Harnessing Research Discoveries to Save Lives

In this section you will learn:

  • Progress against cancer is driven by research discoveries.

  • From August 1, 2016, to July 31, 2017, the FDA approved nine new therapeutics for treating certain types of cancer.

  • During the same period, the FDA authorized new uses for eight previously approved anticancer therapeutics.

  • The number of types of cancer for which immunotherapy is an approved treatment option is increasing rapidly.

  • Cancer genomics research is the foundation for novel clinical trials designed to accelerate the pace at which new therapeutics are approved for patient care.

  • Identifying ways to help survivors meet the many challenges they face after a cancer diagnosis is an area of intensive research investigation.

  • The dedicated efforts of individuals working throughout the cycle of biomedical research have improved and saved lives around the world by driving progress across the continuum of clinical cancer care (see Figure 8).

Contents

Biomedical Research

Progress Across the Clinical Cancer Care Continuum

 

Biomedical Research

Biomedical research is an iterative cycle, building on prior knowledge, with one discovery influencing the next (see Figure 8). In recent years, the cycle has become increasingly efficient as the pace of discovery has increased and new disciplines have been integrated. As a result of these changes, the rate at which research discoveries are being converted to lifesaving advances across the continuum of clinical cancer care has been accelerating. To maintain this momentum it is imperative that we better support investigators throughout their careers, but especially those early in their careers (see sidebar on Supporting Early-Career Investigators) (see Developing and Training the Cancer Workforce of Tomorrow, p. 101).

In short, the biomedical research cycle is set in motion when discoveries with the potential to affect the practice of medicine and public health are made in any area of biomedical research, including basic research, population research, clinical research, and clinical practice. The discoveries lead to questions, or hypotheses, that are tested by researchers performing experiments in a wide range of models that mimic what happens in healthy and diseased conditions. These models range from single cells and tissues from animals and/or humans to whole animals, individuals, and entire populations. The results from these experiments can lead to the identification of a potential therapeutic target, predictive biomarkers, or preventive intervention, or they can feed backward in the cycle by providing new discoveries that lead to more hypotheses.

After a potential therapeutic target is identified, it takes many more years of research before a candidate therapeutic is developed and ready for testing in clinical trials (see sidebar on Therapeutic Development). During this time, candidate therapeutics are rigorously tested to identify an appropriate dose and schedule, as well as any potential toxicity.

Clinical trials are a central part of the biomedical research cycle that ensure that research discoveries ultimately reach the patients who need them the most as quickly and safely as possible. Before most potential new diagnostic, preventive, or therapeutic products can be approved by the FDA and used as part of patient care, their safety and efficacy must be rigorously tested through clinical trials. All clinical trials are reviewed and approved by institutional review boards before they can begin and are monitored throughout their duration. There are several types of cancer clinical trials, including treatment trials, prevention trials, screening trials, and supportive or palliative care trials, each designed to answer different research questions.

In oncology, treatment clinical trials have traditionally been done in three successive phases (see Figure 9). This approach has yielded numerous advances in patient care. However, the multiphase clinical testing process requires a large number of patients and takes many years to complete, making it extremely costly and one of the biggest barriers to rapid translation of scientific knowledge into clinical advances. Other challenges include low participation in clinical trials by adolescents and adults with cancer and a lack of diversity among clinical trial participants, in particular adult clinical trial participants (102–105) (see sidebar on Disparities in Clinical Trial Participation).

Over the past three decades, the FDA has implemented several changes that have altered how clinical trials can be conducted and reviewed in an effort to reduce the length of time it takes to obtain a clear result from a clinical trial, including developing four evidence-based strategies to expedite assessment of therapeutics for life-threatening diseases such as cancer. An increasing number of therapeutics are being approved by the FDA using these review strategies (108). For example, eight of the new anticancer therapeutics approved by the FDA during the 12 months spanning this report were approved using one or more of the expedited review strategies.

In addition, research-driven advances in our understanding of cancer biology, in particular the genetic mutations that underpin cancer initiation and growth (see Cancer Development: Influences inside the Cell), are enabling researchers, regulators, and the pharmaceutical industry to develop new ways of designing and conducting clinical trials, including the emergence of adaptive and seamless clinical trial designs (109, 110). The new approaches aim to streamline the development of new anticancer therapeutics by matching the right therapeutics with the right patients earlier. These approaches can reduce the number of patients who need to be enrolled in clinical trials before it is determined whether or not the therapeutic being evaluated is safe and effective. They can also decrease the length of time it takes for a new anticancer therapeutic to be tested and made available to patients.

In some clinical trials, the cancer-driving genomic alterations and not the anatomic site of the original cancer are being used to identify the patients most likely to benefit from an investigational anticancer therapeutic. If successful, these clinical trials, which are called “basket” trials, have the potential to lead to FDA approvals that are agnostic of the site of cancer origin (see Figure 10). The first such FDA approval occurred in May 2017 (see Releasing the Brakes on the Immune System). The approval came after regulatory review of data from several basket-like studies using two of the expedited-review strategies, highlighting how regulatory and scientific advances are being used together to drive progress against cancer. Another example of a basket trial that has yielded promising early results involves the testing of a molecularly targeted therapeutic called larotrectinib in adult and pediatric patients with any type of cancer characterized by the presence of genetic alterations called TRK fusions (111).

“Umbrella” trials are a second type of genomics-based clinical trial that are becoming increasingly common (see Figure 10). In contrast to the tumor site–agnostic basket trials, umbrella trials test multiple therapeutics across multiple genetic mutations on a group of patients who all have cancer arising in the same anatomic site.

Basket and umbrella trials are likely to become even more common in the future as researchers identify ways to better leverage the enormous amount of genomic data that has accumulated in recent years (see Looking to the Future).

For example, a recent study highlighted the potential for international data-sharing initiatives to facilitate the design of umbrella trials and to identify those patients most likely to be eligible for such trials (112).

As discussed above (see Cancer Development: Integrating Our Knowledge), research has shown that tumor genomics is not the only factor influencing cancer initiation, development, and progression. Factors such as a person’s genome, disease presentation, gender, exposures, lifestyle, and microbiome also play a role (see Figure 3). We are also beginning to learn that these factors may affect a person’s response to a particular treatment, although much more research is needed in this area. For example, a number of studies have shown that the bacterial species in the intestinal microbiota—the microbes that naturally colonize the intestines—of mice influences the anticancer efficacy of cytotoxic chemotherapeutics and immunotherapeutics (113, 114). Recent data suggest that the diversity of the intestinal microbiota may also influence the efficacy of immunotherapeutics in patients with melanoma (115) but much more research is needed in this area.

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Progress Across the Cancer Care Continuum

The translation of research discoveries to new medical products for cancer prevention, detection, diagnosis, treatment, and care is not the end of a linear research process. Rather, it is an integral part of the biomedical research cycle because observations made during the routine use of new medical products can be used to further enhance the use of those products, to accelerate the pace at which similar products are developed, or to stimulate the development of new, more effective products (see Figure 8).

