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1. Define cell cycle.
The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides in half forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0phase.
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2. Define interphase.
Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during the interphase. Interphase proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of mitosis and cytokinesis.
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3. Define G O phase of the cell cycle.
The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.
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4. Describe characteristics of cancer cells in G 0.
They are not killed by chemotherapy or radiation. These cells are resting and can cause reoccurrence when they become active again.
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5. Describe the Growth Fraction/Mitotic Index
Mitotic index is a measure for the proliferation status of a cell population. It is defined as the ratio between the number of cells in mitosis and the total number of cells. Cells in the cell cycle can be identified using antibodies against the nuclear antigen Ki-67. The mitotic index can be worked out from a slide, even with light microscopy. It is the number of cells containing visible chromosomes divided by the total number of cells in the field of view.
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6. Describe the characteristics of the best environment for chemotherapy to work.
Early in the course of the disease, because the cancer population is smaller and more rapidly growing, growth fraction is the highest, before the development of resistant cell lines, larger tumors often have poor vasularity making it difficult for the tumors to penetrate the tumor, before mets are large enough to be symptomatic, treat everything from the beginning. Treat after surgery because G0 cells may renter cell cycle, vascular damage by surgery or radiation may make the remaining cancer cells less sensitive.
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7. Why is it often difficult to adequately penetrate a large tumor with adequate concentrations of chemotherapy drugs?
Larger tumors often have poor vascularity, making it difficult for the drugs to penetrate the tumor.
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8. What is the general correlation of the size of a tumor and the Growth Fractions?
The growth fractions are the cells that are generally active in the cell cycle. The more cells active in the cell cycle, the larger the tumor.
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9. Give 2 reasons the growth rate of a tumor often decreases as the size of the tumor increases.
1. It outgrows its blood supply. 2. low growth fraction.
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10. Give the number of cancer cells believed to be present in a tumor that is of the minimal size for clinical detection.
Greater than or equal to 10^9 (tumor cell burden)
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11. Give 2 reasons large tumors may become hypoxic.
Outgrows its blood supply, and malignant progression.
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12. Give 2 reasons why chemotherapy is often administered with more than one drug.
Provides maximum cell killing within the acceptable toxicity tolerated by the patient for each drug, each drug affects a specific phase of the cell cycle, affect all the subpopulations of the tumor.
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13. List 3 methods of administering chemotherapy drugs.
Oral, Intramuscular, intravenous (central line, hickman, broviac), may be administered (infusion over several days, bolus).
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15. Define the doubling time of a tumor.
In biology, the amount of time it takes for one cell to divide or for a group of cells (such as a tumor) to double in size. The doubling time is different for different kinds of cancer cells or tumors.
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16. What is meant by a tumor being composed of a heterogeneous mass of cancer cells?
A heterogeneous mass means that there are different densities and inclusions (made up of different stuff).
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17. Larger tumors are typically MORE OR LESS sensitive to radiation and/or chemotherapy?
Less sensitive
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18. Describe the rate of growth of cancer cells and normal cells on which chemotherapy will have the greatest effect.
The faster the growth rate the more effect chemotherapy will have on those cells.
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19. Describe the common side effects of chemotherapy.
Myelosuppression (depressed bone marrow), immunosuppression, amenorrhea (loss of menstrual cycle), azoospermia (low sperm), N/V, oncogenisis: AML � 5-10% of patients, distruction of the lining of the digestive tract, stomatitis, mucositis � inflammation of the lining of the oral cavity.
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20. What is the potential number of cancer cells in a patient who is in clinical remission?
10^1 � 10^8
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21. Describe the 3-4 phases of drug testing.
Phase 1 Toxicity Study � trying to determine if the patient can survive the drug/treatment, use terminal patients. Phase 2 Studying Response Rate � Safer, more patients, more dose required. Phase 3 and 4 � Start comparing with gold standard, DH � MOPP � best treatment. ABUD � new drug they studied.
