Harnessing Research Discoveries for Patient Benefit

In this section, you will learn:

  • Progress against cancer is driven by research discoveries.

  • From August 1, 2017, to July 31, 2018, the FDA approved 14 new therapeutics for treating certain types of cancer.

  • During the same period, the uses of 11 previously approved anticancer therapeutics were expanded by the FDA to include additional types of cancer.

  • Our increasing understanding of the genetic, molecular, and cellular characteristics of cancer continues to spur the development of new molecularly targeted therapeutics.

  • A groundbreaking new type of immunotherapy called CAR T-cell therapy was recently approved for treating certain types of cancer.

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

Contents
Biomedical Research

Progress Across the Clinical Cancer Care Continuum


The dedicated efforts of individuals working throughout the cycle of biomedical research are benefiting people around the world by driving progress across the continuum of clinical cancer care (see Figure 8).

Biomedical Research

Biomedical research is an iterative cycle, with each discovery building on knowledge gained from prior research (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 pace at which research discoveries are being converted to lifesaving advances across the continuum of clinical cancer care has been accelerating (see Figure 9). To maintain this momentum, it is imperative that we better support investigators throughout their careers, but especially those early in their careers.

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 or clinical practice (see sidebar on Biomedical Research: What Is It and Who Conducts It?). 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. The results from these experiments can lead to the identification of a potential target for a preventive intervention or therapeutic, or the identification of a predictive or prognostic biomarker. They also can feed backward in the cycle by providing new discoveries that lead to more hypotheses.

After a potential target for a preventive intervention or therapeutic is identified, it takes many more years of research before a candidate preventive intervention or therapeutic is developed and ready for testing in clinical trials (see sidebar on Developing Preventive Interventions and Therapeutics). During this time, candidates are rigorously tested to identify any potential toxicity and to determine the appropriate dose and dosing schedule for testing in a clinical trial.

Before most potential new diagnostic, preventive, or therapeutic products can be approved by the FDA and used as part of patient care, the safety and efficacy of the product 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.

Cancer clinical trials have traditionally been done in three successive phases (see Figure 10). However, the traditional clinical testing process has required a large number of patients and taken many years to complete, making it extremely costly and one of the major barriers to rapid translation of scientific knowledge into clinical advances.

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 the assessment of therapeutics for life-threatening diseases such as cancer (123-124). In recent years, an increasing number of therapeutics have been approved by the FDA using one or more of these review strategies, including 12 of the 14 new anticancer therapeutics approved by the FDA during the 12 months spanning this report (125).

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In addition, advances in our understanding of cancer biology have enabled researchers, regulators, and the pharmaceutical industry to develop new ways of designing, conducting, and reviewing clinical trials. Among the new ways to design clinical trials that have emerged in recent years are adaptive, seamless, and master protocol designs (126-128). These designs aim to streamline the development of new anticancer therapeutics by matching the right therapeutics with the right patients earlier, reducing the number of patients who need to be enrolled in the trial before it is determined whether or not the anticancer therapeutic being evaluated is safe and effective, and/or decreasing the length of time it takes for a new anticancer therapeutic to be tested and made available to patients if the trial shows it is safe and effective.

Master protocol design clinical trials aim to answer multiple questions within a single overall clinical trial (128). The emergence of this clinical trial design has largely been driven by our increased understanding of the genetic mutations that lead to cancer initiation and growth. Two examples of master protocol clinical trials are “basket” and “umbrella” trials (see Figure 11). Basket trials test one given therapeutic on a group of patients who all have the same type of genetic mutation, regardless of the anatomic site of the original cancer. One basket trial that has led to an FDA approval for patients with a rare type of cancer characterized by a defined genetic mutation is highlighted in Molecularly Targeting Blood Cancers (129). Umbrella trials test multiple therapeutics across multiple genetic mutations on a group of patients, all of whom have cancer arising in the same anatomic site.

Even though our growing knowledge of cancer biology has led to new ways of designing, conducting, and reviewing clinical trials that are yielding numerous advances in patient care, there are still opportunities to improve the clinical trial enterprise. Some of the most pressing challenges that need to be overcome are low participation in clinical trials and a lack of diversity among those who do participate (see sidebar on Disparities in Cancer Clinical Trial Participation) (130-133).

These challenges exist even though a poll of the general public showed that more than 30 percent of U.S. adults would be very willing to participate in a cancer clinical trial if asked (135). Thus, understanding the barriers to clinical trial participation for all segments of the population is vital if we are to ensure that all segments of the population benefit from advances against cancer. Current research shows that the barriers to participation are complex and interrelated but often include factors that reduce access to clinical trials such as lack of health insurance, low socioeconomic status, and lack of health literacy (130,132). Overcoming these barriers will require all stakeholders in the biomedical research community to work together to develop a multifaceted approach that includes the development and implementation of new, more effective education and policy initiatives (see sidebar on The Biomedical Research Community: Driving Progress Together).

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Progress across the Clinical Cancer Care Continuum

The hard work of individuals throughout the biomedical research cycle constantly powers the translation of research discoveries to new medical products for cancer prevention, detection, diagnosis, treatment, and survivorship (see Figure 8). The approval of new medical products 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.

The following discussion focuses primarily on medical products approved by the FDA in the 12 months spanning this report, Aug. 1, 2017, to July 31, 2018. In particular, it focuses on the 14 new anticancer therapeutics approved by the FDA during this period (see Table 1). Also highlighted are the 11 previously approved anticancer therapeutics that were approved by the FDA for treating additional types of cancer. Not discussed are FDA approvals related to expanding the use of an anticancer therapeutic previously approved for a given type of cancer to include additional uses during the treatment of the same cancer type; for example, an expansion to include treatment of the same type of cancer at a less advanced stage of disease.

New FDA-approved medical products are used alongside treatments already in use, including surgery, radiotherapy, and cytotoxic chemotherapy, which continue to be the mainstays of clinical cancer care (see Figure 12) (see Supplemental Table 2a, 2b, 2c and Supplemental Table 3).

New medical products improve lives by having an effect across the continuum of clinical cancer care. However, not all patients receive the standard of care recommended for the type and stage of cancer that they have been diagnosed with (see sidebar on Disparities in Cancer Treatment). Thus, it is imperative that all stakeholders in the biomedical research community, including advocates like Karen Eubanks Jackson, work together to address the challenge of disparities in cancer treatment because these can be associated with adverse differences in survival (136-139).