The following discussion focuses primarily on the new FDA-approved medical products, which are improving lives by having an effect across the continuum of clinical cancer care. However, it is important to note that they are used alongside medical products already in clinical use. For example, most patients with cancer are treated with a combination of surgery, radiation, chemotherapy (including both cytotoxic chemotherapeutics and molecularly targeted therapeutics), and/or immunotherapy (see Supplemental Tables 2a, 2b, and 2c, and Supplemental Table 3).

Cancer Prevention, Detection, and Diagnosis

Preventing cancer from developing and, if cancer develops, detecting it at the earliest stage possible are the most effective ways to reduce the burden of cancer. The development of new and better approaches to cancer prevention and early detection have been spurred by research that enhanced our knowledge of the causes, timing, sequence, and frequency of the genetic, molecular, and cellular changes that drive cancer initiation and development.

Simplifying the HPV Vaccination Schedule

Research has shown that almost all cases of cervical cancer, as well as many cases of vulvar, vaginal, penile, anal, and oropharyngeal cancers, in the United States are caused by persistent infection, at the site at which the cancer arises, with certain strains of HPV (see Prevent Infection with Cancer-causing Pathogens). This knowledge led to the development and FDA approval of three vaccines that protect against infection with some of the cancer-causing strains of HPV by triggering long-lasting immune responses against these strains: Cervarix, Gardasil, and Gardasil 9.

Until October 2016, the CDC recommended that individuals receive three doses of any of the HPV vaccines. After reviewing new research showing that people who received two doses of vaccine had immune responses against HPV that were equivalent to those seen in people who received three doses, the FDA approved a two-dose series of Gardasil 9 for vaccination of children ages 9 to 14 in October 2016 (116). Shortly after, the CDC revised its HPV vaccine recommendations such that it recommends that children ages 11 and 12 receive two doses of HPV vaccine at least six months apart (see sidebar on Updated HPV Vaccination Recommendations).

HPV vaccine uptake has been very low compared with the uptake of other vaccines given in childhood and adolescence (79). Thus, it is hoped that the research-driven change in the HPV vaccination schedule will increase uptake of the potentially lifesaving vaccine among children because it will mean fewer visits to the doctor.

Enhancing Cancer Detection and Diagnosis with Technology

Technological advances are driving the development of new medical products to help better detect and diagnose cancer. One such medical product recently cleared by the FDA is LungVision, an imaging system that is designed to enhance localization and biopsy of early-stage lung lesions during bronchoscopic procedures by allowing physicians to plan, visualize, and track endobronchial tools and radiolucent lesions in real time.

In addition, in March 2017, the FDA approved PowerLook Tomo Detection, a computer-aided detection system designed to increase the efficiency with which radiologists read breast tomosynthesis, or three-dimensional mammography exams. Three-dimensional mammography is a relatively recently introduced approach to breast cancer screening that has been shown to detect more breast cancers than two-dimensional mammography but also to result in an increased percentage of false-positive results (117). Many more images are generated during a three-dimensional mammography exam than during a two-dimensional mammography exam. The new system automatically analyses each image and identifies suspicious areas, then blends these with the image to provide radiologists with a single enhanced image. The enhanced image assists radiologists in identifying suspicious areas and directs them to the appropriate three-dimensional image that they can view to confirm or dismiss the finding.

An important step in diagnosing a suspected tissue abnormality as cancer is pathology testing. This involves a pathologist viewing a slide on which there is a slice of the abnormal tissue, obtained through tissue biopsy or during surgery, under a conventional light microscope to determine the size, shape, and appearance of the tissue and the cells. Technological advances led to the development of a digital pathology system called IntelliSite Pathology Solution, which was approved by the FDA in April 2017. The system is comprised of an ultrafast pathology slide scanner, an image management system, and a display. It is supported by advanced software tools to manage the scanning, storage, presentation, reviewing, and sharing of information. The goal of IntelliSite Pathology Solution is to make the process of pathology testing more efficient and collaborative to increase the accuracy of the resulting diagnosis, thereby improving patient care.

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Treatment with Surgery, Radiotherapy, and Cytotoxic Chemotherapy

As research has enhanced our understanding of the genetic, molecular, and cellular changes that underpin cancer biology, we have been able to develop an increasing number of therapeutics that more precisely target specific molecules involved in the development and progression of cancer than do the treatments that have been the mainstay of cancer care for decades.

Molecularly targeted therapeutics tend to be more effective and less toxic than two of the long-standing pillars of cancer treatment—radiotherapy and cytotoxic chemotherapy (see Figure 11). However, not all patients with cancer are treated with molecularly targeted therapeutics. For some patients, this might be because there is no appropriate molecularly targeted therapeutic available. For others, it may be that surgery, radiotherapy, and/or cytotoxic chemotherapy are the best treatment options, as they were for Congressman Jamie Raskin seven years ago. Whatever the reason, the reality is that these traditional therapeutic modalities form the foundation of treatment for almost all patients with cancer, including those for whom molecularly targeted therapeutics and immunotherapeutics are appropriate.

Improving Outcomes# by Combining Existing Treatments

Even though much emphasis is put on developing new, more effective anticancer treatments, a large body of researchers are working to identify new ways to combine the treatments that we already have to improve survival and quality of life for patients.

One recent example of a new combination of existing treatments shown in a phase III clinical trial to substantially improve survival for patients with biliary tract cancer is the addition of treatment with the cytotoxic chemotherapeutic capecitabine after they have had surgery (119). Biliary tract cancer, which include cancers of the bile duct and gallbladder, is a rare type of cancer. It is also a type of cancer for which we have made little progress in recent years. In fact, the 5-year relative survival rate is less than 10 percent among the 20 percent of patients who have tumors that are suitable for surgical removal. In the clinical trial, treating patients whose biliary tract cancer had been completely removed by surgery with capecitabine improved survival by more than a year compared with surgery alone.

Another example of a new combination of existing treatments recently found in a clinical trial to improve outcomes for patients is the addition of the immunotherapeutic pembrolizumab (Keytruda) to treatment with the standard cytotoxic chemotherapeutics pemetrexed and carboplatin for the initial treatment of patients with advanced non–small cell lung cancer (NSCLC) (120). Data from the clinical trial showed that adding pembrolizumab to carboplatin and pemetrexed treatment increased the number of patients who had their tumors shrink. It also extended the amount of time until disease progression. Even though longer follow-up of these patients is needed to determine whether this new combination also improves survival, the promising early results led the FDA to approve pembrolizumab for use in this way in May 2017.

A third example of a new combination of existing treatments recently shown to improve outcomes for patients is the addition of the immunotherapeutic daratumumab (Darzalex) to two standard treatments for multiple myeloma, lenalidomide (Revlimid) and dexamethasone, and bortezomib (Velcade) and dexamethasone. In clinical trials, adding daratumumab to these treatments significantly increased the amount of time until disease progression (121, 122). This led to a November 2016 FDA approval of daratumumab for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for treating patients with multiple myeloma whose disease has progressed after at least one prior therapy.

