This year, more than 14 million people worldwide will learn they have cancer. According to the latest global statistics, nearly 9 million people a year lose their lives to cancer. That equates to approximately 22,000 cancer deaths per day.25 The global cancer burden is expected to grow in the future, reaching 21 million patients with cancer and 13 million deaths per year by 2030, as the world’s population expands and ages. These sobering statistics underscore the urgency of finding better treatments for patients today and in the future.
The number of new FDA approvals in oncology in recent months is reflective of the scientific fervor and innovation underway to fill this need. From November 2016 through October 2017, the FDA approved a record 18 new cancer therapies and 13 new uses of cancer therapies (Appendix Table A1). By comparison, in the same timeframe in the previous year, there were eight new cancer therapies and 13 new uses approved, and a similar number in 2015. Most, if not all, of these new and expanded uses are associated with an improvement in patient survival and/or quality of life.
Also historic, 2017 marked the first approval of a tumor-agnostic therapy and the first adoptive T-cell and gene therapy for cancer, demonstrating that the breakthrough therapy designation and other new approaches in oncology drug development have allowed for a more efficient review and approval process. Research results on other immunotherapies and targeted therapies released in 2017 have changed the treatment paradigms for lung, prostate, and bladder cancer.
Emergence of Tissue-Agnostic Therapies: Treating Patients on the Basis of the Tumor's Genetics, Rather Than Its Location
Historically, cancer therapies have been approved for use on the basis of the tumor’s location in the body and stage of cancer. Last year marked a milestone in the history of precision cancer medicine and cancer drug approvals: In May, the FDA approved the first tissue-agnostic treatment, which means that it was approved for use solely on the basis of the genetic make-up of a person’s cancer, rather than the type of cancer or its location in the body.26 Pembrolizumab was approved for the treatment of adults or children with advanced solid tumors that harbor specific genomic changes—mismatch repair (MMR) deficiency or high microsatellite instability (MSI-H).
FDA approval was based on findings from 149 patients with MMR-deficient or MSI-H solid tumors—90 had colorectal cancer and 59 had one of 14 other types of cancer—who were enrolled in five clinical trials. Tumors shrank in 40% of patients, and in 78% of those patients, tumor response lasted 6 months. In one of the studies that included patients with 12 different types of cancer, 21% of patients experienced a complete remission of cancer (this study was funded, in part, by grants from the NIH).27
Cells with MMR deficiency have a lower ability to repair damage to their genetic material or DNA and, as a result, accumulate a high number of mutations and make many abnormal proteins. Recent research has shown that programmed death-1/programmed death ligand-1 immune checkpoint inhibitors, which work by unleashing the immune response to cancer, are particularly effective against tumors with MMR deficiency. The reason for this is thought to be a stronger immune response to tumors with more abnormal proteins that the immune system recognizes as foreign.
Voices of Cancer Research: Erin Miller
Erin Miller was the primary caregiver for her husband Mike, who was diagnosed with pancreatic cancer. He received several rounds of chemotherapy but eventually became too sick to continue treatment. They were told that he only had a few months to live.
Erin says it was then that Mike began a gene therapy clinical trial for pancreatic cancer. Soon after, he was feeling better and was well enough to coach his daughter’s tee-ball team, go camping with his two sons, and take a ski trip with the family.
Erin is thankful that their family received additional time with Mike, who passed away nineteen months after starting the trial.
“My daughter, who was 4 when Mike was diagnosed, would probably not have remembered him had he not lived those extra months,” Erin says. “Every day was a treasured gift to us.”
Erin Miller, pictured here with her husband Mike, is a Program Services Coordinator at the Lazarex Cancer Foundation.
With this approval, subsets of patients with various types of cancer that are otherwise resistant to treatment gained a highly effective treatment option for controlling the disease, potentially long term. Testing for MMR deficiency or MSI-H will become part of routine diagnostic workup for many patients with solid tumors.
In 2017, researchers presented the early findings from a study of another treatment that seems to work well across many different types of adult and pediatric cancers. The treatment, called larotrectinib, selectively targets a rare genomic abnormality, the tropomyosin receptor kinase (TRK) gene fusion.
It is estimated that this abnormality occurs in approximately 0.5% to 1% of many common cancers. In addition, more than 90% of certain rare cancers, such as salivary gland cancer, pediatric breast cancer, and infantile fibrosarcoma, have TRK fusions.
Of the first 50 adults and children with 17 different cancer types who received larotrectinib in clinical trials, treatment response rate was nearly 80%.28 Responses to larotrectinib have been long lasting, with 79% ongoing at 12 months after starting treatment. The most common adverse effects were fatigue and mild dizziness, which were expected, as the normal TRK protein has a role in controlling balance. No patients needed to stop treatment as a result of adverse effects.
In another clinical trial that enrolled 12 young children with different cancers that harbored TRK fusions (infantile fibrosarcoma, other sarcomas, and papillary thyroid cancer) the response rate to larotrectinib was 92%, and responses were also durable. At 6 months, the cancer had worsened in only one patient.29
These trials that show strong tumor responses in tumors with TRK fusions, regardless of histology, represent a major development in the field. These findings pave the way for a new class of drugs for rare tumors and define a new era in oncology. Equally important, they set a new milestone in precision medicine for pediatric oncology, for which it is just starting to be applied.
