Cancer Complications

Carol Marley wants everyone to know what a life-threatening cancer diagnosis looks like in America today.

Yes, it’s the chemotherapy that leaves you weak and unable to walk across the room. Yes, it’s the litany of tests and treatments – the CT scans and MRIs and biopsies and endoscopies and surgeries and blood draws and radiation and doctor visits. Yes, it’s envisioning your funeral, which torments you day and night.

But none of these is her most gnawing, ever present concern.

That would be the convoluted medical bills that fill multiple binders, depleted savings accounts that destroy early retirement plans and so, so many phone calls with insurers and medical providers.

“I have faith in God that my cancer is not going to kill me,” says Marley, who lives in Round Rock, Texas. “I have a harder time believing that this is gonna get straightened out and isn’t gonna harm us financially. That’s the leap of faith that I’m struggling with.”

Coping with the financial fallout of cancer is exhausting — and nerve-wracking. But the worst part, Marley says, is that it’s unexpected.

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When she was diagnosed with adenocarcinoma of the pancreas head in July, she didn’t anticipate so many bills, or so many billing mistakes. After all, she is a hospital nurse with good private insurance that has allowed her access to high-quality doctors and hospitals.

Randall Marley, a computer systems engineer, says he frequently comes home from work to find his wife feeling unwell and frustrated about having spent a precious day of her recovery making phone calls to understand and dispute medical bills. One recent night she was in tears and “emotionally at a breaking point,” he says. “The hardest part of this is seeing the toll it’s taken on my wife.”

Stress-inducing bills accumulate

More than 42 percent of the 9.5 million people diagnosed with cancer from 2000 to 2012 drained their life’s assets within two years, according to a study published last year in the American Journal of Medicine. Cancer patients are 2.65 times more likely to file for bankruptcy than those without cancer, and bankruptcy puts them at a higher risk for early death, according to research.

But those statistics don’t convey the daily misery of a patient with a life-threatening disease trying to navigate the convoluted financial demands of the U.S. health care system while simultaneously facing a roller coaster of treatment and healing.

Stephanie Wheeler, a professor at the University of North Carolina at Chapel Hill, said the number of bills coming from different providers can be overwhelming.

“It’s oftentimes multiple different bills that are rolling in over a period of several months and sometimes years,” says Wheeler, who has conducted survey research with metastatic cancer patients. “As those bills start to accumulate, it can be very stress inducing.”

Given that many patients can’t work during treatment, these bills may force even relatively well-to-do cancer patients to take out second mortgages, spend college savings or worry about leaving debt behind for their families, Wheeler says.

Carol Marley is a slight woman who dotes on her two dogs and is involved in her church. Her 88-year-old father, who has dementia, had moved in a few years earlier. She and her husband, Randall, pride themselves on living frugally. They pay their credit card off every month and don’t have car payments.

Carol and her daughter, June Marley, who is a second-year college student, have health insurance through Carol’s employer, Ascension Health, a large faith-based health care system with facilities across the nation. Carol’s husband has separate insurance through his job.

They were hoping to retire early, buy an RV and drive around the country. Instead, they see their meticulous plans disappearing, even if Carol recovers.

Their high-deductible insurance policy meant they had to spend $6,000 before their insurance started covering her treatment expenses. They hit their annual out-of-pocket maximum of $10,000 well before the year was over.

But Carol says she was prepared for that. “What I didn’t anticipate is the knock-down, drag-out fight that I would have to engage in to get people to see there were errors and address it.”

Since she’s unable to work, the family lost her nursing salary.

“Money is not coming in, and it’s going out by the thousands,” she says.

From nurse to patient

Carol had treated cancer patients before. She had seen them come in with unexplained aches and leave with devastating diagnoses. Now it was her turn.

Though she didn’t recognize it at the time, her symptoms were textbook. Fatigue. Back pain. Weight loss. In July, doctors told her she had pancreatic cancer.

Her first thought was that she was going to die. One nurse friend asked if she had her affairs in order. That’s because pancreatic cancer is usually discovered too late. Just 9 percent of patients are alive five years after diagnosis, compared with 90 percent of breast cancer patients.

Carol knew she was lucky. Hers hadn’t spread. She might be able to undergo surgery. But first, four months of chemotherapy and five weeks of radiation.

After Carol Marley was diagnosed with pancreatic cancer last July, she worried what it would mean for her family, including her 88-year-old father with dementia.

