Saving Lives Through Research

In this section you will learn:

  • From Aug. 1, 2015, to July 31, 2016, the FDA approved 13 new therapeutic agents for treating certain types of cancer, one new cancer screening test, one new diagnostic test, two new diagnostic imaging agents, and a new medical device. 

  • During the same period, the FDA authorized new uses for 11 previously approved anticancer therapeutics.

  • Different immunotherapeutics work in different ways to unleash the power of a patient’s immune system to fight cancer.

  • Palliative care, given alongside cancer treatment and through the balance of life, can improve quality of life for patients and survivors.

  • The dedicated efforts of individuals working throughout the cycle of biomedical research (see Figure 9) have led to extraordinary advances across the continuum of clinical care that are improving and saving lives in the United States and worldwide.

Contents

Biomedical Research

Progress Across the Clinical Cancer Care Continuum

 

Biomedical Research 

Biomedical research is an iterative cycle, with each discovery building on knowledge gained from prior discoveries (see Figure 9). In recent years, the cycle has become more efficient as the pace of discoveries has increased, and new disciplines have been integrated into the biomedical research enterprise (see sidebar on Biomedical Research: What It Is and Who Conducts It). As a result of these changes, the pace at which research improves lives, like the lives of Harrison McKinion and his family, has accelerated. It is anticipated that this rapid pace of progress will continue or speed up even more in the foreseeable future (see Anticipating Future Progress).

The biomedical research cycle is set in motion when discoveries with the potential to affect the practice of medicine and public health are made by researchers in any area of biomedical research, including laboratory research, population research, clinical research, and clinical practice. The discoveries lead to questions, or hypotheses, which are tested by researchers conducting studies in a wide array of models, ranging 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 or preventive intervention, they can feed back into the cycle by providing new discoveries that lead to more hypotheses, or they can affect the practice of medicine in other ways, for example, by allowing for more precise classification of a patient’s disease, which has the potential to influence treatment decisions (see sidebar on Reclassification of Brain Tumors).

Once a potential therapeutic target is identified, it takes several years of hard work 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 novel 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 often add the investigational anticancer therapeutic to the current standard of care. These types of clinical trials have traditionally been done in three successive phases, each with an increasing number of patients (see sidebar on Phases of Clinical Trials).

As a result of recent, research-powered 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), researchers, regulators, and the pharmaceutical industry have been able to develop new ways of conducting clinical trials. The new approaches aim to streamline the development of new anticancer therapeutics by matching the right therapeutics with the right patients earlier, reducing the number of patients that 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.

At the regulatory level, 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 (see sidebar on FDA’s Expedited Review Strategies). An increasing number of anticancer therapeutics are being approved by the FDA using the most recently introduced of these review strategies—breakthrough therapy designation. A key part of this review strategy is that the FDA engages with those developing the investigational therapeutic early in the clinical trials process and provides continued guidance throughout the review period. It is sometimes used alongside other expedited review strategies, such as accelerated approval.

One of the main changes to the way in which clinical trials are conducted is the increasing use of genomics and adaptive trial designs to identify the patients most likely to benefit from an investigational anticancer therapeutic. These approaches aim to reduce the number of patients that need to be enrolled in a clinical trial to determine whether the therapeutic being evaluated is effective. They largely fall into one of two clinical trial designs: “basket” studies and “umbrella” studies (see Figure 10). 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. 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.

As our knowledge of cancer biology grows at an ever-quickening pace, continued and increased dialogue among researchers, regulators, and the pharmaceutical industry is essential to provide the right patients access to the best anticancer therapeutics that have been proven to be safe and highly effective in well-designed, well-conducted clinical trials at the earliest possible time (105).

Dialogue among researchers, regulators, and the pharmaceutical industry is also important as physician- scientists look to use genomics to identify patients who might benefit from therapeutics not previously FDA approved for their type of cancer, an approach known as drug repositioning or drug repurposing.

One patient who is benefiting from drug repositioning is Luke Theodosiades, who was just 11 years old when he was diagnosed with acute lymphoblastic leukemia (ALL). After his leukemia did not respond well at all to intensive standard-of-care chemotherapy, Luke’s team of physicians at Children’s Hospital of Philadelphia were very concerned and pursued a specialized genomic analysis of his leukemia cells performed by researchers at the University of New Mexico. This analysis found that his leukemia cells had undergone genetic recombination (see sidebar on Genetic Mutations), resulting in the fusion of two genes (GOLGA5 and JAK2). The GOLGA5-JAK2 fusion gene generated anew protein that was driving the multiplication of Luke’s leukemia cells and likely conferred resistance to his initial chemotherapy. Because JAK2 is a protein targeted by ruxolitinib (Jakafi), which was first approved by the FDA in 2011 for treating adults with myelofibrosis, Luke’s physicians added ruxolitinib to his treatment regimen. After several months of combination therapy, no leukemia cells with the GOLGA5-JAK2 fusion protein were detectable in Luke’s bone marrow, making him eligible to receive other treatments to maintain long-term remission.

Additional genomics research has identified JAK2 gene rearrangements in leukemia cells from other​ children with ALL (106). However, before ruxolitinib can become part of the standard treatment for children with this genomically defined form of ALL, it must be proven to be effective in well-designed, well-conducted clinical trials.

The advent of technologies that allow researchers to interrogate all of the changes in a patient’s cancer at one time and to look at all of the proteins in a diseased or healthy tissue simultaneously has revolutionized cancer research and is poised to do so for other diseases as well. Physicians and researchers are beginning to apply the knowledge gained from this research and use it to benefit patients like Luke Theodosiades, as well as Zach Witt, Warren Ringrose, Rita Porterfield, and Maryann Anselmo [all of whom were featured in the AACR Cancer Progress Report 2015 (24)].

However, as we generate more data about all aspects of a patient’s cancer and look to integrate this with the patient’s baseline and long-term medical information, it becomes difficult to convert all of these various data into effective treatment decisions, because physicians are literally swimming in a sea of data. The enormous amount of data is both the problem and a potential solution (see Figure 11).

Recognizing this paradox, several groups have independently started different efforts to address this challenge posed by the explosion of genomic information and the ability to link it to the clinical outcomes of the patients whose tumors have been genetically sequenced. Many of these groups are in the early stages of developing these efforts.

The analysis of the treasure trove of sequencing data has also revealed that the majority of tumors carry mutations that occur very infrequently. If we are to discover which of these mutations actually fuel tumor growth and to develop precision therapeutics that target the consequences of these mutations, many more patient samples will need to be sequenced.

In fact, a comprehensive analysis estimated that to discover all mutations that generate potential therapeutic targets in a patient population would require several thousand patients each with the same host of mutations (111). This analysis underscores the need for even more and bigger data than we currently have, as well as the tools necessary to convert the data into real knowledge that could inform patient treatment.

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Progress Across the Clinical Care Continuum

The hard work of individuals throughout the biomedical research cycle constantly powers the translation of discoveries to new medical products for cancer prevention, detection, diagnosis, treatment, and care (see Figure 9).

