1. LOCO- REGIONAL CANCER TREATMENTS: SURGERY AND RADIOTHERAPY
Assoc prof. L. MIRON

2. Summary Cancer treatment- classification
Principles of surgical oncology
- historical perspective
- roles of surgery in cancer patients
- surgery in multidisciplinary terapeutical plan
Principles of radiation oncology
- physical and chemical basis of radiation action
- biological basis of radiation therapy
- clinical practice of radiation therapy

3. STEPS IN MANAGEMENT OF CANCER PATIENTS
I. DIAGNOSTIC PROCESS
II. STAGING OF DISEASE
III. PRETREATMENT EVALUATION - PROGNOSTIC CATHEGORY
IV. TREATMENT PLAN

4. Types of cancer treatments
I. Loco-regional treatment:
SURGERY
RADIOTHERAPY
II. Systemic treatments:
CYTOTOXIC CHEMOTHERAPY
MOLECULARY TARGETED THERAPY
IMMUNOTHERAPY
HORMONOTHERAPY
GENES THERAPY

5. PRINCIPLES OF CANCER SURGERY
Surgical interventions in cancer

6. Definitions
Surgery is the oldest treatment for cancer and, until recentlly, the only one that cure cancer patients.
Surgery remains the primary method of treatment of most solid malignancies.
In some cases is the only chance for cure for cancer patients.

7. Surgery- history
Historically, surgery is the sole methods used to treating cancer.
The earliest disscussion of surgical treatment of tumors appears in 1600B.C in Edwin Smith papyrus belived writing dating back 3000 B.C.
Surgeon is the part of a multidisciplinary team.
Surgeon is frecquently the “entry point” for patients who are newly diagnosed with cancer
Surgeon must have knowledge of the biology and natural history of the cancer to be treated.

8. Principles of Surgical Oncology

9. Determinants of operative risk

10. Roles for Surgery Prevention of Cancer Diagnosis of Cancer
Treatment of Cancer
Currative: Resection of the Primary Cancer
Palliative: Cytoreductive Surgery
Metastatic Disease
Oncologic Emergencies
Palliation
Reconstruction and Rehabilitation

11. 1. Prevention of cancer
Hyperplastic and dysplastic lesions need not always progress to cancer, but when they do, the process can take years, if not decades.
Cancer requires several genetic alterations during a course of somatic evolution.
Cancer cells are widely believed to have a “mutator phenotype.”

12. Roles for surgery - prevention of cancer
Multiple endocrine neoplasia (MEN) tip 2- profilactic thyroidectomy for medullary familial cell thyroid carcinoma.
Patients with Barett’s oesopagus (with high grade dysplasia)- prophylactic oesophageal resection.
Hereditary diffuse gastric cancer-there are a role for preventive total gastrectomy
Ulcerative colitis – total colectomy
Hereditary colorectal cancer: familial adenomatous polyposis coli and hereditary non-polyposis colorectal cancer (HNPCC) accounts for 5% of all CCR cancers.
Breast cancer carry a mutation BRCA1 and BRCA2 genes are a high risk of developing ovarian cancer- oophorectomy.
Patients with maldescendent testis (cryptochidism) have a higher chance of developping testicular cancer (x 20 times) - orchidopexy

13. 1. Prophylactic surgery

14. 2. Surgery for diagnosis – diagnostic procedures: acquisition of material for diagnosis
Fine needle aspiration cytology(FNA) – involving aspirating tissue fragments through a needle guided into area in which disease is suspected; aspiration of cell-cytology.
Core needle biopsy- the retriveral of a small core of tissue, ussing a specially designed “ core-cutting”, the specimen is usually sufficient for histologic diagnosis of most tumor types. 14-gauge needles.

15. 3. Surgery for diagnosis – diagnostic procedures: acquisition of material for diagnosis
Open byopsy:
Incisional biopsy – removal of small segment of a larger tumor for diagnosis, a wedge of tissue.
Excisional biopsy- total excision of the entire suspected tumor tissue with little or no margins.
Laparoscopic surgery for diagnosis and staging
Laparatomy, lymphadenectomy, sentinel node biopsy (SNB).