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Treatment with Surgery, Radiotherapy, and Cytotoxic Chemotherapy

In the past two decades, we have witnessed the emergence of two new pillars of cancer care, molecularly targeted therapy and immunotherapy (see Figure 12). The therapeutics that form these pillars of cancer care tend to be more effective and less toxic than the treatments encompassed by two of the long-standing pillars of cancer treatment—radiotherapy and cytotoxic chemotherapy. However, not all patients with cancer are treated with molecularly targeted therapy and/or immunotherapy. For some patients, this might be because there is no appropriate molecularly targeted therapeutic or immunotherapeutic available. For others, it may be that surgery, radiotherapy, and/or cytotoxic chemotherapy are the best treatment options (see sidebar on Using Radiation in Cancer Care). Whatever the reason, the reality is that these traditional therapeutic modalities form the foundation of treatment for almost all patients with cancer.

Importantly, the use of surgery, radiotherapy, and cytotoxic chemotherapy is constantly evolving as we develop new forms of these treatments and identify new ways to use those that we already have to improve survival and quality of life for patients. For example, two recent randomized phase II clinical trials suggest that local ablative radiotherapy can extend disease-free survival for patients with lung cancer who have limited metastases and whose disease has not progressed after initial systemic therapy (142-143). The following discussion focuses on some recent changes in the use of the three traditional pillars of clinical cancer care.

Refining the Use of Surgery, Radiotherapy, and Cytotoxic Chemotherapy

Even though surgery, radiotherapy, and cytotoxic chemotherapy are mainstays of cancer treatment, they can have long-term adverse effects on patients. This has led many researchers to investigate whether less aggressive treatment can allow some patients the chance of an improved quality of life without an adverse effect on survival. In the past few years, many approaches to treatment de-escalation have been implemented in the clinic through changes in treatment guidelines. One example of this trend in cancer care for each of surgery, radiotherapy, and cytotoxic chemotherapy is highlighted in the sidebar Less Is Sometimes More in Surgery, Radiotherapy, and Cytotoxic Chemotherapy.

Identifying other situations in which treatment can be de-escalated is an area of intensive research investigation. Several clinical trials studying this have reported results recently and although the results have not yet led to a change in treatment guidelines, the approaches studied are being gradually adopted into clinical practice. For example, stereotactic radiosurgery, which can more precisely target radiation to tumors than traditional radiotherapy, is increasingly being used after surgical removal of a brain metastasis (a tumor that has spread from another part of the body to the brain) because it was shown to cause less neurocognitive deficit compared with whole brain radiation (151). Stereotactic radiosurgery in this medical situation has also been shown to reduce local relapse compared to observation alone (152). In addition, recent results from a large national clinical trial showed that genetic profiling of particular types of breast cancer has the potential to identify women who can safely avoid chemotherapy (153).

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Targeting Radiotherapy to Neuroendocrine Tumors

The FDA recently provided oncologists with a new way to use radiotherapy in the treatment of patients with certain types of neuroendocrine tumors when it approved two targeted radiotherapeutics, lutetium (Lu) 177 dotatate (Lutathera) and iobenguane iodine (I) 131 (Azedra) (see sidebar on Using Radiation in Cancer Care). Lu-177 dotatate was approved for treating gastroenteropancreatic neuroendocrine tumors in January 2018 and iobenguane I-131 was approved for treating pheochromocytomas and paragangliomas in July 2018.

Neuroendocrine tumors arise in cells called neuroendocrine cells, which are specialized hormone-producing cells found in most organs of the body. Gastroenteropancreatic neuroendocrine tumors are among the most common of these cancers. They arise in the pancreas and different parts of the gastrointestinal tract, such as the stomach, intestines, colon, and rectum. Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that arise in the adrenal glands, and along nerve pathways in the head and neck, and in other parts of the body, respectively.

Research has shown that most neuroendocrine tumors have the protein somatostatin receptor on the surface. When the hormone somatostatin attaches to somatostatin receptor on the surface of a cell, it has a suppressive effect on the functions of the cell. This body of knowledge has led to the development of several medical products used in the care of patients with neuroendocrine tumors, including Lu-177 dotatate (see Figure 13).

In Lu-177 dotatate, the radionuclide Lu-177 is linked to a molecule that is analogous to somatostatin. Molecules like this are called somatostatin analogs. The somatostatin analog component of Lu-177 dotatate targets the radiation-emitting component Lu-177 to the somatostatin receptor-positive cancer cells.

Lu-177 dotatate was approved for treating adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors after it was shown in a phase III clinical trial to increase the time to disease progression by more than six-fold (155). This approval is very good news for patients, like Nicole DiCamillo, because there are very few treatment options for what can be a debilitating disease.

Research has shown that most pheochromocytomas and paragangliomas have a protein called the norepinephrine transporter on the surface. It functions to take up norepinephrine, a chemical messenger that transmits signals from one nerve cell to another. This knowledge led to the development of iobenguane I-131.

Iobenguane, which is also known as metaiodobenzylguanidine (MIBG) is a molecule that is analogous to norepinephrine. In iobenguane I-131, the iobenguane is labeled with the radionuclide I-131. Imaging using iobenguane labeled with either I-131 or I-123 has been used to locate pheochromocytomas and paragangliomas in the body during diagnosis and treatment monitoring since the early 1980s.

Azedra is a new version of iobenguane I-131 that delivers more radiation to tumors than the version used for imaging. It was approved for treating patients age 12 and older with locally advanced or metastatic pheochromocytoma or paraganglioma whose tumors test positive for the norepinephrine transporter during iobenguane imaging. The approval was based on results from a phase II clinical trial that showed that 22 percent of patients treated with iobenguane I-131 had tumor shrinkage (156).

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Improving Outcomes with Nanotechnology

Acute myeloid leukemia (AML) is projected to be the second most common type of leukemia diagnosed in the United States in 2018 and the leading cause of leukemia-related death (10). Treatment changed little from the 1970s until 2017, when four new therapeutics were approved by the FDA (157). One of these new therapeutics was discussed in the AACR Cancer Progress Report 2017 (18), two are discussed below (see Molecularly Targeting Blood Cancers), and the fourth is a nanodrug called Vyxeos.