In the 12 months spanning Aug. 1, 2015 to July 31, 2016, the FDA approved 18 new medical products—13 new anticancer therapeutics, one new blood-based companion diagnostic test, one new cancer screening test, two new diagnostic imaging agents, and a new medical device (see Table 1). During this period, the FDA also approved new uses for 11 previously approved anticancer therapeutics, including obinutuzumab (Gazyva).

In February 2016, the FDA approved obinutuzumab for use in combination with the cytotoxic chemotherapeutic bendamustine to treat certain patients with follicular lymphoma, which is the second-most common form of non-Hodgkin lymphoma diagnosed in the United States. This approval followed its November 2013 approval for treating chronic lymphocytic leukemia (CLL), which was highlighted in the AACR Cancer Progress Report 2014 (1). The approval of obinutuzumab for treating follicular lymphoma was based on the results of a phase III clinical trial, which showed that adding obinutuzumab to bendamustine more than doubled the median time to disease progression for patients whose disease had progressed despite treatment that included rituximab (Rituxan) (112).

New FDA-approved medical products are used alongside those already in the physician’s armamentarium. Thus, most patients with cancer are treated with a combination of surgery, radiotherapy, chemotherapy (including both cytotoxic chemotherapeutics and molecularly targeted therapeutics), and/or immunotherapy (see Supplemental Table 2a, 2b and 2c and Supplemental Table 3).

The following discussion primarily highlights recent FDA approvals that are improving lives by having an effect across the continuum of clinical cancer care.

Cancer Prevention and Detection

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 has been spurred by research that led to increasing knowledge of the causes, timing, sequence, and frequency of the genetic, molecular, and cellular changes that drive cancer initiation and development.

Increasing Options for Colorectal Cancer Screening

Colorectal cancer screening has helped reduce U.S. colorectal cancer incidence and mortality rates because it can identify precancerous colorectal abnormalities, which can be removed before they have a chance to develop into cancer, as well as early-stage cancers, which are more easily treated compared with advanced-stage cancers (see sidebar on Consensus Among Cancer Screening Recommendations) (113). However, colorectal cancer remains the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths (3).

One in every three U.S. adults for whom colorectal cancer screening is recommended is not up to date with screening (113). It is clear that new ways to increase participation in colorectal cancer screening could significantly reduce the burden of this common cancer.

Research shows that people who are able to pick the colorectal cancer screening test they prefer are more likely to actually get the test done (115).

In an effort to increase the number of colorectal cancer screening options, and hopefully thereby increase the number of people who are screened, researchers built on the discovery that a specific epigenetic abnormality—the presence in blood of epigenetic marks called methyl groups on part of a gene called Septin-9—is associated with colorectal cancer to develop a blood-based test (116). The new test, Epi proColon, detects the Septin-9 epigenetic abnormality in blood, and it was approved by the FDA for screening those who choose not to be screened by colonoscopy or a standard stool-based test in April 2016. Although further research is needed to determine the long-term benefits of Epi proColon, including whether or not it will help increase the number of people who are screened for colorectal cancer, this approval exemplifies how researchers translate scientific discoveries to new FDA-approved medical products.

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Treatment With Surgery, Radiotherapy, and Cytotoxic Chemotherapy

The discovery that most cancers arise as a result of the accumulation of genetic mutations within cells (see Cancer Development: Influences Inside the Cell), coupled with advances in biology, chemistry, physics, and technology, sets the stage for the new era of precision medicine.

Precision medicine is broadly defined as treating a patient based on characteristics that distinguish that individual from other patients with the same disease (see Figure 2) (25). As we have learned more about 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. This is changing the standard of care for many patients 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.

The molecularly targeted therapeutics that are the foundation of precision medicine tend to be more effective and less toxic than two of the long-standing pillars of cancer treatment—radiotherapy and cytotoxic chemotherapy (see Figure 12). 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. Whatever the reason, the reality is that these therapeutic modalities form the foundation of treatment for almost all patients with cancer, including those for whom molecularly targeted therapeutics and other novel anticancer agents are appropriate.

For many patients with cancer, surgery is a foundation of their treatment plan. 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. In the early 1990s, surgeons began performing minimally invasive laparoscopic surgery for some types of cancer. Subsequently, laparoscopic surgery for some types of cancer was modified to include a computer console that the surgeon uses to manipulate robotic arms attached to the surgical instruments. However, there have been few studies comparing the effectiveness of different forms of surgery (118). One randomized clinical trial showed no difference in disease-free and overall survival among patients with colorectal cancer who had laparoscopic surgery or open surgery (119), while a recent study that looked back at outcomes for patients who underwent robot-assisted laparoscopic prostatectomy or open radical prostatectomy for non metastatic prostate cancer found that the robotic surgery yielded a number of benefits (120). On the other hand, early results from a randomized, controlled phase III trial comparing these two approaches showed there were no
significant differences in intra- and postoperative outcomes (121). Thus, more research is needed to more fully compare the effectiveness of different types of surgery, robotic surgery in particular, which typically costs more than laparoscopic or open surgery, for all types of cancer (118).

The shift from open surgery to minimally invasive laparoscopic surgery for certain types of cancer is not the only surgical advance that has been made to reduce adverse effects that can accompany surgery. One recent advance was to reduce the use of axillary lymph node dissection, an invasive surgical procedure in which large numbers of lymph nodes in the armpit are removed, in the treatment of breast cancer. Up to 40 percent of patients with breast cancer who have an axillary lymph node dissection have been reported to experience lymphedema, swelling of the arm that can limit movement (123). One concern about reducing the use of axillary lymph node dissection was that it might negatively affect outcomes for patients. However, a recent study showed that women with breast cancer that had spread to one or two lymph nodes who were treated with lumpectomy, radiotherapy, and systemic therapy had equally good disease-free and overall survival after 10 years whether or not they had an axillary lymph node dissection (124).

Picturing Cancer More Clearly

The more precise a patient’s diagnosis, the more easily the patient’s physicians can tailor his or her treatment to ensure that it is as effective and innocuous as possible. Among the tools physicians use to make cancer diagnoses is positron emission tomography–computed tomography (PET–CT or PET), a form of imaging that can help physicians precisely locate the position of a patient’s cancer within his or her body and determine the extent to which the cancer may have spread.

Before having a PET scan, patients are injected with a radioactive imaging agent. The PET scan detects where in the body the radioactive agent accumulates. In June 2016, the FDA approved a new kit called Netspot for preparing the injectable radioactive imaging agent gallium (Ga) 68 DOTATATE for use with PET to locate neuroendocrine tumors with the protein somatostatin receptor on the surface. Ga 68 DOTATATE locates these tumors because it is analogous to somatostatin, which naturally attaches to the somatostatin receptor.