16. Principles guide the performance of all surgical biopsies
Needle tracks or scars should be placed so that they can be conveniently removed as part of subsecquent definitive surgical procedure.
Care should be taken to avoid contamining new tissue planes during biopsy procedure; avoid development of large hematomas.
Care should be taken to avoid using instruments that may have come in contact with a tumor when obtaining tissue from a potentially uncontamined area.
Adequate tissue sample must be obtained to meet the needs of the pathologist for diagnosis of selected tumors, electron microscopy, tissue culture, or other tehniques may be necesarry.
It is important to mark distinctive areas of the tumor to facilitate subsequent orientation of the specimen by the pathologist< he hanling of excised tissue is the surgeon’s esponsability.
Placemnt of radiopaque clips during byoposy and staging procedures is sometimes important to delineate areas of known tumor and guide the subsequent delivery of radiation therapy in these areas.

17. 3.Surgery for staging
Staging is the classification of anatomic extent of cancer in an inndividual. Specific staging groups categorize cancers on particular anatomic sites.
Laparatomie and laparoscopic surgery for staging prior to definitive surgery:
- ovarian cancer
- oesophageal cancer
- gastric cancer
- pancreatic cance
- liver cancer
- prostatic cancer

18. 3.Treatment of cancer
Resection of primary tumor: radical versus conservator
Curative surgery
Palliation surgery: cytoreductive surgery - debulking
metastasectomies
oncologic emergencies
reconstuction and reabilitation

19. Surgery for primary cancer
There are three major challenges confronting the surgical oncologist in the definitive treatment of solid tumors:
accurate identification of patients who can bee cured by local treatment alone;
development and selection of local treatments that provide the best balance between local cure and the impact of treatment morbidity on the quality of life;
development and application of adjuvant treatments that can improve the control of local and distant invasive and metastatic disease.

20. Primary resection- principles of surgical resection
The primary goal of cancer is the complete extirpation of local and regional disease for local control and for decreasing the risk of local recuurrence.
Removing the primary lesion with adequate margins of normal surronding tissue to minimize the risk of local recurrences.
Knowledge of the most common avenues of spread of various histologic type (e.g. cancer spread mucosally, submucosally, along the fascial plans or along the nerves).
Knowledge about the possibilities of multidisciplinary approaches: adjuvant chemotherapy.

21. Currative resection: obtain adequate margins of resection
A complete margin of normal tissue arround the primary lesion ( R0 status)
Frozen sections used to evaluate tissue margins in instances of doubt
Complete removal of involved regional lymph nodes
Resection of involved adjacent organ
En bloc resection of biopsy tracts and tumor sinuses.

22. Area of dissection for lymph node dissection for radical nephroureterectomy should be from the superior mesenteric artery to the level of the inferior mesenteric artery, with the anatomic structures identified. The left colon can be reflected from the anterior surface of Gerota's fascia with exposure of the renal artery before ligation and division. The dotted line to the right of the descending colon indicates a line of incision on the left pericolic gutter that should extend superiorly to include division of the splenocolic attachments

23. Risk factors for metastasis: is necessary to associate another treatments at surgery?
Tumor size and regional lymph node involvement are consistently associated with distant relapse.
The involvement of regional lymph nodes is often, but not always, a harbinger for increased risk of distant metastasis.
When tumor cells appear to have aggressive traits on microscopic analysis, this often translates into increased risk for distant disease.
(1) Tumor grade
(2) Depth of invasion beyond normal tissue compartmental boundaries.
(3) Lymphovascular invasion.

24. Radical resection

25. Surgery for palliation
Palliative therapy should be considered for a patient with evidence of widespread malignancy and no hope of cure by resectional therapy.
Goals of treatment: significant improvement in quality of life and alleviation of symptoms which allows patients to resume as manyof their normal daily activities as possible.
EXEMPLE:
relif of intestinal obstruction,
removal of tumors to control pain or hemorrage,
induction of a feeding jejunostomy to permitt adequate nutrition.
Malignant pleural effusion- thoracostomy tube, sclerosis.
Billiary obstruction- stent or choledochojejeunostomy
Bowel obstruction- colostomy with mucous fistula.
Bowell obstructon- gastrojejunostomy
Esophageal obstruction - stent, gastrostomy tube
Advanced breast mastectomy- salvage mastectomy.