Reducing the Adverse Effects of Surgery

For many patients with cancer, surgery is a foundation of their treatment (118). Until 25 years ago, open surgery, whereby the surgeon makes one large cut to remove the tumor, some healthy tissue, and maybe some nearby lymph nodes, was the only approach to cancer surgery. Since then, a number of advances, including the introduction of minimally invasive laparoscopic surgery for some types of cancer, have helped reduce the morbidity of surgery (123). This reduction in postsurgery complications has led to improved patient quality of life and increased ability to receive subsequent therapies.

Another recent advance was shown to have reduced the number of women with breast cancer who undergo additional surgery after initial lumpectomy (124). For many women diagnosed with early-stage breast cancer, the initial treatment is a lumpectomy—surgery to remove a breast tumor and a small amount of normal tissue around it that leaves most of the breast skin and tissue in place. However, more than 20 percent of patients require a second surgery after a lumpectomy because postsurgery analysis of the removed tumor shows an inadequate margin of normal tissue around the tumor, leaving open the possibility that not all of the tumor was removed. A recent study showed that since the Society of Surgical Oncology and the American Society of Radiation Oncology put forth a new recommendation about how to establish adequate margins of normal tissue around breast tumors removed during a lumpectomy, rates of reoperation after initial lumpectomy for breast cancer have significantly declined (124).

To help surgeons visualize gliomas and ensure more complete removal of the tumor, the FDA approved a new imaging agent called aminolevulinic acid hydrochloride (Gleolan) in June 2017. Gliomas are the most common type of cancer arising in the brain. Many patients with glioma are treated with surgery with the goal of removing as much of the cancer as possible without damaging adjacent healthy brain tissue. Surgery can be very challenging, especially for high-grade cancers that are invasive and for cancers in certain locations in the brain. The approval came after several studies showed that aminolevulinic acid hydrochloride was a safe and effective way to visualize gliomas and more completely remove them during surgery, something that has been linked in other studies to improved patient outcomes (125).

Tailoring Radiotherapy: Less Is Sometimes More

Radiotherapy is a mainstay of cancer care (see sidebar on Using Radiation in Cancer Care). However, it can have long-term adverse effects on patients. Thus, physicians are looking to tailor each patient’s radiotherapy to be only as aggressive as is necessary for it to be effective by moving away from a one-size-fits-all approach to one in which treatment decisions are based on a more complete understanding of the biology of the patient’s tumor and the individual’s physiological characteristics and needs.

Children with cancers of the central nervous system, which consists of the brain and spinal cord, are particularly vulnerable to the late effects of radiotherapy. Thus, researchers have been looking for genetic, molecular, or cellular markers that can identify certain groups of children with cancers of the central nervous system who can be spared radiotherapy without compromising treatment outcomes. Spurred by advances in our understanding of the biology of medulloblastoma, the most common malignant brain tumor in children, researchers recently reported that in a phase III clinical trial they had identified a subgroup of young children with medulloblastoma who might be able to forgo radiotherapy to the brain without it affecting their chances of survival (126, 127). These results are highly promising, but need to be confirmed in additional studies before they can result in changes in the treatment of children with medulloblastoma.

Radiotherapy is often used to reduce or control symptoms of cancer. For example, radiotherapy is often used to relieve the problems caused by metastatic tumors pressing against the spinal cord. These tumors, which can be in or near to the spine, can cause pain in the back and neck; numbness or pins and needles in the toes, fingers, and buttocks; unsteadiness on the feet; and bladder or bowel problems. Results from a phase III clinical trial were recently reported to show that a single radiation treatment was as effective at keeping patients with a short life expectancy mobile as five radiation treatments over five days and did not significantly reduce median survival time (128). Reducing the number of treatments, and therefore reducing the number of hospital visits, has the potential to help improve the quality of life for these patients who have short life expectancy.

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Treatment with Molecularly Targeted Therapeutics

The discovery that most cancers arise as a result of the accumulation of genetic mutations within cells (see Comprehending Cancer Development), coupled with advances in biology, chemistry, physics, and technology, set the stage for the new era of precision medicine, an era in which the standard of care for many patients is changing from a one-size-fits-all approach to one in which greater understanding of the patient and his or her tumor dictates the best treatment option for the patient.

Therapeutics directed to the molecules involved in different aspects of the cancer process target the cells within a tumor more precisely than cytotoxic chemotherapeutics, thereby limiting damage to healthy tissues. The greater precision of these molecularly targeted therapeutics tends to make them more effective and less toxic than cytotoxic chemotherapeutics. As a result, they are not only saving the lives of countless patients with cancer, but also allowing these individuals to have a higher quality of life than many who came before them.

In the 12 months spanning August 1, 2016, to July 31, 2017, the FDA approved seven new molecularly targeted anticancer therapeutics (see Table 1). During this period, they also approved new uses for four previously approved molecularly targeted anticancer therapeutics, dabrafenib (Tafinlar), ibrutinib (Imbruvica), regorafenib (Stivarga), and trametinib (Mekinist).

Ibrutinib targets a protein called BTK, which is a component of a signaling pathway that promotes the survival and expansion of immune cells called B cells. In January 2017, the FDA granted accelerated approval to ibrutinib for treating certain patients with a type of non-Hodgkin lymphoma called marginal zone lymphoma, which arises in a certain population of B cells (see sidebar on Accelerated Approval). The approval was based on results from a phase II clinical trial showing that ibrutinib caused significant tumor shrinkage in about 50 percent of patients whose disease had progressed despite standard-of-care treatment (129). This followed approvals in 2013, 2014, and 2015 for chronic lymphocytic leukemia and two other forms of non-Hodgkin lymphoma—mantle cell lymphoma and Waldenström macroglobulinemia—all of which also arise in B cells. These prior approvals were highlighted in earlier editions of the AACR Cancer Progress Report (1, 25).

Regorafenib targets proteins that promote the growth of new blood and lymphatic vessels, which tumors need to grow and survive. In April 2017, the FDA expanded the use of regorafenib to include the treatment of certain patients with the most common form of liver cancer, hepatocellular carcinoma, after it was shown in a phase III clinical trial to improve survival for patients with hepatocellular carcinoma that had progressed despite standard-of-care treatment with sorafenib (Nexavar) compared with placebo (130). The new approval followed approvals in 2012 and 2013 for colorectal cancer and gastrointestinal stromal tumors, which were highlighted in the AACR Cancer Progress Report 2013 (33).

The following discussion focuses on the other FDA approvals for molecularly targeted anticancer therapeutics that occurred in the 12 months covered by this report.

Adding Precision to Treatment for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common type of leukemia diagnosed in the United States, with more than 21,000 new cases anticipated in 2017 (2). It is also the type of leukemia with the lowest overall five-year relative survival rate, 27 percent (5).

Treatment has changed little in the past few decades (131). It usually occurs in two phases. The first, which is known as the induction phase, includes an intensive course of cytotoxic chemotherapy designed to put the leukemia into remission. The second phase is known as the consolidation phase. It includes further cytotoxic chemotherapy or a stem cell transplant and it is designed to keep the leukemia in remission.