Funding cancer research is a moral, fiscal, and national security imperative, and is the priority of every family in every neighborhood of America, regardless of their political party. I will fight to provide researchers with the necessary resources so that they can find cures and save lives.
Representative Kevin Yoder (R-KS-03)
Co-Chair, Cancer Caucus
A Policy Focus: FDA's New Plan to Increase Medical Innovation
The FDA has launched a new Medical Innovation Development Plan designed to facilitate the development of innovative drugs by updating FDA’s regulatory tools and policies. FDA intends to use the new plan to streamline the path to market for targeted therapies and other novel drugs to encourage innovation in therapies. In particular, the plan will focus on facilitating the approval of tumor-agnostic therapies—medicines that work comparatively well in many different types of cancer. As part of the plan, FDA will develop guidance on strategies to improve the efficiency of clinical trials, including adaptive trial designs.
New Treatments Slow Advanced Lung Cancer Growth
Lung cancer is among the most common types of cancer and the leading cause of cancer death in men and women worldwide. Last year, an estimated 156,000 people died of this disease in the United States.30
The good news is that these grim statistics have been steadily improving. After decades of increases, rates of lung cancer deaths began to decline in the early 1990s and have been falling, on average, 2.5% each year between 2005 and 2014. The 5-year survival rate increased from only 11% in 1975 to 18% in the most recent time period measured (2007 to 2013).30 For more information about lung cancer, visit Cancer.Net.
This progress is directly tied to changes in therapy that have occurred during the past two decades, with the development of new therapies that not only work better, but that often also have fewer adverse effects than standard chemotherapy, radiation, and surgery.
In 2017, two new regimens were introduced for the initial treatment of the most advanced form of non–small-cell lung cancer (NSCLC)—a targeted medicine, alectinib, and an immune checkpoint inhibitor, pembrolizumab, combined with chemotherapy. For patients with earlier-stage disease, a clinical trial demonstrated that administering a new immune checkpoint inhibitor, durvalumab, after standard chemotherapy and radiation dramatically slowed cancer growth.
New targeted medicine works better than chemotherapy and with fewer adverse effects.
Up to 7% of NSCLCs have a genetic change known as anaplastic lymphoma kinase (ALK) rearrangement that results in an abnormal ALK protein that causes cells to grow and spread. The first medicine that targets ALK, crizotinib, was approved by the FDA in 2011, and more potent medicines have been introduced since that time. In 2017, two clinical trials showed that one new ALK medicine, alectinib, is more effective than crizotinib for patients with previously untreated NSCLC, and also causes fewer adverse effects.32,33 In the larger of the two trials, during a median follow-up of 18 months, 41% of patients who received alectinib had their cancer worsen, or died, compared with 68% of those who received crizotinib.33 Alectinib was also better at curbing the growth of cancer that had spread to the brain; only 12% of patients had worsening brain metastases compared with 45% of those who received crizotinib.
Changing Paradigms in Lung Cancer Treatment
The first paradigm shift occurred in the mid-1990s with research that demonstrated that giving chemotherapy after surgery, known as adjuvant therapy, helps patients live longer, and that combining chemotherapy with radiation therapy can additionally improve the outlook for some patients with lung cancer. Several new chemotherapies were introduced, such as paclitaxel, docetaxel, gemcitabine, and pemetrexed.
The second paradigm shift in the treatment of advanced lung cancer occurred in 2004, when scientists discovered the association between certain mutations in the epidermal growth factor receptor (EGFR) and response to EGFR-targeted drugs, such as gefitinib. EGFR is a protein that helps cancer cells grow and is mutated in 25% of lung cancers. In the ensuing years, several EGFR-targeted drugs were developed (erlotinib, afatinib, and osimertinib) as well as treatments that target less common genetic alterations (BRAF gene mutations [dabrafenib plus trametinib] and ALK gene rearrangements [crizotinib, ceritinib, and alectinib]).
Finally, the introduction of immunotherapy in 2015 marks the third paradigm shift in the treatment of lung cancer. Immune checkpoint inhibitors, pembrolizumab and nivolumab, were first approved for the treatment of advanced NSCLC that worsens during or after standard chemotherapy, and atezolizumab was approved in 2016. That same year, the FDA approved the first use of immunotherapy for previously untreated advanced NSCLC, pembrolizumab. Currently, immunotherapy is also being studied in earlier stages of disease. In a clinical trial of patients with locally advanced, stage III NSCLC, the checkpoint inhibitor durvalumab delayed disease worsening by nearly 1 year. The ongoing ALCHEMIST immunotherapy trial (ClinicalTrials.gov identifier: NCT02595944) explores whether giving nivolumab after standard treatment of early-stage lung cancer can reduce recurrences and help patients live longer.
Reflecting on these developments, ASCO’s clinical practice guideline for advanced NSCLC was revised in 2017 to add immunotherapy as a standard treatment approach for either first-line or second-line settings.31
Role of immunotherapy continues to expand, slowing advanced cancer growth.
