LOCO- REGIONALLOCO- REGIONAL CANCER TREATMENTS: CANCER TREATMENTS: SURGERY AND SURGERY AND RADIOTHERAPYRADIOTHERAPY

Assoc prof. L. MIRONAssoc prof. L. MIRON

SummarySummary Cancer treatmentCancer treatment- - classification classification Principles of surgical oncologyPrinciples of surgical oncology - historical perspective- historical perspective - roles of surgery in cancer patients- roles of surgery in cancer patients - surgery in multidisciplinary terapeutical plan- surgery in multidisciplinary terapeutical plan Principles of radiation oncologyPrinciples of radiation oncology - p- physical and chemical basis of radiation actionhysical and chemical basis of radiation action

- b- biological basis of radiationiological basis of radiation therapy therapy

- c- clinical linical practice practice of radiationof radiation therapy therapy

STEPS IN MANAGEMENT OF STEPS IN MANAGEMENT OF CANCER PATIENTSCANCER PATIENTS

I. DIAGNOSTIC PROCESSI. DIAGNOSTIC PROCESS

II. STAGING OF DISEASEII. STAGING OF DISEASE

III. PRETREATMENT III. PRETREATMENT EVALUATION - PROGNOSTIC EVALUATION - PROGNOSTIC CATHEGORYCATHEGORY

IV. TREATMENT PLANIV. TREATMENT PLAN

Types of cancer Types of cancer treatmentstreatments

I. I. Loco-regional treatmentLoco-regional treatment:: SURGERYSURGERY RADIOTHERAPYRADIOTHERAPYII. II. Systemic treatmentsSystemic treatments:: CYTOTOXIC CHEMOTHERAPYCYTOTOXIC CHEMOTHERAPY MOLECULARY TARGETED MOLECULARY TARGETED

THERAPYTHERAPY IMMUNOTHERAPYIMMUNOTHERAPY HORMONOTHERAPYHORMONOTHERAPY GENES THERAPYGENES THERAPY

PRINCIPLES OF PRINCIPLES OF CANCER CANCER SURGERYSURGERY

Surgical interventions in Surgical interventions in cancercancer

DefinitionsDefinitions

SurgerSurgery is the oldest treatment for y is the oldest treatment for cancer and, until recentcancer and, until recentllly, the only ly, the only one that one that cure cure cancer cancer patients.patients.

Surgery remains the primary Surgery remains the primary method of treatment of most solid method of treatment of most solid malignancies. malignancies.

In some cases is the only chance for In some cases is the only chance for cure for cancer patients.cure for cancer patients.

Surgery- historySurgery- history HistoricHistoricaally, surgery is the sole methods used to lly, surgery is the sole methods used to

treating cancer.treating cancer. The earliest disscussion of surgical treatment of The earliest disscussion of surgical treatment of

tumors appears in 1600B.C in Edwin Smith tumors appears in 1600B.C in Edwin Smith papyrus belived writing dating back 3000 B.C.papyrus belived writing dating back 3000 B.C.

Surgeon is the part of a multidisciplinary team.Surgeon is the part of a multidisciplinary team. Surgeon is frecquently the “entry point” for Surgeon is frecquently the “entry point” for

patients who are newly diagnosed with cancerpatients who are newly diagnosed with cancer Surgeon must have knowledge of the biology Surgeon must have knowledge of the biology

and natural historand natural historyy of the cancer to be treated. of the cancer to be treated.

Principles of Surgical OncologyPrinciples of Surgical Oncology

Determinants of Determinants of operative riskoperative risk

Roles for SurgeryRoles for Surgery Prevention of CancerPrevention of Cancer Diagnosis of CancerDiagnosis of Cancer Treatment of CancerTreatment of Cancer

CurrativeCurrative: Resection of the Primary Cancer: Resection of the Primary Cancer PalliativePalliative: Cytoreductive Surgery: Cytoreductive Surgery

Metastatic DiseaseMetastatic Disease

Oncologic EmergenciesOncologic Emergencies

PalliationPalliation

Reconstruction and RehabilitationReconstruction and Rehabilitation

1.1. Prevention of cancerPrevention of cancer Hyperplastic and dysplastic lesions need not Hyperplastic and dysplastic lesions need not

always progress to cancer, but when they do, always progress to cancer, but when they do, the process can take years, if not decades.the process can take years, if not decades.

Cancer requires several genetic alterations Cancer requires several genetic alterations during a course of somatic evolution.during a course of somatic evolution.

Cancer cells are widely believed to have a Cancer cells are widely believed to have a ““mutator phenotypemutator phenotype.”.”

Roles for surgeryRoles for surgery - prevention - prevention of cancerof cancer

Multiple endocrine neoplasiaMultiple endocrine neoplasia (MEN) tip 2-(MEN) tip 2- profilactic profilactic thyroidectomy for medullary familial cell thyroid thyroidectomy for medullary familial cell thyroid carcinoma.carcinoma.

Patients with Patients with Barett’s oesopagusBarett’s oesopagus ((with high grade with high grade dysplasia)- prophylactic oesophageal resection.dysplasia)- prophylactic oesophageal resection.

Hereditary diffuse gastricHereditary diffuse gastric cancer-there are a role for cancer-there are a role for preventive total gastrectomypreventive total gastrectomy

Ulcerative colitisUlcerative colitis – total colectomy – total colectomy Hereditary colorectal cancerHereditary colorectal cancer: familial adenomatous : familial adenomatous

polyposis coli and hereditary non-polyposis colorectal polyposis coli and hereditary non-polyposis colorectal cancer (HNPCC) accounts for 5% of all CCR cancers.cancer (HNPCC) accounts for 5% of all CCR cancers.

