Chemotherapy

Overview of Chemotherapy and Cancer

Chemotherapy works by attacking dividing cells. A characteristic of cancer is uncontrolled cell division and growth. This means chemotherapy is more likely to kill cancer cells than normal cells, but collateral damage does occur. It is possible for chemotherapy to provide a cure for cancer, prolong life, or help to control symptoms, but it often has toxic effects [3]. There are only certain limited situations where chemotherapy is given to cure disease [3]. Research shows that many patients with advanced cancers are often unaware that chemotherapy is most likely ineffective [4].

Chemotherapy as a sole treatment option is only considered to be effective for some types of cancer such as lymphoma [5]. For many types of cancer, including carcinoma, chemotherapy rarely has curative effects [5].** **The efficacy of chemotherapy depends significantly on the type of cancer, stage of disease, and a patient’s individual response. Often chemotherapy is only given for palliative effects (symptom relief) [5]. It may prolong survival, but effects are generally modest, and for many types of cancer, overall benefit is under 5% [5]. A large-scale review of 22 major types of adult malignancies has shown that the overall contribution of chemotherapy to 5-year survival is around 2% [6]. Unfortunately, impact on patient quality of life is often not evaluated in clinical studies [3]. Focus is more commonly on overall survival or disease progression [3].

Chemotherapy is associated with numerous severe side effects, which include immediate effects on skin, hair, bone marrow, blood, gastrointestinal tract, and kidneys [5]. All essential organs such as the heart, lungs and brain can also be affected with potential neurotoxic effects [5]. Long-term chronic effects of chemotherapy include drug resistance, infertility, and secondary cancer [5]. Emerging evidence indicates that chemotherapy may potentially promote systemic spread of disease when treating a primary tumor [7] [8].

Great advances have been made in cancer research in recent years [9]. However, outcomes from standard of care cancer treatments have not significantly improved [9] [10]. In light of the shortcomings and potential toxicity of high-dose chemotherapy drugs, many novel strategies have been developed to address issues. These include molecular profiling and advanced biomarkers to improve selection of chemotherapeutic agents, having patients fast before treatment, using insulin to enhance targeting, and fractionated (low-dose) metronomic (frequently applied multi-drug approach) chemotherapy [9] [11].

Sadly, only modest improvements have been made and major risks are still associated with standard of care treatment. As a result, a large percentage of patients are now seeking integrative and complementary alternative approaches to cancer care in an attempt to reduce toxic side effects and improve quality of life [12]. However, most integrative or alternative therapies still require well-designed clinical research to evaluate their safety and efficacy profiles [12].

The History of Chemotherapy

In the early 1900s, a famous German chemist named Paul Ehrlich began developing drugs for the treatment of infectious diseases [1]. Ehrlich coined the term “chemotherapy” and defined it as the use of chemicals to treat disease [1]. His research led to treatments for syphilis and he was interested in finding a cure for cancer, but not optimistic about the chances of success [1].

The origins of modern chemotherapy can be traced back to the discovery of nitrogen mustard as an anticancer agent [2]. In 1942, during World War II (WWII), Louis Goodman and Alfred Gilman were recruited by the US Department of Defense to explore the potential therapeutic effects of a number of toxins that had been developed for chemical warfare [2]. Although gasses were not used on the battlefield in WWII a great deal of research was conducted [1]. Experience from World War I and the effects of an accidental spill of sulfur mustard on WWII troops in Italy led to the observation that bone marrow and lymph nodes were depleted in men exposed to mustard gas [1].

Based on this discovery, Milton Winternitz at Yale School of Medicine, secured a contract to study mustard compounds and requested Goodman and Gilman to explore their therapeutic potential [1]. After successful experiments in mice, the researchers convinced their collaborator, Gustav Lindskog, to treat a patient with non-Hodgkin’s lymphoma and airway obstruction with an injection of nitrogen mustard into the bloodstream [1]. They observed a marked level of tumor regression [2]. The remission lasted only a few weeks but established the principle that drugs could be administered systemically to treat cancer [2]. The use of nitrogen mustard was widely adopted throughout the United States after the publication of these results in 1946 [1].

