Novel And Emerging Concepts In Chemotherapy
Not all patients with the same type of cancer will have the same response to treatment (Rice 2010; Huh 2009; Feddock 2010). Each person metabolizes drugs differently, and tumors and cancer cells—even among cancers of the same type—can differ markedly on a cellular, molecular, and genetic level (Sabaawy 2013; Rivenbark 2013; Ajani 2011; Duffy 2008; Hendlisz 2013; De Palma 2012; Doroshow 2017).
Treatment appraoches that some describe as “cookie-cutter” remain the standard of care in medical oncology, but their overall success rate is far from impressive (Gesme 2011; Kalia 2013; Ajani 2011; Mavroudi 2014; Bagnyukova 2010). A comprehensive review of medical literature on 22 types of adult cancers found that chemotherapy increased 5-year survival rates by just 2.1% in the United States (Morgan 2004). Other authors have questioned the value of non-curative chemotherapy, suggesting it only modestly prolongs life and has a limited impact on quality of life for most patients (Slater 2001; Boeck 2007; Kosuge 2006; Urschel 2002).
Chemosensitivity testing is a novel approach to identifying drugs most likely to be effective against an individual’s cancer (Grigsby 2013; Geng 2013; Herzog 2010; Smith 1990). This approach involves testing a patient’s tumor and cancer cells against a panel of chemotherapy drugs typically used to treat that type of cancer to determine which drugs elicit the most pronounced response (Yoon 2014; Ballard 2010; Smith 2010; Zhao 2011; Grendys 2014; Nakamura 2006; Wakatsuki 2010; Esserman 2012).
A 2012 study on patients with liver metastases from colorectal cancer compared a standard chemotherapy regimen (32 patients) to one selected based on chemosensitivity testing (31 patients). Before treatment, these patients were not eligible for surgery to remove their liver metastases. The response rate to chemosensitivity-based chemotherapy was significantly greater than to standard chemotherapy, resulting in a higher percentage of patients eligible for surgery after treatment (Hur 2012).
A 2013 study used a method called ATP-tumor chemosensitivity assay (ATP-TCA) to select chemotherapy regimens for patients with recurrent ovarian cancer. The ATP-TCA involves incubating tumor cells with chemotherapy drugs for several days, after which the amount of ATP (cellular energy) produced by the tumor cells is measured to determine their viability. Lower levels of ATP indicate reduced cell viability and greater sensitivity to the drug(s) tested (Glaysher 2011; Yoon 2014). Patients chose either ATP-TCA-directed chemotherapy (56 patients) or physician's-choice chemotherapy (57 patients). Overall response rate and progression-free survival were significantly greater in the ATP-TCA group (66% and 7 months) compared with the physician’s-choice group (46% and 4 months). The difference in favor of assay-selected therapy was even greater for patients with platinum-resistant cancer types (Gao, Wu 2013).
In a study of primary peritoneal carcinomatosis, a type of cancer that affects abdominal cavity tissue, and recurrent peritoneal carcinomatosis from ovarian cancer, chemosensitivity testing was a better predictor of clinical response than testing for levels of cancer gene expression biomarkers (Arienti 2011). A study on peritoneal carcinomatosis related to colorectal cancer found similar results (Arienti 2013).
Several private laboratories offer chemosensitivity testing, including:
- Rational Therapeutics – Long Beach, California, USA
These tests require a blood sample or a biopsy of the tumor (Andreotti 1995; Gazzaniga 2010; Gallant 2013). Chemosensitivity tests have limitations due to their inability to mimic the exact conditions inside the body of an individual patient. Chemosensitivity tests also have less predictive ability in metastatic cancer because cancer that has spread may have a different chemosensitivity profile than the primary tumor. Such differing characteristics result from the continuous mutations malignancies undergo, resulting in differing biochemical and genetic characteristics, even in the same tumor (Higashiyama 2012; Perry 2012; Meric-Bernstam 2012).
Genetic and Biomarker Profiling
Cancers are genetically variable. A breast tumor in one person, for instance, may have very different genetics than a breast tumor in another person.
Tumor gene expression analysis, also known as genetic profiling, is a method of characterizing the chemosensitivity of a patient’s unique tumor to specific drugs (Taherian-Fard 2014; Dezso 2014; Michalski 2008; Cobo 2007). Some of the genetic characteristics of tumors can be targeted with specific chemotherapy drugs. This approach contrasts with the standard “one-size-fits-all” approach.
In the future, clinical oncology will likely focus on personalizing cancer treatment based on detailed molecular and genetic analysis of each individual’s cancer (Perry 2012; Kalia 2013; McDermott 2009; Cronin 2011). This will help oncologists tailor treatments specifically for each patient (Garralda 2014; Guan 2012; Mavroudi 2014; Zarogoulidis 2013).