Nanotechnology refers to the manufacturing of objects with dimensions one million times smaller than a millimeter (the smallest width of a human hair is just 50 times smaller than a millimeter). Nanomedicine is the application of nanotechnology to the research and practice of medicine. Nanodrugs comprise an anticancer therapeutic (or therapeutics) and a nanosized carrier that selectively delivers the anticancer therapeutic to the cancer and protects the anticancer therapeutic from being destroyed by the body. As a result, nanodrugs allow the delivery of higher levels of anticancer therapeutic to cancer cells than traditional systemic delivery methods, increasing effectiveness while reducing toxic side effects.

In the case of Vyxeos, the nanosized carriers are liposomes, and the anticancer therapeutics are two of the cytotoxic chemotherapeutics most commonly used to treat AML, daunorubicin and cytarabine. Daunorubicin and cytarabine are currently given separately. With Vyxeos, patients receive a fixed combination of these two cytotoxic chemotherapeutics formulated together in a single nanodrug.

The FDA approved Vyxeos in August 2017 for treating adults with two types of AML that have particularly poor outlooks: newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. The approval was based on results from a phase III clinical trial that showed that patients who received Vyxeos had significantly improved overall survival compared with those who received separate treatments of daunorubicin and cytarabine (158).

Guiding Surgery Magnetically

For many patients with breast cancer, a mastectomy is an early step in their treatment. During surgery, in addition to removing the breast tissue, the surgeon often removes the lymph node or nodes to which the cancer is most likely to first spread to from the initial tumor. These lymph nodes are called sentinel lymph nodes. The presence or absence of cancer cells in these nodes helps determine the extent of the disease and provides information that is central to the development of the rest of the patient’s treatment plan.

To identify the sentinel lymph nodes, patients are injected with a radioactive substance, a blue dye, or both. The surgeon then uses a device that detects radioactivity to find the sentinel node(s) and/or looks for lymph nodes that are stained with the blue dye. In July 2018, the FDA approved a new system for guiding surgeons to sentinel lymph nodes in patients with breast cancer who are undergoing a mastectomy. When using the Magtrace and Sentimag Magnetic Localization System, patients are injected with a magnetic tracer and the surgeon uses a magnetic probe to find the sentinel node(s). The new system was approved after it was shown in a clinical trial to be as good as using both a radioactive substance and blue dye at detecting sentinel lymph nodes. It provides a new option for surgeons and patients who may want to avoid using radioactive materials.

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Treatment with Molecularly Targeted Therapeutics

The discovery of the genetic underpinnings of cancer 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 (see Understanding Cancer Development).

Therapeutics directed to the molecules involved in different aspects of the cancer process target the cells within a tumor more precisely than cytotoxic chemotherapeutics, which target all rapidly dividing cells, 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 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, 2017 to July 31, 2018, the FDA approved nine new molecularly targeted anticancer therapeutics (see Table 1). During this period, they also approved six previously approved molecularly targeted anticancer therapeutics for treating additional types of cancer.

Molecularly Targeting Blood Cancers

Cancers that arise in blood-forming tissue, such as the bone marrow, or in the cells of the immune system are called blood cancers, or hematologic cancers. Seven recent FDA decisions have added molecularly targeted therapeutics as a treatment option for patients with a wide array of hematologic cancers (see sidebar on Recent Advances against Blood Cancers).

As discussed earlier in the report (see Improving Outcomes with Nanotechnology), AML is projected to be the second most common type of leukemia diagnosed in the United States in 2018 (10). In recent years, research has substantially increased our understanding of the biology of AML, in particular the genetic mutations that promote leukemia development (159). This is fueling the emergence of molecularly targeted therapeutics for defined groups of patients with the disease.

Two of the genes known to be mutated in a significant proportion of AML cases are IDH1 and IDH2 (159). This led researchers to develop enasidenib (Idhifa), a therapeutic that targets the altered IDH2 proteins generated by IDH2 mutations, and ivosidenib (Tibsovo), a therapeutic that targets the altered IDH1 proteins generated by IDH1 mutations. Enasidenib and ivosidenb were approved by the FDA in August 2017 and July 2018, respectively, for treating adults who have AML that has not responded to or has relapsed after other treatment, and that harbors a mutation in either the IDH2 or IDH1 gene, respectively, as detected by an FDA-approved test, or companion diagnostic (see sidebar on Companion Diagnostics). At the same time that the molecularly targeted therapeutics were approved, the FDA approved companion diagnostics, the RealTime IDH2 Assay to identify patients with AML with an IDH2 mutation and the RealTime IDH1 Assay to identify patients with AML with an IDH1 mutation.

Enasidenib was approved for the treatment of AML after it was shown that 19 percent of patients treated with the molecularly targeted therapeutic in a phase I/II clinical trial had complete remission, meaning that there was no evidence of disease and full recovery of blood counts after treatment (160). The approval of this new molecularly targeted therapeutic is providing new hope for patients like Chuck Dandridge.

Ivosidenib was approved for the treatment of AML after it was shown that 25 percent of patients treated with the molecularly targeted therapeutic in a phase I clinical trial had complete remission (161).

In September 2017, the FDA approved another molecularly targeted therapeutic for the treatment of AML. Gemtuzumab ozogamicin (Mylotarg) is a type of molecularly targeted therapeutic known as an antibody-drug conjugate. These therapeutics use an antibody to deliver an attached cytotoxic chemotherapeutic directly to the cancer cells that have the antibody’s target on their surfaces. Once the antibody attaches to its target on the surface of a cancer cell, the antibody-drug conjugate is internalized by the cells. This leads to the cytotoxic chemotherapeutic being released from the antibody. Once free, it is toxic to the cancer cells, which ultimately die. The precision of antibody targeting reduces the side effects of the cytotoxic chemotherapeutic compared with traditional systemic delivery.

In the case of gemtuzumab ozogamicin, the cytotoxic chemotherapeutic calicheamicin is attached to a CD33-targeted antibody. In most patients, AML cells have the molecule CD33 on the surface. The recent approval of gemtuzumab ozogamicin is for these patients. This approval followed an approval in 2000 for patients more than 60 years of age who had AML that had relapsed or who were unable to be treated with standard chemotherapy. However, the FDA requested that gemtuzumab ozogamicin be withdrawn from that use in 2010 after results from a clinical trial showed that the antibody-drug conjugate might not benefit patients and raised safety concerns. These challenges have been overcome through two approaches; the new approval is for a lower recommended dose of gemtuzumab ozogamicin and for use of the molecularly targeted therapeutic in a more precisely defined patient population, those with CD33-positive AML.