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22. Be familiar with specific advanced stage tumors in which chemotherapy is effective.
Breast, Testicular, Colon
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23. Give the criteria for determing a patient's response to a therapy.
Complete response: NED � no evidence of disease, below clinical ability to detect, 100% responsive. Partial response � decrease tumor by 50%. No Change 0 � 49% decrease in size. Progression � tumor keeps growing. All but NED are treatment failures.
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24. List all the alkylating agents.
Melphalan, Cytoxan (cyclophophamide), Busulfan, Chlorambucil, Temodar � GBM, Nitosureas (BCNU), nitrogen mustard, Thiotepa, Cisplatin (used in a lot of solid tumors � kidney damage), Carboplatin.
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25. List the toxicities associated with alkylating agents.
Myelosuppression (depressed bone marrow), immunosuppression, amenorrhea (loss of menstrual cycle), azoospermia (low sperm), N/V, oncogenisis: AML � 5-10% of patients, distruction of the lining of the digestive tract, stomatitis, mucositis � inflammation of the lining of the oral cavity.
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26. List 3 drugs commonly known to be radiation sensitizers.
Cisplatin, 5FU, Hydroxyurea, Gemcitabine, Taxanes, Bleomycin, Adriacycin, Act D, Mit C
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27. Describe a recall reaction.
Radiation Reaction outline on skin may return when patient receives certain drugs.
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28. List the 2 drugs known to cause the recall reaction.
Actinomycin D Adriamycin, Cytoxan, Hydroxyurea
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29. Which drug is known to have significant lung toxicity?
Bleomycin � relevant in treating Hodgkins disease.
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30. Which 2 drugs are known to have cardiac toxicities?
Adriamycin
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31. What effect does the use of concurrent chemotherapy and radiation have on acute toxicities?
Especially increased acute toxicities.
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32. Describe the types of cancer cells in which chemotherapy and radiation should be most effective.
Organ Preservation � Anus, esophagus, ENT, breast. Tumor inoperable at diagnosis. Some tumors believed to be primarily systemic from beginning � small cell cancer. Static results with advanced cancers. Can used decreased amounts of radiation.
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33. Which 2 types of cancer treatment are most frequently local/regional?
Surgery, radiation.
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34. Give 2 examples of systemic radiation.
Chemo, hormonal
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35. Give 2 examples of when chemotherapy would likely be used in the treatment of patients. Surgery?
Widespread mets, high risk
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36. What is the current estimate of the percentage of patients being treated for cure with surgery?
60%
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37. Define operative mortality.
Death within 30 days of surgery.
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38. List 3 conditions in which a patient with a technically operable tumor may be medical inoperable.
Heart issues � recent heart attack or cognitive heart failure, COPD, morbidly obese, age.
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39. Describe the rationale of prophylactic surgery.
Preventative.
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40. Give examples of prophylactic surgery.
Familial Polyposis (inherited), Ulcerative colitis � both of these colon cancer, Leukoplakia/Erythroplakia � abnormal patches in ENT, Crytoorchidism (undescended testicle), large congenital nevus � malignant melanoma, family history of ovarian cancer, history of breast cancer, men syndrome, thyroid.
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41. What is the purpose of palliative surgery?
Increase quality of life.
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42. Give examples of palliative surgery.
Relief of obstruction, stop hemorrhaging, decrease dyspnea (trouble breathing), relief of spinal cord compression, removal of lesion causing pain or disfigurement, stent placement to fix obstruction, feeding tube.
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43. What condition must be met before reconstructive surgery will probably be performed?
Control local disease
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44. Describe the characteristics of an en bloc resection?
The primary and nodes are removed in one section. In these cases, the goal is to spare as much normal tissue as possible. Example is limb sparing. Hemipelvectomy, total colectomy, pelvic exenteration (take whole pelvis).
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45. Which 2 factors determine the amount of "normal tissue" margin that is resected around a tumor?