In 2017, the FDA granted accelerated approval to pembrolizumab combined with standard chemotherapy (carboplatin and pemetrexed) as an initial treatment of metastatic NSCLC.34 The approval was based on an early clinical trial that found that the chance of cancer worsening was cut nearly in half by adding pembrolizumab to chemotherapy. The median time until cancer worsening was 13 months with pembrolizumab and chemotherapy versus 9 months with chemotherapy alone; however, the incidence of serious treatment-related adverse effects was higher with combined modality treatment (41%) than chemotherapy alone (28%). An international phase III clinical trial is underway to confirm these findings (ClinicalTrials.gov identifier: NCT02578680).
A newer immune checkpoint inhibitor, durvalumab, also seems to have a role in lung cancer treatment. These findings mark the first advance in years for the treatment of stage III, locally advanced NSCLC. This type of cancer accounts for approximately one-third of all NSCLCs. The standard treatment of patients with tumors that cannot be surgically removed is chemotherapy with radiation, or chemoradiotherapy. Despite this treatment, cancer quickly worsens, and only 15% of patients are alive 5 years after diagnosis.
In this trial, patients whose cancer did not worsen after chemoradiotherapy were randomly assigned to receive durvalumab or placebo.35 The median time until cancer worsening was 16.8 months with durvalumab and 5.6 months with placebo, and the median time until patients died or the cancer spread to distant parts of the body was 23.2 months versus 14.6 months, respectively.
Continued Research on Immune Checkpoint Inhibitors
Uses for immune checkpoint inhibitors—treatments that help unleash the body’s immune response to cancer—continue to expand to more cancer types, which has affirmed the role of this strategy, and particularly agents that target the programmed death-1/programmed death ligand-1 checkpoint in cancer treatment. Key recent studies in this area are listed in Table 1.
Immunotherapy Changes the Treatment Paradigm for Bladder Cancer
Bladder cancer is another type of cancer for which immunotherapy has transformed the outlook for patients. The most common type of bladder cancer, urothelial cancer, is difficult to treat at advanced stages. With standard chemotherapy, only 5% of patients are alive 5 years after diagnosis. For more information about bladder cancer, visit Cancer.Net.
After 30 years of limited progress, the outlook for these patients is now improving with the arrival of a series of immunotherapies (Table 2). For some patients, immunotherapy has opened a treatment option where none previously existed. For others, it offers a chance to live longer with fewer treatment-related adverse effects.
In May 2016, atezolizumab became the first immune checkpoint inhibitor to receive FDA approval for the treatment of advanced bladder cancer.49 In 2017, the FDA approved four other immune checkpoint inhibitors for patients with previously treated urothelial cancer that worsened, despite platinum-based chemotherapy—nivolumab, avelumab, pembrolizumab, and durvalumab.50-53 In a large clinical trial that led to the approval of pembrolizumab, patients who received the immunotherapy lived approximately 3 months longer than those who received chemotherapy. Meanwhile, the rate of serious treatment-related adverse effects was more than three times lower in the pembrolizumab group than in the chemotherapy group (15% v 49%).54
Recent clinical trials also point to the potential use of immunotherapy as an initial treatment for advanced bladder cancer. As a result of physical frailty and certain health conditions, up to two-thirds of patients are not eligible for cisplatin-based chemotherapy, which is the standard initial treatment of this disease. Alternative chemotherapies exist, but are less effective; therefore, many such patients receive only supportive care.
In 2017, the FDA granted accelerated approval to pembrolizumab for this indication.53 The approval was based on a clinical trial of patients with locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-containing chemotherapy.55 At a median follow-up of 8 months, treatment response rate was 28%, and responses lasted up to 18 months (median duration not reached). Pembrolizumab was well tolerated, with serious adverse effects occurring in 18% of those treated.
In another clinical trial, atezolizumab also was proven to be effective as an initial therapy for patients with advanced urothelial cancer who cannot receive cisplatin-containing chemotherapy.56
At a median follow-up of 18 months, the treatment response rate was 23% and median survival was nearly 16 months. These advances have defined new standards of care for patients with advanced bladder cancer.
A Policy Focus: Promoting Patient Participation in Clinical Trials
Clinical trials are critical for the advancement of new cancer treatments, but only a small percentage of patients (< 3%) in the United States participate in clinical trials.57 In clinical trials, eligibility criteria define the trial population and protect the safety of trial participants, particularly those who may be more vulnerable to the adverse effects of treatment in a clinical trial; however, overly restrictive eligibility criteria can make trial findings more difficult to apply to the treatment of real-world patients with cancer.
ASCO, in collaboration with the nonprofit advocacy organization, Friends of Cancer Research, issued a joint research statement calling for the use of more inclusive eligibility criteria for cancer clinical trials. The statement, published in Journal of Clinical Oncology, provides recommendations to address eligibility criteria in five areas: minimum age requirements for trial enrollment, patients with HIV/AIDS, patients with brain metastases, patients experiencing organ dysfunction, and patients with prior and concurrent malignancies.
ASCO is working with the FDA and clinical trial sponsors to identify additional opportunities to safely expand eligibility criteria for oncology trials.
New Approaches Help People With Brain Cancer Live Longer
Two new regimens extend survival in patients with glioblastoma.
Grade IV glioma, or glioblastoma (GBM), is one of the most common and deadliest types of brain cancer in adults. With current therapies, fewer than one in 10 patients live 5 years after a diagnosis of GBM. There are now two new strategies that can possibly lengthen life for people with GBM. For more information about GBM and other brain tumors, visit Cancer.Net.