PET imaging using Ga 68 DOTATATE has been shown to more precisely locate somatostatin receptor–positive neuroendocrine tumors compared with previous approaches, which has the potential to affect patient treatment in a number of ways (125). For example, it can better identify disease sites for potentially curative surgery or determine if a patient has metastases that cannot be removed by surgery such that he or she requires additional treatment approaches. It also reduces radiation exposure for patients​ compared with an imaging agent that has been used for the past few decades (indium-111 radiolabeled octreotide) (125).

In clinical cancer care, PET imaging is not only used to help identify cancer initially, but also to monitor patients for potential disease recurrence. In May 2016, the FDA approved the radioactive imaging agent fluciclovine fluorine (F) 18 (Axumin) for use with PET to screen men whose prostate cancer was suspected to have recurred based on elevated prostate specific antigen (PSA) levels after previous successful treatment. Fluciclovine F 18 comprises an F 18 radiolabeled synthetic amino acid (a building block of proteins) that is preferentially taken up by many types of cancer cells, including prostate cancer cells, compared with surrounding normal tissues.

Recurrent prostate cancer is usually detected by a rise in PSA levels; however, the location and extent of the disease cannot always be detected using currently available imaging tools. In a recent small study in which men with suspected prostate cancer recurrence underwent PET imaging with fluciclovine F 18 and PET imaging with the currently used radioactive imaging agent choline C 11, fluciclovine F 18 located sites of prostate cancer recurrence in more men (126). Precisely locating sites of prostate cancer recurrence is important for physicians as they tailor a man’s next treatments. For example, a single site of recurrence might be treatable with local therapy, such as surgery or radiotherapy, whereas multiple sites of recurrence might require systemic treatment, such as antihormone therapy or chemotherapy.

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Tailoring Treatments to Reduce Adverse Effects

Radiotherapy and cytotoxic chemotherapy are mainstays of cancer care (see sidebar on Using Radiation in Cancer Care). However, both types of treatment can have long-term adverse effects on patients. Thus, physicians are looking to tailor each patient’s treatment to be only as aggressive as is necessary for it to be effective. They are doing so 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.

Many patients with early-stage breast cancer are treated with breast-conserving surgery followed by whole breast radiotherapy. For several decades, the radiotherapy portion of this treatment regimen has comprised 5 to 7 weeks of daily radiotherapy. A few years ago, long-term follow-up from several clinical trials showed that hypofractionated radiotherapy, whereby patients receive fewer but higher doses of radiotherapy over a shorter time period, was as effective as the traditional course of radiotherapy at preventing local breast cancer recurrence (127, 128). New research shows that hypofractionated radiotherapy also significantly reduces adverse treatment effects compared with the traditional course of radiotherapy (129, 130).

Compared with a traditional course of radiotherapy, hypofractionated radiotherapy requires fewer visits to the radiation oncologist, which could help lower health care costs and increase convenience for patients (131). However, few U.S. patients with breast cancer for whom hypofractionated radiotherapy would be a suitable option currently receive the treatment. Researchers hope that the new data showing a reduction in adverse effects will help increase the number of women who have their radiotherapy tailored to be as effective yet innocuous as possible.

One approach that researchers are using to reduce the adverse effects of chemotherapy is to develop nanotechnology-based forms of cytotoxic chemotherapeutics. These allow the delivery of higher levels of cytotoxic chemotherapeutics to cancer cells than the usual forms of the anticancer agents, thereby increasing effectiveness while reducing adverse effects.

In October 2015, the FDA approved a nanotechnology- based form of the cytotoxic chemotherapeutic irinotecan, which is used in the conventional form to treat some patients with several types of cancer, including colorectal, lung, and ovarian cancers. The new nanotechnology- based anticancer agent, irinotecan liposome injection (Onivyde), can now be used in combination with two other cytotoxic chemotherapeutics, fluorouracil and folinic acid (leucovorin), for treating patients with advanced pancreatic cancer that has progressed despite treatment with gemcitabine-based chemotherapy. The decision was made after results from a large clinical trial showed that patients lived significantly longer when irinotecan liposome injection was added to fluorouracil and folinic acid (132).

Increasing Options for Patients With Soft Tissue Sarcoma

Soft tissue sarcoma is a relatively rare type of cancer, with 12,310 U.S. adults expected to be diagnosed with the disease in 2016 (3). It is actually not one type of cancer, but instead is a group 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. Two of the most common types of adult soft tissue sarcomas are liposarcoma and leiomyosarcoma. Liposarcomas arise in fat cells in any part of the body, but most commonly fat cells in the muscles of the limbs or in the abdomen. Leiomyosarcomas arise in smooth muscle cells, most frequently those in the uterus or abdomen.

Patients with advanced soft tissue sarcoma have a poor prognosis; median survival is estimated to be just 12 to 15 months (133). Those for whom surgery is not a possibility are usually treated with various combinations of cytotoxic chemotherapeutics to control the growth of the tumor, but no chemotherapy treatments have been shown to improve survival, and options are limited.

This situation changed recently, when results from  a large-scale clinical trial showed that the cytotoxic chemotherapeutic eribulin mesylate (Halaven) significantly improved survival for certain patients with liposarcoma compared with the cytotoxic chemotherapeutic dacarbazine (134). These results led the FDA to approve eribulin mesylate for patients with liposarcoma that cannot be removed by surgery or that is advanced and that has progressed despite treatment with a chemotherapy regimen that includes a type of cytotoxic chemotherapeutic called an anthracycline—for example, doxorubicin—in January 2016. With eribulin mesylate having previously been approved for treating metastatic breast cancer, this new approval both expands the number of patients who may benefit from the cytotoxic chemotherapeutic and increases the return on prior investments in biomedical research.

In October 2015, the FDA added another cytotoxic chemotherapeutic to the armamentarium for physicians treating patients with soft tissue sarcomas when it approved trabectedin (Yondelis) for treating some liposarcomas and leiomyosarcomas. The decision was based on the fact that trabectedin extended the average time before disease progressed compared with dacarbazine for patients whose tumors could not be surgically removed or had advanced disease and who had been previously treated with an anthracycline-containing chemotherapy regimen (133). This approval is providing new hope to patients like Nancy McGuire.

Working Together to Treat Colorectal Cancer

Although screening for colorectal cancer has helped lower U.S. colorectal cancer incidence and mortality rates (113) (see Increasing Options for Colorectal Cancer  Screening,  p. 57), the disease remains the second leading cause of cancer- related death in the United States (3). In September 2015, the FDA provided fresh hope for patients with the disease when it approved a new treatment option for advanced colorectal cancer that is no longer responding to other treatments: a combination of drugs formulated together in a single tablet called Lonsurf (previously known as TAS-102).

 

The two therapeutics in TAS-102—trifluridine and tipiracil—work together to target colorectal cancer. Trifluridine is a cytotoxic chemotherapeutic that causes damage to DNA in the rapidly multiplying cancer cells, which can ultimately trigger cell death; tipiracil prevents rapid breakdown of trifluridine, thereby maintaining adequate levels of trifluridine in the body.

