HC21: Medical oncology

Oncology

An oncologist is a doctor who treats cancer and provides medical care for a person diagnosed with cancer. The field of oncology has 3 major areas:

• Surgery
• Radiation
• Medical

A medical oncologist treats cancer using hormonal therapy, chemotherapy or other medications such as targeted therapy or immunotherapy.

Breast cancer treatment

Drug treatments can attack all the cancer cells throughout the body. Most breast cancer cells metastasize to the lymph nodes.

Goals:

Goals of breast cancer treatment are:

• Regression of metastases
• Improvement in symptoms and quality of life
• Improvement in survival time
  • There isn’t a cure for metastatic breast cancer yet
• Balance toxicity of treatment with relief symptoms due to tumors

Types:

There are 4 types of therapy for breast cancer:

• Endocrine therapy
• Chemotherapy
• Targeted therapy
• Immunotherapy

Factors:

Factors deciding a certain therapy in metastatic breast cancer are:

• Patient age
• Menopausal status
  • Levels of estrogen are much higher in premenopausal women than in postmenopausal women
• General health
• Tumor estrogen receptor (ER) status (and the less important progesterone receptor (PgR) status
  • Endocrine therapy is the preferred choice for ER+ metastatic breast cancer → has less side effects than chemotherapy
• Tumor HER-2 status
  • Targeted therapy is the preferred choice
• Good/poor responses to previous treatments

Hormonal therapy

Hormonal therapy is directed towards tumors which are hormonal dependent for their growth:

• Breast cancer
  • Estrogen receptor positive (ER+)
• Prostate cancer
  • Testosterone dependent
• Endometrial carcinoma
  • Progesterone dependent

Estrogen:

Estrogen is a steroid which binds to the estrogen receptor on ER+ breast cancer cells → stimulates tumor cell growth. Approximately 60-70% of breast cancers express estrogen and/or a progesterone receptors. The goal of hormonal treatment is to block the stimulating of cancer growth by steroids.

There are 2 types of hormonal treatment of ER+ breast cancer:

• Blockade of estrogen action on the cancer cell
  • Tamoxifen: blocks the estrogen receptors on the surface cells → prevents estrogen from entering the cells
    • A selective estrogen receptor modulator
    • A very old, inexpensive drug
    • Relatively little side effects
  • Treatment for pre- and postmenopausal women with ER+ tumors
• Blockade of estrogen synthesis in the body
  • Removal of both ovaries in premenopausal women or the use of LHRH agonists
    • Removal of the ovaries isn’t very effective in postmenopausal women → estrogen production hardly goes down
  • Aromatase inhibitors: block the enzyme aromatase → block the conversion of steroid precursors to their active form
    • Anastrozole/armidex
    • Only in postmenopausal women
    • Aromatase is an enzyme in fat, the liver, muscles and the brain → blocks conversions of testosterone and androstenedione into estrogens
      • A source of estrogen in postmenopausal women

Side effects:

Side effects of hormonal treatment are very hard to see. Doctors may perceive that the treatment is going well and that there aren’t any side effects, while this actually is not the case. People who know the patient better are more prone to notice side effects. Side effects of hormonal treatment are:

• Hot flashes
• Depression
• Nausea
• Joint complaints
• Rash
• Edema
• Thrombosis
• Endometrial carcinoma
  • Only in case of tamoxifen, which is a blocker and small stimulator of ERs at the same time
• Osteoporosis
  • Only in case of aromatase inhibitors
  • Estrogen protects the body from osteoporosis → the beneficial effects of estrogen go down

Generally, these side effects are a little more common in case tamoxifen is used.

Chemotherapy

Most chemotherapeutic drugs are given intravenously.

Goals:

Goals of chemotherapy are:

• Eliminate the cancer, shrink the tumor and prolong survival
• Kill all tumor cells and obtain cure
• Prevent cancer from spreading
• Relieve symptoms from cancer
  • Such as pain
  • A form of palliative treatment

Chemotherapy for metastatic breast cancer:

There still is no cure for metastatic breast cancer patients. The process can be slowed down by chemotherapy:

• Sequential single agent chemotherapy
  • Less toxicity than combination chemotherapy
  • There is no data to support optimal sequence
• Combination chemotherapy
  • Rapid clinical progression
  • In case rapid symptom/disease control is necessary
  • Used for life-threatening visceral metastases
    • Mainly liver metastases

Mixed responses often occur due to tumor heterogeneity → 1 or more metastases may grow while the others become smaller. The chance of emergence of resistance to treatment is less likely after combining 2, 3 or more chemotherapeutic agents.

