells are called negative.

Up to 40% of women with early-stage breast cancer have positive margins after lumpectomy. In such cases, physicians often recommend a second surgery to remove more tissue, because any remaining cancer cells increase the risk of recurrence.


from 21% to 10%

A recent study suggests that the need for additional surgery could be reduced.35 The study explored a new technique called cavity shave, which involves removing additional tissue around the tumor during initial lumpectomy to improve the odds of achieving negative margins. The new technique decreased the rates of additional breast surgery by half (from 21% to 10%), and women perceived no difference in cosmetic outcomes with the new approach.

The findings of this study are immediately applicable to a large number of women with breast cancer. The new approach will spare them the trauma of an additional procedure and allow them to start curative treatments sooner. It may also ultimately reduce the number of patients who opt for mastectomy instead of a re-excision surgery, as well as reduce overall cost of breast cancer care.


In Their Own Words: Karen Durham

Karen Durham

I was originally diagnosed with Stage II invasive breast cancer in 1989, at the age of 38. I completed surgery, chemotherapy, and reconstruction by the end of 1991. At that time, having a lumpectomy was not an option for me because it had not quite yet become a developed and accepted procedure. Also at that time, there was not testing to see what subtype a tumor was.

Since then, treatments for cancer have come so far. Many drugs are targeted to a specific tumor makeup, and a lot of treatments can now be given orally. Another benefit is that the side effects are much more manageable, and less severe. The newer drugs are less toxic. Since I was diagnosed metastatic in 2009, 19 years later, I have led a near normal life. When I was on treatment in 1989/1990, I was practically bedridden and barely functioning.

I am very much in favor of anyone participating in a clinical trial if at all possible. Only 3-4% of adult cancer patients participate in a clinical trial, most because they are never asked. Without clinical trials participants, new potential life-saving drugs will never come to the FDA for approval and be on the market for use.

Karen is a 26-year breast cancer survivor, Advocate Komen Scholar for Susan G. Komen, and member of the ASCO CancerLinQ Patient Advisory Committee.


Advances In Radiation Therapy For Early-Stage Breast Cancer

Many women with early-stage breast cancer receive radiation therapy after breast-conserving surgery (lumpectomy) to reduce the risk of cancer recurrence in the breast and nearby tissue. In specific circumstances, such as having a larger tumor or cancer spread in many lymph nodes, radiation therapy may also be recommended after mastectomy.

After a lumpectomy, most women receive a type of radiation therapy known as whole-breast irradiation. Another type of radiation therapy, regional node irradiation, is only recommended to certain women, such as those with cancer that has spread to nearby lymph nodes or those who are deemed to be at a higher risk of recurrence. For such patients, regional node irradiation has been shown to reduce recurrence and improve survival.

Two large clinical trials published last year explored whether adding regional lymph node irradiation to whole-breast irradiation improved outcomes after surgery for women with early breast cancer. The findings of both studies suggest that the addition of regional lymph node irradiation offers no survival benefit but reduces the risk  of recurrence.

federally funded research logo

The first trial included women with early-stage breast cancer that was either node positive or node negative with a high risk of recurrence (this study was funded in part by a grant from the NIH).36 After lumpectomy and systemic adjuvant therapy, the women received either whole-breast irradiation plus regional nodal irradiation or whole-breast irradiation alone. There was no difference in the survival rate at 10 years between the two groups (82.8% v 81.8%), but the disease-free survival rate was higher in the nodal irradiation group (82% v 77%).

The second clinical trial assessed adding regional node irradiation to either whole-breast or chest-wall irradiation for women who had undergone lumpectomy or mastectomy.37 At 10 years, the addition of regional node irradiation did not improve overall survival rates but did slightly increase disease-free survival rates (72.1% v 69.1%). Breast cancer–related deaths were less frequent in the nodal irradiation group (14.4% v 12.5%).

Regional nodal irradiation may increase the risk of treatment complications, such as lung inflammation, lymphedema (a condition in which extra lymph fluid builds up in tissues and causes swelling), heart disease, and second cancers. More research is needed to identify patients who might benefit the most from the combination of whole-breast and regional nodal irradiation therapy. 

Recent Clinical Practice Guidelines

Each year, research yields new knowledge that helps inform all aspects of cancer care, including prevention, detection, diagnosis, treatment, and survivorship. Evidence-based clinical practice guidelines help to distill knowledge on a particular topic and provide recommended care options to assist clinicians in delivering the best treatment and care to each patient.