Breast cancer carry a Breast cancer carry a mutation BRCA1mutation BRCA1 and and BRCA2BRCA2 genes are a high risk of developing ovagenes are a high risk of developing ovarrian cancer- ian cancer- oophorectomy.oophorectomy.

Patients with Patients with maldescendent testismaldescendent testis (cryptochidism) (cryptochidism) have have a higher chance of developping testicular cancer (x 20 a higher chance of developping testicular cancer (x 20 times) - times) - orchidopexyorchidopexy

1. 1. Prophylactic surgeryProphylactic surgery

2. 2. Surgery for dSurgery for diagnosis – diagnostic iagnosis – diagnostic procedures: acquisition of matprocedures: acquisition of mateerial for rial for

diagnosisdiagnosis Fine nFine needle aeedle aspiration cytology(FNA)spiration cytology(FNA)

–– involving aspirating tissue involving aspirating tissue fragments through a needle guided fragments through a needle guided into area in which disease is into area in which disease is suspected;suspected; aspiration of cell-cytology. aspiration of cell-cytology.

Core needleCore needle biopsy-biopsy- the retriveral of a the retriveral of a small core of tissue, ussing a specially small core of tissue, ussing a specially designed “ core-cutting”, the designed “ core-cutting”, the specimen is usually sufficient for specimen is usually sufficient for histologic diagnosis of most tumor histologic diagnosis of most tumor types.types. 14-gauge needles. 14-gauge needles.

33. . Surgery for dSurgery for diagnosis – diagnostic iagnosis – diagnostic procedures: acquisition of matprocedures: acquisition of mateerial for rial for

diagnosisdiagnosisOpen byopsy:Open byopsy:

Incisional biopsyIncisional biopsy – removal of small – removal of small segment segment of a larger tumor for diagnosis, a of a larger tumor for diagnosis, a wedge of wedge of tissuetissue..

Excisional bExcisional biiopsy-opsy- total total excision of the entire excision of the entire suspected tumor tissuesuspected tumor tissue with little or no with little or no marginsmargins..

Laparoscopic surgeryLaparoscopic surgery for for diagnosis and diagnosis and stagingstaging

Laparatomy, lymphadenectomyLaparatomy, lymphadenectomy, sentinel node , sentinel node biopsy (SNB).biopsy (SNB).

Principles guide the Principles guide the performance of all surgical performance of all surgical

biopsiesbiopsies Needle tracks or scars should be placed so that they can be Needle tracks or scars should be placed so that they can be

conveniently removed as part of subsecquent definitive surgical conveniently removed as part of subsecquent definitive surgical procedureprocedure..

Care should be taken to avoid contamining new tissue planes during Care should be taken to avoid contamining new tissue planes during biopsy procedure; avoid development of large hematomasbiopsy procedure; avoid development of large hematomas..

Care should be taken to avoid using instruments that may have come Care should be taken to avoid using instruments that may have come in contact with a tumor when obtaining tissue from a potentially in contact with a tumor when obtaining tissue from a potentially uncontamined area.uncontamined area.

Adequate tissue sample must be obtained to meet the needs of the Adequate tissue sample must be obtained to meet the needs of the pathologist for diagnosis of selected tumors, electron microscopy, pathologist for diagnosis of selected tumors, electron microscopy, tissue culture, or other tehniques may be necesarry.tissue culture, or other tehniques may be necesarry.

It is important to mark distinctive areas of the tumor to facilitate It is important to mark distinctive areas of the tumor to facilitate subsequent orientation of the specimen by the pathologist< he subsequent orientation of the specimen by the pathologist< he hanling of excised tissue is the surgeon’s esponsability.hanling of excised tissue is the surgeon’s esponsability.

Placemnt of radiopaque clips during byoposy and staging procedures Placemnt of radiopaque clips during byoposy and staging procedures is sometimes important to delineate areas of known tumor and guide is sometimes important to delineate areas of known tumor and guide the subsequent delivery of radiation therapy in these areas.the subsequent delivery of radiation therapy in these areas.

3.3.Surgery for stagingSurgery for staging Staging is the classification of anatomic Staging is the classification of anatomic

extent of cancer in an inndividual. Specific extent of cancer in an inndividual. Specific staging groups categorize cancers on staging groups categorize cancers on particular anatomic sites.particular anatomic sites.

Laparatomie and laparoscopic surgeryLaparatomie and laparoscopic surgery for for staging prior to definitive surgery:staging prior to definitive surgery:

- ovarian cancer- ovarian cancer -- oesophageal cancer oesophageal cancer - - gastric cancergastric cancer - pancreatic cance- pancreatic cance - liver cancer- liver cancer - prostatic cancer- prostatic cancer

3.Treatment of cancer3.Treatment of cancer

Resection of primary tumorResection of primary tumor: radical : radical versuversus conservators conservator

Curative surgeryCurative surgery Palliation surgery: cytoreductive Palliation surgery: cytoreductive

surgery - debulking surgery - debulking mmetastasectomiesetastasectomies oncologic emergenconcologic emergenciesies reconstuction and reabilitationreconstuction and reabilitation

Surgery for primary cancerSurgery for primary cancer

There are three major challenges confronting There are three major challenges confronting the surgical oncologist in the definitive the surgical oncologist in the definitive treatment of solid tumors:treatment of solid tumors:

accurate identification of patients who can accurate identification of patients who can bee cured by local treatment alonebee cured by local treatment alone;;

development and selection of local development and selection of local treatments that provide the best balance treatments that provide the best balance between local cure and the impact of between local cure and the impact of treatment morbidity on the quality of life;treatment morbidity on the quality of life;

development and application of adjuvant development and application of adjuvant treatments that can improve the control of treatments that can improve the control of local and distant invasive and metastatic local and distant invasive and metastatic disease.disease.