Two other antibody-drug conjugates have been approved recently by the FDA for treating patients with particular types of hematologic cancer. Inotuzumab ozogamicin (Besponsa) was approved for treating certain adults with acute lymphoblastic leukemia (ALL) in August 2017. In most cases, ALL arises in immune cells called B cells, which have a protein called CD22 on the surface. Inotuzumab ozogamicin comprises a CD22-targeted antibody linked to the same cytotoxic chemotherapeutic that is found in gemtuzumab ozogamicin, calicheamicin. The approval of the new molecularly targeted therapeutic for treating adults with B-cell precursor ALL that has not responded to or has relapsed after another treatment was based on results from a phase III clinical trial. These results showed that the rate of complete remission for those who received inotuzumab ozogamicin was more than double the rate for those who received standard chemotherapy (162).

In November 2017, brentuximab vedotin (Adcetris) was approved for treating primary cutaneous anaplastic large cell lymphoma and CD30-expressing mycosis fungoides, which are types of cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas are types of non-Hodgkin lymphoma that arise in immune cells called T cells. In nearly all cases of primary cutaneous anaplastic large cell lymphoma and many cases of mycosis fungoides, the cancerous T cells have a molecule called CD30 on the surface. Brentuximab vedotin comprises the cytotoxic agent monomethyl auristatin E attached to a CD30-targeted antibody using a linker. It was approved for treating adults who have primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides that has progressed despite prior treatment. The approval was based on results from a phase III clinical trial showing that more than 50 percent of patients who received brentuximab vedotin had either partial or complete tumor shrinkage compared with 13 percent of patients who received cytotoxic chemotherapy (163). In addition, the time that patients had no disease progression was more than four times longer among those who were treated with brentuximab vedotin. The new approval for brentuximab vedotin followed previous approvals for classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma in 2012.

Acalabrutinib (Calquence) is a new molecularly targeted therapeutic that the FDA approved for treating a type of non-Hodgkin lymphoma called mantle cell lymphoma in October 2017. Like many other hematologic cancers, mantle cell lymphoma arises in B cells. Acalabrutinb targets a protein called Bruton tyrosine kinase (BTK), which is one component of a signaling pathway that promotes the survival and expansion of mantle cell lymphoma B cells. The approval of acalabrutinib for treating patients with mantle cell lymphoma that has not responded to or has relapsed after another treatment was based on results from a phase II clinical trial. These results showed that 40 percent of patients treated with the molecularly targeted therapeutic had complete tumor shrinkage and another 41 percent had partial tumor shrinkage (164).

Copanlisib (Aliqopa) is another new molecularly targeted therapeutic approved recently by the FDA. It was approved for treating adults who have follicular lymphoma that has relapsed after they have received at least two other treatments. Follicular lymphoma is another type of non-Hodgkin lymphoma that arises in B cells. Copanlisib targets a molecule called phosphatidylinositol 3-kinase, which is a component of a signaling pathway that has a key role in promoting the survival and expansion of follicular lymphoma B cells. Copanlisib was approved after 14 percent of patients with follicular lymphoma who received the molecularly targeted therapeutic through a phase II clinical trial had complete tumor shrinkage (165). Another 44 percent of the trial participants had partial tumor shrinkage.

In November 2017, the FDA approved the molecularly targeted therapeutic vemurafenib (Zelboraf) for treating a rare hematologic cancer called Erdheim-Chester disease. Erdheim-Chester disease arises through overproduction of a type of immune cell called a histiocyte. Genomic analysis has shown that more than 50 percent of these cancers are fueled by specific mutations in the BRAF gene, called the BRAF V600 mutations. Vemurafenib targets BRAF proteins generated by BRAF V600 mutations.

Vemurafenib was first approved by the FDA in August 2011 for treating patients with melanoma positive for a specific BRAF V600 mutation, the BRAF V600E mutation. Its success as a treatment for these patients led researchers to launch a phase II basket trial in which they evaluated vemurafenib as a treatment for patients with any type of cancer harboring any BRAF V600 mutation, except for patients with melanoma (129) (see Figure 11). Vemurafenib treatment led to tumor shrinkage in more than half of the 22 patients with BRAF V600 mutation–positive Erdheim-Chester disease who were enrolled in the trial (166). As a result, the FDA approved vemurafenib for the treatment of patients like these.

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Increasing Options for Patients with Breast Cancer

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 (10). Recent FDA decisions have the potential to power even more progress against breast cancer because they have provided new treatment options for certain patients with the disease.

For many patients with breast cancer, one factor determining what treatment options could be considered is the presence or absence of three tumor biomarkers, two hormone receptors (HRs) and HER2. About 70 percent of breast cancers diagnosed the United States are characterized as hormone receptor–positive, HER2-negative (13). Potential treatment options for these patients include therapeutics such as tamoxifen, which works by preventing the hormone estrogen from attaching to its receptor, and aromatase inhibitors, which work by lowering the level of estrogen in the body. Treatment with these therapeutics is often called endocrine therapy.

Unfortunately, most advanced, hormone receptor–positive breast cancers that initially respond to endocrine therapy eventually progress because they have become treatment resistant (see sidebar on The Challenge of Treatment Resistance). Recently, the FDA approved the molecularly targeted therapeutic abemaciclib (Verzenio) for use in several ways to help address this challenge.

Abemaciclib works by blocking the function of two proteins that play a role in driving cell multiplication—cyclin-dependent kinase (CDK) 4 and CDK6. In September 2017, the FDA approved abemaciclib for treating adults with hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer that has progressed during or after endocrine therapy and/or cytotoxic chemotherapy. This approval was based on results from two clinical trials (167-168). One, a phase III clinical trial, showed that adding abemaciclib to fulvestrant (a type of endocrine therapy) increased the time before disease progressed for patients who had previously received endocrine therapy but not cytotoxic chemotherapy (167). The other, a phase II clinical trial, showed that abemaciclib alone led to complete or partial tumor shrinkage for some patients whose metastatic disease had been treated with endocrine therapy and cytotoxic chemotherapy (168).