Shortly after WWII, Sydney Farber, a pathologist at Harvard Medical School, conducted research on the effects of folic acid on patients with leukemia [2]. He determined that the vitamin stimulated the proliferation (rapid growth) of acute lymphoblastic leukemia (ALL) [2]. Farber collaborated with medicinal chemists to synthesize folate analogues (first aminopterin and then methotrexate) to block enzymes that convert folic acid. He administered these compounds to children with ALL and successfully managed to induce short-lived remission [2]. This established the principle that antifolates could suppress the growth of malignant cells [2]. Methotrexate later proved to have antitumor effects on a range of cancer types including breast, ovarian, bladder, and head and neck cancers [2].

In the 1960s medical oncology did not even exist as a clinical speciality and doctors that administered chemotherapy were deemed prolific underachievers at best [1]. At the time, many in the medical community believed that cancer drugs caused more harm than good and the thought of curing cancer with chemical drugs was considered insanity [1]. The prevailing attitude towards chemotherapy can only be described as hostile and anticancer drugs were frequently referred to as poisons [1]. In 1971, The National Cancer Act was passed in the United States, which marked the launch of the nation’s ever controversial “War on Cancer” [1]. This had a profound effect on funding for research and furthering the development of chemotherapy.

In the 1970s a breakthrough was made with the discovery of a drug called cisplatin that was effective against testicular cancer and less toxic than previous chemotherapy drugs [1]. This became a model for the development of other targeted cancer drugs [1]. Over the following decades, the targeted-therapy revolution began. Many other chemotherapy drugs were developed that are still currently used such as paclitaxel, docetaxel, and gemcitabine [1] [2]. These drugs were designed to target specific types of cancer cells and had fewer side effects [1].

Since the 1940s, cancer drug development has transformed from a low-budget government-supported research effort to a high-stakes, multi-billion dollar industry [2]. Today, chemotherapy has become much more sophisticated and targeted with recent advances in cancer research. However, many challenges still remain for the next generation of cancer researchers to improve the efficacy of chemotherapy drugs and reduce toxicity-related side effects [2].

Research supporting Chemotherapy

Chemotherapy has been widely studied and evaluated in terms of its effectiveness in the treatment of various types of cancer. Overall, chemotherapy appears to have a statistically significant but modest benefit on overall survival and disease progression (<5% on average) [5]. It can also negatively impact quality of life. However, results appear to vary greatly depending on the type and stage of cancer as well as individual patient factors.

A systematic review and meta-analysis published in The Lancet Oncology in 2015 evaluated the efficacy of chemotherapy in advanced non-small-cell lung cancer (NSCLC) [13]. Data were obtained from 2,714 patients from 16 randomized controlled trials (RCTs). Results showed a significant benefit of chemotherapy equivalent to a relative increase in survival of 23%, or an absolute improvement in survival of 9% (12 months). Researchers concluded that chemotherapy conclusively improved overall survival and disease progression. Another systematic review and meta-analysis published in JAMA Oncology in 2018 evaluated the efficacy of chemotherapy in metastatic breast cancer [14]. The study found that chemotherapy significantly improved overall survival compared to other treatments, such as hormone therapy or targeted therapy, but the benefits were modest and varied depending on the patient population [14].

With all of the advancements in cancer research and new breakthroughs in cancer drug development, patients are becoming more optimistic than ever regarding their treatment outcomes [9]. However, while efficacy has improved modestly, chemotherapy is not curative in most cases [4]. A study from 2012 from The New England Journal of Medicine found that out of a cohort of 1193 patients with Stage IV cancer, about 69% of patients with lung cancer and 81% with colorectal cancer did not understand that chemotherapy was not at all likely to cure their cancer [4]. Researchers concluded that many patients do not realize that chemotherapy is not curative, which could compromise their ability to make informed treatment decisions in terms of risks and benefits [4].

The criteria for the evaluation of therapeutic effects, as defined by the WHO, include the extent of tumor remission (tumor response), remission time, survival, and toxicity [5]. Studies have shown that chemotherapy can be effective in the treatment of various lymphomas [5]. However, chemotherapy is often not curative for many other cancer types such as carcinoma, but may modestly prolong survival [5]. A 2019 study from the International Journal of Oncology states that an overall survival benefit of less than 5% has been achieved in the adjuvant treatment (after surgery) of breast, colon, and head and neck cancers [5]. Often, chemotherapy is given simply for palliative effects (to manage or reduce symptoms) without any significant impact on survival.