Primary resection- Primary resection- principles of surgical principles of surgical

resectionresection The primary goal of cancer is the complete The primary goal of cancer is the complete

extirpation of local and regional disease for extirpation of local and regional disease for local control and for decreasing the risk of local local control and for decreasing the risk of local recuurrence.recuurrence.

Removing the primary lesion with adequate Removing the primary lesion with adequate margins of normal surronding tissue to minimize margins of normal surronding tissue to minimize the risk of local recurrences.the risk of local recurrences.

Knowledge of the most common avenues of Knowledge of the most common avenues of spread of various histologic type (e.g. cancer spread of various histologic type (e.g. cancer spread mucosally, submucosally, along the spread mucosally, submucosally, along the fascial plans or along the nerves).fascial plans or along the nerves).

Knowledge about the possibilities of Knowledge about the possibilities of multidisciplinary approaches: adjuvant multidisciplinary approaches: adjuvant chemotherapy.chemotherapy.

Currative resection: obtain Currative resection: obtain adequate margins of adequate margins of

resectionresection A complete margin of normal A complete margin of normal ttissue issue

arround the primararround the primaryy lesion ( R0 status) lesion ( R0 status) FroFrozzen sections used to evaluate tissue en sections used to evaluate tissue

margins in instances of doubtmargins in instances of doubt Complete removal of involved regional Complete removal of involved regional

lymph nodeslymph nodes Resection of involved adjacent organResection of involved adjacent organ En bloc resection of biopsy tracts and En bloc resection of biopsy tracts and

tumor sinuses.tumor sinuses.

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

Risk factors for metastasis: is Risk factors for metastasis: is necessary to associate another necessary to associate another

treatments at surgery?treatments at surgery? Tumor size and regional lymph node involvement are Tumor size and regional lymph node involvement are

consistently associated with distant relapse.consistently associated with distant relapse. The involvement of regional lymph nodes is often, but The involvement of regional lymph nodes is often, but

not always, a harbinger for increased risk of distant not always, a harbinger for increased risk of distant metastasis.metastasis.

When tumor cells appear to have aggressive traits on When tumor cells appear to have aggressive traits on microscopic analysis, this often translates into microscopic analysis, this often translates into increased risk for distant disease.increased risk for distant disease. (1) Tumor grade(1) Tumor grade (2) Depth of invasion beyond normal tissue (2) Depth of invasion beyond normal tissue

compartmental boundaries.compartmental boundaries. (3) Lymphovascular invasion.(3) Lymphovascular invasion.

Radical resectionRadical resection

Surgery for palliationSurgery for palliation

Palliative therapyPalliative therapy should be considered for a patient should be considered for a patient with evidence of widespread malignancy and no hope of cure with evidence of widespread malignancy and no hope of cure by resectional therapy. by resectional therapy.

Goals of treatmentGoals of treatment: significant improvement in quality of : significant improvement in quality of life and alleviation of symptoms which allows patients to life and alleviation of symptoms which allows patients to resume as manyof their normal daily activities as possible.resume as manyof their normal daily activities as possible.

EXEMPLEEXEMPLE: : relif of intestinal obstruction, relif of intestinal obstruction, removal of tumors to control pain or hemorrage, removal of tumors to control pain or hemorrage, induction of a feeding jejunostomy to permitt adequate induction of a feeding jejunostomy to permitt adequate

nutrition.nutrition. Malignant pleural effusion- thoracostomy tube, sclerosis.Malignant pleural effusion- thoracostomy tube, sclerosis. Billiary obstruction- stent or choledochojejeunostomyBilliary obstruction- stent or choledochojejeunostomy Bowel obstruction- colostomy with mucous fistula.Bowel obstruction- colostomy with mucous fistula. Bowell obstructon- gastrojejunostomyBowell obstructon- gastrojejunostomy Esophageal obstructionEsophageal obstruction - stent, gastrostomy tube- stent, gastrostomy tube Advanced breast mastectomy- salvage mastectomy.Advanced breast mastectomy- salvage mastectomy.

Palliative surgeryPalliative surgery

- Surgery for debulking ( surgery for Surgery for debulking ( surgery for residual disease)residual disease) cytoreductive cytoreductive surgerysurgery

- Second-look proceduresSecond-look procedures- Surgery for metastatic diseaseSurgery for metastatic disease- Surgery for reconstructio and Surgery for reconstructio and

rehabilitaionrehabilitaion- Surgical management of Surgical management of

complications therapiescomplications therapies

Laparoscopic view of Laparoscopic view of carcinomatosiscarcinomatosis

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

Specialised surgical Specialised surgical proceduresprocedures

Vascular accesss:Vascular accesss:

A.A. Percutaneous cathetersPercutaneous catheters

B.B. Indwelling cuffed cathetersIndwelling cuffed catheters

C.C. Implantable infusion portsImplantable infusion ports

The placement of operating ports in the insufflated The placement of operating ports in the insufflated abdomen provides access to the abdominal cavity for abdomen provides access to the abdominal cavity for

laparoscopic surgery. The exact locations for port placement laparoscopic surgery. The exact locations for port placement vary based on the planned procedure as well as the patients' vary based on the planned procedure as well as the patients'

individual anatomic situation.individual anatomic situation.