Trifluridine damages DNA in a similar way to the cytotoxic chemotherapeutic fluorouracil, which has been used as a treatment for colorectal cancer for decades. However, in the phase III clinical trial that led to the FDA approval of TAS-102, the new combination chemotherapy tablet improved survival compared with placebo even for those patients who had colorectal cancer that was no longer responding to treatment with fluorouracil-containing chemotherapy regimens (135).

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Treatment With Molecularly Targeted Therapeutics

Research is powering the field of precision medicine in many ways, including by increasing our understanding of the genetic, molecular, and cellular changes that lead to cancer initiation and development. Therapeutics directed to the molecules involved in different stages of the cancer process target the cells within a tumor more precisely than cytotoxic chemotherapeutics. 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.

Helping Some Lung Cancer Patients Breathe Easier

Research has spurred tremendous progress against lung cancer in recent years through the identification of the genetic, molecular, and cellular changes that fuel cancer growth in certain patients and the development of therapeutics that target these changes. Unfortunately, the majority of lung cancers that initially respond to the new molecularly targeted therapeutics eventually progress and are said to have become treatment resistant (see sidebar on The Challenge of Treatment Resistance).

Two FDA decisions in late 2015 have helped address the problem of treatment resistance for two groups of patients with non–small cell lung cancer (NSCLC)—the most commonly diagnosed form of lung cancer in the United States (3).

In November 2015, the FDA approved a molecularly targeted therapeutic called osimertinib (Tagrisso) for patients with NSCLC that has become resistant to other therapeutics that target the same molecule, EGFR. At the same time, the FDA approved a new test, or companion diagnostic, to identify the patients for whom osimertinib is approved, the cobas EGFR Mutation Test v2 (see sidebar on Companion Diagnostics).

About 10 to 20 percent of patients with NSCLC have tumors that are fueled by mutations in the EGFR gene (136), and the FDA has previously approved three EGFR-targeted therapeutics, afatinib (Gilotrif), erlotinib (Tarceva), and gefitinib (Iressa), for treating these patients. Although most NSCLCs fueled by EGFR mutations respond to afatinib, erlotinib, and gefitinib, not all do, and even those that do respond initially eventually become resistant to these EGFR-targeted therapeutics (136). The most frequent cause of resistance is the acquisition by some cells in the tumor of a new mutation in the EGFR gene called the EGFR T790M mutation.

Osimertinib specifically targets cancer-driving mutant forms of EGFR, including that produced by the EGFR T790M mutation. It is the only FDA-approved therapeutic that can target NSCLCs with this mutation, providing new hope for patients like Ginger Tam. In phase II clinical trials, osimertinib treatment led to tumor shrinkage or disappearance in patients with NSCLC fueled by the EGFR T790M mutation (137), and it is hoped that future studies will reveal that the molecularly targeted therapeutic also extends survival for these patients.

In December 2015, the FDA approved a molecularly targeted therapeutic called alectinib (Alecensa) for treating patients with NSCLC that harbors mutations in the ALK gene and who are not responding to the ALK-targeted therapeutic crizotinib (Xalkori), which was FDA approved for treating this group of patients in August 2011.

ALK gene mutations fuel 3 to 7 percent of NSCLCs (138). Although crizotinib benefits many patients with NSCLC driven by ALK, not all patients respond. Moreover, the majority of patients who initially respond to crizotinib treatment eventually relapse because the cancer becomes resistant to the ALK-targeted therapeutic (138).

One cause of crizotinib resistance is the emergence of new mutations in ALK. Alectinib is able to block many of the unique forms of ALK that result from these new mutations and in phase I/II clinical trials, treatment with alectinib caused tumor shrinkage or disappearance in patients with crizotinib-resistant NSCLC driven by ALK. Alectinib was even able to shrink tumors that had metastasized to the brain, which is something the other ALK-targeted therapeutics are less able to do (138). It is hoped that future studies will show that alectinib also improves survival for patients with ALK-fueled NSCLC.

About 1 percent of patients with NSCLC have tumors that are fueled by mutations in the ROS1 gene, which generates a protein that is related to ALK (139). In March 2016, the FDA approved crizotinib for treating patients with ROS1- fueled NSCLC after a phase I clinical trial showed that the anticancer therapeutic caused partial or complete tumor shrinkage in patients with this type of NSCLC (139). This new approval both expands the number of patients with NSCLC who may benefit from crizotinib and increases the return on prior investments in biomedical research.

Most patients with EGFR-mutant NSCLC have the nonsquamous cell type of NSCLC (140). Even though EGFR mutations are rarely detected in the less common squamous cell type of NSCLC, most of these cancers have elevated levels of EGFR protein on their surface (140). This observation suggested to researchers that EGFR-targeted therapeutics might benefit patients with squamous NSCLC.

In fact, phase III clinical trials showed that two different EGFR-targeted therapeutics, afatinib and necitumumab (Portrazza), improved survival for patients with advanced squamous NSCLC (140, 141). These two molecularly targeted therapeutics were approved by the FDA in April 2016 and November 2015, respectively. Of note, afatinib is approved as a stand-alone treatment for patients whose disease has progressed despite treatment with a platinum- based cytotoxic chemotherapeutic. Necitumumab is approved for use in combination with the cytotoxic chemotherapeutics gemcitabine and cisplatin for treating patients who have not previously received medication specifically for their advanced squamous NSCLC.

Progress against lung cancer in the 12 months from Aug. 1, 2015 to July 31, 2016, is not limited to the five molecularly targeted therapeutic FDA approvals highlighted here (see Figure 13). During this period, the FDA also approved two immunotherapeutics for treating certain patients with the disease (see Releasing Brakes on the Immune System). In addition, the first liquid biopsy test was approved by the FDA for use in identifying which patients with metastatic NSCLC may benefit from treatment with the EGFR therapeutic erlotinib.

A biopsy is the removal of cells or tissues from a patient for testing to help physicians diagnose a condition such as cancer or monitor how it changes in response to treatment. Traditionally, biopsies are invasive procedures. However, research has shown that during the course of cancer development and treatment, tumors routinely shed detectable cells, lipid-encapsulated sacs called exosomes, and free DNA into a patient’s blood. Researchers have shown in clinical trials that it is possible to use a blood sample, or liquid biopsy, rather than a traditional tissue biopsy, to obtain material that can be analyzed to provide information about the genomic alterations in a patient’s cancer. Liquid biopsies have the potential to transform patient care across the clinical cancer care continuum.

The revolution in cancer diagnosis and monitoring began in June 2016, when the FDA approved the first liquid biopsy companion diagnostic test for identifying whether or not a patient with metastatic NSCLC is eligible for treatment with the EGFR-targeted therapeutic erlotinib. The cobas EGFR Mutation Test v2 was already approved by the FDA for testing tumor tissue samples obtained by a traditional biopsy. The new approval allows the test to be used to analyze plasma, the colorless liquid component of blood.