The first involves a novel technology known as tumor-treating fields (TTFs). These are low-intensity electrical fields that are thought to slow cancer growth by blocking cell division. TTFs are delivered to the brain tumor through the skin from a device that patients wear on their head continuously at least 18 hours a day. Preliminary findings from a clinical trial of TTFs led to the FDA approval of the device in 2015 for use in combination with temozolomide chemotherapy, after surgery, chemotherapy, and radiation, for patients with newly diagnosed GBM.58
In 2017, researchers reported longer follow-up findings from the same clinical trial.59 The risk of death was reduced by 37% for patients who used the device compared with those who received chemotherapy alone, with a median survival of 21 months with TTFs and chemotherapy, versus 16 months with chemotherapy alone. The addition of TTFs also doubled the 5-year survival rate, from 5% to 13%.
The second advance is the discovery that adding temozolomide chemotherapy to short-course radiotherapy results in longer survival than radiotherapy alone in elderly patients with GBM.60 The prognosis for elderly patients with GBM is poor and questions remain about the optimal treatment of older patients.
In the study, patients who received temozolomide with radiotherapy had a 33% lower risk of death and lived longer than those who received radiotherapy alone (median, 9.3 months v 7.6 months, respectively), whereas quality of life was similar between the two groups. Researchers also confirmed prior findings that suggested that a genomic biomarker, methylation of the O6-methylguanine–DNA methyltransferase (MGMT) gene, predicts better outcomes in patients with GBM. Among patients with methylated MGMT, median survival with radiotherapy plus temozolomide was 13.5 months compared with 7.7 months with radiotherapy alone.
Adding chemotherapy to radiation slows glioma growth.
Grade III glioma, or anaplastic glioma, commonly occurs in young adults. This type of brain tumor can grow quickly and can recur as GBM despite treatment.
For patients with anaplastic glioma with a genomic abnormality known as 1p19q codeletion (loss of chromosome arms 1p and 19q) there is clear evidence that adding chemotherapy to radiation therapy improves survival; however, there are conflicting reports of the value of adjuvant (postsurgery) chemotherapy for anaplastic glioma without 1p19q codeletion. Preliminary findings from a large clinical trial have clarified the role of adjuvant temozolomide in this patient population.61
The 5-year survival rate was markedly longer when temozolomide was added to radiation therapy (56%) than when patients received radiation therapy alone (44%). Addition of temozolomide after radiation therapy delayed disease worsening by more than 2 years (median, 43 months v 19 months, respectively). Temozolomide was well tolerated, with serious adverse effects occurring in only 12% of patients. These findings have established this regimen as a new standard of care for patients with anaplastic glioblastoma without 1p19q codeletion.
New Targeted Therapy Regimens for Breast Cancer
For BRCA-related breast cancer, olaparib is more effective than chemotherapy.
Findings from a large clinical trial of women with advanced, BRCA-related breast cancer point to a new type of treatment for the disease—poly (ADP-ribose) polymerase (PARP) inhibitors. Compared with standard chemotherapy, the PARP inhibitor olaparib lowered the risk of cancer worsening by 42% and extended the time until the cancer worsened by approximately 3 months.62 Severe adverse effects were less common with olaparib, occurring in 37% of patients compared with 50% of those who were treated with chemotherapy. For more information about advanced breast cancer, visit Cancer.Net.
Whereas several PARP inhibitors are already approved by the FDA for the treatment of ovarian cancer, this is the first study to demonstrate clinical benefit from this approach in patients with breast cancer. Several other large clinical trials of olaparib in breast cancer are underway (ClinicalTrials.gov identifiers: NCT02032823 and NCT03167619).
Up to 3% of all breast cancers occur in women who carry inherited changes in genes BRCA1 and BRCA2. These changes undermine the ability of the cell to repair damaged DNA. Because of their underlying defect in DNA repair, cancer cells with BRCA mutations are particularly vulnerable to treatments that target PARP, another key component of the cell’s DNA repair machinery.
Dual targeted therapy lowers the risk of invasive breast cancer in some women.
A clinical trial of nearly 5,000 women with early, human epidermal growth factor receptor 2 (HER2)-positive breast cancer has suggested that adding a second HER2-targeted medicine, pertuzumab, to the standard regimen of the HER2-blocking therapy trastuzumab and chemotherapy may help some women.63
Recurrences were reduced by approximately one fifth in patients who received pertuzumab with trastuzumab after surgery compared with those who received trastuzumab and placebo. At 3 years, an estimated 94.1% of patients in the pertuzumab group were free of invasive breast cancer compared with 93.2% of patients in the placebo group. Addition of pertuzumab did not increase the rate of heart problems, which is the greatest concern with HER2-targeted therapy.
Treatment benefit was particularly evident in patients with breast cancer that had spread to lymph nodes—an estimated 92% were free of invasive cancer compared with 90.2% of those who received placebo at 3 years. In contrast, in patients with node-negative cancer, pertuzumab did not improve invasive disease–free survival.
These findings may set a new standard of care for some patients with node-positive, HER2-positive, hormone receptor–negative breast cancer who have a higher risk of developing invasive breast cancer.