In 2004, a review of randomized clinical trials on the 5-year survival benefit of chemotherapy was carried out, which included 154,971 patients from the USA and 72,903 patients from Australia [6]. It included newly diagnosed cancer patients with 22 different major adult malignancies. The overall contribution of chemotherapy to 5-year survival was estimated to be only 2.3% in Australia and 2.1% in the USA [6]. The five most ‘chemo-sensitive’ cancers (testicular cancer, Hodgkin’s and non-Hodgkin’s lymphoma, cervical cancer and ovarian cancer) accounted for 8.4% of the total cancer cases in Australia in 1998 [5]. The authors conclude that it is clear chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and use of chemotherapy, they called for a rigorous re-evaluation of the cost-effectiveness and impact on quality of life.

Chemotherapy is known to have significant side effects, including nausea, vomiting, fatigue, hair loss, and increased risk of infection. It can therefore significantly affect patient quality of life. A 2020 review of 13 studies on chemotherapy use and quality of life in cancer patients at end of life found that palliative chemotherapy actually reduced quality of life [15]. A study published in the Journal of Clinical Oncology in 2018 evaluated the impact of chemotherapy on quality of life in patients with advanced cancer [16]. The study found that patients who received chemotherapy reported lower quality of life scores during treatment and similar quality of life scores compared to those who did not receive chemotherapy at six months and one year follow-up.

In view of the common issues and failings of chemotherapy for many cancer types, a 2014 study outlines that integrative therapies are commonly used by breast cancer survivors for various indications, including the management of side effects of cancer therapy and improving quality of life [12]. The study also reveals that worldwide an estimated 33% to 47% of individuals diagnosed with cancer use complementary, alternative, or integrative therapies as part of their treatment programs [12]. However, most integrative or alternative therapies still require well-designed clinical research to better determine their effects on treatment outcomes, overall survival, and quality of life [12].

Moreover, an emerging picture is coming to light in cancer biology that, paradoxically, chemotherapy can actively induce changes that promote the spread of cancer and disease progression [17]. Numerous studies are starting to show that chemotherapy may promote drug resistance and metastasis (spread of disease) while only inhibiting the growth of primary tumors [7] [8] [17] [18]. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, which results in increased escape of cancer cells into the bloodstream [17]. Chemotherapy also changes the tissue microenvironment around the body making it more susceptible and hospitable to cancer cells. Chemotherapy may therefore have potentially harmful pro-metastatic effects and promote spread of cancer [17].

Overall, research shows that chemotherapy can provide benefits for patients with cancer under certain circumstances. However, the risk-benefit profile of chemotherapy depends greatly on the individual patient’s context, type of cancer, and stage of disease. Chemotherapy as a sole therapy is rarely curative, can have serious side effects, and is not suitable in all situations.

Potential Applications of Chemotherapy for cancer

Chemotherapy is a versatile treatment that can be used in many different ways to help manage and treat cancer. The specific application of chemotherapy depends on the type and stage of cancer, as well as the individual patient's specific requirements and goals. There are three primary goals for chemotherapy in cancer care [19]:

1. Cure
2. Control
3. Palliation

There are several scenarios where chemotherapy can be used for cancer patients. The potential applications and related terminology is outlined below.

1. Curative intent: In some cases, chemotherapy can be used with curative intent, meaning it is given with the goal of curing the cancer. This is most often used for cancers that have not spread beyond their primary site, or for some types of blood cancers [20].
2. Adjuvant therapy: Adjuvant chemotherapy is given after surgery or radiation therapy to kill any remaining cancer cells and reduce the risk of the cancer coming back. This is often used for cancers that have a high risk of recurrence, such as breast cancer and colon cancer [21].
3. Neoadjuvant therapy: Neoadjuvant chemotherapy is given before surgery or radiation therapy to shrink the tumor and make it easier to remove. This is often used for cancers that are too large or invasive to be removed with surgery alone [22].
4. Palliative care: In cases where the cancer has spread or cannot be cured, chemotherapy can be used as palliative care to relieve symptoms, slow the growth of the cancer, and improve quality of life. This is often used for advanced-stage cancers, such as lung cancer and pancreatic cancer [20] [23].
5. Combination therapy: Chemotherapy can be used in combination with other treatments, such as radiation therapy or targeted therapy, to improve outcomes. For example, combining chemotherapy with radiation therapy can improve survival rates for certain types of cancer, such as head and neck cancer [24].
6. Maintenance therapy: Maintenance chemotherapy involves giving low doses of chemotherapy over an extended period of time to help prevent the cancer from coming back. This is often used for some types of blood cancers and some solid tumors, such as ovarian cancer [25].