In recent years, research has substantially increased our understanding of the biology of AML, in particular the genetic mutations that fuel leukemia growth (132). One of the genes most frequently mutated in AML is FLT3, and patients with this form of AML have particularly poor outcomes (133).

This knowledge ultimately led to the first new FDA-approved treatment for AML in almost three decades, midostaurin (Rydapt). Midostaurin is also the first molecularly targeted therapeutic approved for treating AML. It targets several related molecules called tyrosine kinase receptors, including FLT3 and KIT, and it was approved by the FDA in April 2017 for treating adults newly diagnosed with AML harboring a mutation in the FLT3 gene, as detected by an FDA-approved test, or companion diagnostic (see sidebar on Companion Diagnostics). At the same time, the FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to identify patients with AML with the FLT3 mutation.

Midostaurin was approved for use in both the induction and consolidation phases of treatment for AML after it was shown in a phase III clinical trial that patients with FLT3-mutated AML who received midostaurin and standard induction and consolidation cytotoxic chemotherapy had a more than 20 percent improvement in overall survival compared with those patients who received placebo with standard treatment (134).

In April 2017, the FDA also approved midostaurin for treating adults with certain aggressive forms of a rare disorder known as systemic mastocytosis. In patients with this disorder, immune cells called mast cells accumulate in internal organs such as the liver, spleen, bone marrow, and small intestines.
Research has shown that most cases of systemic mastocytosis are caused by mutations in the gene that encodes the KIT tyrosine kinase receptor, which is one of the targets of midostaurin (135). The approval of midostaurin for treating aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia was based on clinical trial results showing that a proportion of patients with these disorders benefited from the molecularly targeted therapeutic (136).

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Targeting Soft Tissue Sarcoma

Soft tissue sarcomas are a diverse group of more than 70 types of cancers that arise in soft tissues of the body, such as the muscles, tendons, fat, blood vessels, lymph vessels, nerves, and tissues around joints. These cancers are rare; 12,390 U.S. adults are expected to be diagnosed with a soft tissue sarcoma in 2017 (2).

Patients with metastatic soft tissue sarcoma have a poor prognosis. Many are treated with the cytotoxic chemotherapeutic doxorubicin, either alone or in combination with other cytotoxic chemotherapeutics, but even then overall survival is estimated to be just 12 to 16 months (137).

In October 2016, the FDA made a decision that provides a new treatment option for patients with advanced soft tissue sarcoma. Specifically, the agency granted accelerated approval to the molecularly targeted therapeutic olaratumab (Lartruvo) for treating patients with soft tissue sarcoma who cannot be cured with radiation or surgery and who have any type of soft tissue sarcoma that would normally be treated with a cytotoxic chemotherapeutic such as doxorubicin (see Figure 12). The FDA accelerated approval program was initiated to expedite the assessment of therapeutics for life-threatening diseases such as cancer (see sidebar on Accelerated Approval). A requirement of such approvals is that additional clinical testing must be undertaken to confirm that the therapeutic does indeed provide clinical benefit for patients as anticipated. If the outcome of a clinical trial is not as anticipated, the FDA will review the decision and could remove the therapeutic from the market.

Olaratumab is a monoclonal antibody that targets the protein platelet-derived growth factor receptor-alpha (PDGFRA). The rationale for testing it as a potential treatment for soft tissue sarcoma came from numerous lines of research, including a study showing that targeting PDGFRA had antitumor activity in animal models of certain sarcomas (139).

Consistent with this rationale, a phase II clinical trial that included patients with more than 25 subtypes of metastatic soft tissue sarcomas showed that adding olaratumab to doxorubicin treatment nearly doubled median overall survival extending it by almost a year (140). This is very good news for patients like Evan Freiberg (see p. 66). Given that the FDA decision for olaratumab was an accelerated approval, confirmation of the benefit of the molecularly targeted therapeutic is being evaluated in a phase III clinical trial.

Increasing Options for Patients with Ovarian Cancer

Ovarian cancer is the fifth most common cause of cancer-related death among U.S. women (2). In 2017 alone, it is expected that 14,080 women will die from the disease. One reason that ovarian cancer poses such a large challenge is that 60 percent of patients are first diagnosed when the cancer is already at an advanced stage.

Platinum-based cytotoxic chemotherapeutics are part of treatment for most women with advanced ovarian cancer. However, the majority of ovarian cancers that initially respond to this treatment eventually recur and are said to have become treatment resistant (141). In some patients, a second round of chemotherapy that includes additional or higher doses of platinum-based cytotoxic chemotherapeutics can be beneficial.

In March 2017, the FDA approved the molecularly targeted therapeutic niraparib (Zejula) for use in helping to address the challenge of resistance to platinum-based cytotoxic chemotherapeutics. Specifically, the agency approved niraparib for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers that are responding to platinum-based cytotoxic chemotherapeutics. The approval was based on results from a phase III clinical trial showing that niraparib significantly extended the time to disease progression for women whose ovarian cancer had recurred after initial treatment but still remained responsive to platinum-based cytotoxic chemotherapeutics (142). Although the benefit was seen when considering all the women in the trial together, the improvement in progression-free survival was greater among patients who had inherited mutations in either the BRCA1 or BRCA2 genes than among those who had not inherited mutations in these genes. This approval is providing hope for patients with ovarian cancer, like Teri Woodhull.

The reason that the presence or absence of BRCA1 or BRCA2 mutations is relevant relates to the way that niraparib works. Niraparib blocks the function of poly ADP-ribose polymerase (PARP) proteins. Basic research has shown that a key function of both PARP and BRCA proteins is repairing damaged DNA. Although they work in different DNA repair pathways, the pathways are interrelated and disruption to both pathways can ultimately trigger cell death. As a result, cancer cells harboring cancer-associated BRCA gene mutations that disable the ability of BRCA proteins to repair damaged DNA are particularly susceptible to PARP inhibitors, which work, at least in part, by blocking the DNA repair function of PARP proteins (see Figure 13).

Before the niraparib approval, in December 2016, the FDA granted accelerated approval to another PARP inhibitor, rucaparib (Rubraca) (see sidebar on Accelerated Approval). This approval was for treating women who have advanced ovarian cancer that harbors cancer-associated BRCA1 and BRCA2 gene mutations and that has progressed despite treatment with two or more cytotoxic chemotherapy regimens. At the same time, the FDA approved a new companion diagnostic, the FoundationFocus CDxBRCA test, to detect cancer-associated BRCA1 and BRCA2 gene mutations in ovarian cancer tissue samples and thereby identify those patients eligible for rucaparib treatment.

The approvals of rucaparib and FoundationFocus CDxBRCA were based on clinical trial results showing that rucaparib treatment led to tumor shrinkage in about 50 percent of patients with recurrent, advanced ovarian cancer with a cancer-associated BRCA1 or BRCA2 gene mutation (144, 145). The proportion of patients who benefited from rucaparib was greatest among those whose tumors were still responsive to platinum-based cytotoxic chemotherapeutics.

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Keeping Breast# Cancer Cells at Bay

Despite major advances in the treatment of breast cancer, the disease is the second-leading cause of cancer-related death for women in the United States (2).