Anna Gorman/KHN

The chemotherapy — seven or eight rounds, she can’t quite remember — drained her. “I couldn’t put words together in my head,” she says. She had muscle spasms and developed fevers that landed her in the emergency room.

As she became weaker, Carol realized she could no longer care for her father at home. On a recent morning in early January, she sat down with a nurse from a memory-care facility where a space had become available. Holding back tears, Carol told the nurse she knew this day would come. “I didn’t think it would be so soon, and I didn’t know under these circumstances.”

Different insurers lead to different bills

Later that same day, Carol’s energy was up. She adjusted the colorful scarf on her head, turned on her computer and pulled out a pen. Some days she spends hours trying to clarify and fix medical bills. “But I don’t do that frequently because it is so fruitless and it is stressful,” she said.

Often, she is just trying to figure out what different bills mean. “Even as a nurse, I feel like it’s impossible to understand,” she said. “I can’t make heads or tails of it.”

Sometimes there are errors.

Part of the problem, she contends, is that one insurance company covers visits with Ascension providers and hospitals and another company covers pharmacy claims, specialty drugs and providers outside Ascension’s network. Some of the bills, including a $1,400 one from an ER visit — were sent to the wrong insurer, she says.

Carol cites other issues. An $18,400 chemotherapy bill was submitted with missing information and then denied because it arrived late. An $870 MRI bill was denied because the provider said there was no pre-authorization.

“It’s not any one individual. It’s not any one system or provider,” she says. “The whole system is messed up. … There’s no recourse for me except to just keep making phone calls.”

On this particular afternoon, Carol has a long list of calls to make. One to figure out why she couldn’t access her insurance claims online. Another to a medical provider that urged her to pay $380, even though it acknowledged that it owed her about $80 of that total.

Someone who answers the phone suggests again that Carol pay the entire amount. “Once it’s posted to your account and it goes through, we would send you a check,” the woman says.

Carol shakes her head. “I’m sure y’all are fine people over there, but I’m not trusting a refund to come,” she responds, reflecting on her experience as a consumer of cancer care. “The problem is, they want their money and they are going to get it one way or the other.”

As for her hospital bills, Ascension declined to comment, citing protected health information. But spokesman Nick Ragone said, “The matter at issue was favorably resolved.”

He didn’t say which issue was resolved.

How to treat cancer

A class of drugs is emerging that can attack cancer cells in the body without damaging surrounding healthy ones. They have the potential to replace chemotherapy and its disruptive side effects, reshaping the future of cancer care.

The complex biological medicines, called antibody drug conjugates (ADCs), have been in development for decades, and are now generating renewed excitement because of the success of one ADC in late-stage testing, a breast cancer treatment called DS-8201.

The fervor over ADCs is such that AstraZeneca Plc in March agreed to pay as much as $6.9 billion to jointly develop DS-8201 with Japan’s Daiichi Sankyo Co., the British drugmaker’s biggest deal in more than a decade. The investment was widely seen to be a validation of DS-8201’s potential — and the ADC class of drugs as a whole — as an alternative for chemotherapy, the most widely used treatment, for some types of cancer.

DS-8201, which will be filed for U.S. approval by the end of September, is so well-regarded that some analysts already predict it will surpass the $7 billion in annual sales for Roche Holding AG’s breast cancer drug Herceptin, which it aims to replace.

“DS-8201 may become one of the largest cancer biologic drugs,’’ said Caroline Stewart, an analyst at Bloomberg Intelligence, who estimates sales of the drug to eventually approach $12 billion globally — that’s a level attained by only a handful of biologics, which are drugs based on a living organism. “While the field has advanced and there are several companies focusing on ADCs, Daiichi in particular seems to have developed a unique expertise.”

Analysts say DS-8201 could triple the number of patients who get powerful targeted treatment for breast cancer, the most common tumor in women that kills more than half a million annually. As importantly, its ability to target cancer cells without affecting normal cells is a key advantage over the take-no-prisoners approach of chemotherapy.

Daiichi’s treatment has been seen to double survival time for advanced breast cancer patients to 20 months from 10, former UBS Securities Japan Co. analyst Atsushi Seki said in March. In trials, patients using DS-8201 experienced less nausea and hair loss compared with chemotherapy.