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Triggering Leukemia Cell Death

CLL is the second most common type of leukemia diagnosed in the United States, with almost 19,000 new cases projected to be diagnosed in 2016 (3). Tremendous progress has been made against CLL in the past 2 years, with several new molecularly targeted therapeutics approved by the FDA for treating patients with the disease, like David Rampe [who was featured in the AACR Cancer Progress Report 2014 (1)].

Although the new therapeutics benefit many patients with CLL, not all patients have a response to these treatments. Moreover, many patients whose CLL initially responds eventually have disease progression. Patients who have CLL characterized by a genetic mutation called the 17p deletion are particularly prone to poor outcomes.

In April 2016, the FDA approved the molecularly targeted therapeutic venetoclax (Venclexta) for treating CLL shown to have a 17p deletion with the Vysis CLL FISH Probe Kit companion diagnostic. This approval provided new hope to patients like Brian Parkinson).

Venetoclax is the first in a new class of anticancer therapeutics called BCL2 inhibitors. BCL2 is a protein that promotes cell survival by preventing cells from undergoing a natural self-destruct process called apoptosis (see Figure 14). CLL cells often express elevated levels of BCL2, and by blocking this protein, venetoclax triggers the cells to die by apoptosis.

The approval of venetoclax by the FDA was based on phase II clinical trial results showing that venetoclax benefited the majority of patients with CLL with a 17p deletion that had progressed despite treatment with at least one other therapeutic (142).

Each of the four new molecularly targeted therapeutics approved for treating CLL in the past 3 years— obinutuzumab, ibrutinib (Imbruvica), idelalisib (Zydelig), and venetoclax—targets a different molecule involved in CLL biology. This highlights how our increasing knowledge of a given cancer, which is gained through research, can yield multiple new approaches to treatment.

Making Treatment More Convenient

The number of treatment options for patients with multiple myeloma—one of the most commonly diagnosed hematological malignancies, or blood cancers, in the United States—has dramatically increased in the past decade.

Two of the molecularly targeted therapeutics approved by the FDA for treating multiple myeloma in this period target the proteasome. The proteasome is a machine naturally found in cells that breaks down proteins the cell no longer needs. This process helps control cell division and survival. By preventing the natural breakdown of proteins, these two therapeutics, bortezomib (Velcade) and carfilzomib (Kyprolis), are highly toxic to myeloma cells, causing them to die.

Bortezomib and carfilzomib are administered to patients by injection, either into the veins or, in the case of bortezomib, under the skin. In November 2015, the FDA approved the first proteasome inhibitor that can be taken by mouth, ixazomib (Ninlaro), providing patients with multiple myeloma with a more convenient treatment option.

Ixazomib is intended for use in combination with the immunomodulatory agent lenalidomide (Revlimid) and the steroid dexamethasone to treat patients with multiple myeloma that has progressed despite treatment with at least one prior therapy. Its approval was based on the fact that adding ixazomib to lenolidamide and dexamethasone significantly increased the average time before disease progressed for patients enrolled in a phase III clinical trial (143).

Ixazomib is just one of three new therapeutics approved in November 2015 for treating multiple myeloma (see sidebar on Recent Advances Against Multiple Myeloma). The other two therapeutics work by exploiting the power of the immune system and are discussed in Directing the Immune System to Cancer Cells (below).

Combining Therapeutics to Improve Outcomes

Melanoma is the deadliest form of skin cancer: It accounts for only 1 percent of all U.S. skin cancer cases but the majority of skin cancer deaths (3). Before Jan. 1, 2011, the FDA had not approved a new systemic treatment for melanoma in more than 20 years. Since that time, the agency has approved a wide array of molecularly targeted therapeutics and immunotherapeutics, for use as single agents or in combination, to treat patients with metastatic melanoma (see Figure 15).

The most recent of these approvals came in November 2015, when the FDA approved a combination of molecularly targeted therapeutics, cobimetinib (Cotellic) and vemurafenib (Zelboraf), for treating metastatic melanoma fueled by certain mutations in the BRAF gene.

About 50 percent of melanomas are driven by genetic mutations that lead to an abnormal protein called BRAF V600E (144). This knowledge led to the development and subsequent FDA approval of two BRAF V600E–targeted therapeutics, vemurafenib and dabrafenib (Tafinlar). Although these molecularly targeted therapeutics benefit many patients with melanoma fueled by the BRAF V600E protein, the majority of those whose cancers initially respond to vemurafenib and dabrafenib have disease progression within a year of starting treatment owing to treatment resistance (145, 146).

Trametinib and cobimetinib block the activity of two proteins, MEK1 and MEK2, that function in the same signaling network as abnormal BRAF proteins. Trametinib is FDA approved for use alone or in combination with dabrafenib for treating patients with  metastatic melanoma shown to be fueled by either BRAF V600E or another abnormal BRAF protein called BRAF V600K. The combination of dabrafenib and trametinib almost doubles the length of time before metastatic melanoma becomes resistant to treatment and progresses compared with either molecularly targeted therapeutic used alone (147).

Similarly, adding cobimetinib to vemurafenib significantly increased the time before disease progressed for patients with metastatic melanoma fueled by BRAF V600E or BRAF V600K, as determined in a phase III clinical trial using the FDA-approved companion diagnostic cobas 4800 BRAF V600 Mutation Test (144).

The combinations of dabrafenib and trametinib, and cobimetinib and vemurafenib, are the first molecularly targeted therapeutic combinations to have been approved by the FDA for treating any type of cancer. As our understanding of the biology of cancer continues to grow, it is highly likely that combinations of molecularly targeted therapeutics will become an integral part of cancer treatment in the near future.

Blocking the Blood Supply to Tumors

Research has shown that many solid tumors need to establish their own blood and lymphatic vessel network to grow and survive. It has also led to the identification of many molecules that control the growth of the new blood and lymphatic vessels within a tumor, as well as the development of anticancer therapeutics that specifically target these molecules. These molecularly targeted therapeutics are sometimes referred to as antiangiogenic therapeutics. Currently, there are 11 such therapeutics to have been approved by the FDA.

In many cases, antiangiogenic therapeutics not only target molecules that stimulate blood and lymphatic vessel growth, but they also target molecules that promote tumor growth and cancer progression in other ways, such as triggering cancer cell multiplication.

Many antiangiogenic therapeutics are approved by the FDA for treating a number of different types of cancer. In April 2016, the FDA increased the number of types of cancer for which the antiangiogenic agent cabozantinib can be used as a treatment, when it approved a tablet form of the molecularly targeted therapeutic (Cabometyx) for treating patients with advanced renal cell carcinoma that has progressed despite treatment with at least one other antiangiogenic therapeutic. This approval was based on results from a phase III clinical trial comparing cabozantinib with everolimus (Afinitor)—a recommended treatment for patients with renal cell carcinoma who have previously received one or more antiangiogenic therapeutics (see Expanding the Use of an Anticancer Therapeutic below) (148). The trial showed that cabozantinib increased the time before disease progressed and improved survival. The April 2016 approval followed the November 2012 FDA approval of a capsule form of cabozantinib (Cometriq) for treating patients with metastatic thyroid cancer.