Significant advances have been made in cancer research in recent years [9]. However, outcomes from standard of care cancer treatments have unfortunately not improved greatly [9] [10]. Chemotherapy can potentially be curative in subsets of patients with certain advanced cancers, including Hodgkin's and non–Hodgkin's lymphoma, acute lymphoblastic and acute myelogenous leukemia, germ cell cancer, small cell lung cancer, ovarian cancer, and choriocarcinoma [1]. In children, the potentially curable cancers include acute leukemias, Burkitt's lymphoma, Wilm's tumor, and embryonal rhabdomyosarcoma [1]. There is an expanding role of chemotherapy to treat a wide range of solid tumors, but the treatment is not often curative. For many of the most common types of cancer such as breast, colon, and head and neck cancers, adjuvant chemotherapy appears to only have a minimal positive impact on overall survival (under 5%) according to some studies [5]. Other research suggests there has been improvement in progression-free survival with the use of neoadjuvant chemotherapy for anal, bladder, breast, gastroesophageal, rectal head and neck cancers, and osteogenic and soft tissue sarcomas [1].

A hallmark characteristic of cancer is its abnormal and uncontrolled growth [9]. The mechanism of action for chemotherapy to combat cancer involves inhibiting the replication of cancer cells [9]. Chemotherapeutic agents are injected into the bloodstream, which then circulate throughout the body and target cells that are actively dividing [9]. Not all tumor cells are in the same stage of replication. Some cells may be in a rest phase, which means chemotherapeutics are unable to destroy them [9]. This is why chemotherapy is sometimes given in cycles and often cannot kill all cancer cells [9]. Furthermore, chemotherapy can also destroy normal cells that are dividing and replicating, which causes undesired damage. Chemotherapy is associated with numerous severe adverse effects, which include immediate and chronic toxicity [5].

In light of the shortcomings and potential side effects of standardized maximum tolerated doses (MTD) of chemotherapy drugs, numerous new therapeutic strategies have been developed in an attempt to improve treatment results. More recent methodologies include molecular profiling and advanced biomarkers to select the most effective chemotherapeutic agents for a patient’s specific cancer type [9]. Other novel strategies include administering chemotherapy while patients are fasting, in conjunction with insulin (insulin potentiation therapy), or other biological response modifiers for enhanced targeting [9]. Micro-doses of chemotherapy (fractionated chemotherapy) is another method that enables increased frequency of administration (metronomic chemotherapy) [9] [26]. Fractionated metronomic chemotherapy allows for multiple targeted chemotherapy drugs to be used at the same time, which may help to overcome drug resistance and reduce side effects [9] [26].

Risk and Side Effects of Chemotherapy

Given that chemotherapy drugs are unable to distinguish between rapidly dividing cancer cells and rapidly dividing healthy cells, they can potentially cause significant collateral damage [27]. Side effects of chemotherapy drugs can be serious and negatively impact patient quality of life during treatment. Each chemotherapeutic drug has different side effects, and not every drug causes all side effects [28].

Chemotherapy is associated with both immediate toxicity and chronic toxicity [5].According to the WHO classification, the intensity of chemotherapy side effects can be mild (grade 1), moderate (grade 2), severe (grade 3) or life-threatening or disabling (grade 4) [5]. Immediate effects are normally observed in skin, hair, bone marrow, blood, gastrointestinal tract and kidneys [5]. All organs can be affected including essential organs such as heart, lungs and brain. Grade 3 and 4 adverse effects include neurotoxicity, which can induce paralysis, ataxia (loss of muscle control and coordination), spasms and coma [5]. Chronic effects are often related to drug resistance, secondary cancer, and infertility [5].

Potential risks and side effects of chemotherapy include [27] [28]:

• Anemia
• Appetite changes
• Diarrhea
• Fever
• Hair loss
• Infection
• Low blood cell counts
• Mouth sores or changes in taste
• Dry, sore or itchy skin
• Nausea and vomiting
• Urinary incontinence and other urination changes
• Constipation
• Fatigue
• Fluid retention or swelling
• Memory or thinking problems
• Sexual health issues

Other long-lasting or late-developing side effects include [28]:

• Infertility
• Weakened heart muscle and other heart problems
• Kidney problems
• Nerve damage or neuropathy (tingling of the fingers and toes)
• Damaged lung tissue
• Risk of second cancer