Magic Bullet

DS-8201’s full potential is still years away, as it will take time for data to validate the drug’s efficacy in a wide range of patients. Still, the potential of ADCs is already jolting Big Pharma. Roche, whose Herceptin loses patent exclusivity in the U.S. this year, has added ADCs to its portfolio with its Kadcyla breast cancer treatment. Pfizer Inc. has Mylotarg, an ADC that treats myeloid leukemia.

About 56 pharmaceutical companies are developing ADC candidates, including ImmunoGen Inc. and Seattle Genetics Inc., and they could be targets for acquisitions or licensing deals from global pharmaceuticals anxious for a piece of the ADC pie, according to Cowen Inc.

“ADCs are being positioned as a chemo replacement,’’ Cowen analysts including Boris Peaker wrote in an April note. “There is significant potential for partnership activity.’’

The global ADC market was valued at $1.57 billion in 2017 and is projected to grow 26% every year through 2025 to almost $10 billion, according to a report by Grand View Research.

The concept behind ADCs was envisioned in 1900 by German Nobel laureate Paul Ehrlich, who formed the idea of a “magic bullet” in which a single toxic molecule would be delivered to attack a diseased cell without damaging surrounding healthy cells.

The actual use of ADCs began in 2000, but the interest in the sector cooled down as many failed to live up to expectations. The therapies belong to a broader category of cancer immunotherapies that include Merck & Co.’s Keytruda and Novartis AG’s CAR T-cell therapy Kymriah that harness the immune system to kill tumors.

Another Level

Daiichi Sankyo’s drug takes ADCs to another level. Its advantage is that it carries eight payloads stably to cancer cells, double the number of the industry standard, said Toshinori Agatsuma, head of oncology research at Daiichi Sankyo who led a team that discovered the therapy.

“Currently available ADCs are far from being perfect technically because the payload linked to antibodies aren’t properly delivered to cancer cells,’’ said Agatsuma. “We wanted to challenge and improve that. We were a latecomer in biotech, but I knew it was an area where we could catch up, compete and win.’’

About 2.1 million women are diagnosed with breast cancer each year, according to the World Health Organization. Some 18% of cases are driven by a protein called HER2, and their first treatment is chemotherapy alongside Roche’s Herceptin and Perjeta, a related drug. While DS-8201 is currently in testing for later-stage cancer, the plan is to go up against the first-line treatment in the next two years.

“It would be transformative” if the drug were to become the sole first-line treatment, said David Fredrickson, president of AstraZeneca’s oncology business. “If we can eliminate the side effects associated with chemotherapy, that would be a tremendous benefit for women.”

Drugs like Herceptin only target high levels of HER2, and women with lower levels must rely on hormone therapy or chemotherapy. That’s where DS-8201 has the potential to serve far more patients, treating those with both higher and lower levels of HER2.

‘It’s Different’

“We need more evidence, but my gut feeling is that DS-8201 is the most effective among existing medicines targeting HER2 positive patients, including Herceptin and chemotherapy,’’ said Shunji Takahashi, deputy director at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, who took a part in an early-stage DS-8201 trial. He noted that interstitial pneumonia is a concern as a side effect, and needs to be monitored.

For Daiichi Sankyo, the development of DS-8201 has helped resurrect the Japanese company after it struggled for years to set a path for growth, weighed down by a failed acquisition of India’s Ranbaxy Laboratories Ltd. and a shortage of blockbuster products.

“A single drug has a potential to transform Daiichi Sankyo and I didn’t expect it a year ago,’’ SMBC Nikko Securities Inc. analyst Yasuhiro Nakazawa said. “Daiichi Sankyo had a track record of betraying market expectations with previous drug developments. But with this one, I can really feel that it’s different this time.’’

Evolution of Cancer Treatment Therapies

Cancer therapy has been characterized throughout history by ups and downs, not only due to the ineffectiveness of treatments and side effects, but also by hope and the reality of complete remission and cure in many cases. Within the therapeutic arsenal, alongside surgery in the case of solid tumors, are the antitumor drugs and radiation that have been the treatment of choice in some instances. In recent years, immunotherapy has become an important therapeutic alternative, and is now the first choice in many cases. Nanotechnology has recently arrived on the scene, offering nanostructures as new therapeutic alternatives for controlled drug delivery, for combining imaging and treatment, applying hyperthermia, and providing directed target therapy, among others. These therapies can be applied either alone or in combination with other components (antibodies, peptides, folic acid, etc.). In addition, gene therapy is also offering promising new methods for treatment. Here, we present a review of the evolution of cancer treatments, starting with chemotherapy, surgery, radiation and immunotherapy, and moving on to the most promising cutting-edge therapies (gene therapy and nanomedicine). We offer an historical point of view that covers the arrival of these therapies to clinical practice and the market, and the promises and challenges they present.