In May 2016, the FDA approved a second use for the antiangiogenic therapeutic lenvatinib (Lenvima), when it approved it for use in combination with everolimus for treating patients with advanced renal cell carcinoma that has progressed despite treatment with at least one other antiangiogenic therapeutic. The approval was based on the fact that adding lenvatinib to everolimus increased the time before disease progressed and improved survival for patients enrolled in a phase II clinical trial (149). The first use for lenvatinib was approved by the FDA in February 2015: It was approved for treating patients with metastatic differentiated thyroid cancer like Lori Cuffari [who was featured in the AACR Cancer Progress Report 2015 (24)].

These new approvals both expand the number of patients who may benefit from the antiangiogenic therapeutics and increase the return on prior investments in biomedical research.

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Expanding the Use of an Anticancer Therapeutic

Everolimus is another molecularly targeted therapeutic to have its use in clinical cancer care expanded by the FDA in the 12 months leading up to July 31, 2016. In February 2016, it was approved for treating certain patients with neuroendocrine tumors—those with progressive, well-differentiated,  nonfunctional,  neuroendocrine tumors of gastrointestinal or lung origin that cannot be removed by surgery or that have progressed. The latest approval came almost 7 years after the first, which was for treating patients with renal cell carcinoma that has progressed despite treatment with an antiangiogenic therapeutic (see Blocking the Blood Supply to Tumors above).

Everolimus targets a protein called mTOR, which research has shown is part of a signaling network that promotes several important cellular processes, including cell multiplication. Research has also shown that the mTOR signaling network is excessively active in many types of cancer. Thus, one rationale for testing everolimus as an anticancer therapeutic is that it can dampen the excessive mTOR signaling network activity that helps fuel cancer cell multiplication.

In fact, blocking mTOR with everolimus almost tripled the time before disease progressed, compared with placebo, for patients with advanced, progressive, well-differentiated, nonfunctional, neuroendocrine tumors of gastrointestinal or lung origin enrolled in a phase III clinical trial (150).

Neuroendocrine tumors are a group of cancers that form from neuroendocrine cells, which are cells that release hormones into the blood in response to a signal from the nervous system. Although they can arise anywhere in the body that there are neuroendocrine cells, more than 80 percent arise in the gastrointestinal tract, lungs, or pancreas (151). The new approval for everolimus, combined with its May 2011 approval for treating patients with advanced, progressive neuroendocrine tumors of pancreatic origin, made it the first molecularly targeted therapeutic to have shown anticancer activity across much of the spectrum of neuroendocrine tumor types.

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Treatment With Immunotherapeutics

In the past 5 years, immunotherapy has emerged as one of the most exciting new approaches to cancer treatment that has ever entered the clinic. This is in part because some of the patients who have been treated with these revolutionary anticancer treatments have had remarkable and durable responses, raising the possibility that they might be cured, and also in part, because some of the immunotherapeutics have been shown to benefit patients with an increasing number of types of cancer (see Figure 16). In fact, one immunotherapeutic, nivolumab (Opdivo), was recently approved by the FDA for four new uses in just 12 months (see Releasing Brakes on the Immune System below).

Cancer immunotherapy refers to therapeutics that can unleash the power of a patient’s immune system to fight cancer the way it fights pathogens. These therapeutics are called immunotherapeutics. Not all immunotherapeutics work in the same way (see sidebar on How Immunotherapeutics Work).

Given that our scientific understanding of the immune system and how it interacts with cancer cells is rapidly increasing, there are many novel immunotherapeutics in development and new ways being tested to use those that we already have. The new agents and treatment strategies that are on the horizon hold extraordinary promise for the future. A glimpse of this future is discussed in Anticipating Future Progress. Here, we focus on immunotherapeutics that were approved by the FDA in the 12 months covered by this report, Aug. 1, 2015 to July 31, 2016.

Releasing Brakes on the Immune System

Research has shown that immune cells called T cells are naturally capable of destroying cancer cells (see sidebar on Key Players in the Immune System). 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. Brakes on the surface of T cells are called immune-checkpoint proteins.

This knowledge has led researchers to look for ways to release the brakes on T cells.

As of July 31, 2016, the FDA has approved four immunotherapeutics that work by releasing brakes on the immune system for treating certain patients with a growing array of cancer types (see Figure 16). In March 2011, ipilimumab (Yervoy) was the first of these agents to be approved, after it was shown to be the first treatment ever to extend overall survival for patients with metastatic melanoma (see Figure 15) (152). 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.

Nivolumab and pembrolizumab (Keytruda) are the second and third immunotherapeutics that work by releasing brakes on the immune system. They target an immune- checkpoint protein called PD-1, which applies brakes to T cells after attaching to PD-L1 or PD-L2. Nivolumab and pembrolizumab work by preventing PD-1 from attaching to PD-L1 and PD-L2, thereby releasing the brakes on T cells. They were both approved by the FDA for treating patients with metastatic melanoma in late 2014. Longer follow-up of patients enrolled in some of these clinical trials recently revealed that more than one third of patients who received nivolumab are still alive 5 years after starting treatment and that 49 percent of patients who received pembrolizumab are still alive 2 years after starting treatment (153). These numbers are extremely exciting given that the 5-year relative survival rate for patients with metastatic melanoma diagnosed between 2005 and 2011 was just 17 percent (3).

In 2015, nivolumab and pembrolizumab were both approved by the FDA for treating certain patients with advanced lung cancer whose disease has progressed during or after other treatments. In the case of nivolumab, it was approved in March of that year for treating patients with the squamous cell type of NSCLC and in October 2015, for patients with the more common nonsquamous cell type of NSCLC, like Donna Fernandez [who was featured in the AACR Cancer Progress Report 2015 (24)]. These approvals were based on the fact that in phase III clinical trials, nivolumab extended overall survival for patients compared with the cytotoxic chemotherapeutic docetaxel, which is standard of care for patients with advanced NSCLC that has progressed during or after initial chemotherapy (154, 155).

In October 2015, pembrolizumab was approved for treating patients with advanced NSCLC that has progressed during or after other treatments. At the same time, the FDA also approved the PD-L1 IHC 22C3 pharmDx test, a companion diagnostic for identifying those patients for whom pembrolizumab is a treatment option—those whose tumors have the PD-L1 protein on their surface. These decisions were based on clinical trial results showing that pembrolizumab treatment led to tumor shrinkage in more than 40 percent of patients with advanced NSCLC positive for PD-L1 using the PD-L1 IHC 22C3 pharmDx test (156). Subsequent results from another clinical trial showed that the immunotherapeutic improved overall survival compared with docetaxel (157).