Surgical interventions in Surgical interventions in cancer- scancer- summaryummary of key of key

pointspoints Surgeon is part of multidisciplinary team.Surgeon is part of multidisciplinary team.

Role of surgery in cancer management:Role of surgery in cancer management: - prevention of cancer ( criptorhidism)- prevention of cancer ( criptorhidism) - screening of cancer ( genetic testing)- screening of cancer ( genetic testing) - diagnosis of cancer based on a histologically confirmed diagnosis- diagnosis of cancer based on a histologically confirmed diagnosis - staging of cancer - the classification of the anatomic extent of - staging of cancer - the classification of the anatomic extent of

cancer in an individual.cancer in an individual. Surgical treatment of cancer:Surgical treatment of cancer: - surgery for primary cancer- surgery for primary cancer - surgery of metastasis- surgery of metastasis - surgery for debalking- surgery for debalking - paliative surgery- paliative surgery - reconstructive and reabilitatative surgery- reconstructive and reabilitatative surgery - vascular access- vascular access - surgery for oncologic emergencies- surgery for oncologic emergencies

Reconstruction and Reconstruction and reabilitationreabilitation

Surgery techniques are being refined that aid in the Surgery techniques are being refined that aid in the reconstruction and reabilitation of cancer patients after reconstruction and reabilitation of cancer patients after definitive treatmentdefinitive treatment

The ability to reconstruct anatomic defects can The ability to reconstruct anatomic defects can substanially improve function and cosmetic appearancesubstanially improve function and cosmetic appearance

The development of free flaps using microvascular The development of free flaps using microvascular anastomotic techniques is having a profund impact on anastomotic techniques is having a profund impact on the ability to bring resh tissue to resected or heavily the ability to bring resh tissue to resected or heavily treatet areas.treatet areas.

Lost function, especially of extremities often can be Lost function, especially of extremities often can be restored by surgical approaches. This include lysis of restored by surgical approaches. This include lysis of contracture or muscletransposition to restore muscular contracture or muscletransposition to restore muscular function that have beendamaged by previous surgery or function that have beendamaged by previous surgery or radiation therapy.radiation therapy.

PRINCIPLES OF RADIATION PRINCIPLES OF RADIATION

ONCOLOGYONCOLOGY

L. MironL. MironClinica Oncologică, Spitalul Clinic de Urgenţe “Sf. Spiridon” IaşiClinica Oncologică, Spitalul Clinic de Urgenţe “Sf. Spiridon” Iaşi

DefinitionsDefinitions

Radiation oncologyRadiation oncology is a discipline is a discipline specialised in the use of radiation for specialised in the use of radiation for therapeutic purposes.therapeutic purposes.

Radiation therapyRadiation therapy (RT) is a treatment (RT) is a treatment modality in wmodality in whhich ionizing radiation is ich ionizing radiation is used for patients with cancers and other used for patients with cancers and other diseases. diseases.

50- 60% of patients w50- 60% of patients whhith cancer receive ith cancer receive RTRT

40- 50% of 40- 50% of cancerscancers can be cured. can be cured.

Historical perspectiveHistorical perspective 1896 Discovery of X-ray1896 Discovery of X-ray 1898 Discovery of radium1898 Discovery of radium 1899 Succesfull treatment of skin cancer with X-ray1899 Succesfull treatment of skin cancer with X-ray 1915 Treatment of cervical cancer with radium 1915 Treatment of cervical cancer with radium

implantimplant 1922 Cure of laryngeal cancer with a course of X-1922 Cure of laryngeal cancer with a course of X-

rays therapyrays therapy 1928 Roengen defined as unit of radiation exposure1928 Roengen defined as unit of radiation exposure 1934 Dose fractionation principles proposed1934 Dose fractionation principles proposed 1950’s Radiactive cobalt teletherapy ( 1 MeV energy)1950’s Radiactive cobalt teletherapy ( 1 MeV energy) 1960’s Production of megavoltage X-rays by liniar 1960’s Production of megavoltage X-rays by liniar

acceleratorsaccelerators 1990’s 3-dimension radiotherapy planning1990’s 3-dimension radiotherapy planning

Radiation oncology- Radiation oncology- summarysummary

Physical and chemical basis of Physical and chemical basis of radiation actionradiation action

Biological basis of radiationBiological basis of radiation

Clinical basis of radiationClinical basis of radiation

1. 1. Physical and chemical Physical and chemical basis of radiation actionbasis of radiation action

Types of radiation used in radiation therapyTypes of radiation used in radiation therapyIONIZING RADIATIONIONIZING RADIATION could be split: could be split:

Electromagnetic radiationElectromagnetic radiation :: energy range energy range used for RT can cause the ejections or orbital used for RT can cause the ejections or orbital electrons and results in the ionization of atoms electrons and results in the ionization of atoms or molecules: or molecules:

- - fotonsfotons ( are x-rays or ( are x-rays or γγ-rays), -rays), - - αα particles particles,, ßß particles(atomic particles(atomic particles) particles)

and and - - γγ-rays-rays ( (energy wayenergy way)) CorpuscularCorpuscular: electrons, protons, neutrons, : electrons, protons, neutrons,

heavy ionsheavy ions

Electromagnetic radiationElectromagnetic radiation

Many types of radiation are used for treatment Many types of radiation are used for treatment of both benign and malignant diseases.of both benign and malignant diseases.