ASCO develops its clinical practice guidelines through a rigorous systematic review of relevant medical literature and clinical interpretation from a multidisciplinary panel of content experts and patient representatives. In 2015, ASCO issued new clinical practice guidelines, updates, and guideline endorsements on a variety of topics to help inform patient care. View the latest guidelines on the Institute for Quality website. 

List of guidelines from ASCO with publication dates


ASCO Clinical Practice Guidelines, Endorsements, and Clinical Opinions, January - October 2015



  1. Stupp R, Taillibert S, Kanner A, et al: Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial. J Clin Oncol 33, 2015 (suppl; abstr 2000)
  2. US Food and Drug Administration: NovoTTF-100A System: P100034.
  3. US Food and Drug Administration: FDA approves expanded indication for medical device to treat a form of brain cancer.
  4. Francis PA, Regan MM, Fleming GF, et al; SOFT Investigators; International Breast Cancer Study Group: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015
  5. Margolese R, Cecchini RS, Julian TB, et al: Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. J Clin Oncol 33, 2015 (suppl; abstr LBA500)
  6. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014
  7. Ou SH, Ahn J, De Petris L, et al: Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer patients who have failed prior crizotinib: An open-label single-arm, global phase II study. J Clin Oncol 33, 2015 (suppl; abstr 8008)
  8. US Food and Drug Administration: FDA approves new oral therapy to treat ALK-positive lung cancer.
  9. Awad MM, Shaw AT: ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol 12:429-439, 2014
  10. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-1971, 2014
  11. Drilon A, Sima C, Somwar R, et al: Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. J Clin Oncol 33, 2015 (suppl; abstr 8007)
  12. Planchard D, Groen HJ, Kim T, et al: Interim results of a phase II study of BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in patients with BRAFV600E mutated metastatic non-small-cell lung cancer. J Clin Oncol 33, 2015 (suppl; abstr 8006)
  13. Frampton GM, Ali SM, Rosenzweig M, et al: Comprehensive genomic profiling of advanced cancers to identify MET exon 14 alterations that confer sensitivity to MET inhibitors. J Clin Oncol 33, 2015 (suppl; abstr 11007)
  14. Treon SP, Tripsas CK, Meid K, et al: Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med 372:1430-1440, 2015
  15. US Food and Drug Administration: FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma.
  16. Röllig C, Müller-Tidow C, Hüttmann A, et al: Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: Results from 267 patients treated in the randomized placebo-controlled SAL-Soraml Trial. Presented at the 2014 American Society of Hematology Annual Meeting, December 7, 2014
  17. US Food and Drug Administration: FDA approves Lynparza to treat advanced ovarian cancer. htm?source=govdelivery&utm_medium=email&utm_ source=govdelivery
  18. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852-861, 2014
  19. Oza AM, Cibula D, Benzaquen AO, et al: Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: A randomised phase 2 trial. Lancet Oncol 16:87-97, 2015
  20. Liu JF, Barry WT, Birrer M, et al: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol 15:1207-1214, 2014
  21. Ledermann JA, Perren TJ, Raja FA, et al: Randomized double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum-sensitive ovarian cancer: Results of the ICON6 trial. Presented at the European Cancer Congress, September 30, 2013 (abstr 10)
  22. McNeish IA, Oza AM, Robert L et al: Results of ARIEL2: A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol 33, 2015 (suppl; abstr 5508)
  23. Patch AM, Christie EL, Etemadmoghadam D, et al; Australian Ovarian Cancer Study Group: Whole-genome characterization of chemoresistant ovarian cancer. Nature 521:489-494, 2015
  24. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015
  25. US Food and Drug Administration: FDA approves Ibrance for postmenopausal women with advanced breast cancer.
  26. Turner NC, Ro J, André F, et al; PALOMA3 Study Group: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209-219, 2015
  27. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1814-1823, 2015
  28. Noh SH, Park SR, Yang H-K, et al; CLASSIC trial investigators: Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 15:1389-1396, 2014
  29. Schöffski P, Maki RG, Italiano A, et al: Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol 33, 2015 (suppl; abstr LBA10502)
  30. Demetri GD, von Mehren M, Jones RL, et al: A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced liposarcoma (LPS) or leiomyosarcoma (LMS). J Clin Oncol 33, 2015 (suppl; abstr 10503)
  31. US Food and Drug Administration: FDA approves new therapy for certain types of advanced soft tissue sarcoma.
  32. D’Cruz AK, Vaish R, Kapre N, et al; Head and Neck Disease Management Group: Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 373:521-529, 2015
  33. Mehanna HM, Wong WL, McConkey CC, et al: PET-NECK: A multi-centre, randomized, phase III, controlled trial (RCT) comparing PETCT guided active surveillance with planned neck dissection (ND) for locally advanced (N2/N3) nodal metastases (LANM) in patients with head and neck squamous cell cancer (HNSCC) treated with primary radical chemoradiotherapy (CRT). J Clin Oncol 33, 2015 (suppl; abstr 6009)
  34. Bonjer HJ, Deijen CL, Abis GA, et al; COLOR II Study Group: A randomized trial of laparoscopic versus open surgery for rectal cancer. N Engl J Med 372:1324-1332, 2015
  35. Chagpar AB, Killelea BK, Tsangaris TN, et al: A randomized, controlled trial of cavity shave margins in breast cancer. N Engl J Med 373:503-510, 2015
  36. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators: Regional nodal irradiation in early-stage breast cancer. N Engl J Med 373:307-316, 2015
  37. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups: Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015