Most breast cancers are characterized by the presence of proteins called hormone receptors. The growth of these breast cancers is fueled by hormones, which attach in a lock-and-key fashion to the hormone receptors on individual breast cancer cells, stimulating the cells to multiply and survive. This knowledge led to the development of therapeutics such as tamoxifen, which is an antiestrogen that works by preventing the hormone estrogen from attaching to its receptor, and letrozole, which is an aromatase inhibitor that works by lowering the level of estrogen in the body. These therapeutics have been used successfully for decades to treat patients with hormone receptor–positive breast cancer.

Unfortunately, most advanced, hormone receptor–positive breast cancers that initially respond to antiestrogens and aromatase inhibitors eventually progress because they have become treatment resistant. A recent FDA decision is helping to address this challenge by providing a way to prolong the time before a cancer becomes resistant to treatment.

In March 2017, the FDA approved the molecularly targeted therapeutic ribociclib (Kisqali) for use in combination with an aromatase inhibitor for treating postmenopausal women with hormone receptor–positive, HER2–negative, advanced breast cancer.

Ribociclib works by blocking the function of two specific proteins that play a role in driving cell multiplication—cyclin-dependent kinase (CDK) 4 and CDK6 (see Figure 14). Its FDA approval was based on results from a phase III clinical trial that showed that adding ribociclib to the aromatase inhibitor letrozole significantly increased the time to disease progression among postmenopausal women newly diagnosed with advanced, hormone receptor–positive, HER2–negative breast cancer (146). Longer follow-up of these patients has recently shown that the combination also improves overall survival (147).

Research has shown that other breast cancers are characterized by the presence of elevated levels of the protein HER2 and that signaling networks triggered by HER2 stimulate the breast cancer cells to multiply and survive. HER2-positive breast cancers tend to be aggressive; the outcome for patients was typically very poor until researchers harnessed the basic understanding of the biology of these cancers to develop a number of therapeutics that target HER2. Trastuzumab (Herceptin) was the first of these molecularly targeted therapeutics to be approved by the FDA in 1998.

One use for trastuzumab in the treatment of patients with HER2-positive breast cancer is as an adjuvant treatment for those with early-stage disease, meaning it is given after the patient has completed his or her initial treatment to lower the risk that the cancer will recur. In this setting, trastuzumab is usually given for one year after surgery and chemotherapy.

Even though one-year adjuvant trastuzumab significantly improved outcomes for patients with early-stage HER2-positive breast cancer, more than 20 percent of patients still have disease recurrence (148, 149). A recent FDA decision is helping to address this challenge by providing a way to reduce the risk of recurrence.

In July 2017, the FDA approved the HER2-targeted therapeutic neratinib (Nerlynx) for use as an extended adjuvant treatment for patients with early-stage HER2-positive breast cancer who have completed one year of adjuvant treatment with trastuzumab. The approval was based on results from a phase III clinical trial that showed after two years of follow-up, women with early-stage HER2-positive breast cancer who received 12 months of neratinib after one year of trastuzumab were significantly less likely to have invasive disease recurrence compared with those who received placebo (150). Given that diarrhea was a common adverse event among those who received neratinib, the FDA recommends that patients receiving the newly approved HER2-targeted therapeutic should be given antidiarrheal prophylaxis for the first 56 days of treatment and as needed thereafter.

Helping Some Lung Cancer# Patients Breathe Easier

Recent advances against lung cancer are grounded in research discoveries, including the identification of several genetic changes that fuel cancer growth in certain patients and the development of therapeutics that target these changes.

The most recent of these advances occurred in June 2017, when the FDA approved the use of a combination of molecularly targeted therapeutics, dabrafenib (Tafinlar) and trametinib (Mekinist), for the treatment of non–small cell lung cancer (NSCLC) harboring a specific mutation in the BRAF gene called BRAF V600E.

This approval was built upon prior research focused on melanoma (151). The discovery that 50 percent of melanomas are fueled by the abnormal BRAF V600E protein generated as a result of the BRAF V600E mutation had led to the development of several BRAF V600E–targeted therapeutics, including dabrafenib, and several therapeutics, including trametinib, that block the activity of two other proteins, MEK1 and MEK2, that function in the same signaling network as BRAF V600E. The combination of dabrafenib and trametinib was approved by the FDA for treating melanoma with BRAF mutations, including BRAF V600E mutations, in January 2014.

More recently, we have learned that the BRAF V600E protein fuels the growth of 1 to 2 percent of NSCLCs (152). The dabrafenib and trametinib combination was approved to treat patients with metastatic NSCLC fueled by the BRAF V600E protein after it was shown to cause complete or partial tumor shrinkage in about 60 percent of patients (152).

At the same time as approving dabrafenib and trametinib for treating NSCLC, the FDA approved a companion diagnostic to identify patients eligible for the combination treatment (see sidebar on Companion Diagnostics). The Oncomine Dx Target Test is the first companion diagnostic to use next-generation sequencing technology, which means it can provide information on not just one gene but on multiple genes. In fact, it provides information on 23 genes, including BRAF, EGFR, and ROS1. There are FDA-approved molecularly targeted therapeutics for treating NSCLC harboring EGFR and ROS1 mutations, gefitinib (Iressa) and crizotinib (Xalkori), respectively. Thus, the FDA has approved the Oncomine Dx Target Test for identifying patients with NSCLC eligible for treatment with crizotinib, gefitinib, and the dabrafenib and trametinib combination.

Unfortunately, most lung cancers that initially respond to molecularly targeted therapeutics eventually progress because they have become treatment resistant.

In April 2017, the FDA  granted accelerated approval to a molecularly targeted therapeutic called brigatinib (Alunbrig), providing a new option to help patients with NSCLC harboring mutations in the ALK gene address the challenge of treatment resistance.

Research has shown that ALK gene mutations fuel 3 to 7 percent of cases of NSCLC, which is the most commonly diagnosed form of lung cancer in the United States (2). This has led to the development of a number of anticancer therapeutics targeting ALK. Crizotinib was the first of these to be approved by the FDA, in August 2011, and it is now the standard of care for patients with metastatic ALK-positive NSCLC. Unfortunately, not all patients with NSCLC driven by ALK have tumor shrinkage after crizotinib treatment. Moreover, the majority of patients whose cancer initially responds to the ALK-targeted therapeutic eventually relapse because the cancer becomes resistant to the agent.

In many cases, crizotinib resistance emerges because NSCLC cells acquire additional ALK mutations. Research has shown that brigatinib is able to block many of the unique forms of ALK that result from these new mutations (153). It was approved after phase II clinical trial results showed that brigatinib treatment caused complete or partial tumor shrinkage in about 50 percent of patients with advanced, crizotinib-resistant NSCLC driven by ALK (154). Brigatinib was also able to shrink tumors that had metastasized to the brain in more than 40 percent of patients who had measurable brain metastases, which is something that not all ALK-targeted therapeutics are able to do so effectively.