Research in this area is ongoing, and scientists have already made exciting discoveries. In patients with non-small cell lung cancer, for example, a tumor biomarker correlated with cisplatin resistance, excision repair cross-complementation group 1 (ERCC1), has been identified. The presence or absence of this tumor biomarker may also predict cisplatin resistance or response in patients with gastric, ovarian, and colorectal cancer (Cobo 2007). Early clinical studies on the use of new predictive biomarkers in chronic and acute leukemias, colon cancer, breast cancer, non-small cell lung cancer, and melanoma have shown promising results (Eustace 2014; Ugurel 2009; Yiu 2016; Selli 2016; Perez-Callejo 2016; Yeh 2016).
Some genetic tests are already commercially available. For example, organizations such as the International Strategic Cancer Alliance offer molecular analysis of circulating tumor cells to help guide treatment. Their contact information is:
International Strategic Cancer Alliance
- 873 E. Baltimore Pike #333
- Kennett Square, PA 19348
- By Phone at: 610-628-3419
Other commercially available prognostic gene expression signature tests include MammaPrint, Oncotype DX, and PAM50 (ProSigna). These tests are approved for use in certain populations to provide algorithmic scores that help inform clinical decisions (Wang 2014; Klein 2013; Slodkowska 2009; Colombo 2011). Patients determined through such testing to be high risk are offered adjuvant chemotherapy, whereas those that are low risk are not (Goncalves 2013; Rutgers 2011).
Monoclonal Antibody-Targeted Chemotherapy
Chemotherapeutic drugs’ indiscriminate toxicity toward cancerous and non-cancerous cells is a major challenge for oncology medicine. Because most existing chemotherapeutic drugs enter cells indiscriminately, dosages necessary to kill cancer cells often exert considerable toxicity on rapidly dividing healthy cells (Hilchie 2011). Developing strategies for delivering chemotherapeutic drugs directly to cancer cells without affecting healthy cells is an active area of research.
One promising strategy is to attach chemotherapeutic drugs to molecular chaperones (antibodies) that specifically target cancer cells. These compounds, called antibody-drug conjugates, have shown promise in preclinical and clinical research (Sapra 2013; Beck 2012; Anderl 2013). Monoclonal antibodies, specialized antibodies that target certain cells or cell surface markers, are used in the preparation of antibody-drug conjugates (NCI 2014d).
One antibody-drug conjugate, trastuzumab emtansine (T-DM1, Kadcyla), targets breast cancer in patients whose tumors express a marker known as human epidermal growth factor receptor 2 (HER2). Trastuzumab emtansine is composed of the HER2-targeting monoclonal antibody trastuzumab linked to the cytotoxic agent emtansine. A phase III trial compared trastuzumab emtansine to treatment chosen by physician in patients with advanced HER2-positive breast cancer. All of the participants had recurrent or metastatic breast cancer that was progressing despite two or more chemotherapy regimens directed specifically at HER2. The trial found that trastuzumab emtansine resulted in a higher rate of progression-free survival (median 6 months with trastuzumab versus 3 months in the physician’s-choice group). The study also found that trastuzumab emtansine was associated with fewer severe adverse side effects than physician-choice treatment (Krop 2014). The FDA has approved trastuzumab emtansine for the treatment of patients with metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane (FDA 2013). Additional antibody-drug conjugates are currently in development for a variety of cancer types (Anderl 2013).
Hyperthermia as an Adjunct to Chemotherapy
Hyperthermia involves the use of heat to either directly treat a tumor or increase the vulnerability of cancer cells to other forms of treatment such as chemotherapy or radiation therapy. Types of hyperthermia include local, regional, and whole-body hyperthermia; heating methods include laser, ultrasound, radiofrequency, and microwave radiation (ACS 2013b; Brace 2010).
In local hyperthermia, heat is applied to a small area to heat the tumor and local blood vessels. In a type of local hyperthermia called thermal ablation, extremely high temperatures directly destroy cells. Regional hyperthermia involves heating a specific region of the body such as a limb, organ, or body cavity, generally to lower temperatures than local hyperthermia. In whole-body hyperthermia, the temperature of the entire body is increased to a temperature as high as 108°F; this method is being studied to improve the cytotoxic effect of chemotherapy in metastatic cancer (ACS 2013b; Skitzki 2009; Hildebrandt 2002).
Increasing tissue temperature exerts several anticancer actions, including direct cytotoxicity and activation of several aspects of the immune system. Hyperthermia may also sensitize tumors to chemotherapy and radiation, and appears to do so with minimal damage to normal, healthy cells. Hyperthermia is usually combined with chemotherapy or radiotherapy to treat advanced and recurrent cancers (Owusu 2013; NCI 2011; Hildebrandt 2002; Oei 2015; Skitzki 2009).
Hyperthermia is a promising treatment option for several types of cancer, including non-small cell lung cancer (Wang, Lin 2013), bladder cancer (Colombo 2013; Owusu 2013), advanced cervical cancer (Heijkoop 2012), rectal cancer (Shelygin 2014), and malignant pleural mesothelioma (Okonogi 2012).
The side effects of hyperthermia are usually temporary, but in rare cases can be serious. Local hyperthermia can lead to localized pain, burns, bleeding, infection, blood clots, and other problems. Regional and whole body hyperthermia can cause nausea, diarrhea, vomiting, and, less frequently, problems with blood vessels and the heart (ACS 2013b; NCI 2011).