26. Palliative surgery
Surgery for debulking ( surgery for residual disease) cytoreductive surgery
Second-look procedures
Surgery for metastatic disease
Surgery for reconstructio and rehabilitaion
Surgical management of complications therapies

27. Laparoscopic view of carcinomatosis

28. Intraoperative appearance of advanced epithelial ovarian cancer, with multiple tumor implants involving the peritoneal surface of the upper abdomen.

30. Specialised surgical procedures
Vascular accesss:
Percutaneous catheters
Indwelling cuffed catheters
Implantable infusion ports

31. The placement of operating ports in the insufflated abdomen provides access to the abdominal cavity for laparoscopic surgery. The exact locations for port placement vary based on the planned procedure as well as the patients' individual anatomic situation.

32. Surgical interventions in cancer- summary of key points
Surgeon is part of multidisciplinary team.
Role of surgery in cancer management:
- prevention of cancer ( criptorhidism)
- screening of cancer ( genetic testing)
- diagnosis of cancer based on a histologically confirmed diagnosis
- staging of cancer - the classification of the anatomic extent of cancer in an individual.
Surgical treatment of cancer:
- surgery for primary cancer
- surgery of metastasis
- surgery for debalking
- paliative surgery
- reconstructive and reabilitatative surgery
- vascular access
- surgery for oncologic emergencies

33. Reconstruction and reabilitation
Surgery techniques are being refined that aid in the reconstruction and reabilitation of cancer patients after definitive treatment
The ability to reconstruct anatomic defects can substanially improve function and cosmetic appearance
The development of free flaps using microvascular anastomotic techniques is having a profund impact on the ability to bring resh tissue to resected or heavily treatet areas.
Lost function, especially of extremities often can be restored by surgical approaches. This include lysis of contracture or muscletransposition to restore muscular function that have beendamaged by previous surgery or radiation therapy.

34. PRINCIPLES OF RADIATION ONCOLOGY
L. Miron
Clinica Oncologică, Spitalul Clinic de Urgenţe “Sf. Spiridon” Iaşi

35. Definitions
Radiation oncology is a discipline specialised in the use of radiation for therapeutic purposes.
Radiation therapy (RT) is a treatment modality in which ionizing radiation is used for patients with cancers and other diseases.
50- 60% of patients whith cancer receive RT
40- 50% of cancers can be cured.

36. Historical perspective
1896 Discovery of X-ray
1898 Discovery of radium
1899 Succesfull treatment of skin cancer with X-ray
1915 Treatment of cervical cancer with radium implant
1922 Cure of laryngeal cancer with a course of X-rays therapy
1928 Roengen defined as unit of radiation exposure
Dose fractionation principles proposed
1950’s Radiactive cobalt teletherapy ( 1 MeV energy)
1960’s Production of megavoltage X-rays by liniar accelerators
1990’s 3-dimension radiotherapy planning

37. Radiation oncology- summary
Physical and chemical basis of radiation action
Biological basis of radiation
Clinical basis of radiation

38. 1. Physical and chemical basis of radiation action
Types of radiation used in radiation therapy
IONIZING RADIATION could be split:
Electromagnetic radiation : energy range used for RT can cause the ejections or orbital electrons and results in the ionization of atoms or molecules:
- fotons ( are x-rays or γ-rays),
- α particles, ß particles(atomic particles) and
- γ-rays (energy way)
Corpuscular: electrons, protons, neutrons, heavy ions

39. Electromagnetic radiation
Many types of radiation are used for treatment of both benign and malignant diseases.
The most form of irradiation is external-beam photons or electrons ( x-rays, γ-rays) bundles of energy.
- x-rays is used to describes radiation that is produced by machines.
- γ-rays define radiation that is emitted from radiatioactive isotopes (Cobalt 60, Cesiu 137, Radium, Radon, Poloniu).