Brigatinib is the fourth ALK-targeted therapeutic to be approved for treating patients with metastatic NSCLC fueled by ALK mutations. Two, crizotinib and ceritinib (Zykadia), are approved for use as the initial treatment for patients newly diagnosed with this disease. The other two, brigatinib and alectinib (Alecensa), are approved only for treating patients whose cancer has either progressed after treatment with crizotinib or has failed to respond to crizotinib in the first place. Identifying the order in which the four FDA-approved ALK-targeted therapeutics should be used to provide the maximum benefit for patients is an area of intensive research investigation. Initial results from one large phase III clinical trial recently showed that alectinib treatment significantly lengthened the time before disease progressed among patients newly diagnosed with metastatic NSCLC fueled by ALK mutations compared with crizotinib treatment (155). Whether this holds true for patient survival and how it affects long-term outcomes following sequential use of the four FDA-approved ALK-targeted therapeutics requires further research.

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Treatment with Immunotherapeutics

Cancer immunotherapeutics work by unleashing the power of a patient’s immune system to fight cancer the way it fights pathogens like the virus that causes flu and the bacterium that causes strep throat. Not all immunotherapeutics work in the same way (see sidebar on How Immunotherapeutics Work).

The use of immunotherapeutics in the treatment of cancer is referred to as cancer immunotherapy. In recent years, it has emerged as one of the most exciting new approaches to cancer treatment that has entered the clinic. This is in part because some of the patients with metastatic disease who have been treated with these revolutionary anticancer treatments have had remarkable and durable responses, raising the possibility that they might be cured. It is also because some of the immunotherapeutics have been shown to work against an increasingly broad array of cancer types (see Figure 15).

Despite the significant advances that have been made, only a minority of patients who are treated with an FDA-approved immunotherapeutic have a remarkable and durable response. In addition, the current FDA-approved immunotherapeutics are not highly active against all types of cancer. Identifying ways to increase the number of patients for whom treatment with an immunotherapeutic yields a remarkable and durable response is an area of intensive basic and clinical research investigation.

Several approaches are already being tested in clinical trials for a wide array of cancer types, including evaluating how well immunotherapeutics that are already FDA approved work in combination and how well they work in combination with investigational immunotherapeutics that function in novel ways, such as by directly boosting the killing power of cancer-fighting immune cells. Also being tested are various ways to combine FDA-approved immunotherapeutics with other types of anticancer treatments, including radiotherapy, cytotoxic chemotherapeutics, and molecularly targeted therapeutics (see Improving Outcomes by Combining Existing Treatments).

As research deepens our scientific understanding of the immune system and how it interacts with cancer cells, we are likely to develop many new immunotherapeutics and identify novel ways to use those that we already have. One approach that is already showing incredible promise, in particular for children with acute lymphocytic leukemia, is referred to as CAR T-cell therapy (156, 157). Here, however, we focus on immunotherapeutics that were approved by the FDA in the 12 months covered by this report, August 1, 2016, to July 31, 2017.

Releasing the Brakes on the Immune System

Research has shown that immune cells called T cells are naturally capable of destroying cancer cells. It has also shown that some tumors evade destruction by T cells because they have high levels of proteins that attach to and trigger brakes on T cells, stopping them from attacking the cancer cells. These brakes, which are on the surface of T cells, are called immune-checkpoint proteins.

This knowledge has led researchers to develop immunotherapeutics that release T-cell brakes. These immunotherapeutics are called checkpoint inhibitors.

The first checkpoint inhibitor to be approved by the FDA was ipilimumab (Yervoy). It targets the immune-checkpoint protein CTLA4, protecting it from the proteins that attach to it and trigger it to put the brakes on T cells. The approval of ipilimumab for treating certain patients with metastatic melanoma in March 2011 followed almost 25 years of basic and clinical research (see Figure 16). In October 2015, the FDA expanded the approved uses of ipilimumab to include its use as adjuvant therapy for patients with stage 3 melanoma to reduce the risk of disease recurrence after surgery.

Motivated by the success of ipilimumab and the need to provide new treatment options for patients who did not respond long-term to ipilimumab, researchers focused on targeting a second checkpoint protein, PD-1, as well as one of the proteins that attaches to it, PD-L1. The first FDA approval of a checkpoint inhibitor targeting PD-1 or PD-L1 occurred in September 2014, when pembrolizumab (Keytruda), which targets PD-1, protecting it from being triggered, was approved for treating certain patients with metastatic melanoma (see Figure 16). By July 31, 2016, two other checkpoint inhibitors targeting PD-1 or PD-L1 had been approved by the FDA—atezolizumab (Tecentriq), which targets PD-L1, and nivolumab (Opdivo), which targets PD-1—and the three immunotherapeutics were approved for treating several types of cancer (see Figure 15).

From August 1, 2016, to July 31, 2017, the number of checkpoint inhibitors that target PD-1 or PD-L1 approved by the FDA increased from three to five. In addition, the FDA substantially expanded the approved uses for each of the three previously approved PD-1/PD-L1–targeted checkpoint inhibitors to include additional types of cancer (see Figure 15).

One of the expanded uses for PD-1/PD-L1–targeted checkpoint inhibitors was the May 2017 accelerated approval of pembrolizumab for treating certain adults and children with solid tumors characterized by the presence of specific molecular characteristics, or biomarkers, called microsatellite instability–high and DNA mismatch–repair deficiency. These biomarkers are found in a small proportion of cancers arising at numerous sites in the body, including the colon, endometrium, stomach, and rectum (167). As of July 31, 2017, this is the only FDA approval of an anticancer therapeutic based on a common biomarker and not the location in the body where the cancer originated. It is also an example of precision immunotherapy, whereby a patient’s immunotherapy is tailored to the molecular characteristics of his or her tumor (see Figure 17).

The approval was based on data from several clinical trials showing that pembrolizumab treatment led to tumor shrinkage in about 40 percent of patients with an unresectable or metastatic, microsatellite instability–high or DNA mismatch–repair deficient solid tumor that had progressed despite prior treatment (169). The patients included in the analysis had been diagnosed with any one of 15 types of cancer, most commonly colorectal cancer. Their tumors had been shown to be microsatellite instability–high and DNA mismatch–repair deficient using specific molecular tests, such as those that are already in use for identifying patients with Lynch syndrome, a disorder caused by inherited mutations in DNA mismatch–repair genes that significantly increases a person’s risk of developing certain types of cancer, including colorectal cancer and endometrial cancer (see Table 3). Thus, the approval provides new treatment options and new hope to patients with a wide range of types of cancer, in particular for those with Lynch syndrome, like Adrienne Skinner.

The FDA also expanded the uses for PD-1/PD-L1–targeted checkpoint inhibitors to include the treatment of squamous cell carcinoma of the head and neck, which is the most common form of head and neck cancer, providing new hope for patients like Bill McCone. In late 2016, nivolumab and pembrolizumab were both approved by the FDA for treating patients with recurrent or metastatic squamous cell carcinoma of the head and neck that has progressed despite treatment with a platinum-containing chemotherapeutic. In the case of pembrolizumab, accelerated approval was granted based on the fact that treatment with the checkpoint inhibitor led to tumor shrinkage in up to 20 percent of patients (170). For nivolumab, full approval was granted based on results from a phase III clinical trial that showed that nivolumab improved survival compared with a cytotoxic chemotherapeutic, which is the standard of care for patients with recurrent or metastatic squamous cell carcinoma of the head and neck that has progressed despite treatment with a platinum-containing chemotherapeutic (171).