In February 2018, the FDA added an approval for using abemaciclib in combination with an aromatase inhibitor as an initial treatment for postmenopausal women with hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer. This approval was based on results from a phase III clinical trial that showed that adding abemaciclib to aromatase inhibitor treatment for this group of patients almost doubled the time to disease progression (169).

Another recent FDA decision that is a major advance in breast cancer treatment is the approval of the molecularly targeted therapeutic olaparib (Lynparza) for treating those patients with HER2-negative, metastatic breast cancer who have already received cytotoxic chemotherapy and who have inherited a known or suspected cancer-associated mutation in the BRCA1 or BRCA2 gene. At the same time, the FDA granted marketing authorization for a companion diagnostic, the BRACAnalysis CDx test, to help identify patients with breast cancer with a known or suspected cancer-associated mutation in the BRCA1 or BRCA2 gene (see sidebar on Companion Diagnostics).

About 5 percent of all breast cancers diagnosed in the United States are attributable to an inherited mutation in the BRCA1 or BRCA2 gene (170).

Olaparib targets poly ADP-ribose polymerase (PARP) proteins. Decades of basic research have shown that a key function of both PARP and BRCA proteins is repairing damaged DNA (see Figure 14). 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.

Olaparib was first approved by the FDA in December 2014 for treating women with advanced ovarian cancer who have inherited a known or suspected cancer-associated mutation in the BRCA1 or BRCA2 gene. Its success as a treatment for these patients led researchers to test whether the molecularly targeted therapeutic might also benefit patients with breast cancer who have inherited a known or suspected cancer-associated mutation in the BRCA1 or BRCA2 gene, like Lisa Quinn. Olaparib was approved for these patients after it was shown in a phase III clinical trial to significantly increase the time to disease progression compared with treatment with a cytotoxic chemotherapeutic (170).

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Keeping Prostate Cancer at Bay

Prostate cancer is the most commonly diagnosed cancer among men in the United States (10). It is also the second-leading cause of cancer death for U.S. men.

Most men who die from prostate cancer have metastatic disease. Thus, one goal of prostate cancer researchers is to identify new ways to increase the time before early-stage disease progresses and becomes metastatic. The molecularly targeted therapeutic apalutamide (Erleada) recently became the first treatment approved by the FDA based on this outcome.

At the time of diagnosis, the growth of most prostate cancers is fueled by hormones called androgens. Androgens, such as testosterone, attach in a lock-and-key fashion to androgen receptors on individual prostate cancer cells, stimulating the cancer cells to multiply and survive. This knowledge led researchers to develop treatments that lower androgen levels in the body or stop androgens from attaching to androgen receptors. This approach to prostate cancer treatment is called androgen-deprivation therapy. It is an important part of care for many men with the disease.

Unfortunately, most prostate cancers that initially respond to androgen-deprivation therapy eventually begin to grow again. At this point they are said to be castration resistant.

Even though the approaches to androgen-deprivation therapy that become the mainstay of prostate cancer treatment (bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist) reduce androgen levels in the body, they do not eliminate these hormones completely. Thus, castration-resistant prostate cancer growth is often fueled by androgens. Researchers, therefore, began developing a new generation of therapeutics that more effectively deprive prostate cancer of androgens. The first of these therapeutics, abiraterone (Zytiga) and enzalutamide (Xtandi), were approved by the FDA for treating men with metastatic castration-resistant prostate cancer in 2011 and 2012, respectively. Apalutamide is the first to be approved for treating men with nonmetastatic castration-resistant prostate cancer, such as Ron Scolamiero.

The February 2018 approval of apalutamide for treating men with nonmetastatic castration-resistant prostate cancer was based on results from a phase III clinical trial that showed that adding apalutamide to standard androgen-deprivation therapy increased the time before prostate cancer metastasized by more than two years (173).

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Combining Molecularly Targeted Therapeutics

The first time the FDA approved the use of two molecularly targeted therapeutics as a combination treatment for cancer was January 2014 (1). The approval was for the use of dabrafenib (Tafinlar) and trametinib (Mekinist) for treating patients with metastatic melanoma that tests positive for certain mutations in the BRAF gene known as BRAF V600E and BRAF V600K mutations. The two therapeutics target different components of the BRAF signaling pathway. Dabrafenib targets BRAF proteins generated by BRAF V600 mutations, while trametinib targets MEK1 and MEK2, which are two protein that function further downstream in the BRAF signaling pathway. The combination was approved after it was shown to almost double the length of time before disease progression compared with dabrafenib alone (174).

In May 2018, this same combination of molecularly targeted therapeutics was approved for treating certain patients with a rare but highly aggressive type of thyroid cancer called anaplastic thyroid cancer. The combination of dabrafenib and trametinib was tested as a potential treatment for this type of cancer after genomic research showed that up to 50 percent of these cancers are fueled by BRAF V600 gene mutations (175). The approval, which is for the treatment of patients with BRAF V600E mutation–positive anaplastic thyroid cancer, was based on results from a phase II clinical trial that showed that treatment with dabrafenib and trametinib led to tumor shrinkage in more than 60 percent of the patients in a phase II clinical trial (175).

In June 2018, a new combination of therapeutics targeting the BRAF pathway was approved by the FDA for treating metastatic melanoma testing positive for a BRAF V600E or BRAF V600K mutation. Encorafenib (Braftovi) targets BRAF proteins generated by BRAF V600 mutations and binimetinib (Mektovi) targets MEK1 and MEK2. The approval was based on results from a phase III clinical trial, which showed that the time that patients had no disease progression was twice as long among those treated with the combination of encorafenib and binimetinib compared with those treated with vemurafenib (Zelboraf), which is another therapeutic that targets BRAF proteins generated by BRAF V600 mutations (176).

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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 such as 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 the past decade, it has revolutionized the treatment of an increasingly broad array of cancer types (see Figure 15). In fact, a decade ago, on August 1, 2008, there were only four immunotherapeutics approved by the FDA and six types of cancer that could be treated by these agents. As of July 31, 2018, there were 19 immunotherapeutics approved by the FDA and one or more of these agents can be used to treat 19 types of cancer and to treat any type of solid tumor characterized by the presence of a specific molecular signature or biomarker.

One of the reasons that immunotherapy is considered one of the most exciting new approaches to cancer treatment that have ever entered the clinic is that 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. Unfortunately, only a minority of patients have such incredible responses. In addition, the current FDA-approved immunotherapeutics do not work 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.

