Principles of Cancer Treatment

Misael Cruz, M.D. | 01.22.16 | INTERNAL MEDICINE

PRINCIPLES OF CANCER TREATMENT BLACK TEXTS = Texts from the presentation / lecture; ITALICIZED TEXTS = Transcripts from the recording / Lecturers inputs; GREEN TEXTS = Texts / Info from the old file/previous transes; BLUE TEXTS = Input from the reference book RED TEXTS = Emphasized content

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LECTURE OUTLINE Overview of Cancer Goals of Cancer Treatment Types of Cancer Treatment a. Surgery b. Radiation Therapy c. Chemotherapy d. Biologic Therapy

OVERVIEW OF CANCER ORIGIN OF THE WORD “CANCER”  Came from the Father of Medicine, Hippocrates, a Greek Physician.  Hippocrates used the Greek words, CARCINOS, to describe tumors, thus calling cancer, KARKINOS (crab or crayfish).  The Greek terms comes from the appearance of the cut surface of a solid malignant tumor, with the veins stretched on all sides as the animal has its feet along the sides as well.  Crabs do not actually cause cancer but it is necessary to limit the intake of seafoods, as well as any other food in excess, due to possible accumulation of toxins, which may – or may not – cause cancer. OVERVIEW

Our bodies are well designed for homeostasis, for the balancing of things within our bodies, and all of us have mutations, several in reality, damaged, scarred cells we cannot deny. These damaged cells, once exposed to factors that either cause too much cellular proliferation or alter factors that cause cell death, will have the high chance of turning into malignant mutations, causing cancer. These factors are nearly anything we live within our times today, all facets of technology, which may damage cells, allow alterations, cause reproduction of several more mutated cells, clump together, and form several malignant cells, and end up as cancer eventually. THE FIRST DOCUMENTED CASE OF CANCER (two versions) 1. The world’s oldest documented case of cancer from ancient Egypt, in 1500 BC, recorded on a papyrus, documenting 8 cases of tumors occurring on the breast. It was treated by cauterization, a method to destroy tissue with a hot instrument, called, Fire Drill. 2. Two of them, known as the “Edwin Smith” and “George Ebers” papyri, contain descriptions of cancer written around 1600 BC and are believed to date from sources as early as 2500 BC. CANCER THERAPY  1600 BC – Surgery was written on papyri  17th Century – Cancer surgery  1903 – Radiation as treatment  1910 – Chemotherapy  1928 – Biologic Therapy  20th Century – Gene Therapy

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GOALS OF TREATMENT The goal of cancer treatment is first to eradicate the cancer. If this primary goal cannot be accomplished, the goal of cancer treatment shifts to palliation, the amelioration of symptoms, and preservation of quality of life while striving to extend life. The dictum primum non nocere may not always be the guiding principle of cancer therapy. o When cure of cancer is possible, cancer treatments may be considered despite the certainty of severe and perhaps life-threatening toxicities.

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Every cancer treatment has the potential to cause harm, and treatment may be given that produces toxicity with no benefit. The therapeutic index of many interventions may be quite narrow, with treatments given to the point of toxicity. o Conversely, when the clinical goal is palliation, careful attention to minimizing the toxicity of potentially toxic treatments becomes a significant goal. Cure – eradicate tumor cells Control – stabilize the disease without causing symptoms Palliate – amelioration of symptoms, preserve the quality of life. Primum non nocere VS Primumm Succerrere. In chemotherapeutics, we deal with the irony of initially hastening the disease prior to managing the disease itself.

TYPES OF CANCER TREATMENT Types of Treatment: 1. Surgery 2. Chemotherapy 3. Radiation Therapy 4. Biologic Therapy

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SURGERY Prevention to prevent the progression of the disease. a. Premalignant Lesions such as moles, familial polyposis in the colon, etc. b. HIGH RISK for Cancer: i. Underlying disease ii. Genetic predisposition iii. Developmental anomaly Diagnosis a. Excisional biopsy – get a small amount b. Incisional biopsy – cut a large amount c. Core needle biopsy d. Fine needle biopsy *CNB and FNB most commonly used for diagnosis of breast malignancies Staging Treatment a. Primary – in 40% of cases b. Combined: o Surgery, chemotherapy, radiation therapy (multidisciplinary management) o For local control o Preservation of organ function o Debulking or downsizing the tumor