A new type of cancer for which checkpoint inhibitors became an FDA-approved treatment is a rare, aggressive form of skin cancer called Merkel cell carcinoma. In March 2017, one of the new checkpoint inhibitors, avelumab (Bavencio), which targets PD-L1, preventing it from attaching to PD-1 and triggering its brake function, was approved for treating patients with metastatic Merkel cell carcinoma. The accelerated approval was based on the fact that treatment with avelumab led to tumor shrinkage in about 30 percent of patients enrolled in a phase II clinical trial (172). With this decision, avelumab became the first treatment approved by the FDA for Merkel cell carcinoma, providing new hope to patients like Carrie Best.

The second new checkpoint inhibitor to be approved by the FDA in the 12 months covered by this report is durvalumab (Imfinzi), which also targets PD-L1. It was granted accelerated approval for treating certain patients with the most common form of bladder cancer, urothelial carcinoma, in May 2017. Specifically, it was approved for treating patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed despite treatment with a platinum-based cytotoxic chemotherapeutic. The decision was based on the fact that treatment with durvalumab led to tumor shrinkage in about 16 percent of patients enrolled in a phase II clinical trial.

Three of the other PD-1/PD-L1–targeted checkpoint inhibitors were also approved by the FDA for treating patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed despite treatment with a platinum-based cytotoxic chemotherapeutic in 2017. The accelerated approvals for nivolumab and avelumab, which were made in February 2017 and May 2017, respectively, were based on phase II clinical trial results showing that treatment with the checkpoint inhibitors led to tumor shrinkage in up to 20 percent of patients (173, 174). The May 2017 full approval for pembrolizumab was based on results from a phase III clinical trial that showed that treatment with the checkpoint inhibitor improved survival compared with treatment with a cytotoxic chemotherapeutic, which is the standard of care for patients with locally advanced or metastatic urothelial carcinoma that has progressed despite treatment with a platinum-containing cytotoxic chemotherapeutic (175). The fifth PD-1/PD-L1–targeted checkpoint inhibitor, atezolizumab, was granted accelerated approval for treating both patients with locally advanced or metastatic urothelial carcinoma that has progressed despite treatment with a platinum-containing cytotoxic chemotherapeutic and those for whom a platinum-containing cytotoxic chemotherapeutic is not an option.

In addition, in March 2017, pembrolizumab was granted accelerated approval for treating patients with classical Hodgkin lymphoma that has not responded to treatment or that has relapsed after three or more different treatments. The approval was based on results from a phase II clinical trial showing that pembrolizumab treatment led to tumor shrinkage in the majority of patients (176).

The number of uses for which atezolizumab is an FDA-approved treatment option was also expanded during the 12 months covered by this report. In October 2016, it was approved by the FDA for treating patients with metastatic NSCLC that has progressed despite treatment with a platinum-based cytotoxic chemotherapeutic or an appropriate molecularly targeted therapeutic. The approval was based on results from a phase III clinical trial that showed that atezolizumab improved survival compared with the cytotoxic chemotherapeutic docetaxel, which is standard of care for patients with metastatic NSCLC that has progressed during or after initial chemotherapy (177).

The successes highlighted here have led to clinical trials in which PD-1/PD-L1–targeted checkpoint inhibitors are being tested as a potential treatment for numerous other types of cancer. Results are not available yet for most of these trials. However, initial data show that pembrolizumab may benefit some patients with gastric cancer and mesothelioma (178, 179) and that nivolumab may benefit some patients with liver cancer (180).

Despite the rapid expansion in the number of FDA-approved checkpoint inhibitors and the number of FDA-approved uses for these revolutionary immunotherapeutics, it is important to note that several of the approvals were granted through the FDA accelerated approval program (see sidebar on Accelerated Approval). As such, additional clinical testing is ongoing to confirm that the checkpoint inhibitors do indeed provide clinical benefit for patients as anticipated.

Additional clinical trials and longer follow-up of patients in the initial clinical trials are vital for deepening our understanding of the benefits and potential harms of checkpoint inhibitors. They may also lead to the identification of biomarkers that identify the patients most likely to benefit from a given treatment. This is important because it could allow a patient unlikely to benefit from a particular checkpoint inhibitor to be spared the potential toxicity of the treatment and to immediately start an alternative treatment, saving patients precious time in their race to find an effective therapy.

Currently, the only biomarkers used in the clinic for identifying which patients are most likely to benefit from a given PD-1/PD-L1 checkpoint inhibitor are the presence of PD-L1 in a tumor and the presence of microsatellite instability–high or DNA mismatch–repair deficiency in a solid tumor (see Figure 17). These biomarkers are used for identifying those patients with lung cancer and those with solid tumors, respectively, who are most likely to benefit from pembrolizumab. In some other cases—for example, the use of durvalumab as a treatment for bladder cancer and the use of nivolumab as a treatment for lung cancer—the presence of high tumor levels of PD-L1 has been linked to a greater chance of benefit from a PD-1/PD-L1 checkpoint inhibitor. However, some patients whose tumors lack PD-L1 also benefited from these treatments. Thus, it is clear that new biomarkers are needed for identifying patients most likely to benefit from treatment with a checkpoint inhibitor, and this is an area of intensive research investigation (181).

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Supporting Cancer Patients and Survivors

Research is driving advances in cancer detection, diagnosis, and treatment that are helping more and more people to survive longer and lead fuller lives after a cancer diagnosis. According to the latest estimates, more than 15.5 million U.S. adults and children with a history of cancer were alive on January 1, 2016, compared with just 3 million in 1971, and this number is projected to rise to 20.3 million by January 1, 2026 (182, 183).

Each of these people has a unique experience and outlook, which can range from successful treatment and living cancer free for the remainder of his or her life to living continuously with cancer for the remainder of life. Therefore, not all people who receive a cancer diagnosis identify with the frequently used term “cancer survivor.”

Cancer survivorship encompasses three distinct phases: the time from diagnosis to the end of initial treatment, the transition from treatment to extended survival, and long-term survival. Each phase of cancer survivorship is accompanied by a unique set of challenges (see sidebar on Life after a Cancer Diagnosis in the United States). Recent advances in cancer treatment were discussed in the previous three sections of the report (see Treatment with Surgery, Radiotherapy, and Cytotoxic Chemotherapy; Treatment with Molecularly Targeted Therapeutics; and Treatment with Immunotherapeutics). Several of the advances highlighted in these sections are helping to reduce the short-term adverse effects of treatment as well as the long-term and late effects of treatment. Here, the discussion focuses primarily on other recent advances that can help improve outcomes and quality of life for individuals in each distinct phase of cancer survivorship.