40. 2. Bilogical effects of radiation
Cellular kill occurs when critical targets within cell are damaged by radiation and the cell is unable to repair that damage.When X-rays pass through living tissue, energy is absorbed, resulting in ionisation of a number of molecules with generation of fast-mooving electrons and free radicals.
DNA is the main target for biologic effect of raditation.
DIRECT: DNA damage can be direct: single strand breaks, double strand breaks, and sugar damage, DNA-DNA and DNA-protein links.
INDIRECT: DNA dam age- water molecules surronding the DNA are ionized by the radiation. The ionizing of water creates hidroxil radicals, hidrogen peroxide, hydated electrons and other oyigen free radicals capable of interacting with DNA andcausing damage. ( 80% of cell is composedof water, suggesting that indirect damage of DNA is common).
Chromosome aberations results from faculty DNA double- strand break.
The major mechanism of DNA damage is liniar transfer of energy (LET) – low LET - fotons ( x-ray), γ-rys and electrons are termed low liner energy transfer
LET high- protons and neutrons.

41. BIOLOGIC EFFECTS OF RADIATION

42. Factors that effect the response of tumours to radiation
Biological effect of radiotherapy relate to both the dose of radiation and timing of delivery of this treatment.
It results in preferential paring of noramal tissue damage, allowing safe delivery of hiher total doses of radiation with increased cancer cell kill.
DNA repair – non homologous recombination
- homologous recombination
Tumor oxigenation- role of hipoxia in radiotherapy
Strategies to increase tumor oxigenation- erytropoieins

43. 4 Role of fractionation radiobiology
Fractionation is the division of a total dose of external beam radiotherapy into a small, often once daily doses.
Reoxygenation- the damage of tissues by radiation depends largely on the formation of OH- radicals.
Repopulation – the normal tissue cells repopulate more adequtley than the malignant cells during treatment course.
Repair – repair machinery within cells can reverse partial damage caused by a small fraction of the radiation dose by sublethal damage ( SLD) repair.
Redistribution –cells exhibits differential sensitivities toward radiation at different phases of cell cycle. Cells are more resistant phase ( late S-phase), and more sensitive at the jonction G2/M phase. After a an initial fraction of dose, the cells are in more resistent phase S and may survie but then progress to the sensitive phase when given the second dose..

44. Tehnical modalyties
Ionizing radiation can be delivered in three technical modalities:
1. External percutaneous beam irradiation (teletherapy) from sources at distance from the body: telecobaltotherapy and linear accelerators are used for fractionated radiation therapy.
External beam radiation therapy equipment comprises:
Superficial X-ray machine, KVp, 5-10 mA HVL=1-8 mm Al, TSD (Target-Skin-Distance)=15-20cm, e.g. Phillips-Muller 100kV tube (Figure 8.1)
Orthovoltage X-ray machine KVp, mA, HVL=1-4 mm Cu, SSD (Source-Skin Distance) = cm
60 Cobalt machine (Figure 8.2), 1.17 MeV and 1.33 MeV photon energy; with 50% penetration at 10 cm, SAD (Source-Axis Distance) = 80 cm (Figure 8.2)
Linear accelerators, MeV, producing high energy photons or electrons (Figure 8.3).
2. Brachytherapy, in which the radiation sources (137Cs, 192Ir) are in a close contact with the target volume (interstitial or intracavitary in remote afterloading units) producing continuous irradiation or as permanent implants of short-lived radionuclides such as 125I.
3. Systemic irradiation from radioactive isotopes (131I, 32P, 89Sr) administrated intravenously, intracavitary, or via the digestive tube.

45. 3. Clinical basis of radiation therapy
Clinical types of radiation therapy include:
teletherapy (e.g., treatment from a cobalt-60 source),
external beam x-rays (from a linear accelerator), and
brachytherapy (using a source of radiation inserted or implanted into the patient).