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Can also be curative in some metastatic lesion (liver, lung) o Abscopal effect on rare occasions o Ex: renal cancers, splenectomy in lymphoma o For example, you have a patient with renal carcinoma who developed a metastatic lesion in the lungs. There is a possibility that when you do nephrectomy, the metastatic lesion would also disappear without treating it. This is called the abscopal effect. 5. Palliation a. Insertion of CV catheters b. Removal of pericardial, pleural and ascetic fluid c. Caval interruption for recurrent pulmonary emboli d. Stabilization of weakened bone e. Control of hemorrhage f. Surgical bypass g. Splenectomy 6. Rehabilitation o Orthopedic procedures o Breast reconstruction o Plastic and reconstruction surgery Evolution of Surgery ANCIENT SURGERY  MANUAL EXCISION  LAPAROSCOPIC SURGERY  ROBOTICS SURGERY CHEMOTHERAPY Medical Oncology is a subspecialty of Internal Medicine that deals with the use of drugs as treatment approach to patients with cancer, alone or in conjunction with surgery or radiation therapy. Indications: 1. As adjuvant – for local lesion a. Organ preservation b. Sensitize tumors 2. Tumor response (primary): a. Complete – total eradication/disappearance b. Partial – 50% eradication c. Progression – 25% increase d. Stable – no change 3. Palliation – quality of life

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Eastern Cooperative Oncology Group Performance Status (ECOG-PS): 0 – Without symptom 1 – Mild symptom, no treatment 2 – Symptoms with treatment 3 – Disabling symptoms with ambulation >50% of the day 4 – Ambulation < 50% Four (4) Broad Types: 1. Conventional Chemotherapy –small molecules could cause regression of experimental tumors in animals  Target a large amount of molecules in the cells causing a lot of side effects  Still being used nowadays 2. Targeted Agents – small molecules interact with a defined molecular target  Identify specific targets of molecule in the cell, thereby preventing some side effects  Used nowadays 3. Hormonal Therapies – targets the biochemical pathways underlying estrogen and androgen function 4. Biologic Therapies – with a particular target with a capacity to orchestrate and regulate the host response to kill the tumor Mechanism of Action: a. Direct DNA interactive agents b. Indirect effects on DNA function c. Mitotic spindle inhibitors d. Hormonal effect e. Targeted molecules f. Biologic effect Direct DNA Interactive Agents 1. Alkylating Agents – phase non-specific; forms cross linkage of DNA strands and appearance of breaks: a. Nitrogen mustard – aseptic thrombophlebitis b. Cyclophosphamide – chemical cystitis, pulmonary fibrosis c. Chlorambucil – azoospermia, myelosuppression d. Nitrosoureas – bone marrow toxicity e. Melphalan – mucositis f. Streptozotocin – Fanconis syndrome, RTA g. Procarbazine – CNS effects, disulfiram like syndrome h. Cisplatin – nephrotoxicity, neurotoxic i. Carboplatin, temozolamide, oxaliplatin

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2. Antitumor Antibiotics and Topoisomerase Poisons – produced by bacteria, bind directly to DNA and generate free radicals a. Doxorubicin – cardiotoxicity b. Bleomycin – pulmonary fibrosis c. Dactinomycin – severe myelosuppression d. Mitomycin C – hemolytic uremic syndrome e. Mitoxantrone – cardiotoxicity, acute promyelocytic leukemia f. Etoposide – myelosuppression g. Camptothecin (Topotecan, CPT 11) – mucositis Indirect Effects to DNA Function: 1. Antimetabolites – through misincorporation into DNA, abnormal timing or progression through DNA synthesis, altered function of purin and pyrimidine synthesis a. Methotrexate – inhibits dihydrofolate reductase b. 5 Flurouracil – capecitabine (oral homologue) c. Cytosine arabinoside – gemcitabine d. Fludarabine phosphate – CNS dysfunction e. Premetrexed – folate directed antimetabolite f. Asparaginase – bacterial enzyme, stop DNA synthesis Mitotic Spindle Inhibitors – prevent spindle formation; cellular scaffolding; disaggregation of microtubules 1. Vincristine – blocks growing cells in M phase; neurotoxic 2. Vinblastine – myelotoxic 3. Vinorelbine – oral 4. Taxanes (Paclitaxel, Docetaxel) – stabilize microtubules and will function abnormally 5. Estramustine – causes metaphase arrest Hormonal Agents – family of steroid hormone receptor molecules that can alter gene transcription and apoptosis; interacts with activity of hormones in the body 1. Glucocorticoids – induces apoptosis; Cushing syndrome 2. Tamoxifen – partial estrogen receptor antagonist; thromboembolic phenomenon and endometrial carcinoma 3. Diethylstilbestrol – down regulate LH to decreased testosterone; CAD; not being used anymore 4. Luteinizing hormone releasing hormone agonist – leuprolide, goserelin 5. Aromatase Inhibitors – catalyzes the formation of estrogen Anastrazole, Ietrazole (reversible), Exemestane (irreversible)