Meanwhile, researchers are trying to identify biomarkers that may help predict which groups of patients will benefit most from pertuzumab. The good news from this trial is that patients with HER2-positive breast cancer—the group of patients that used to have the worst prognosis—are doing so well on trastuzumab alone.
Voices of Cancer Research: Teri Pollastro
At 43 years old, Teri received her second breast cancer diagnosis, though this time the cancer had spread to other parts of her body. “I had very little hope,” she says.
Teri had two young daughters to raise, so she focused intently on finding new therapies that could treat metastatic cancer, trying different therapeutic approaches over the years. She is thankful that she had access to state-of-the-art treatments not available in many parts of the world, as well as innovative clinical trials evaluating vaccine therapy and stereotactic radiation.
Teri is grateful to cancer research for giving her more than 14 years with her family since her diagnosis.
“Without advances in cancer research, I would not have been able to raise my two daughters,” says Teri, who celebrated her 25th wedding anniversary with her husband in November. “With the novel treatments I continue to receive, I am able to enjoy ‘the good stuff’ in life. Additionally, I am able to advocate for myself and those who cannot for more metastatic cancer research with the hope of finding cures.”
Teri is a volunteer with the Seattle Cancer Care Alliance, MBC Alliance, Susan Komen Puget Sound, and Translational Breast Cancer Research Consortium.
Research Supports Extended Hormone Therapy for Patients With Higher-Risk Breast Cancer
To lower the chance of cancer recurrence, many women with early breast cancer receive hormone therapy after surgery. Until recently, the recommended standard duration of such therapy had been 5 years, but new research findings suggest that extending hormone therapy may benefit some patients.
In 2016, a large clinical trial found that in women with hormone receptor–positive, early breast cancer who received the aromatase inhibitor letrozole for 10 years, breast cancer recurrences or new cancers in the opposite breast were reduced by approximately one third compared with women who received 5 years of aromatase inhibitor therapy.64 Later that year, an even larger trial reported a similar (29%) reduction in the risk of breast cancer recurrence or cancer in the opposite breast for women who received 5 additional years of letrozole after 5 years of aromatase inhibitor therapy (this study was funded, in part, by a grant from the NCI).65 However, longer hormone therapy did not improve overall or disease-free survival—the primary endpoint of the study—and was accompanied by a small increase in the risk of blood clots.
In late 2017, researchers reported on an improvement in disease-free survival for women who received extended aromatase inhibitor therapy after tamoxifen.66 In that clinical trial, 5-year disease-free survival was 83% among women who received anastrozole for 6 years, and 79% among those who received it for 3 years; however, patients in the 6-year therapy group had more adverse effects, including joint and muscle pain.
Taken together, these findings support longer hormone therapy for women with early breast cancer who have a higher risk for recurrence on the basis of tumor features and patient-specific factors. Discussion of therapy duration should take into consideration the adverse effects the patient experienced during initial hormone therapy, as well as ongoing health conditions. If patients are carefully selected for extended hormone therapy, breast cancer mortality can be additionally reduced without overtreatment.
Bevacizumab May Help Some Women With Ovarian Cancer Live Longer
Women with recurrent ovarian cancer have a short life expectancy and limited treatment options. In late 2016, the FDA approved a new regimen that improves their outlook—adding bevacizumab to standard platinum-based chemotherapy. This was the first approval of a new treatment of platinum-sensitive ovarian cancer in more than a decade. Bevacizumab had been previously approved for the treatment of women with platinum-resistant ovarian cancer. For more information about ovarian cancer, visit Cancer.Net.
This new approval was based on a clinical trial in which women received standard chemotherapy alone or bevacizumab with standard paclitaxel plus carboplatin chemotherapy, followed by maintenance therapy with bevacizumab (this study was funded, in part, by a grant from the NCI).67 Addition of bevacizumab significantly extended median time until cancer worsening to 13.8 months compared with 10.4 months with chemotherapy alone. Overall survival was also longer with bevacizumab than with chemotherapy alone (median, 42 months v 37 months), but this difference was not statistically significant; however, the rate of severe adverse effects was higher in the bevacizumab group (96%) than in the standard therapy group (86%), with high blood pressure and fatigue being the most common adverse effects with bevacizumab.
New Maintenance Therapies Keep Recurrent Ovarian Cancer From Worsening
Maintenance therapy for ovarian cancer is critical because of the high rate of recurrence, despite initial response to standard platinum-based chemotherapy. In 2017, the FDA approved a new maintenance treatment, the PARP inhibitor olaparib, for women with recurrent ovarian cancer who responded to platinum-based chemotherapy.68 Approval was based on a clinical trial in which olaparib was demonstrated to markedly slow cancer growth.69 Median time until cancer worsening was 19.1 months with olaparib versus 5.1 months with placebo. The most common severe adverse effects of olaparib were anemia and fatigue.
Meanwhile, in a clinical trial of maintenance therapy with the PARP inhibitor rucaparib, the growth of platinum-sensitive, recurrent ovarian cancer was also slowed.70 Overall, rucaparib delayed cancer worsening by approximately 5 months longer than placebo (10.8 months v 5.4 months, respectively). Benefit was greatest among women with BRCA mutations (median time until cancer worsening was 16.6 months with rucaparib v 5.4 months with placebo), as well as women with tumors that harbored defects in DNA repair machinery (median time until cancer worsening was 13.6 months with rucaparib v 5.4 months with placebo). The most common severe adverse effects of rucaparib were anemia and liver enzyme abnormalities. These findings have been submitted to the FDA for the approval of rucaparib in this setting.