Fortunately, our scientific understanding of the immune system and how it interacts with cancer cells is rapidly increasing, and there are already clinical trials under way testing many novel immunotherapeutics and testing new ways to use those that we already have (177). The new immunotherapeutics and treatment strategies that are on the horizon hold extraordinary promise for the future. Here, however, we focus on new immunotherapeutics that were approved by the FDA in the 12 months covered by this report, Aug. 1, 2017 to July 31, 2018, and previously approved immunotherapeutics that were approved for use against additional types of cancer during the same period.

Boosting the Killing Power of the Immune System

Research has shown that immune cells called T cells are naturally capable of destroying cancer cells. It has also shown that in patients with cancer there are insufficient cancer-killing T cells, or the cancer-killing T cells that are present are unable to find the cancer cells or are unable to destroy the cancer cells for one of several reasons.

This knowledge has led researchers to identify several ways to boost the ability of T cells to eliminate cancer cells (see sidebar on How Immunotherapeutics Work).

One of the most recently developed ways to boost the killing power of T cells is through adoptive T-cell therapy (178). The goal of this approach to immunotherapy is to dramatically increase the number of functional cancer-killing T cells that a patient has. Adoptive T-cell therapy is a complex medical procedure that is customized for each patient. During treatment, T cells are harvested from a patient, expanded in number and/or genetically modified in the laboratory, and then returned to the patient, where they attack and potentially eliminate the cancer cells (see sidebar on Types of Adoptive T-Cell Therapy).

As of July 31, 2018, two of these revolutionary new types of immunotherapy had been approved by the FDA, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah). Both are categorized as chimeric antigen receptor (CAR) T-cell therapy. Given that CAR T-cell therapy involves genetic modification of a patient’s cells, it is sometimes referred to as cell-based gene therapy. For both axicabtagene ciloleucel and tisagenlecleucel, a patient’s T cells are genetically modified to have a CAR that targets the molecule CD19.

CD19 is a protein found on the surface of immune cells called B cells. Several types of leukemia and lymphoma arise in B cells, including most cases of ALL and most cases of non-Hodgkin lymphoma.

ALL is the most common cancer diagnosed among children ages 0 to 14 in the United States, with more than 3,000 new cases projected to be diagnosed in 2018 (10). In August 2017, tisagenlecleucel was approved for treating children and young adults up to the age of 25 with B-cell ALL that has not responded to standard treatments or has relapsed at least twice. The approval was based on results from a phase II clinical trial that showed that more than 80 percent of the children and young adults who were treated with tisagenlecleucel had remission within three months of receiving the CAR T-cell therapy (179). Results from earlier, smaller clinical trials suggest that for some patients, like Tori Lee, remission following tisagenlecleucel treatment is durable, but further follow-up is needed to determine long-term overall survival rates (180).

In 2018, it is estimated that there will be almost 75,000 new cases of non-Hodgkin lymphoma diagnosed in the United States (10). The term non-Hodgkin lymphoma encompasses many different types of cancer. Two recent FDA decisions made axicabtagene ciloleucel and tisagenlecleucel approved treatment options for certain patients with non-Hodgkin lymphoma classed as large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Specifically, the CAR T-cell therapies are approved for those patients whose disease has not responded to or has relapsed after two other treatments.

The approvals of axicabtagene ciloleucel and tisagenlecleucel for large B-cell lymphoma, in October 2017 and May 2018, respectively, were based on results from phase II clinical trials (181-182). In the axicabtagene ciloleucel clinical trial, more than 50 percent of the patients treated with the CAR T-cell therapy had complete responses, meaning that no cancer was detectable during at least one follow-up examination (181). In the other clinical trial, 32 percent of those treated with tisagenlecleucel had complete responses (182). Further studies are needed to determine whether axicabtagene ciloleucel and tisagenlecleucel improve overall survival. However, early results suggest that responses are durable for many patients (181-182), providing new hope to patients like Mike Delia who was treated with axicabtagene ciloleucel in July 2016.

Like all cancer treatments, CAR T-cell therapy can have adverse effects. Some of the adverse effects of CAR T-cell therapy can be very severe and, in some cases, life-threatening. One of the most concerning is cytokine-release syndrome. This can occur as the CAR-modified T cells attack the cancer cells because part of their job is to release substances called cytokines. In patients affected by cytokine-release syndrome, there is an overwhelming release of cytokines into the bloodstream, which can cause high fevers, flu-like symptoms, and a dramatic drop in blood pressure. For many patients, treatment with steroids can relieve the cytokine-release syndrome. However, others require treatment with tocilizumab (Actemra), which blocks a cytokine called IL-6. Tocilizumab had previously been approved by the FDA for treating several forms of arthritis, but was approved to treat severe or life-threatening cytokine-release syndrome caused by CAR T-cell therapy in August 2017. This approval highlights how discoveries in one disease area can offer new ideas for the treatment of other diseases.

Given that CAR T-cell therapy can sometimes cause severe or life-threatening cytokine-release syndrome and other serious adverse effects, including potentially life-threatening swelling in the brain, the FDA has put in place a risk evaluation and mitigation strategy that requires that health care facilities using axicabtagene ciloleucel and tisagenlecleucel be specially certified. Researchers also are working hard to identify new ways to reduce the severe adverse effects of CAR T-cell therapies without decreasing the therapeutic benefit of these immunotherapeutics (183-185).

In addition, several approaches to expand the utility of CAR T-cell therapy are already being tested in clinical trials, including evaluating T cells modified to have CARs that target proteins other than CD19 (178). For example, treatment with T cells modified to have a CAR targeting the molecule CD22, which is found on the surface of B cells, benefited some patients with B-cell ALL in a phase I clinical trial (186). In another phase I clinical trial, treatment with T cells modified to have a CAR targeting the molecule BCMA, which is found on some types of B cell, benefited some patients with multiple myeloma (187). However, these are preliminary results, and additional follow-up and clinical testing are needed to determine exactly how effective these CAR T-cell therapies will be.

Releasing the Brakes on the Immune System

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Research has shown that one of the reasons that cancer-killing T cells present in a patient are unable to destroy the cancer cells is that some tumors have high levels of proteins that attach to and trigger brakes on T cells, stopping them from attacking. 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.