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Targeted Therapies (Molecular)  Products of oncogenes and tumor suppressor gene  Regulators of cell death pathway  Mediators of cellular immortality  Molecules for microenvironmental molding *Microenvironment – house of tumor; within the cell; within chromosome/mitochondria of cell  For hematopoietic neoplasm 1. Imatinib mesylate (Gleevec) – CML 2. Tretinoin 3. Bortezomib 4. Vorinostat 5. Gemtuzumab 6. Ozogamicin  For solid neoplasm 1. Erlotinib 2. Lapatinib 3. Sorafenib 4. Sunitinib Biologic Therapy  Goal: To manipulate the host-tumor interaction in favour of the host  They differ from Molecular Targeted Therapy in that it requires an active response on the part of the tumor or host to allow the therapeutic effect 1. Cellular Mediated Immunity  Allogenic T cells  Autologous T cells  Tumor vaccines (HPV, Hepa B) 2. Antibodies  Antibodies against CD20 o Rituximab o Trastuzumab  EGFR directed antibodies o Cetuximab o Panitumomab  Anti-VEGF antibodies o Bevacizumab 3. Cytokines  Tumor Necrosis Factor (TNF)  Interferon (INF)  Chemokines  Note: Only interferon alpha, interleukin2 are routinely used

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CHEMOTHERAPY

Effects of Chemotherapy 1. Myelosuppression 2. Nausea and vomiting 3. Diarrhea 4. Gonadal dysfunction 5. Alopecia 6. Mucositis RADIATION THERAPY Radiation Oncology  Clinical and scientific discipline devoted to management of cancer and other disease by ionizing radiation Radiation Therapy  Clinical specialty dealing with the use of ionizing radiation for the following goals: o Curative o Palliative  Applications: o Definitive radiation o In combination with surgery and chemotherapy: Pre-op, Intra-op, Post-op o Palliative radiation Types of Ionizing Radiation 1. Electromagnetic Radiations a. X-rays b. Gamma rays 2. Particulate Radiations – deeper types, not commonly used in practice Ex. Electrons, protons, neutrons, alpha particles, heavily charged ions

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Biologic Effects of Radiation: 1. Direct Action: when gamma rays are absorbed in biologic matter, some of the energy is converted to fast electrons, which can interact directly with the critical targets of the cell – DNA. Beta rays are electrons and may also react directly. 2. Indirect Action: the radiation may interact with other atoms of molecules in the cell to produce free radicals that are able to reach and damage the critical target – DNA. Double Strand Break  Most important lesion produced in chromosome which can cause cell killing mutations, and chromosomal aberration Types of Radiotherapy 1. Teletherapy – ‘far’ from the target organ a. Conventional Roentgen Teletherapy b. External Radiotherapy with High Energy b.1. Cobalt – uses gamma rays b.2. Linear Accelerator – uses x-rays 2. Internal Radiotherapy (Brachytherapy) – ‘near’ the target organ a. Intracavitary: placing the radioactive source inside body cavity b. Interstitial: implanting radioactive source c. Transluminal: inserting the radioactive source inside the lumen d. Surface: applied directly to the skin or surface of the target

Manual Plan

Manual planning is done when there is no available complex 3D Planning. We measure the size of a lesion, put a mark at the center of the target lesion.