Varies depending of the location and tumor behavior.
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46. Give the typical margins associated with cancer surgery.
A margin of 1-5 cm is often reported.
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47. Give 2 examples of when a solitary metastasis can be resected with a curative aim.
Solitary lung metastasis from sarcoma (30% cure), solitary liver metastasis from colon primary (25% cure).
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48. What is the benefit of cytoreductive surgery?
By reducing the number of cancer cells, it is hoped that subsequent radiation and chemotherapy will be more effective. Take away core that is less sensitive to radiation an chemo. Reduce size of tumor.
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49. List 5 potential benefits of surgery.
No biologic resistance of cancer cells, no carcinogenic effect, canc cure a significant portion of tlocalized tumors without additional morbidities of RT and CT, provides the most acute stage of the cancer � whether margins are positive, nodal status and to some degree the status of hematogenous mets.
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50. List 5 potential disadvantages of surgery and Radiation.
No specificity to the cancer cells, normal and malignant cells are equally damaged, slight immediate threat to life, may result in deformity or loss of function, if cancer has spread beyond the local regional site, surgery alone is not curative.
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51. Know the TD 5/5 for all normal tissues
See Attached
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52. Know the toxicity for each organ.
See Attached
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53. Define TD 5/5
Normal tissue tolerance dose. The dose when given to a population of patients under standard treatment conditions will result in no more than a 5% complication rate within 5 years.
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54. Define TD 50/5
The dose that will result in a 50% severe complication rate within 5 years.
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55. Be prepared to calculate the Absolute Granulocyte Count.
Refers to the number of neutrophils in the blood. Healthcare providers use ANC to help monitor the risk of infection in patients undergoing cancer treatment. (% neutrophils + % bands) * WBC = ANC
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56. Know the normal range for all formed elements of the blood.
WBC: 5, 000 � 10,000, RBC: HCT 36-42 (less than 30 bad), HGB 12-18 (less than 10 bad), Platelets 150,000 � 500,000 (less than 50,000 bad).
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57. Describe the potential problems of a depression of each of the formed elements of the blood.
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58. Know the approximate values at which point additional radiation treatments may be withheld until the blood values recover.
WBC � less than 5,000, RBC less than HCT 30 or less than HGB 10, less than 50,000 platelets.
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59. Be able to identify tissues of origin that are highly radiosensitive and tissues of origin that are poorly radiosensitive.
See attached
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60. Describe the difference in morbidity of a Class I organ versus a Class III organ.
Class one is higher risk, more morbidity.
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61. List the 7 primary areas of red bone marrow production.
sternum, scapula, ribs, ends of long bones, skull.
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62. Identify the 2 areas that account for the majority of bone marrow development.
Pelvis, vertebrae
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63. Describe skin care instructions for patients receiving radiation.
Wear loose soft clothing, avoid excessive sun exposure, keep baths short.
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64. Describe instructions for patients receiving radiation to the following areas:breast, chest, pelvis, brain, head & neck.
Drink a lot of liquids, do not wear deodorant if in treatment site, take Imodium as needed, do not put lotion on before treatment.
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65. Be prepared to identify tissues of origin and tumors of high radiosensitivity and low radiosensitivity.
See attached
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66. Define hyper fractionation.
Goal is to increase normal tissue tolerance. � standard per fraction, 100 cGy in the morning, 100 cGy in the afternoon 6 hr later. Used in big tumors and brain tumors. Decreases toxicities.
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67. Differentiate between the 2 types of hyper fractionation; give indications for the use of each.
Standard and Accelerated. See above for standard. Accelerated hyper fractionation increases the daily dose to keep up with rapidly growing tumor. Decrease length of time for a dose. 120 cGy in the morning and 120 cGy 6 hours later, or 160 for both. Increases toxicities both acute and late.
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68. What is the advantage of regular hyper fractionation vs. accelerated hyper fractionation?