Advances in Patient Care

Physicians treating patients with cancer continuously strive not only to extend their patients’ lives but also to improve their well-being. In the case of childhood cancers, intensive therapies can eradicate the disease, but many survivors face risks of late effects, such as second cancers and heart disease. However, a major study in 2015 indicates that today, much fewer survivors are dying as a result of such complications compared with three decades ago.

Cancer care is also increasingly focused on the whole patient, which includes meeting the patient’s physical, emotional, psychological, and spiritual needs. This is achieved through improved communication between physicians and their patients, as well as collaboration across physician specialties and with nonphysician practitioners. For all patients, and particularly those with advanced or incurable cancer, it is important to ensure that the goals of treatment are aligned with patients’ preferences.

Multidisciplinary care teams are now common, and more patients are benefiting from palliative care services. New research has confirmed that the earlier patients with advanced cancer begin receiving palliative care, the longer they live. In addition, researchers found that family caregivers who themselves receive palliative care services early are better able to cope with caregiving. Research reported in 2015 has also provided valuable new insights into the risks and benefits of a type of radiation therapy for patients with cancer that has spread to the brain.

Advances In Childhood Cancer

Childhood Cancer Survivors Are Living Longer

For decades, physicians have strived to avoid the paradox in which children survive cancer, only to become sick or die years later because of complications from the very treatment that cured them of cancer. Close monitoring of late effects has led to changes in therapy for the most common childhood cancers.

By carefully reducing treatment intensity, physicians have extended the lifespan of many childhood cancer survivors since the 1970s. Cancer cure rates have increased alongside a decrease in deaths resulting from complications of cancer treatment, such as second cancers and heart and lung diseases. 

federally funded research logo

A recent analysis of roughly 34,000 childhood cancer survivors shows major gains in long-term survival achieved over three decades (this study was funded by a grant from the NIH).1 The study explored mortalityrates among 5-year childhood cancer survivors diagnosed with cancer between 1970 and 1999.

The rate of death resulting from any cause within 15 years of a cancer diagnosis decreased from 12.4% among patients diagnosed in the 1970s to 6% among those diagnosed in the 1990s. This reduction in mortality was associated with changes in therapy that occurred during the same time period, such as decreased use of anthracyclines, alkylating agents, and cranial irradiation. This is promising news for the more than 370,000 childhood cancer survivors in the United States today.

Transplant Options For Children With ALL Expanded

Most children with ALL can be cured with chemotherapy, but those with high-risk disease require additional treatment. Hematopoietic stem-cell transplantation, also called bone marrow transplantation, is the standard of care for such high-risk patients.

It is estimated that only 20% to 25% of children who are candidates for stem-cell transplantation have matched sibling donors. A match is found when the HLA of one sibling’s bone marrow matches that of the other, and there is only a 25% chance that bone marrow HLA will match between siblings. Fortunately, the availability of unrelated volunteer donors has increased over recent decades.

A new study comparing matched sibling versus unrelated donor transplantation provides reassurance for continued use of unrelated donor stem cells.2 The survival of children with high-risk ALL was not affected by donor selection. The incidence of relapse was low in both groups of patients.

Furthermore, the rates of acute graft-versus-host disease, a serious complication of stem-cell transplantation, did not differ between sibling and unrelated donor use. Chronic graft-versus-host disease occurred more frequently after sibling donor transplantation. However, severe infections were more common among children who underwent unrelated-donor transplantation. These findings suggest that stem-cell transplantation using a well-matched unrelated donor could be a viable alternative for children with ALL who are at high risk of relapse but do not have a matched sibling donor. 