Ipilimumab (Yervoy) was the checkpoint inhibitor to be approved by the FDA, in March 2011. Ipilimumab targets the immune-checkpoint protein CTLA-4, protecting it from the proteins that attach to it and trigger it to put the brakes on T cells. Its approval for metastatic melanoma followed almost 25 years of basic and clinical research (see Figure 16).

This was a landmark moment.

Ipilimumab was the first treatment ever to extend overall survival for patients with metastatic melanoma (196). In addition, the success of ipilimumab motivated researchers to focus on targeting other immune-checkpoint proteins.

Between September 2014 and May 2017, the FDA approved five other checkpoint inhibitors. These all release a different T-cell braking system compared with ipilimumab. They target either the immune-checkpoint protein PD-1 or PD-L1, which is one of the proteins that applies the PD-1 brake on T cells. Nivolumab (Opdivo) and pembrolizumab (Keytruda) target PD-1, while atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) target PD-L1.

Since the initial approval of each checkpoint inhibitor, the FDA has expanded the number of cancer types for which they are approved. During the 12 months spanning this report, Aug. 1, 2017, to July 31, 2018, the FDA expanded the uses of four of these immunotherapeutics—durvalumab, ipilimumab, nivolumab, and pembrolizumab—to include the treatment of additional types of cancer. These approvals mean that as of July 31, 2018, one or more checkpoint inhibitors were approved for treating 12 types of cancer and for treating any type of solid tumor characterized by the presence of specific molecular characteristics (see Figure 17).

One of the new types of cancer for which a checkpoint inhibitor is now an approved treatment option is hepatocellular carcinoma, which is the most common form of primary liver cancer (meaning cancer arising in the liver) to be diagnosed in the United States. In September 2017, nivolumab was approved for treating patients with hepatocellular carcinoma that has progressed despite treatment with the molecularly targeted therapeutic sorafenib (Nexavar), which is the standard treatment for the disease. The approval was based on results from a phase I/II clinical trial that showed that some patients had partial or complete tumor shrinkage after nivolumab treatment (197). Among those whose tumors shrank, the responses were durable, with most of them lasting 12 months or longer.

Another new type of cancer for which checkpoint inhibitors became an FDA-approved treatment is stomach cancer (gastric cancer). In September 2017, the FDA approved pembrolizumab for treating patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma that has progressed despite two other treatments and that tests positive for PD-L1 using a defined companion diagnostic (see sidebar on Companion Diagnostics). The approval was based on the fact that pembrolizumab treatment led to tumor shrinkage in just over 10 percent of patients enrolled in a phase II clinical trial (198).

In June 2018, the use of pembrolizumab was further expanded to include the treatment of certain patients with cervical cancer and certain patients with non-Hodgkin lymphoma. Specifically, pembrolizumab was approved for treating patients with recurrent or metastatic cervical cancer that tests positive for PD-L1 using a defined companion diagnostic and that has progressed despite treatment with cytotoxic chemotherapy, and for treating patients with primary mediastinal large B-cell lymphoma, which is an aggressive type of non-Hodgkin lymphoma, that has not responded to or has relapsed after two or more other treatments. The approvals were based on phase II clinical trial results showing that treatment with pembrolizumab led to tumor shrinkage in 14 percent and 45 percent of patients, respectively.

In addition, in August 2017, the FDA expanded the approved uses of nivolumab to include certain patients with colorectal cancer characterized by the presence of specific molecular characteristics, or biomarkers, called microsatellite instability–high and DNA mismatch–repair deficiency. Among these patients, nivolumab is intended for those whose cancer has progressed despite treatment with chemotherapy. The approval was based on results from a phase II clinical trial that showed that nivolumab treatment led to tumor shrinkage in more than 30 percent of patients (199).

The number of uses for which durvalumab is an FDA-approved treatment option was also expanded during the 12 months covered by this report. In February 2018, it was approved by the FDA for treating patients with stage III non–small cell lung cancer (NSCLC) whose cancer cannot be removed surgically and has not progressed after standard concurrent treatment with a platinum-based cytotoxic chemotherapeutic and radiotherapy. The approval was based on the fact that durvalumab treatment almost tripled the median length of time before disease progressed for patients enrolled in a phase III clinical trial (200).

The successes with the five PD-1/PD-L1–targeted checkpoint inhibitors highlighted here have led to clinical trials in which these and other checkpoint inhibitors are being tested as a potential treatment for other types of cancer. Results are not available yet for most of these trials. However, initial results show that pembrolizumab may benefit some patients with mesothelioma (201), and that a new, investigational checkpoint inhibitor called cemiplimab may benefit some patients with cutaneous squamous cell carcinoma, which is the second deadliest skin cancer after melanoma (202).

Despite the tremendous achievements, treatment with FDA-approved checkpoint inhibitors yields remarkable and durable responses for only a minority of patients. Thus, researchers are testing various ways to increase the number of patients who benefit from these immunotherapeutics, including evaluating how well they work in combination. In May 2018, the FDA approved using ipilimumab in combination with nivolumab to treat certain patients with the most common form of kidney cancer, renal cell carcinoma. Among these patients, the combination is intended for those who have advanced renal cell carcinoma that is classed as of intermediate or high risk for a poor outcome with standard treatment with a molecularly targeted therapeutic such as sunitinib (Sutent). The approval was based on results from a phase III clinical trial that showed that the combination significantly improved overall survival rates compared with sunitinib (203).

In July 2018, the combination of ipilimumab and nivolumab was also approved for treating patients with colorectal cancer that is characterized by either the microsatellite instability–high or DNA mismatch–repair deficiency biomarker and that has progressed after treatment with a cocktail of cytotoxic chemotherapeutics. This approval was based on results from a phase II clinical trial that showed that 46 percent of patients who were treated with the combination had tumor shrinkage.

The idea of combining checkpoint inhibitors with immunotherapeutics that work in different ways, as well as with other types of anticancer treatments, including radiotherapy, cytotoxic chemotherapeutics, and molecularly targeted therapeutics, is also being tested in clinical trials for a wide array of types of cancer.

Another area of intensive research investigation is defining biomarkers that identify the patients most likely to benefit from a given checkpoint inhibitor. This is important because it could allow a patient unlikely to benefit to be spared the potential toxicity of the checkpoint inhibitor and to immediately start an alternative treatment. Currently, the presence of PD-L1 in a tumor and the presence of microsatellite instability–high or DNA mismatch–repair deficiency are used to identify the patients with certain types of cancer most likely to benefit from particular checkpoint inhibitors. However, these biomarkers do not work well for many types of cancer (204). Thus, there is an urgent need for new biomarkers. One showing early promise in a clinical trial evaluating nivolumab as a treatment for non–small cell lung cancer is high tumor mutational burden (205), but additional research is needed to determine how broadly this biomarker might be applicable before it can be used in the clinic.