A Policy Focus: Learning More About Older Adults With Cancer
More than 60% of cancer diagnoses in the United States occur in people age 65 years or more—a population that will grow rapidly over the coming years. Whereas 70% of cancer deaths occur in older adults, and older adults make up the majority of survivors of cancer, the evidence base for treating this population is sparse. Older adults are underrepresented in clinical trials, and trials designed specifically for older adults are rare.
ASCO and the FDA held a workshop in November 2017 to discuss ASCO’s recommendations to improve the evidence base for treating older adults. ASCO is continuing to urge federal agencies and the cancer research community to increase the enrollment of older adults in clinical trials and use other strategies to collect evidence on this population of patients.
Voices of Cancer Research: Kenneth Monarrez
Kenneth is a father, coach, marathon runner and sales director at a mobile tech company. He was diagnosed with kidney cancer on New Year’s Day, 2013, and had a recurrence several years later.
Genetic testing revealed that Kenneth had a mutation in the BAP1 gene, which left him with no proven treatment options. He now participates in clinical studies where researchers monitor his progress closely with scans every three months while working to develop new medicines that target this particular gene.
“By participating in research, you are taking a risk,” Kenneth says, “but serving a greater good.”
Kenneth, pictured with his family, is a board member at the Gateway for Cancer Research.
Precision Medicine Helps People With Melanoma Live Longer
Whereas early-stage melanoma is curable with surgery, patients with stage III melanoma face a much higher chance of recurrence after surgery, and many ultimately die of metastatic disease. New findings suggest that a precision medicine approach that combines two targeted medicines can improve outcomes for a subset of patients.
The study was conducted in patients with tumors that harbored BRAF gene mutations, which occur in approximately 40% of all melanomas. BRAF mutations turn on a molecular pathway known as mitogen-activated protein kinase. Prior research has demonstrated that blocking this pathway with two medicines in combination—dabrafenib and trametinib—helps patients with metastatic, BRAF-mutated melanoma live longer (the FDA approved this regimen in 2014).
In 2017, researchers reported that the combination of dabrafenib and trametinib can also help patients with stage III melanoma by lowering the risk for recurrence after surgery.71 Estimated 3-year relapse-free survival rates were 58% with targeted therapy and 39% with placebo. Overall survival rates were 86% with targeted therapy versus 77% with placebo.
Combined targeted treatment was associated with a considerable rate of serious adverse effects (36%), including potentially fatal pneumonia. Overall, 26% of patients had to stop treatment earlier than the planned 12-month duration as a result of adverse effects. Currently, there is insufficient evidence to inform the most beneficial duration of adjuvant therapy for stage III melanoma. For more information about melanoma, visit Cancer.Net.
New Treatment Paradigms Help Men With Prostate Cancer Live Longer
Adding hormone therapy to radiation boosts the long-term survival rate.
More than 30% of men who receive surgery for localized prostate cancer experience a recurrence of cancer. Patients who experience a local recurrence after surgery receive radiation therapy, but despite the therapy, the cancer eventually worsens in up to 50% of men. For more information about prostate cancer, visit Cancer.Net.
A recent large clinical trial found that adding androgen-deprivation therapy to radiation therapy helps men, who experience a local recurrence after surgery, live longer (this study was funded, in part, by a grant from the NCI).72 The study enrolled men with prostate-specific (PSA) levels between 0.2 ng/mL to 4 ng/mL at least 8 weeks after surgery. Men were randomly assigned to receive androgen-deprivation therapy bicalutamide during and 24 months after radiation therapy or radiation therapy and placebo. Survival rate at 12 years was 76% in the bicalutamide group versus 71% in the placebo group. More men in the placebo group developed metastatic prostate cancer (23% v 14%, respectively) and more died of the disease (13% v 6%, respectively). Late effects of radiotherapy were similar between groups, but gynecomastia (swelling of breast tissue) was much more common with bicalutamide, occurring in 70% of men compared with 11% of those who received placebo.
Whereas other clinical trials are investigating the use of newer hormonal therapies with radiation therapy after prostate cancer surgery (ClinicalTrials.gov identifiers: NCT00541047 and NCT00423475), these findings provide strong evidence to support the combination of androgen-deprivation therapy with radiation therapy for men who experience a local recurrence after surgery.
A new standard of care for advanced prostate cancer.
Two large studies presented in 2017 demonstrated that adding abiraterone to standard androgen-deprivation therapy helps men with metastatic prostate cancer live longer. Whereas androgen-deprivation therapy slows prostate cancer growth by preventing the testicles from making testosterone, certain other organs in the body continue making small amounts of testosterone and other androgens. Abiraterone stops the production of both testosterone and other androgens throughout the body by blocking an enzyme that converts other hormones to androgens.
In the first study, patients with high-risk metastatic prostate cancer were randomly assigned to receive androgen-deprivation therapy with either abiraterone or placebo.73 At a median follow-up of 30 months, men who received abiraterone had a 38% lower risk of death than did those who received placebo. Abiraterone also more than doubled the median time until cancer worsening from 15 months to 33 months.
