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).