The most form of irradiation is external-The most form of irradiation is external-beam photons or beam photons or electronelectronss ( x- ( x-raysrays, , γγ-rays) -rays) bundles of energy.bundles of energy.

- - x-raysx-rays is used to describes radiation that is used to describes radiation that is produced by machines.is produced by machines.

- - γγ-rays-rays define radiation that is emitted define radiation that is emitted from radiatioactive isotopes (Cobalt 60from radiatioactive isotopes (Cobalt 60,, Cesiu 137,Cesiu 137, Radium Radium, Radon, Poloniu)., Radon, Poloniu).

22. Bilogical effects of . Bilogical effects of radiationradiation

Cellular kill occurs when critical targets within cell are damaged by Cellular kill occurs when critical targets within cell are damaged by radiation and the cell is unable to repair that damage.When X-rays radiation and the cell is unable to repair that damage.When X-rays pass through living tissue, energy is absorbed, resulting in ionisation pass through living tissue, energy is absorbed, resulting in ionisation of a number of molecules with generation of fast-mooving electrons of a number of molecules with generation of fast-mooving electrons and free radicals.and free radicals.

DNA is the main target for biologic effect of raditation.DNA is the main target for biologic effect of raditation. DIRECTDIRECT: DNA damage can be : DNA damage can be directdirect: single strand breaks, double : single strand breaks, double

strand breaks, and sugar damage, DNA-DNA and DNA-protein links.strand breaks, and sugar damage, DNA-DNA and DNA-protein links. INDIRECTINDIRECT: : DNA dam age- water molecules surronding the DNA are DNA dam age- water molecules surronding the DNA are

ionized by the radiation. The ionizing of water creates hidroxil ionized by the radiation. The ionizing of water creates hidroxil radicals, hidrogen peroxide, hydated electrons and other oyigen free radicals, hidrogen peroxide, hydated electrons and other oyigen free radicals capable of interacting with DNA andcausing damage. ( 80% radicals capable of interacting with DNA andcausing damage. ( 80% of cell is composedof water, suggesting that indirect damage of DNA of cell is composedof water, suggesting that indirect damage of DNA is common).is common).

Chromosome aberations results from faculty DNA double- strand Chromosome aberations results from faculty DNA double- strand break.break.

The major mecThe major mechhanism of DNA damage is liniar transfer of energyanism of DNA damage is liniar transfer of energy (LET) – low LET (LET) – low LET - - fotons fotons ( ( xx--rayray), ), γγ-rys and electrons are termed low -rys and electrons are termed low liner energy transferliner energy transfer

LET high-LET high- protons and neutrons. protons and neutrons.

BIOLOGIC EFFECTS OF BIOLOGIC EFFECTS OF RADIATIONRADIATION

Factors that effect the Factors that effect the response of tumours to response of tumours to

radiationradiation Biological effect of radiotherapy relate to both Biological effect of radiotherapy relate to both

the dosethe dose of radiation and of radiation and timingtiming of delivery of of delivery of this treatment.this treatment.

It results in preferential paring of noramIt results in preferential paring of noramaal tissue l tissue damage, allowing safe delivery of hiher total damage, allowing safe delivery of hiher total doses of radiation with increased cancer cell kill.doses of radiation with increased cancer cell kill.

DNA repairDNA repair – non homologous recombination – non homologous recombination - homologous recombination- homologous recombination Tumor oxigenation-Tumor oxigenation- role of hipoxia in role of hipoxia in

radiotherapyradiotherapy

Strategies to increase tumor oxigenation- Strategies to increase tumor oxigenation- erytropoieins erytropoieins

4 R4 Roleole of fractionation of fractionation radiobiologyradiobiology

FractionationFractionation is the division of a total dose of external beam is the division of a total dose of external beam radiotherapy into a small, often once daily doses.radiotherapy into a small, often once daily doses.

ReoxygenationReoxygenation- the damage of tissues by radiation depends - the damage of tissues by radiation depends largely on the formation of OH- radicals.largely on the formation of OH- radicals.

Repopulation Repopulation – the normal tissue cells repopulate more adequtley – the normal tissue cells repopulate more adequtley than the malignant cells during treatment course.than the malignant cells during treatment course.

RepairRepair – repair machinery within cells can reverse partial damage – repair machinery within cells can reverse partial damage caused by a small fraction of the radiation dose by caused by a small fraction of the radiation dose by sublethal sublethal damage ( SLD) repairdamage ( SLD) repair..

Redistribution Redistribution –cells exhibits differential sensitivities toward –cells exhibits differential sensitivities toward radiation at different phases of cell cycle. Cells are more resistant radiation at different phases of cell cycle. Cells are more resistant phase ( late S-phase), and more sensitive at the jonction G2/M 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 phase. After a an initial fraction of dose, the cells are in more resistent phase S and may survie but then progress to the resistent phase S and may survie but then progress to the sensitive phase when given the second dose.sensitive phase when given the second dose...