Decrease acute and late toxicities for regular, increased accelerated. Takes less time to do accelerated.
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69. Describe the 3 types of brachytherapy.
Different types of brachytherapy can be defined according to (1) the placement of the radiation sources in the target treatment area, (2) the rate or �intensity� of the irradiation dose delivered to the tumour, and (3) the duration of dose delivery. The two main types of brachytherapy treatment in terms of the placement of the radioactive source are interstitial and contact. HDR vs LDR, and also temporary or permanent.
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70. What is the goal of curative attempt radiotherapy?
Complete Destruction of all cancer cells.
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71. Compare the general dose guidelines of curative attempt and palliative radiotherapy.
200 cGy x 30 fractions � 5000 cGy is curative�..300 x 10 fractions � 3000 total dose
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72. Why is curative attempt radiotherapy often administered at standard fractionation?
It is the quickest they can deliver the dose since they are worried about toxicities. Palliation they do not worry as much about long term toxicities and it provides quick relief.
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73. Define standard fractionation.
180 � 200 cGy per fraction. Maximum dose before normal tissue complications.
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74. Compare typical field volumes for epithelial tumors and sarcomas.
Epithelial include a primary (GTV), plus a margin varying from 1cm � 5 cm (CTV) of normal tissue, plus a regional lymph nodes. Typically 1 beyond known disease. Sarcomas include a primary, plus a margin of normal appearing tissue, without nodes.
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75. Give the 2 factors that determine the tumorcidal dose.
Tumor Size and histology.
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76. Give 2 reasons that larger tumors require larger doses of radiation.
As the size of the tumor increases, the does necessary to destroy the tumor increases. Reasons are increased number of cancer cells, and increased size of hypoxic compartment.
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77. 1 Gy= 50 Gy= 1 rad=
1 Gy = 100 cGy, 50 Gy = 5000 cGy, 1 rad = 1 cGy = 1 J/kg, 33ev discrete energy deposition.
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78. What is the purpose of low dose pre-operative radiotherapy?
Decrease the release of viable cancer cells during surgery.
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79. Give 2 examples of low dose radiotherapy.
500 cGy/single/immediate surgery, 2000 cGy/5 fractions/surgery witin a couple of days.
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80. Compare the time interval before surgery is done following low-dose and high- dose radiotherapy.
2-4 weeks with moderate, more immediate with low dose or at most a couple of days.
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81. Give 2 indications for moderate dose pre-operative radiotherapy.
Tumor shrinkage to downstage the tumor, and by decreasing the size of the tumor, you can make it operable in size.
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82. List and explain the disadvantages of pre-operative radiotherapy.
Impaired healing of wound made during surgery because of the damage in the bood vessels. Delay in surgery, the higher the does the longer the break, tumor could regrow.
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83. Why is pre-operative radiotherapy usually limited to 50 Gy/5 weeks?
That is the maximum dose that the tissues can handle.
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84. What is the goal of post-op radiotherapy?
To sterilize known or suspected micro or macro tumor following surgery. If risk is 20% or greater.
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85. List 4 indications for post-operative radiotherapy.
High grade tumor, positive margins, vascular invasion, lymph node involvement.
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86. Why is the radiation field often larger in a post-op setting as opposed to a pre- op setting?
The entire surgical scar is often included in the treatment field.
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87. List 4 advantages of post-op radiotherapy.
Target volume can be better identified tailored to the tumor, clips may be place at surgery. Higher TD can be delivered in a post op setting, since you do not need to worry about wound healing, smaller number of cancer cells left behind and hypoxic core has been removed. Better determination of the exact extent of the disease, pathologic vs clinical.
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88. List 6 potential complications of post-op radiotherapy.
Have to wait since RT will impair the healing by destroying fibroblasts, Tumor regrowth could occur since you have to wait, cannot decrease the probability of seeding cancer cells into the wound, surgery damages the blood vessels making it less sensitive to RT, Adheasions of loops of small intestines making them fixed an more damaged by the RT, field sizes are large.