Keywords: cancer, immunotherapy, nanotechnology, gene therapy, nanomedicine
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1. Introduction

Chemotherapy, surgery and radiotherapy are the most common types of cancer treatments available nowadays. The history of chemotherapy began in the early 20th century, but its use in treating cancer began in the 1930s. The term “chemotherapy” was coined by the German scientist Paul Ehrlich, who had a particular interest in alkylating agents and who came up with the term to describe the chemical treatment of disease. During the First and Second World Wars, it was noticed that soldiers exposed to mustard gas experienced decreased levels of leukocytes. This led to the use of nitrogen mustard as the first chemotherapy agent to treat lymphomas, a treatment used by Gilman in 1943. In the following years, alkylating drugs such as cyclophosphamide and chlorambucil were synthesized to fight cancer [1,2]. Kilte and Farber designed folate antagonists such as aminopterin and amethopterin, leading to the development of methotrexate, which in 1948 achieved leukemia remission in children [3]. Elion and Hitchings developed 6-thioquanine and 6-mercaptopurine in 1951 for treating leukemia [4,5]. Heidelberger developed a drug for solid tumors, 5-fluorouracil (5-FU), which is up to now an important chemotherapy agent against colorectal, head and neck cancer [6]. The 1950s saw the design of corticosteroids, along with the establishment of the Cancer Chemotherapy National Service Center in 1955, whose purpose was to test cancer drugs. At that time, monotherapy drugs only achieved brief responses in some types of cancers [7]. By 1958, the first cancer to be cured with chemotherapy, choriocarcinoma, was reported [8]. During the 1960s, the main targets were hematologic cancers. Better treatments were developed, with alkaloids from vinca and ibenzmethyzin (procarbazine) applied to leukemia and Hodgkin’s disease [9-11]. In the 1970s, advanced Hodgkin’s disease was made curable with chemotherapy using the MOMP protocol [12,13], which combined nitrogen mustard with vincristine, methotrexate and prednisone, and the MOPP protocol [14,15], containing procarbazine but no methotrexate. Patients with diffuse large B-cell lymphoma were treated with the same therapy and, in 1975, a cure for advanced diffuse large B-cell lymphoma was reported using protocol C-MOPP, which substituted cyclophosphamide for nitrogen mustard [16].

Surgery and radiotherapy were the basis for solid tumor treatment into the 1960s. This led to a plateau in curability rates due to uncontrolled micrometastases. There were some promising publications about the use of adjuvant chemotherapy after radiotherapy or surgery in curing patients with advanced cancer. Breast cancer was the first type of disease in which positive results with adjuvant therapy were obtained, and also the first example of multimodality treatment, a strategy currently employed for treatment of numerous types of tumors. In the late 1960s, the use of adjuvant chemotherapy changed the concept of localized treatment.

There was significant progress in 1978 when higher cure rates of metastatic germ cancer were achieved by combining cisplatin, bleomycin and vinblastine [17-19]. The experience with polychemotherapy in hematologic cancer brought to light the fact that different drugs act against tumor cells in different phases of their cellular cycle. One of these solid tumor drugs was CMF (cytoxan, methotrexate and fluorouracil), a standard therapy for treating breast cancer for over 30 years. Understanding of molecular changes in cancer cells quickly developed after the 1970s. As a consequence, numerous drugs with various mechanisms of action were introduced during the 1980s. Subsequent advances and developments led to liposomal therapy, which places drugs inside liposomes (vesicles made of lipid bilayers), decreasing some of the side effects of chemotherapy such as cardiotoxicity. Examples of liposomal drugs include liposomal doxorubicin and daunorubicin, one of the first steps in nanotechnology-based approaches. The 1990s sparked the beginning of targeted chemotherapy by screening for specific critical molecular targets. These advances in modern chemotherapy and studies on genetics and molecular biology contributed to the ongoing decline in death rates. Data from the genome sequence suggested that many dysfunctions associated with cancer could be due to the abnormal function of some protein kinases. The current pharmacological trend has been to develop kinase inhibitors [20,21]. The first tumors targeted with drugs approved by the FDA (Food and Drug Administration) and the EMEA (European Medicines Agency) were renal cell cancer, hepatocellular cancer and gastrointestinal stromal tumors. In recent years, numerous specific tumors have been tested with various kinase inhibitors and there is a trend towards combining chemotherapy with these new targeted therapies.