Representative Chuck Fleischmann of Tennesee

"We all worry about ourselves, family, friends being touched by cancer. When an oncologist walks into our offices, we want to hear what you have to say, what we can do to ensure high-quality, high-value care for all cancer patients. We can fight this fight together." 

— Rep. Chuck Fleischmann (R-TN)

Reducing The Disparities In The Care Of Minorities

Minorities have historically been underrepresented in clinical trials. Despite improvements in the two decades since Congress required that research funded by the NIH include minorities, only 10% of patients enrolled in clinical trial are minorities.

The participation of adult minorities in cancer clinical trials is still not proportional to the overall representation of minorities in the United States. This lack of diversity makes it difficult to generalize clinical trial findings to real-world populations.

federally funded research logo

Barriers to minority participation in clinical research are complex and multifaceted. The IMPaCT (Increasing Minority Participation in Clinical Trials) project was the first to use patient navigation to address such barriers (this study was funded by a grant from the NIH).3

Between 2007 and 2014, more than 400 African American patients with cancer were referred to IMPaCT. Patient navigators matching the demographic characteristics of patients provided guidance to project participants.

Nearly 80% of the study participants who were eligible for a clinical trial enrolled. Patient navigation also improved retention in clinical trials. The trial completion rates were 74% for those who used patient navigation support while participating in a clinical trial, compared with 34% for those who did not have the support of a patient navigator. 

Selecting Care To Preserve Quality of Life 

Approximately one in four patients with cancer experiences brain metastases. Lung and breast cancers are the two cancers that are most likely to spread to the brain. Generally, patients with brain metastases have a short life expectancy, but prognosis can vary significantly from patient to patient.

The initial treatment of most patients with limited brain metastases is stereotactic radiosurgery (SRS). SRS is a type of radiotherapy that aims beams precisely at the area of the brain tumor. After SRS, some patients also receive adjuvant whole-brain radiation therapy (WBRT).

federally funded research logo

The use of WBRT in patients with limited brain metastases has been controversial. Although WBRT does control tumor growth, it can have detrimental effects on quality of life. Preliminary findings from a federally funded study have provided new insights into the impact of adjuvant WBRT on cognition (this study was funded by a grant from the NIH).4

Patients with one to three small brain metastases who received WBRT after SRS were more likely to experience cognitive decline within the first 3 months than those who received SRS alone. Specifically, those who received WBRT had a greater decline in memory and verbal communication. There was no significant survival benefit from WBRT, compared with SRS alone.

The results strongly suggest it may be preferable to forgo WBRT in favor of SRS, because SRS can preserve a patient’s cognitive function as long as possible. Longer-term follow-up to assess late neurocognitive effects of WBRT is pending.

Nonetheless, WBRT decreases recurrence of brain metastases, and it is possible that it may prolong survival in certain patients. A smaller Japanese study identified one such patient group.5 Patients with NSCLC who had one to four brain metastases and a favorable prognosis lived 6 months longer when treated with SRS and WBRT compared with SRS alone. No such survival advantage was observed among patients with a poor prognosis. Larger prospective studies are needed to confirm these findings. 


In Their Own Words: Desirée Walker

Desirée Walker

After being diagnosed with breast cancer at the tender age of 38, I was forced to learn a new language (i.e. “breast cancer lingo”). I never thought I would be a statistic (i.e. young African American diagnosed with breast cancer). After all, I had never met any young women diagnosed with the disease, and at the time, African Americans had a lower incidence of the disease. 

In my search for support, I began sharing my journey through a faith-based organization that conducts breast and cervical cancer outreach in the African American community to build awareness around the diseases. I soon realized that telling my story was as therapeutic for me as it was inspiring for others.

It is vital for people with cancer to participate in clinical trials whenever possible. Everyone’s involvement helps determine the efficacy of treatments and increase the knowledge around the disease’s effect in all racial/ethnic groups.

I do believe that federal funding for cancer research should be increased for innovative research proposals whose end goal is to find a cure (i.e. prevent cancer and metastasis). New research should include diverse populations and be patient-centered to ensure a patient’s quality of life is paramount. Too many treatments allow people to be alive but are too harsh for them to enjoy life fully.

Desirée is a 14-year breast cancer survivor, member of the Young Survival Coalition Board of Directors, SHARE volunteer, and patient advocate for the National Breast Cancer Coalition, National Coalition for Cancer Survivorship, and National Center for Health Research.