2D Simulator Based

2D Plan and Cerrobend Blocks

Radiation Therapy

Cerrobend blocks are made of 10% lead.

Cobalt Therapy is available at PGH and Jose Reyes Memorial Medical Center. Linear accelerator 2D is available at Chinese General Hospital. 3D-IMRT-IGRT is a more complex machine where you can apply the function of CT Scan and evaluate the status of the lesion while treating the patient. This is already available here at Sacred Heart Medical Center. The latest is the tomotherapy which is like a CT Scan that delivers the radiation ‘around’.

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3D Radiotherapy CT Based

Interstitial Brachytherapy (Tongue)

In here, we use needles. Those are where the radiation passes through. Interstitial Brachytherapy (Prostate) Needles are inserted inside the prostate. It is CT guided. Stereotactic Radiosurgery (SRS)

SRS is another complex form of radiotherapy for smaller brain lesions where we only treat patients in a single session, target the affected area, and so the rest of the brain parenchyma is not being treated.

Transluminal Brachytherapy (Lungs) For endobronchial malignancies. We put a catheter inside via bronchoscopy then we target the malignancy

Intracavitary Brachytherapy (Cervical) As mentioned previously, brachytherapy is near the patient. That is why we use this applicator for cervical malignancies where radiation travels.

Intracavitary Brachytherapy (Nasopharynx) We use these tubes, placed through the nostrils

Surface Brachytherapy (Skin) Rarely used today. May cause secondary malignancies like sarcoma of the hand because in the olden times, patients just hold the radioactive material. RADIATION THERAPY Toxicities  Acute o Occurring during the treatment and 3 months after completion of radiation

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Fatigue, alopecia (depending on the area to be treated) , skin discoloration, diarrhea, nausea, vomiting, anorexia, esphagitis, xerostomia The difference between the side effects of radiation and chemotherapy is that chemotherapy is systemic. It goes around the entire body so the effect is generalized. In radiation therapy, the effect is localized. (Ex. If you are treating the abdomen, you will not expect alopeci.) Chronic o Occurring from 3 months onwards o Cataract, stenosis, strictures, fibrosis, pericarditis, enteritis, secondary tumors These are not rarely being seen nowadays because of the technology used.

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Ex. Acupuncture for pain COMPONENTS o Surgery o Pharmaceutical Drugs o Herbal Medicine o Nutritional Medicine o Lifestyle and Behavior o Mind/Body Medicine o Energy Medicine o Manipulative Therapies

Other forms of therapy: 1. Systemic Therapy  Uses radionucleotide targeted to a site of the tumor  Ex. Nulear medicines iodine 131, strontium 89 Nuclear medicine is different from radiation therapy and radiation oncology. Nuclear medicine uses radioactive isotopes for thyroid malignancies, strontium which is a radioactive seed that they use for bone pain that cannot be treated with conventional or extraconventional management. 2. Photodynamic Therapy  Uses light (high energy) in a chemical structure form and taken by cancer cells and produce free radicals then die. 3. Cryotherapy  Uses very low temperature emissions for the treatment of malignancy. 4. Gene Therapy  None have been approved for routine clinical use  Still under experimental studies. Strategies being done: 1. Use of virus that cannot replicate 2. Virus that can replicate but only in the tumor cells 3. Virus that express antigen and promote host mediated immune response 5. Integrative Therapy  This is accepted in oncology. It follows the principle of yin and yang. It helps with whatever conventional/ western/ scientific medicine fails to do and it complements it. PI: Arellano | Gagui | Galvan | Pamintuan | Timbang INTERNAL MEDICINE | Principles of Cancer Treatment PROPERTY OF AUFSOM Batch 2017 V3.2 s2015-2016

THINGS TO REMEMBER:  Cancer treatment goals include cure, control and palliation  Cancer treatment includes surgery, radiation therapy, chemotherapy, biologic therapy, integrative medicine, gene therapy  Primum succerrere o First, hasten to help. o You hasten the disease first before you treat the patient  Advancements are still experimental ongoing and still on experimental stage

CANCER is a word, not a sentence. :) Page 7 of 7