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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, as Congressman Mark DeSaulnier discovered after his 2015 diagnosis with chronic lymphocytic leukemia (CLL). 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 26.1 million by 2040 (206-208).

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 patient and survivor vary, depending on many factors, including gender, age at diagnosis, type of cancer diagnosed, general health at diagnosis, and type of treatment received. Recognizing that follow-up care for cancer patients can be complicated, the National Academy of Medicine recommends that after completing cancer treatment, every patient should be given a record of all the care he or she received and a tailored survivorship care plan that details the posttreatment care he or she needs to maintain or improve health and quality of life (209). For example, the survivorship care plan should include recommendations for cancer screening and the schedule on which it should be performed. However, survivorship care plans are not widely used, and more research is needed to determine how beneficial they are for patients and survivors to identify the best way to improve the quality of care and quality of life of cancer survivors after they complete their treatment (210).

Individuals diagnosed with cancer 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 fact, a recent study found that individuals who have been successfully treated for childhood cancer have experienced an average of 17 chronic health conditions by age 50, five of which were serious or disabling, life threatening, or fatal (211). By comparison, individuals in the general population have experienced an average of nine chronic health conditions by the same age, only two of which are serious or disabling, life threatening, or fatal.

Individuals diagnosed with cancer as young adults (ages 20–39) have the additional challenge of adapting to long-term cancer survivorship while beginning careers and thinking about starting families of their own (see sidebar on Preserving Fertility). Being proactive and talking to health care providers about the possible long-term and late effects of particular treatments before treatment begins can help some individuals identify ways to overcome the potentially life-altering effects of treatment, as it did for Emily Bennett Taylor, Laurie Trotman, and Greg Aune (see sidebar on Looking Beyond Cancer Treatment).

Unfortunately, certain segments of the U.S. population are disproportionately affected by the adverse effects of cancer and cancer treatment, which can negatively affect quality of life after a cancer diagnosis (see sidebar on Disparities in Quality of Life after a Cancer Diagnosis). This disparity is not unique to the United States. In many developing countries, most patients and survivors receive no help in overcoming the physical, emotional, and psychosocial challenges that can occur as a result of a cancer diagnosis and treatment (212). For example, nearly all cancer patients in developing countries die with untreated pain, whereas this occurs very rarely in developed countries (212). Thus, it is imperative that all stakeholders in the global biomedical research community work together to address disparities in the care of cancer patients and survivors.

It is not just cancer patients and 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.

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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 survivors and their families is palliative care (see sidebar on What Is Palliative Care?). Palliative care can be given throughout a person’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 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.

Recent research shows that integrating palliative care during the early stages of cancer care can significantly improve quality of life (215-216). In addition, quickly integrating palliative care into the care that patients with serious illnesses such as cancer receive when hospitalized can significantly lower hospital costs (217). Thus, it is imperative that we increase awareness among both the general public and health care providers of the important role that palliative care can play across the continuum of clinical cancer care because there are still many patients who do not receive palliative care or even know what it is (218).

Preventing and Palliating Physical Symptoms

Preventing and palliating the physical symptoms and adverse effects of cancer and its treatment are becoming important because more and more people are living longer after a cancer diagnosis than ever before.

In January 2018, the FDA approved a new treatment for preventing bone complications in patients with multiple myeloma, the molecularly targeted therapeutic denosumab (Xgeva). In patients with multiple myeloma, the cancer cells accumulate in bone marrow—the soft, sponge-like tissue in the center of certain bones—which can damage and weaken the bone. Thus, bone complications, including bone pain and fractures, are adverse effects of the disease. Most patients are treated with bisphosphonates to help prevent bone complications arising. However, the use of these therapeutics is often limited by their adverse effects. Denosumab works in a different way from bisphosphonates to maintain bone density and strength. Its approval for preventing bone complications in patients with multiple myeloma was based on results from a phase III clinical trial (219). The results showed that it was as good as the bisphosphonate zoledronic acid in delaying the time to the first bone complication. Given that bone complications can be debilitating for patients with multiple myeloma, this approval provides a new option for maintaining their quality of life.

Acupuncture is a form of complementary medicine that has been shown to palliate some of the adverse effects of cancer and its treatment, and to improve quality of life for patients. For example, one recent study showed that acupuncture can reduce joint pain for postmenopausal women with early-stage breast cancer receiving treatment with an aromatase inhibitor (220). In another study, it significantly reduced the severity of insomnia among a group of cancer survivors clinically diagnosed with the condition (221). Other forms of complementary medicine have not been well studied, so we do not know if they are safe or effective. Thus, it is clear that there is an urgent need for more research in this area.

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 and decreased survival (222-223).

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Modifying Behaviors to Improve Outcomes

Many factors related to lifestyle that increase a person’s risk of developing cancer can also increase the risk of cancer recurrence and reduce survival time (see Figure 3). 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, recent research showed that men with localized prostate cancer who continue to smoke cigarettes during treatment are at higher risk of experiencing recurrence, metastasis, and death from prostate cancer (228). Fortunately, all cancer patients who are current smokers can improve their outlook by quitting smoking (52). Despite this knowledge, one study found that 9 percent of cancer survivors continue to smoke (229). Thus, more research is needed to develop optimal strategies to provide patients with cancer with the best chance of quitting smoking (230).

In recent years, evidence has emerged that regular aerobic exercise can reduce recurrence and mortality in survivors of several types of cancer, including early breast cancer, childhood cancer, colorectal cancer, and prostate cancer (231-232). Evidence is also emerging that eating a diet rich in vegetables, fruits, and whole grains, or a diet high in fiber after a diagnosis of nonmetastatic colon cancer, can reduce mortality (233-234). This evidence has largely come from observational studies. Determining if and how diet and exercise can be modified to improve outcomes for cancer survivors will require large, randomized, controlled studies. However, until definitive results from these are available, experts recommend that cancer survivors achieve and maintain a healthy body weight, participate in regular physical activity, and eat a diet rich in vegetables, fruits, and whole grains (235).

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