Palliative Care Benefits Extend Beyond The Patient

Palliative care is focused on the relief of suffering throughout the course of a patient’s illness, starting from the time of diagnosis. It is a partnership between the patient, medical specialists, and the patient’s family, with the goal of improving outcomes for both the patient and the family. Benefits of palliative care range from improved quality of life and treatment satisfaction to extended survival and reduced overall cost of care.

Unfortunately, many patients do not benefit from the full range of palliative care services, because palliative care is often introduced late in the course of cancer treatment. In 2012, ASCO recommended concurrent use of palliative care with cancer care early in the course of illness for any patient with metastatic cancer and/or high symptom burden.6

The randomized clinical trial Educate, Nurture, Advise, Before Life Ends (ENABLE) III has provided new evidence in favor of early palliative care. The study was one of the first to test concurrent palliative care interventions for patients and caregivers (this study was funded by a grant from the NIH).7

Researchers compared outcomes of patients with advanced cancer who received palliative care consults at the time of diagnosis of advanced cancer versus 3 months later. Although there were no differences in quality in life between the two groups, patients who received palliative care early lived longer. The 1-year survival rate for those who received early palliative care consults was 63%, compared with 48% for those who received delayed consults.

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The same study also assessed a telephone-based palliative care intervention for the family caregivers of the patients who participated (this study was funded by a grant from the NIH).8 Because most study participants resided in rural areas, a telephone intervention improved access to palliative care services. The intervention began either shortly after the patient’s diagnosis or 3 months later. An early intervention was associated with lower caregiver depression compared with delayed intervention, and quality of life was comparable between the two groups.

Family caregivers are a crucial part of the patient care team. They provide daily assistance with symptom relief, emotional and spiritual support, personal care, transportation, and care coordination. Coupled with the emotional burden of their loved ones’ suffering, caregivers endure considerable strain that can affect their well-being. In fact, prior research has shown that a caregiver may experience psychological distress that is greater than the patient’s own.

Because the well-being of caregivers affects the well-being of patients, both parties benefit when caregivers receive palliative care. It is apparent that the earlier the palliative care services can be introduced to caregivers, the better they will be able to cope with their experience in the caregiving role. Future caregiver interventions should be tested in larger and more diverse populations.

The mounting evidence for the benefits of early palliative care has also spurred efforts to expand the availability of such services to all patients who need them. There are still many barriers to achieving this goal, from lack of trained personnel to insufficient funding.

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Recent research points to one barrier to awareness and education that may be relatively easy to address (this study was funded by a grant from the NIH).9 The study found that some physicians are more likely to refer patients with cancer to end-of-life hospice care than others. That is, those physicians who had previously referred patients to hospice were approximately twice as likely to send other patients to hospice.

Moreover, the characteristics of the treating physicians were stronger predictors of hospice enrollment than the patients’ medical status, age, gender, or sex. The findings show that more effort is required to ensure that palliative care referrals are driven primarily by the alignment of patients’ needs and preferences with the assessment of the treating physicians. 

The Appendix lists additional notable advances in patient care.


  1. Armstrong, GT, Yasui Y, Chen Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS). J Clin Oncol 33, 2015 (suppl; abstr LBA2)
  2. Peters C, Schrappe M, von Stackelberg A, et al: Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors—The ALL-SCT-BFM-2003 trial. J Clin Oncol 33:1265-1274, 2015
  3. Fouad M, Acemgil A, Bae S, et al: Patient navigation as a model to increase minority participation in cancer clinical trials. J Clin Oncol 33, 2015 (suppl; abstr 6559)
  4. Brown PD, Asher AL, Ballman KV, et al: NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol 33, 2015 (suppl; abstr LBA4)
  5. Aoyama H, Tago M, Shirato H; Japanese Radiation Oncology Study Group 99-1 (JROSG 99-1) Investigators: Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: Secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA Oncol 1:457-464, 2015
  6. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012
  7. Bakitas MA, Tosteson TD, Li Z, et al: Early versus delayed initiation of concurrent palliative oncology care: Patient outcomes in the ENABLE III randomized controlled trial. J Clin Oncol 33:1438-1445, 2015
  8. Dionne-Odom JN, Azuero A, Lyons KD, et al: Benefits of early versus delayed palliative care to informal family caregivers of patients with advanced cancer: Outcomes from the ENABLE III randomized controlled trial. J Clin Oncol 33:1446-1452, 2015
  9. Obermeyer Z, Powers BW, Makar M, et al: Physician characteristics strongly predict patient enrollment in hospice. Health Aff (Millwood) 34:993-1000, 2015