The number of cancer types for which nivolumab is an FDA-approved treatment option was recently expanded to include renal cell carcinoma and Hodgkin lymphoma, providing new hope for patients like Philip Prichard. In November 2015, it was approved for treating patients with advanced renal cell carcinoma that has progressed despite treatment with at least one antiangiogenic therapeutic after it was shown to improve overall survival for patients enrolled in a phase III clinical trial compared with everolimus, are commended treatment in this situation (158) (see Blocking the Blood Supply to Tumors above). The approval for Hodgkin lymphoma came in May 2016, after results from early-stage clinical trials showed that it caused partial or complete shrinkage of tumors in the majority of patients with classical Hodgkin lymphoma that had relapsed or progressed despite treatment with an autologous hematopoietic stem cell transplant and post- transplantation brentuximab vedotin (Adcetris) (159).

The fourth immunotherapeutic to be approved by the FDA that works by releasing brakes on the immune system is atezolizumab (Tecentriq). Atezolizumab targets PD-L1, preventing it from attaching to PD-1 and triggering its brake function. It also prevents PD-L1 from attaching to and triggering another brake on T cells called B7.1 (160). In May 2016, atezolizumab was approved for treating patients with locally advanced or metastatic urothelial carcinoma that has progressed despite treatment with a platinum-based cytotoxic chemotherapeutic. The decision was based on the fact that atezolizumab treatment led to partial shrinkage or complete disappearance of tumors for patients enrolled in a phase II clinical trial (161). This approval provides tremendous hope for patients with urothelial carcinoma because atezolizumab is the first new treatment shown to improve outcomes for patients, like Dave Maddison, in 30 years.

 

The spectacular successes highlighted here have motivated researchers to begin testing these revolutionary immunotherapeutics as a potential treatment for numerous other types of cancer. Results are not yet available for most of these clinical trials. However, initial results show that nivolumab and pembrolizumab may benefit some patients with head and neck cancer (162, 163), and that pembrolizumab may benefit a subgroup of patients with colorectal cancer (164).

Despite the tremendous achievements, treatment with FDA- approved immunotherapeutics that work by releasing brakes on the immune system does not yield remarkable and long- term responses for all patients. As a result, researchers are testing various ways to help increase the number of patients who may benefit from these immunotherapeutics, including evaluating how well they work in combination. The FDA approved the first of these combinations, ipilimumab and nivolumab, in September 2015, after it was shown in a phase II clinical trial that adding nivolumab to ipilimumab increased the percentage of patients with metastatic melanoma to have tumor shrinkage or disappearance more than five-fold (165).

The concept of combining members of this burgeoning class of immunotherapeutics with immunotherapeutics that work in different ways, as well as 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.

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Directing the Immune System to Cancer Cells

Before an immune cell can destroy a cancer cell, it must find it. Many therapeutic antibodies that have been approved by the FDA for treating patients with a wide range of cancer types (see Supplemental Tables 2a, 2b, and 2c) work, at least in part, by helping immune cells find cancer cells. The most recent additions to this group of immunotherapeutics are daratumumab (Darzalex) and elotuzumab (Empliciti), which were both approved by the FDA in November 2015 for treating patients with multiple myeloma that has progressed despite treatment with a number of other therapeutics.

Multiple myeloma is one of the most commonly diagnosed hematological malignancies, or blood cancers, in the United States, with 30,330 new cases expected to be diagnosed in 2016 (3). In recent years, the development and FDA approval of new therapeutics—including proteasome inhibitors like bortezomib and carfilzomib and immunomodulatory agents like lenalidomide—have improved outcomes for patients like Congressman Bob Carr, who was featured in the AACR Cancer Progress Report
2012 (87). Despite the advances, many patients whose disease initially responds to the new therapeutics eventually relapse owing to treatment resistance.

Daratumumab works by attaching to a protein called CD38, which is found at high levels on the surface of myeloma cells. This attachment has several effects on the myeloma cells, most notably flagging them for immune cells, which upon attaching to another part of daratumumab are triggered to destroy the myeloma cells. Daratumumab was approved by the FDA after it was shown in early-stage clinical trials to lead to tumor shrinkage or disappearance in a significant number of patients whose multiple myeloma had relapsed despite several other treatments (167). It is hoped that future studies will reveal that the immunotherapeutic also extends survival for patients.

Elotuzumab attaches to another protein that is found at high levels on the surface of myeloma cells, SLAM7F. This protein is also found at high levels on immune cells called natural killer cells (see sidebar on Key Players in the Immune System). Elotuzumab has distinct effects on myeloma cells and natural killer cells after attaching to SLAM7F on their surfaces, thus providing a two-pronged attack on multiple myeloma. It directly activates natural killer cells, enhancing their ability to kill myeloma cells, and it flags myeloma cells for a number of immune cell types, which once directed to the myeloma cells, attack and destroy them.

Elotuzumab was approved for use in combination with lenalidomide and dexamethasone for treating patients who have multiple myeloma that has worsened despite treatment with other therapeutics. This decision was based on phase III clinical trial results, which showed that adding elotuzumab to lenalidomide and dexamethasone significantly increased the number of patients who had their tumors shrink or disappear, as well as the time before disease progressed (168).

These approvals, together with the November 2015 approval of ixazomib (see sidebar on Recent Advances Against Multiple Myeloma), have provided patients with multiple myeloma, like Stephen Herz, not only new treatment options, but also new hope.

Boosting the Killing Power of the Immune System

Another approach to cancer immunotherapy is to enhance the ability of T cells to eliminate cancer cells. If we use the analogy of a car, this approach is like stepping on the accelerator, and it can be done in a number of ways (see sidebar on How Immunotherapeutics Work).

One form of immunotherapy that appears to work, in part, by boosting the killing power of the immune system is oncolytic virotherapy. Oncolytic viruses are viruses, which may or may not be genetically modified in some way, that can infect and destroy cancer cells. As the cancer cells are destroyed, they release molecules that can trigger immune cells that have the natural potential to destroy yet more cancer cells. These immunotherapeutics are injected directly into patients’ tumors, rather than being given orally or by intravenous infusion.

In October 2015, the first oncolytic virotherapeutic, talimogene laherparepvec (Imlygic), was approved by the FDA for the treatment of melanoma lesions in the skin and lymph nodes that cannot be removed completely by surgery.

The new immunotherapeutic, which was called T-Vec during development, is a herpes simplex virus (HSV) type 1 that has been genetically modified in a number of ways so that it is less able to cause disease, is more selective for cancer cells, and is more likely to promote an anticancer immune response. One of these modifications is the addition of a gene that provides the instructions for making an immune system–boosting factor called GM-CSF.

The exact way in which T-Vec works has not been definitively determined by researchers and remains an area of active investigation. However, it appears that after injection directly into melanoma lesions, T-Vec enters cancer cells, where it multiplies and promotes the production of GM-CSF. As it multiplies, T-Vec causes the cancer cells to rupture and die. Rupturing cancer cells release GM-CSF and cell contents that together can boost the killing power of the immune system.