46. Radiosensitivity of normal tissues
High sensitive: lymphocites, germ cells
Moderate sensitive: epithelial cells
Resistant: CNS, connective tissue

47. Unit of mesure, tissues tolerance
The unit for dose of radiation is gray ( GY), energy absorbed per unit mass ( joules/ kilograme).
Tolerance doses in normal tissues
Some tissue are particularly radiosensitive and doses to them must be limited in order to minimize the risk of late damage. If 2Gy/ fraction is given, then tolernce doses are:
- testis Gy
- lents of the eye 10Gy
- whole kidney Gy
- whole lung Gy
- spinal cord Gy
- brain Gy

48. Basis for prescription of radiation therapy
Evaluation of tumor extent ( staging), including radiographyc, radioisotope, and other studies.
Knowledge of pathologic characteristics of the disease.
Definitions of goal of therapy ( cure versus palliation).
Selection of appropiate treatment modalities ( irradiation alone or combined with surgery, chemotherapy, or both).
Determination of the optimal dose of irradiation and volume to be treated, according to the anatomic, location, histologic type, stage, potential regional nodal involvement, and other characteristics of the tumor, and the normal structures present in the region.
Evaluation of the patient’s general condition, periodic assessment to tolerance to treatment,tumor response, and status of the normal tissues treated.

49. Treatment planning
Suceeessful treatment planning is imperative to the success of a radiation treatment couse.
The optimal dose of irradiation depends of: the volume to be treated, the anatomic location, the histologic type of the tumor, the stage andpotential regional spread.
The dose-limiting factor usually is one or more normal structures of the region.
The goal is to identify the full extend and areas of possible spread.

50. Acute effects of radiotherapy (I)
Occur within weeks of treatment:
Skin, GI tract, bone marrow
Severity depends on total dose of radiation and lenth of time over which radiotherapy is delivered
Treatment doses selected to that complete recovery is usual
Types: nausea and vomiting, parotid sweling, hypotension, fever, diarroea ( day 5).

51. Acute radiation effects in specific tissues (II)
Skin: acute effects – erythema “sunburn” reaction starting week dequmation, ulceration
cronic- late effect: athrophy, fibrosis, teleangiectasia.
Oral mucosa: erythema starting week 2-3, painful ulceration, dry mouth ( week 4-6)
Gastrointestinal tract: acute mucositis, oesophagitis, gastric/ small bowel-5HT3 mediated nausea and vomiting.
distal small bowel/colon- diarrhoea
rectum – tenesmus, mucous discharge, bleeding.
Late effects – mucosal ulceration, fibrosis/ obstruction, necrosis.
Heart months pericarditis ( self limiting
after 2years cardiomiopathy and conduction block

52. Acute radiation effects in specific tissues(III)
Lung – acute: deterioration airways obstruction after large doses ( 8Gy)
cough, dyspnoea, reversible X-ray changes.
chronic ( 6-12 moths):irreversible lung fibrosis
Kidney – no acute response.
radiation nephropathy: proteinuria, hipertension, renal failure
CNS - no acute reaction
- 2-6 months: demiyelinisation effect:
brain-somnolence;
spinal cord –Lehrmite’s syndrome( shooting pains radiating down limbs below of injury, sometimes provoked by spinal flexion).
1-2 years, radiation necrosis ( irreversible neurological deficit).

53. CLINICAL APPLICATION OF RADIOBIOLOGIC PRINCIPLES

54. Late effects of radiotherapy
Severity depends on toal dose of radiation and dose per fraction ( small dose per fraction protects)
Recovery may be incomplete.
Exemples: pneuminitis ( dspnoea) somnolence ( 6-8 wheeks), cataracts, hormonal changes, hypothyroidism,

55. Late sequelae Brain- hearing loss, damage to ear, pituitary
gland, cataract foramtion, brain necrosis.
Lung – progresive fibrosis, dyspnea, chronic cough.
Abdomen - proctitis, sigmoiditis, rectal
stricture, colonic perforation or
obstruction.
Pelvis- contracted bladder, urinary incontinence, hematuria, cystitis, vesico-vaginal fistula, legedema, scroal edema, sterilisation.
Skin – subcutaneous fibrosis
Bone – bone necrosis.
Induction of second malignaciey.