The second study, which included men with high-risk, locally advanced or metastatic prostate cancer, found that patients who received abiraterone with standard androgen-deprivation therapy had a 37% lower risk of death than those who received androgen-deprivation therapy alone.74 The 3-year survival rate was 76% with standard therapy alone and 83% with standard therapy plus abiraterone.
Taken together, these findings define a new standard of care for men with metastatic prostate cancer.
Research Informs Decision Making for Early Prostate Cancer Treatment
Men with early (localized) prostate cancer can choose one of three standard treatments, which include surgery, radiation therapy, or active surveillance. A recent clinical trial found no significant differences in 10-year survival with any approach, although active surveillance was associated with a higher risk of cancer worsening and metastasis.75
A subsequent analysis of patient-reported outcome data from the same clinical trial showed that adverse effects differed among the three approaches.76 Surgery had a greater negative impact on sexual function and urinary continence than either radiation therapy or active surveillance. In the active surveillance group, sexual and urinary function declined gradually. Bowel function problems were worse in the radiotherapy group than in the other two groups at 6 months, but subsequently recovered somewhat. There were no significant differences among the treatment groups in anxiety, depression, or general health-related or cancer-related quality of life.
Another clinical trial that compared surgery with active surveillance found that men who received surgery had more sexual dysfunction and urinary incontinence through 10 years than did those who received active surveillance (this study was funded, in part, by grants from the US Department of Veterans Affairs, the Agency for Healthcare Quality and Research, and the NCI).77 Limitations in activities of daily living through 2 years were also greater in the surgery group.
In addition, two large, population-based studies that observed men with localized prostate cancer for 3 years also found that patterns of adverse effects differed depending on the type of treatment men received. 78,79
Taken together, these findings from clinical trial participants as well as real-world patients will help clinicians better counsel patients about the risks and benefits of various treatments for localized prostate cancer.
Less Is More: Preserving Quality of Life With Less Treatment
Shorter chemotherapy for colon cancer is safe and lowers the chance of nerve damage.
For patients with stage III colon cancer, administering chemotherapy after surgery (adjuvant chemotherapy) lowers the chance that the cancer will come back. The standard 6-month course of adjuvant oxaliplatin-based chemotherapy can cause peripheral neuropathy. Symptoms of this condition, which include pain, tingling, numbness, and muscle weakness, sometimes persist indefinitely. Longer chemotherapy also typically means more diarrhea and fatigue, more doctor appointments, blood draws, and time away from work and social gatherings.
Six clinical trials with 12,800 patients in North America, Europe, and Japan explored whether adjuvant chemotherapy regimens that consisted of either FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) could be shortened to 3 months without compromising survival. In 2017, researchers reported on the analysis of pooled data from the trials (this study was funded, in part, by a grant from the NCI).80
The chance of being free from colon cancer at 3 years was only slightly lower with 3 months of chemotherapy than with 6 months (74.6% v 75.5%, respectively). For patients with a lower risk of cancer recurrence (T1 to T3 N1 colon cancer), the chance of being cancer free at 3 years was nearly identical between the two groups—83.1% in those who received a 3-month course and 83.3% in patients who received a 6-month course.
The rate of clinically meaningful nerve damage differed depending on the type of chemotherapy regimen received but was consistently lower for people who received 3 months versus 6 months of chemotherapy (15% v 45% with FOLFOX and 17% v 48% with CAPOX, respectively).
These findings, relevant to approximately 400,000 patients with stage III colon cancer worldwide, should inform conversations between oncologists and their patients. For patients with lower-risk stage III colon cancer, the shorter 3-month course will likely become the new standard of care. For patients with higher-risk cancer, decisions on shorter-duration therapy will have to be carefully weighed against the risks of recurrence, patient ability to tolerate chemotherapy and patient preferences. For more information about colon cancer, visit Cancer.Net.
Less extensive surgery for melanoma spares patients complications.
Many patients with intermediate-thickness melanomas (1.2 mm to 3.5 mm) routinely receive sentinel lymph node biopsy, a procedure that removes the first lymph node to which cancer cells are likely to spread. The lymph node is then checked for cancer. If cancer cells are found in this sentinel node, the patient is more likely to experience a recurrence of melanoma after surgery.
To lower the chances of recurrence in patients with cancer in sentinel nodes, removal of the remaining lymph nodes near the tumor is usually recommended; however, this more extensive surgery increases the risk for complications, particularly long-term swelling of an arm or leg from the build-up of lymph fluid in tissues, known as lymphedema. Experts have therefore questioned the value of this surgical procedure in patients with positive sentinel lymph nodes.
A large clinical trial reported in 2017 suggests that the removal of additional lymph nodes may not be necessary (this study was funded, in part, by a grant from the NCI).81 At 3 years, the rate of melanoma-specific survival (the percentage of people who had not died of melanoma) was the same (86%) whether patients received additional surgery to remove lymph nodes or were only observed.
Patients who received additional surgery had a lower risk of regional recurrence but also had more health complications. The rate of lymphedema was four times higher in the surgery group than in the observation group (24% v 6%, respectively). Given that lymph node surgery does not improve survival, it may be possible to avoid this treatment in many patients and spare them an additional surgery with its associated complications.