Tehnical modalTehnical modalyyttiieses Ionizing radiation can be delivered in three technical modalities:Ionizing radiation can be delivered in three technical modalities: 1. 1. External percutaneousExternal percutaneous beam irradiation ( beam irradiation (teletherapy) from sources teletherapy) from sources

at distance from the body: telecobaltotherapy and linear accelerators are at distance from the body: telecobaltotherapy and linear accelerators are used for fractionated radiation therapy.used for fractionated radiation therapy.

External beam radiation therapy equipment comprisesExternal beam radiation therapy equipment comprises:: Superficial X-ray machineSuperficial X-ray machine, 50-150 KVp, 5-10 mA HVL=1-8 mm Al, TSD , 50-150 KVp, 5-10 mA HVL=1-8 mm Al, TSD

(Target-Skin-Distance)=15-20cm, e.g. Phillips-Muller 100kV tube (Figure (Target-Skin-Distance)=15-20cm, e.g. Phillips-Muller 100kV tube (Figure 8.1)8.1)

Orthovoltage X-ray machineOrthovoltage X-ray machine 150-500 KVp, 10-20 mA, HVL=1-4 mm Cu, 150-500 KVp, 10-20 mA, HVL=1-4 mm Cu, SSD (Source-Skin Distance) = 40-50 cmSSD (Source-Skin Distance) = 40-50 cm

60 Cobalt60 Cobalt machine (Figure 8.2), 1.17 MeV and 1.33 MeV photon energy; 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 with 50% penetration at 10 cm, SAD (Source-Axis Distance) = 80 cm (Figure 8.2)(Figure 8.2)

Linear acceleratorsLinear accelerators, 6-8-10-12 MeV, producing high energy photons or , 6-8-10-12 MeV, producing high energy photons or electrons (Figure 8.3).electrons (Figure 8.3).

2. 2. BrachytherapyBrachytherapy,, in which the radiation sources (137Cs, 192Ir) are in a in which the radiation sources (137Cs, 192Ir) are in a close contact with the target volume (interstitial or intracavitary in close contact with the target volume (interstitial or intracavitary in remote afterloading units) producing continuous irradiation or as remote afterloading units) producing continuous irradiation or as permanent implants of short-lived radionuclides such as 125I.permanent implants of short-lived radionuclides such as 125I.

3. 3. SystemicSystemic irradiationirradiation from radioactive isotopes from radioactive isotopes (131I, 32P, 89Sr) (131I, 32P, 89Sr) administrated intravenously, intracavitary, or via the digestive tube.administrated intravenously, intracavitary, or via the digestive tube.

3. Clinical basis3. Clinical basis of radiation of radiation therapytherapy

Clinical types of radiation therapy include:Clinical types of radiation therapy include:

teletherapy (e.g., treatment from a cobalt-60 teletherapy (e.g., treatment from a cobalt-60 source), source),

external beam x-rays (from a linear accelerator), external beam x-rays (from a linear accelerator), and and

brachytherapy (using a source of radiation inserted brachytherapy (using a source of radiation inserted or implanted into the patient). or implanted into the patient).

Radiosensitivity of Radiosensitivity of normal tissuesnormal tissues

High sensitive: lymphocites, germ High sensitive: lymphocites, germ cellscells

Moderate sensitive: epithelial cellsModerate sensitive: epithelial cells

Resistant: CNS, connective tissueResistant: CNS, connective tissue

Unit of mesure, tissues Unit of mesure, tissues tolerancetolerance

The unit for dose of radiation is gray ( GY), energy The unit for dose of radiation is gray ( GY), energy absorbed per unit mass ( joules/ kilograme).absorbed per unit mass ( joules/ kilograme).

Tolerance doses in normal tissuesTolerance doses in normal tissues Some tissue are particularly radiosensitive and Some tissue are particularly radiosensitive and

doses to them must be limited in order to doses to them must be limited in order to minimize the risk of late damage. If 2Gy/ fraction minimize the risk of late damage. If 2Gy/ fraction is given, then tolernce doses are:is given, then tolernce doses are:

- testis 2 Gy- testis 2 Gy - le- lennts of the eye 10Gyts of the eye 10Gy - whole kidney 20Gy- whole kidney 20Gy - whole lung 20Gy- whole lung 20Gy - spinal cord 50 Gy- spinal cord 50 Gy - brain 60 Gy- brain 60 Gy

Basis for prescription of Basis for prescription of radiation therapyradiation therapy

Evaluation of tumor extent ( staging), including radiographyc, Evaluation of tumor extent ( staging), including radiographyc, radioisotope, and other studies.radioisotope, and other studies.

Knowledge of pathologic characteristics of the disease.Knowledge of pathologic characteristics of the disease.

Definitions of goal of therapy ( cure versus palliation).Definitions of goal of therapy ( cure versus palliation).

Selection of appropiate treatment modalities ( irradiation alone Selection of appropiate treatment modalities ( irradiation alone or combined with surgery, chemotherapy, or both).or combined with surgery, chemotherapy, or both).

Determination of the optimal dose of irradiation and volume to Determination of the optimal dose of irradiation and volume to be treated, according to the anatomic, location, histologic type, be treated, according to the anatomic, location, histologic type, stage, potential regional nodal involvement, and other stage, potential regional nodal involvement, and other characteristics of the tumor, and the normal structures present characteristics of the tumor, and the normal structures present in the region.in the region.