T-Vec was approved after it was shown in a phase III clinical trial to significantly increase the number of patients who had skin and lymph node melanoma lesions shrink or disappear compared with GM-CSF (169). Even though T-Vec has not been shown to improve overall survival or to have an effect on melanoma that has spread to other parts of the body, it provides patients like Bob Ribbans with new treatment options and new hope.

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Living With or Beyond Cancer

Research is powering 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 Jan. 1, 2016, compared with just 3 million in 1971, and this number is projected to rise to 20.3 million by Jan. 1, 2026 (4, 169).

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 now commonly 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. Recent progress in cancer treatment was discussed in the previous three sections of the report (see Treatment With Surgery, Radiotherapy, and Cytotoxic ChemotherapyTreatment With Molecularly Targeted Therapeutics; and Treatment With Immunotherapeutics, above). 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 and highlights some of the challenges they continue to face (see sidebar on Life After a Cancer Diagnosis in the United States).

Each phase of cancer survivorship is accompanied by a unique set of challenges. Moreover, 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), like Jameisha (Meisha) Brown, [who was featured in the AACR Cancer Progress Report 2014 (1)], are particularly at risk for critical health-related problems because their bodies were still developing at the time of treatment (see sidebar on Surviving a Cancer Diagnosis as a Child or Adolescent). 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.

Importantly, 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.

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Optimizing Quality of Life Across the Continuum of Cancer Care

In recent years, numerous changes have been made across the continuum of cancer care in an effort to improve the quality of life of people who are receiving cancer treatment or living long term with no evidence of disease. Many efforts have focused on reducing the risk of long-term and late effects of treatment, and a recent study found that these changes are bearing fruit for survivors of cancer diagnosed in childhood (173). The researchers found that far fewer survivors were dying as a result of late effects of cancer treatment, such as a second cancer or heart disease, compared with 3 decades ago.

Among the changes in treatment that are helping to reduce the short-term effects of treatment as well as the long- term and late effects of treatment, and thereby improve quality of life for the duration of the patient’s life, is the increasing development and use of molecularly targeted therapeutics (see Treatment With Molecularly Targeted Therapeutics, p. 67). Because these anticancer therapeutics more precisely target a patient’s cancer compared with cytotoxic chemotherapeutics, this has helped reduce the adverse effects of treatment for some patients.

Researchers are also looking for ways to increase the precision with which we use radiotherapy and cytotoxic chemotherapy to achieve maximal patient benefit with minimal harm. One promising approach is to use genomics to more precisely distinguish those patients with a given type of cancer who need aggressive treatment from those who would not gain benefit from it. To this end, in one recent phase III clinical trial, the use of a 70-gene signature MammaPrint genetic test identified 46 percent of a group of patients with early-stage breast cancer traditionally classed as at high risk for disease recurrence as unlikely to benefit from adjuvant cytotoxic chemotherapy (cytotoxic chemotherapy given after surgery) (173). In this case, the use of a genetic test has the potential to spare many patients from an aggressive treatment they will not benefit from.

One approach that can be used across the continuum of cancer care to improve the quality of life for patients and their families is palliative care (see sidebar on 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. Thus, palliative care specialists are trained to manage patient concerns such as anxiety, pain, nausea, vomiting, fatigue, difficulty sleeping, loss of appetite, and how to navigate the health care system.

Research shows that in addition to increasing quality of life, providing palliative care administered by a specialist palliative care team to patients who are being treated for cancer can also improve survival and that the sooner palliative is initiated after a cancer diagnosis, the more patients benefit (175, 176). Moreover, a recent study found that family caregivers of cancer patients who received palliative care had a better quality of life and fewer symptoms of depression compared with family caregivers of those patients who did not receive palliative care (176).

Despite the growing evidence that specialist palliative care has tremendous benefits for patients with cancer and their families, there is a need for additional carefully designed clinical trials to more clearly determine the best time to initiate palliative care after a cancer diagnosis and the best way to deliver the care to achieve the maximum benefit for patients and their families (177). Two ongoing randomized clinical trials, which recently reported early data indicating that integrating specialist palliative care during the early stages of cancer care improved quality of life, should help provide insight in this regard (179, 180). Moreover, 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 (180).

Hair loss is one adverse effect of treatment with many cytotoxic chemotherapeutics that has been reported to negatively affect quality of life, especially for women with breast cancer (181). In December 2015, the FDA approved a medical device to help address this quality of life issue for women being treated with cytotoxic chemotherapeutics after a breast cancer diagnosis. The device, which is called the Dignitana DigniCap 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 to be effective at reducing hair loss in numerous clinical trials (183).

Some forms of complementary and alternative medicine have been shown to improve quality of life for patients with cancer. For example, studies have shown that yoga, yoga breathing, acupuncture, and ginger reduce certain adverse effects of chemotherapy and radiotherapy, including fatigue, nausea, sleep disturbance, anxiety, and joint pain (184-187). In addition, relaxing acupressure was recently shown in a large randomized clinical trial to reduce fatigue and improve sleep quality and quality of life among patients with breast cancer who had completed cancer treatment (187). Other forms of complementary and alternative medicine have not been well studied, so we do not know if they are safe or effective. Despite this, a recent study showed that U.S. out- of-pocket spending on complementary health approaches reached $30.2 billion in 2012 (188). Thus, it is clear that there is an urgent need for more research in this area.

Modifying Behaviors to Improve Outcomes

A major concern for all cancer survivors who successfully complete their initial treatment is whether their cancer will return or cause their death. 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 3). Thus, modifying behaviors to eliminate or avoid these risk factors can improve outcomes and quality of life for cancer survivors.

For example, research shows that quitting smoking can improve outcomes for cancer survivors: it reduces risk of death from cancer, and it also reduces risk for developing a second cancer (34). Even in the face of this knowledge, a recent study found that 9 percent of cancer survivors continue to smoke (190). Therefore, enhanced provision of cessation assistance to all patients with cancer who use tobacco or who have recently quit smoking is urgently needed, as is further research to improve our understanding of how best to help individuals quit (191).

In addition to adversely affecting outcomes for patients with cancer, tobacco use is an important source of variation in cancer treatment clinical trials (191). Despite the fact that tobacco use has the potential to affect both how a patient might respond to the treatment being tested and the ability of researchers to interpret the results of the trial, a trial participant’s tobacco use and possible exposure to secondhand smoke are often not recorded. To address this issue, researchers have developed a new tool that they hope will be routinely used by clinical trialists to help us gain a clearer understanding of the significance of tobacco use and cessation in clinical trials and for cancer patients more broadly (191).

Evidence is also beginning to emerge that regular aerobic exercise can reduce recurrence and mortality in survivors of early breast, prostate, and colorectal cancers (192). More recently, clinical trial results showed that breast cancer survivors who participated in a weight training program had increased muscle strength and experienced less deterioration of physical function (194, 195). This finding is important because deterioration of physical function and loss of muscle strength have been linked to increased risk for bone​ fractures and other health issues that limit quality of life. However, more research is required to confirm these observations and fully understand whether and how changes in physical activity after diagnosis might affect outcomes.​​​​​​​​

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