A Policy Focus: Streamlining Adverse Events Reporting for Cancer Clinical Trials
Regulations require research sponsors to report certain serious adverse events experienced by patients in a clinical trial to the FDA via an expedited process. The current challenge with reporting is the high volume of uninformative reports, which hinders patient safety, imposes a substantial toll on the FDA, research site time, and resources. In March 2017, ASCO held a workshop on streamlining adverse events reporting. Attended by stakeholders from across the cancer research community, including researchers, industry representatives, patient advocates, and officials from the FDA and the NCI, the workshop discussed ways to decrease over-reporting as well as best practices for adverse events reporting for both sponsors and research sites. Recommendations developed through this effort were published in late 2017 in the Journal of Clinical Oncology.
Fewer women having additional breast surgery after lumpectomy.
Performing a second surgery after initial lumpectomy for early-stage breast cancer was previously common. Second surgery was often recommended as a result of positive or close margins, which means that some cancer cells were found along the edge of the cancer tissue removed by lumpectomy; however, there has been controversy over what constitutes a negative margin.
In 2014, the Society of Surgical Oncology and the American Society of Radiation Oncology published an evidence-based consensus statement, endorsed by ASCO, that recommended that if there are no cancer cells adjacent to any inked edge/surface of the surgical specimen, the margins should be considered negative and a second surgery is not required.82
A recent large, population-based study assessed the effect of this recommendation on the rates of breast cancer surgery (this study was funded, in part, by a grant from the NCI).83 From 2013 to 2015, the rate of initial lumpectomy remained stable at 67%, but the rate of second breast surgery declined by 16%, and fewer women underwent a subsequent mastectomy. This study demonstrates the important role of clinical practice guidelines in reducing overtreatment.
Delaying rectal cancer surgery lowers the risk of complication.
Radiation therapy before surgery lowers the risk of local recurrence in patients with rectal cancer. In the past, it was considered important to perform surgery soon after the completion of radiation therapy, but a new study in Sweden found that delaying surgery by a few weeks is safe and results in fewer complications.84
There was no difference in local recurrence between patients who received the standard short-course radiation therapy with surgery within 1 week and those who received surgery 4 weeks to 8 weeks after either short-course radiation or long-course radiation therapy. Patients who received short-course radiation therapy with delayed surgery had a nearly 40% lower risk of complications after surgery than those who received standard short-course radiation without a delay in surgery.
Although common in Europe, short-course radiation therapy before surgery is not used in the United States, where the standard approach is chemotherapy and radiation. An ongoing clinical trial is exploring whether radiation therapy can be eliminated from the treatment of high-risk, locally advanced rectal cancer (ClinicalTrials.gov identifier: NCT01515787).
Lowering radiation therapy dose for throat cancer reduces long-term complications.
HPV-associated oropharyngeal cancer responds well to treatment, but the standard radiation therapy administered with chemotherapy can lead to debilitating long-term complications. As patients with HPV-associated oropharyngeal cancer tend to be younger, they may carry the burden of these complications for decades.
Two separate clinical trials found that lowering the standard radiation dose by 15% to 20% in patients with a favorable prognosis (ie, a complete clinical response is achieved with initial chemotherapy) does not compromise survival. In the first study, the 2-year survival rate was 94% for patients who were treated with 54 Gy and 96% for those who received 54 Gy or less, and adverse effects were milder with the lower dose (this study was supported, in part, by grants from the NCI and the US Department of Health and Human Services).85 At 12 months, markedly fewer patients in the lower-dose group had difficulty swallowing solids (40% v 89%, respectively) or impaired nutrition (10% v 44%, respectively) compared with patients who received higher doses of treatment. In the second study, where patients with a more favorable prognosis received a dose of 54 Gy and others received 60 Gy, cancer had not worsened for 92% of patients overall at 2 years. 86
If confirmed in a larger clinical trial, these findings will lead to a change in the standard of care for patients with lower-risk, HPV-related oropharyngeal cancer (eg, those with a minimal smoking history and small tumor size). For more information about oropharyngeal cancer, visit Cancer.Net.
Voices of Cancer Research: T.J. Sharpe
T.J. Sharpe was 37 years old, and his newborn son only four weeks old, when he was diagnosed with advanced melanoma.
Since then, T.J. has participated in more than one clinical trial. In one study, he was the first patient ever to receive a new combination of immunotherapies for melanoma. When that treatment stopped working, he enrolled in a second trial of a different immunotherapy. Thanks to this trial, five years since his diagnosis, T.J. has no detectable signs of cancer.
“Without patients willing to participate in clinical trials, the pace of drug development, and its life-improving, life-extending, and life-saving results, slows to a trickle,” T.J. says.
T.J. is pictured here with his oncologist, ASCO member Ena Segota, MD.
For additional advances in cancer treatment, please see Appendix Table A2.
Recent ASCO Clinical Practice Guidelines
Clinical practice guidelines help to distill knowledge about a particular clinical issue and provide recommendations to help clinicians deliver the best treatment and care to every patient. ASCO develops its clinical practice guidelines through a rigorous, systematic review of relevant medical literature and clinical interpretation from a multidisciplinary panel of experts and patient representatives. In 2017, ASCO issued more than 14 clinical practice guidelines, guideline updates, and provisional clinical opinions (Table 3). To view ASCO guidance by clinical area, visit the Quality and Guidelines page.