Evaluation of the patient’s general condition, periodic Evaluation of the patient’s general condition, periodic assessment to tolerance to treatment,tumor response, and assessment to tolerance to treatment,tumor response, and status of the normal tissues treated.status of the normal tissues treated.

Treatment planningTreatment planning

Suceeessful treatment planning is imperative to Suceeessful treatment planning is imperative to the success of a radiation treatment couse.the success of a radiation treatment couse.

The optimal dose of irradiation depends of: The optimal dose of irradiation depends of: the volume to be treated, the anatomic the volume to be treated, the anatomic location, the histologic type of the tumor, the location, the histologic type of the tumor, the stage andpotential regional spread.stage andpotential regional spread.

The dose-limiting factor usually is one or The dose-limiting factor usually is one or more normal structures of the region.more normal structures of the region.

The goal is to identify the full extend and The goal is to identify the full extend and areas of possible spread.areas of possible spread.

Acute effects of Acute effects of radiotherapy (I)radiotherapy (I)

Occur within weeks of treatment:Occur within weeks of treatment: Skin, GI tract, bone marrowSkin, GI tract, bone marrow Severity depends on total dose of Severity depends on total dose of

radiation and lenth of time over which radiation and lenth of time over which radiotherapy is deliveredradiotherapy is delivered

Treatment doses selected to that Treatment doses selected to that complete recovery is usualcomplete recovery is usual

Types: Types: nausea and vomiting, parotid nausea and vomiting, parotid sweling, hypotension, fever, diarroea ( sweling, hypotension, fever, diarroea ( day 5).day 5).

Acute radiation effects in Acute radiation effects in specific tispecific tissssuesues (II) (II)

SkinSkin:: acute effects – erythema “sunburn” reaction starting acute effects – erythema “sunburn” reaction starting week 2-3 - dequmation, ulcerationweek 2-3 - dequmation, ulceration

cronic- late effect: athrophy, fibrosis, teleangiectasia.cronic- late effect: athrophy, fibrosis, teleangiectasia. Oral mucosaOral mucosa: erythema starting week 2-3, painful : erythema starting week 2-3, painful

ulceration, dry mouth ( week 4-6)ulceration, dry mouth ( week 4-6) Gastrointestinal tractGastrointestinal tract: acute mucositis, oesophagitis, : acute mucositis, oesophagitis,

gastric/ small bowel-5HT3 mediated nausea and gastric/ small bowel-5HT3 mediated nausea and vomiting.vomiting.

distal small bowel/colon- diarrhoeadistal small bowel/colon- diarrhoea rectum – tenesmus, mucous discharge, bleeding.rectum – tenesmus, mucous discharge, bleeding. Late effects – mucosal ulceration, fibrosis/ obstruction, Late effects – mucosal ulceration, fibrosis/ obstruction,

necrosis.necrosis. Heart- Heart- 6- 24 months pericarditis ( self limiting6- 24 months pericarditis ( self limiting after 2years cardiomiopathy and conduction blockafter 2years cardiomiopathy and conduction block

Acute radiation effects in Acute radiation effects in specific tispecific tissssuesues(III)(III)

Lung Lung – acute: deterioration airways obstruction after large doses ( – acute: deterioration airways obstruction after large doses ( 8Gy)8Gy)

cough, dyspnoea, reversible X-ray changes.cough, dyspnoea, reversible X-ray changes.

chronic ( 6-12 moths):irreversible lung fibrosischronic ( 6-12 moths):irreversible lung fibrosis KidneyKidney – no acute response. – no acute response.

radiation nephropathy: proteinuria, hipertension, renal radiation nephropathy: proteinuria, hipertension, renal failurefailure

CNSCNS - no acute reaction - no acute reaction

- 2-6 mo- 2-6 monnths: demiyelinisation effect:ths: demiyelinisation effect:

brain-somnolence;brain-somnolence;

spinal cord –Lehrmite’s syndrome( shooting pains radiating spinal cord –Lehrmite’s syndrome( shooting pains radiating down limbs below of injury, sometimes provoked by spinal down limbs below of injury, sometimes provoked by spinal flexion).flexion).

1-2 years, radiation necrosis ( irreversible neurological deficit).1-2 years, radiation necrosis ( irreversible neurological deficit).

CLINICAL APPLICATION OF CLINICAL APPLICATION OF RADIOBIOLOGIC PRINCIPLESRADIOBIOLOGIC PRINCIPLES

Late efLate efffects of ects of radiotherapyradiotherapy

Severity depends on toal dose of Severity depends on toal dose of radiation and dose per fraction radiation and dose per fraction ( small dose per fraction protects)( small dose per fraction protects)

Recovery may be incomplete.Recovery may be incomplete. Exemples: pneuminitis ( dspnoea) Exemples: pneuminitis ( dspnoea)

somnolence ( 6-8 wheeks), cataracts, somnolence ( 6-8 wheeks), cataracts, hormonal changes, hypothyroidism, hormonal changes, hypothyroidism,

Late sequelaeLate sequelae BrainBrain- hearing loss, damage to ear, pituitary - hearing loss, damage to ear, pituitary gland, cataract foramtion, brain necrosis.gland, cataract foramtion, brain necrosis. LungLung – progresive fibrosis, dyspnea, chronic – progresive fibrosis, dyspnea, chronic

cough.cough. Abdomen Abdomen - proctitis, sigmoiditis, rectal - proctitis, sigmoiditis, rectal stricture, colonic perforation or stricture, colonic perforation or obstruction.obstruction. PelvisPelvis- contracted bladder, urinary incontinence, - contracted bladder, urinary incontinence,

hematuria, cystitis, vesico-vaginal fistula, hematuria, cystitis, vesico-vaginal fistula, legedema, scroal edema, sterilisation.legedema, scroal edema, sterilisation.