56. GOALS OF RADIATION THERAPY
CURATIVE: the patient has a long-term survival after adequate therapy. Oncologists may be willing to risk both acute and chronic complications as a result of therapy in an attempt to eradicate the malignant disease.
In curative therapy, some side effect, even though undesirable, may be acceptable.
PALLIATIVE: there is no hope that patient will survive for extended periods; symptoms that produce disconfort or an impeding condition that impair the confort or self-sufficiency of the patient require treatment.
In palliative treatment no major side effects should be seen.

57. Palliative radiotherapy
There is no hope that the patient will survive for extended periods;
Treating symptoms that produce disconfort or an impending condition that may impair the confort or self-sufficiency of the patient require treatment.
Syptoms palliate by RT:
- pain from bone metastases
- relief of the obstruction urether, esophagus, bronchus.
- healing of surface wounds caused by tumor.

58. Steps in prescription of radiation therapy
A. Evaluation of tumor extend ( staging), including radiographic, radioisotope, nd other studies.
B. Knowledgeof the patologic characteristics of the disease
C. Definition of goal of therapy ( cure versus paliation)
D. Selection of apropiate treatment modalities ( iradiation alone or combined with surgery, chemotherapy, or both).
E. Determination of optimal dose of irradiation and the volume to be treated according to the anatomic location, histological type, stage, potential regional nodal involvement.
F. Evaluation of the patient’s general condition, periodic assessment of tolerance to treatment, tumor response, an status of the normal tissue treated.

59. Steps in planning process
Beam dosimetry
Planning computer
Target drawing
Dose planning
- beam size
- beam direction
- number of beams
- elative dose per beam ( beam weigt)
- wedging
- use of compensator
Tratament verification
Tratment prescription and deliver

60. Areas of development of radiotherapy
3D planning
Conformal treatment with multileaf colimators
Dynamic radiotherapy/ intensity modulated radiotherapy (IMRT)

61. Combintion of therapeutic modalities
Irradiation and surgery
Irradiation and chemotherapy
- concomitent chemotherapy
- adjuvant chemotherapy
- neoadjuvant
Integrating multimodality cancer management

66. Axial dose distribution for a 49-year-old man with a T2N2C squamous cell carcinoma of the left tonsillar fossa. The patient received 76.8 Gy at 1.2 Gy per fraction twice daily with three-dimensional conformal radiotherapy followed by a left neck dissection. The patient is disease free without complications 3 years after treatment.

67. Radiation therapy - summary of key points (I)
Radiotherapy is a loco-regional method to treat cancers. X-ray were discovert by W. Conrad Roengen in 1895.
Several different types of radiation are used to treat patients; most cause low liniar energy transfer ( LET).
Radiation interact with matter via several processes, o of wich the most important in clinical radiation is Compton scatter: megavoltage photons from liniar accelerator’s have a skin-sparing effect, with the maximum dose deposited at depth.
Direct and indirect damage of DNA in cells particularly double-strand breaks, is belived to be dominant form of radiation-indiced cell kill; RT causes diverse cellular responses that induce molecular mechanisms for DNA damage reapir, cell cycle arrest, and cell death.
The radiosensitivity of cells change as they progress through different stages of cell cycle; cells are most radiosensitivity in G2 and M phases. The response of cells to radiation is highly oxigen dependent an effect expresed by oxigen enhancement ratio (OER).

68. Radiation therapy - summary of key points (II)
New modalities in radiation therapy:
- brahytherapy delivers extremely high-dose radiation
- systemic targeted radionuclide therapy has been a significant advance in the treatment of hematologic malignancies and is being investigated for the treatament of solid cancers.
- intensity-modulated radiation therapy ( IMRT) uses multiple radiation beam intensities to try to improve the therapeutic ratio.
- proton therapy has radiobiologic advantages over photon therapy, and it may be used to deliver high doses of radiation to tumors in close proximity to normal structures.