Classes of chemotherapy:

Chemotherapy can be cell cycle phase specific or nonspecific:

• Cell cycle phase specific agents
  • Agents with major activity in a particular phase of the cell cycle
  • Schedule dependent
• Cell cycle phase nonspecific agents
  • Agents with significant activity in multiple phases
  • Dose dependent

Toxicities:

Chemotherapy is not tumor specific and will damage all fast dividing tissues, such as:

• Bone marrow
• GIT
• Hair follicles

There are potential side effects for each specific chemotherapy. Individual patients will not experience all side effects. Some side effects can be prevented. Common chemotherapy toxicities are:

• Myelosuppression/bone marrow suppression
  • Neutropenia
  • Anemia
    • Thrombocytopenia
• GIT toxicity
  • Mucositis
  • Vomiting
• Alopecia
  • Chemotherapy almost always leads to hair loss
• Sterility/infertility

Bone marrow suppression following chemotherapy may lead to decrease in blood cell levels. By the start of the next treatment, the levels are expected to return to normal. Blood cells of the bone marrow are:

• Red blood cells: carry oxygen to body cells
• White blood cells: fight infection
• Platelets: form blood clots

Treatment of early stage breast cancer

Breast cancer is most curable when detected early. Micrometastases can exist at the time of diagnosis in many patients at the time of surgery of the breast tumor, leading to eventual recurrence. Adjuvant therapy can help prevent this → multidisciplinary care is critical for the best outcomes:

• Surgery
• Radiation therapy
• Adjuvant systemic drug therapy
  • Reduces the risk of recurrence and death
• Neo-adjuvant treatment
  • Effective drugs are given before the surgical removal of the breast tumor

Adjuvant treatment:

In the 1970s, it was stated that adjuvant chemotherapy has survival benefits in both node positive and negative breast cancer. In the 1980s, the neo-adjuvant chemotherapy concept for operable breast cancer was developed. The aim of both adjuvant and neo-adjuvant therapies is to provide a higher chance of breast conservative surgery and a decrease in the outgrowth of micrometastases.

Tamoxifen is effective in both pre- and postmenopausal women:

• Adjuvant tamoxifen doesn’t impact recurrence in ER negative breast cancer
• Adjuvant tamoxifen significantly reduces recurrence in ER positive breast cancer

In post-menopausal women, anastrozole adjuvant treatment works better than tamoxifen. This can be explained by them having lower levels of estrogen. Survival after adjuvant chemotherapy is better than without adjuvant treatment. However, hormonal treatment remains the most effective in ER+ breast cancer. In ER- aggressive tumors, the benefit of adjuvant chemotherapy is often the same or better than hormonal therapies, but the magnitude of benefit is much smaller than that of adjuvant hormonal therapy in ER+ tumors.

Target therapy

Target therapy consists of drugs which inhibit a protein or molecule that only is expressed in cancer or which only the cancer is dependent on. This promises reduced side effects compared to less targeted drugs.

HER-2 inhibitors:

HER-2 receptors are a family of trans-membranal receptors. HER-2 can dimerize with itself or with other HER family members. In 20-30% of breast cancer cases, HER-2 proteins are overexpressed due to gene amplification:

• There are <10.000 HER-2 proteins on a normal breast cell
• There are 2 million HER-2 proteins on a cancer cell

HER-2 amplification is associated with a poor prognosis. HER-2 receptors can be blockesd by HER-2 inhibitors:

• Trastuzumab (Herceptin)
• Pertuzumab (perjeta)

Testicular cancer

Testicular cancer first metastasizes to para-aortic lymph nodes, from which it metastasizes to other parts of the body.

Cisplatin:

Cisplatin-based chemotherapy results in high cure rates in low and intermediate prognosis testicular cancer. The prognosis of testicular cancer can be made based on the levels of AFP and HCG:

• Good prognosis: 92% 5-year survivals
• Intermediate prognosis: 80% 5-year survival
• Poor prognosis: 16% 5-year survival

Side effects:

Because testicular cancer is often cured, long term side effects are much more important than types of cancer which have a more slim chance of survival. Side effects of chemotherapy in testicular cancer are:

• Low serum testosterone and high LH
• Low sperm counts and reduced motility, or no sperm at all
  • Azoospermia: no sperm at all
  • Semen is preserved prior to chemotherapy
• Infertility

Cured patients also have a higher chance of cardiovascular disease and metabolic problems → are more prone to obesity, diabetes and hypertension.

Prostate cancer

Prostate cancer is sensitive to androgens such as testosterone, which are high in young men. 95% of testosterone is produced by the testicles and 5% is produced by the adrenal glands.

Hormonal treatment:

Prostate cancer can be treated with:

• Orchiectomy: surgical removal of the testicles
  • Gives a good antitumor response for 2-3 years in patients with metastatic prostate cancer
• LH-RH agonists
  • Have the same clinical efficacy as orchidectomy

For castrate refractory patients, there are other treatment options such as blocking the testosterone production outside the testicles or in the direct surrounding of the tumor cells.

Orchiectomy and LH-RH agonists both are forms of hormonal treatment for prostate cancer, also known as androgen deprivation therapy (ADT). Both treatments lower the serum testosterone levels by 95% → only 5% of the total body testosterone production remains.

Side effects:

Side effects of hormonal treatment (ADT) in prostate cancer are:

• Loss of libido
• Erectile dysfunction
• Gynecomastia
• Osteoporosis
• Hot flashes

Men with too little testosterone may also have problems with cognitive function.

Kidney cancer

Target therapy is very effective for renal cell cancers (RCC). RCCs are highly vascularized tumors because they produce VEGF, which causes angiogenesis → helps the tumor survive by supplying oxygen and nutrients. Therefore, the standard of RCC care consists of VEGFR-targeted therapy. VEGFR blocks fit into the ATP pocket of VEGFRs, blocking them from being activated.