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89. Differentiate between the 2 general methods of administering radiation.
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90. Give 3 potential reasons why surgery and either pre or post-op radiation may be used.
Large tumor, disease has not spread, increase local tumor control.
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91. What is the advantage of the shrinking field technique?
Can give higher amounts of radiation to the areas at risk without exceeding normal tissue tolerance.
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92. What are 3 guidelines of palliative radiotherapy?
Appropriate when cure is not realistic, not attempt to destroy tumor or include all in the field, only the areas causing problems are treated, dose necessary to relieve patient is delivered, goal is to palliate as quick as possible.
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93.List potential dose schedules of palliative radiotherapy.
3000 cGy in 10 fractions, 2000 cGy in 5 fractions, 3600 cGy in 18 fractions, 4000 cGy in 20 fractions, 2000 cGy in a single fraction.
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94. Compare the life expectancy of a patient receiving 2000/1 week and a patient receiving 5000/5 weeks.
2000 in 1 week has a shorter life expectancy.
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95. Give the characteristics of prophylactic radiotherapy.
Treat 1 lymph node beyond known disease, do not know disease is there.
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96. Provide justification for the usual dose schedule in a prophylactic setting.
A usual dose schedule could be used for ENT T2N1M0, Breast cancer, and cervix cancer. Breast you treat the whole breast with 50, then boost the site of lumpectomy. Cervix 5000 cGy then a boost with brachytherapy.
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97. Compare the typical failure pathways for surgery vs. radiation.
- Radiation usually fails in the central core where the hypoxic core is usually the highest.
- The rim of the tumor is usually well vascularized, so well oxygenated and therefore radiosensitive. After surgery, most likely fail on edges of the tumor. Surgery may be limited in the amount of normal tissue that can be removed, resulting in edges being left behind.
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98. What is the usual time interval between surgery and the beginning of post-op RT?
2-4 weeks.
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99. What is the potential problem if an excessive length of time elapses between surgery and the beginning of RT? How can it be managed?
Tumor regrowth may begin, managed by beginning as soon as possible.
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100. List the 4 "Rs" of radiotherapy, and indicate which affects the tumor control and which affects normal tissue tolerance.
Increase normal tissue tolerance � repair SLD PLD to normal tissue, Repopulation of normal tissue between fractions. Increase Tumor Damage � Reoxygenation of tumor through gradual shrinkage of tumor, and Redistribution of cancer cells back into radiosensitive phases of the cell cycle between fraction.
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101. Explain how repair and repopulation increase normal tissue tolerance.
The normal tissues are repairing and repopluaing its cells allowing for it to tolerate more radiation.
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102. Explain how redistribution and reoxygenation increase tumor radiosensitivity.
They are located in areas of the cell cycle that allows for radiation damage to occur, more oxygen increases radiosensitivety.
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103. Give the 2 ways to improve the TR.
Increase normal tissue tolerance and increase tumor damange.
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104. Give examples of very positive TRs, radio responsive TRs and very negative TRs.
Positive are seminomas, dysgerminomas, lymphomas, Hodgkins. Negative are osteosarcomas, GBM, lymphoma, adenocarcimoa of kidney, small intestines.
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105. What is the most clinically relevant method of improving the TR.
Fractionation
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106. Be prepared to explain how each of the 11 ways to increase normal tissue tolerance works.
Fractionation, Precise treatment planning, precise preproduction, conformal planning, selection of best modality and energy, implants, hyperfractiation, low dose per fraction, amifostine.
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107. Be prepared to explain how each of the 11 ways to increase tumor damage works.
Fractionation, Precise treatment planning, precise preproduction, conformal planning, selection of best modality and energy, implants, hyperfractiation, concurrent CT, increase HCT, hyperthermia.
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108.Be prepared to indentify the TR of specific tumors(size and histology) in specific locations(TD5/5).
See attached
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