Chemotherapy is curative in some types of advanced cancer, including acute lymphoblastic and acute myelogenous leukemia, Hodgkin’s and non–Hodgkin’s lymphoma, germ cell cancer, small cell lung cancer, ovarian cancer and choriocarcinoma. In pediatric patients, curable cancers include acute leukemia, Burkitt’s lymphoma, Wilms’ tumor and embryonal rhabdomyosarcoma. Although treatment is not always curative for these cancers, there has been significant improvement in progression-free and overall survival. Another modality of treatment is neoadjuvant therapy, which aims to reduce the size of the primary tumor and prevent micrometastases. This type of treatment improves on more conservative surgical techniques in preserving the functionality of important organs. Neoadjuvant chemotherapy is indicated for anal, breast, lung, gastroesophageal, rectal, bladder and head and neck cancer, as well as some types of sarcoma. There are many cancers for which adjuvant chemotherapy has been established with curative effect, and with the new effective drugs and combinations the curability rates are expected to rise even more. Since 1990, the incidence and mortality of cancer have been declining and despite the increase in the elderly population [22], mortality rates for the United States declined from 2005 to 2007.

In 1890, Halsted performed the first radical mastectomy, believing that cancer would be more curable if surgical techniques were more aggressive, thus avoiding regional recurrences. He had many followers at that time, but thanks to advances in chemotherapy, radiotherapy, biology and technology, the outlook now is quite different. Radical surgery has now been replaced by less extensive operations.

The turn of the 20th century marked the beginning of the development of cancer surgery techniques, with the first abdominoperineal resection performed in 1908 by Miles [23], the first lobectomy being performed in 1912 [24,25] and the first radical hysterectomy performed by Wertheim in 1906, all carried out under oncological criteria. Additionally, in 1904, Young made the first radical suprapubic prostatectomy. Modern surgery has changed significantly, with Halstedian techniques replaced by non-invasive procedures such as laparoscopic colectomy (for the removal of colon cancer) [26], videothoracoscopy, radiofrequency ablation and radiosurgery techniques such as Cyberknife® [27]. Breast-conserving surgery with sentinel-node removal has been used to improve esthetic results and avoid lymphedema [28]. Another example of conservative surgery is the use of laryngoscopic laser surgery in early laryngeal cancer [29]. The most recent development is the Da Vinci®, a robotic system for the removal of cancer from prostate and kidney [30].

The discovery of X-rays and radiation by Becquerel and Rontgen in the late 19th century was the first step towards radiation treatment. Marie Curie’s work greatly contributed to the development of radiotherapy. The first cancer case cured exclusively by radiation occurred in 1898. After World War II, technological progress allowed charged particles to be propelled through a vacuum tunnel called linac, or linear accelerator. In 1960, Ginzton and Kaplan began to use a rotational linac radiotherapy called “Clinac 6”, which was used to concentrate X-rays more deeply thereby they not affecting the skin as much. The development of modern computers enabled three-dimensional X-ray therapy, such as intensity-modulated radiation therapy (IMRT) using mapping information from Computed Tomography (CT) scans. This provides a three-dimensional reconstruction, which helps avoid toxicity since the contours of the tumor are targeted and separated from healthy tissues. In 2003, a specific type of IMRT was developed called the TomoTherapy® system. This treatment uses CT-guided IMRT technology that directs the radiation source by rotating it around the patient, which makes the morphological limits of a tumor easier to trace with the beam [31]. Another significant trend is the use of charged particle radiotherapy with proton or helium ions for specific types of patients with melanoma of the uveal tract. It is also used as adjuvant therapy for skull base chondroma, chondrosarcoma and spine (usually cervical). In summary, the lines of development have been fractionated dose delivery, technological advances in X-ray production and delivery and improvement of computer-based treatment planning.

The latest advance in scanning technology with radiotherapy therapy is four-dimensional (4D) conformal radiotherapy [32], which records a video sequence of tumor movement. This therapy uses dynamic CT images of the body that compensate for any movement by the target, including movements when patients breathe. There are two forms of this therapy: Image-guided radiation therapy (IGRT) and Image-guided adaptive radiation therapy (IGART).