Importantly, the issues facing each survivor vary depending on many factors, including gender, age at diagnosis, type of cancer diagnosed, general health at diagnosis, and type of treatment received. Survivors of cancer diagnosed during childhood or adolescence (ages 0–19) are particularly at risk for critical health-related problems because their bodies were still developing at the time of treatment. In addition, those diagnosed with cancer as adolescents (ages 15–19) and young adults (ages 20–39) have to adapt to long-term cancer survivorship while beginning careers and thinking about starting families of their own.

It is not just cancer survivors who are affected after a cancer diagnosis, but also their caregivers, and this population is growing proportionally with the number of cancer survivors. Caregivers are at risk for poor health outcomes, and this is often compounded by the fact that a subset of caregivers are already cancer survivors themselves.

Optimizing Quality of Life across the Continuum of Cancer Care

One approach that can be used across the continuum of cancer care to optimize the quality of life for patients and their families is palliative care (see sidebar on What Is Palliative Care?). Palliative care can be given throughout a patient’s experience with cancer, beginning at diagnosis and continuing through treatment, follow-up, survivorship, and end-of-life care. The goal is not to treat the patient’s cancer but to provide an extra layer of care that prevents or treats the symptoms and adverse effects of the disease and its treatment, as well as addresses the psychological, social, and spiritual challenges that accompany a cancer diagnosis.

Palliating Physical Symptoms

As research drives advances in cancer detection, diagnosis, and treatment, more and more people are living longer after a cancer diagnosis than ever before. As a result, palliating the physical symptoms and adverse effects of cancer and its treatment is becoming increasingly important.

In February 2017, the FDA approved a new treatment for palliating diarrhea in patients with carcinoid syndrome, telotristat ethyl (Xermelo). Carcinoid syndrome is a combination of symptoms that occur when a rare type of cancer called a carcinoid tumor secretes serotonin and other substances into the bloodstream. The symptoms include flushing of the face, diarrhea, and sudden drops in blood pressure. Treatment often includes therapeutics called somatostatin analogs, which work by blocking the release of serotonin and the other substances that cause carcinoid syndrome. However, these therapeutics do not control symptoms of carcinoid syndrome for all patients and even in those for whom they do work initially, symptoms usually return eventually. Telotristat ethyl works in a different way from somatostatin analogs to reduce the production of serotonin and has been shown in clinical trials to significantly reduce the frequency of bowel movements for patients with carcinoid syndrome when given in combination with a somatostatin analog (185). Given that uncontrolled diarrhea can be debilitating for patients, this approval provides a new option for improving their quality of life.

Hair loss is an adverse effect of treatment with many cytotoxic chemotherapeutics that has been reported to negatively affect quality of life, especially for women with breast cancer (186). In April 2017, the FDA cleared the use of a medical device to help palliate this quality of life issue for women with breast cancer. The device—the Paxman Scalp Cooling System—is worn by the patient while chemotherapy is administered. The cap cools the scalp, which is thought to reduce hair loss in two ways: First, by reducing blood flow to the scalp, which reduces the amount of chemotherapy that reaches cells in the hair follicles (hair roots) and second, by slowing down multiplication of cells in the hair follicles, which makes them less affected by chemotherapy. The cooling system was approved after it was shown in a clinical trial to be effective at reducing hair loss for women being treated with cytotoxic chemotherapeutics after a breast cancer diagnosis (187). In July 2017, the FDA expanded the number of cleared uses of a second cooling device, the Dignitana DigniCap Cooling System, from reducing hair loss for women with breast cancer being treated with cytotoxic chemotherapeutics to reducing hair loss for all patients with solid tumors being treated with cytotoxic chemotherapeutics.

Clearly, for a symptom to be treated, a health care provider has to know that the patient is experiencing the symptom. However, one study found that there is frequently no mention of a symptom in a patient’s electronic medical record even if he or she has reported it on a patient-provided information form, suggesting that symptoms among patients with cancer are frequently undetected by the health care provider (188). The results from a recent study suggest that monitoring of electronic patient-reported symptoms might help address this issue (189). In this study, patients who provided self-reporting of 12 common symptoms at and between visits via a web-based patient-reported outcomes questionnaire platform had improved overall survival compared with those who had usual care. A report of a severe or worsening symptom triggered an email alert to a nurse who would respond, for example, by calling to provide symptom management counseling, providing supportive medications, modifying chemotherapy dose, or referring the patient for follow-up. Exactly how monitoring of the electronic patient-reported symptoms improved survival is not known, but it is possible that patients were able to tolerate chemotherapy longer as a result of symptom palliation.

This is just one example of the potential for patient-reported outcomes to enhance clinical care. Improved implementation of patient-reported outcomes into all phases of clinical care and into clinical trials is essential if we are to accelerate the pace at which we improve survival and quality of life for cancer patients and survivors.

Psycho-oncology

A cancer diagnosis does not just pose physical challenges; it also poses behavioral, emotional, psychological, and social challenges. Researchers and health care practitioners working in the field of psycho-oncology are committed to developing new approaches to address these challenges, which include treatment-related cognitive impairment, fear of cancer recurrence, anxiety, depression, stress, and feelings of despair (see sidebar on Helping Patients with Cancer through Psycho-oncology Research). Addressing these challenges is important not just for improving quality of life, but also for improving outcomes because challenges such as depression and anxiety are often associated with decreased adherence to cancer treatment, prolonged hospitalization during cancer treatment, and decreased survival (190–193).

Modifying Behaviors to Improve Outcomes

Many factors related to lifestyle that increase a person’s risk of developing cancer can also increase risk of cancer recurrence and reduce survival time (see Figure 4). In some cases they have also been shown to increase a patient’s risk of cancer treatment toxicity. Thus, modifying behaviors to eliminate or avoid these risk factors has the potential to improve outcomes and quality of life for cancer patients and survivors.

For example, research shows that quitting smoking can reduce risk of radiation-induced toxicity, risk of death from cancer, and risk for developing a second cancer (34). Even in the face of this knowledge, one study found that 9 percent of cancer survivors continue to smoke (200). Thus, more research is needed to develop optimal strategies to provide patients with cancer the best chance of quitting tobacco.

In addition, despite the knowledge that most cases of melanoma are attributable to UV light from the sun, sunlamps, tanning beds, and tanning booths (201), a recent study found that 19.5 percent of melanoma survivors report having had a sunburn in the previous year and 1.7 percent report having used a tanning booth or bed (202). Thus, it is clear that we need to develop more effective programs educating melanoma survivors, and indeed everyone, about the risks of UV exposure and to do more to address skin cancer as a serious public health challenge.

Evidence is also emerging that regular aerobic exercise can reduce recurrence and mortality in survivors of several types of cancer including early breast, prostate, and colorectal cancers (203). This evidence has largely come from observational studies, but it was recently shown in a small randomized exercise trial that patients with breast cancer who participated in supervised exercise, either aerobic or resistance, during chemotherapy tended to have improved disease-free and overall survival compared with those who did not have supervised exercise (204). The results of ongoing larger studies should provide more definitive answers about the role of exercise in improving cancer outcome (205).


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