SkinSkin – subcutaneous fibrosis – subcutaneous fibrosis BoneBone – bone necrosis. – bone necrosis. Induction of second malignacieyInduction of second malignaciey..

GOALS OF RADIATION GOALS OF RADIATION THERAPYTHERAPY

CURATIVECURATIVE: : the patient has a long-term survival the patient has a long-term survival after adequate therapy. Oncologists may be willing after adequate therapy. Oncologists may be willing to risk both acute and chronic complications as a to risk both acute and chronic complications as a result of therapy in an attempt to eradicate the result of therapy in an attempt to eradicate the malignant disease.malignant disease.

In curative therapy, some side effect, even though In curative therapy, some side effect, even though undesirable, may be acceptable.undesirable, may be acceptable.

PALLIATIVEPALLIATIVE: : there is no hope that patient will there is no hope that patient will survive for extended periods; symptoms that survive for extended periods; symptoms that produce disconfort or an impeding condition that produce disconfort or an impeding condition that impair the confort or self-sufficiency of the patient impair the confort or self-sufficiency of the patient require treatment. require treatment.

In palliative treatment no major side effects should In palliative treatment no major side effects should be seen.be seen.

Palliative radiotherapyPalliative radiotherapy

There is no hope that the patient will survive There is no hope that the patient will survive for extended periods;for extended periods;

Treating symptoms that produce disconfort or Treating symptoms that produce disconfort or an impending condition that may impair the an impending condition that may impair the confort or self-sufficiency of the patient require confort or self-sufficiency of the patient require treatment.treatment.

Syptoms palliate by RT:Syptoms palliate by RT:

- pain from bone metastases- pain from bone metastases

- relief of the obstruction urether, esophagus, - relief of the obstruction urether, esophagus, bronchus.bronchus.

- healing of surface wounds caused by tumor.- healing of surface wounds caused by tumor.

Steps inSteps in prescription of prescription of radiation therapyradiation therapy

A. A. Evaluation of tumor extendEvaluation of tumor extend ( staging), including ( staging), including radiographic, radioisotope, nd other studies.radiographic, radioisotope, nd other studies.

B. B. Knowledgeof the patologic characteristics of the Knowledgeof the patologic characteristics of the diseasedisease

C. C. Definition of goal of therapyDefinition of goal of therapy ( cure versus paliation) ( cure versus paliation)D. D. Selection of apropiate treatment modalitiesSelection of apropiate treatment modalities ( iradiation ( iradiation

alone or combined with surgery, chemotherapy, or both).alone or combined with surgery, chemotherapy, or both).E. E. Determination of optimal dose of irradiationDetermination of optimal dose of irradiation and the and the

volume to be treated according to the anatomic location, volume to be treated according to the anatomic location, histological type, stage, potential regional nodal histological type, stage, potential regional nodal involvement.involvement.

F. F. Evaluation of the patient’s general conditionEvaluation of the patient’s general condition, periodic , periodic aassessment of tolerance to treatment, tumor response, ssessment of tolerance to treatment, tumor response, an staan stattus of the normal tissue treated.us of the normal tissue treated.

Steps in planning Steps in planning processprocess

Beam dosimetryBeam dosimetry Planning computerPlanning computer Target drawingTarget drawing Dose planningDose planning - beam size- beam size - beam direction- beam direction - number of beams- number of beams - elative dose per beam ( beam weigt)- elative dose per beam ( beam weigt) - wedging- wedging - use of compensator- use of compensator Tratament verificationTratament verification Tratment prescription and deliverTratment prescription and deliver

Areas of development of Areas of development of radiotherapyradiotherapy

3D planning3D planning Conformal treatment with multileaf Conformal treatment with multileaf

colimatorscolimators Dynamic radiotherapy/ intensity Dynamic radiotherapy/ intensity

modulated radiotherapymodulated radiotherapy (IMRT)(IMRT)

Combintion of therapeutic Combintion of therapeutic modalitiesmodalities

Irradiation and surgeryIrradiation and surgery Irradiation and chemotherapyIrradiation and chemotherapy

- concomitent chemotherapy- concomitent chemotherapy

- adjuvant chemotherapy- adjuvant chemotherapy

- neoadjuvant- neoadjuvant Integrating multimodality cancer Integrating multimodality cancer

managementmanagement

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

Radiation therapy - Radiation therapy - ssummary of key pointsummary of key points (I) (I)

Radiotherapy is a loco-regional method to treat cancers. X-ray Radiotherapy is a loco-regional method to treat cancers. X-ray were discovert by W. Conrad Roengen in 1895.were discovert by W. Conrad Roengen in 1895.

Several different types of radiation are used to treat patients; Several different types of radiation are used to treat patients; most cause low liniar energy transfer ( LET).most cause low liniar energy transfer ( LET).

Radiation interact with matter via several processes, o of wich the Radiation interact with matter via several processes, o of wich the most important in clinical radiation is Compton scatter: most important in clinical radiation is Compton scatter: megavoltage photons from liniar accelerator’s have a skin-megavoltage photons from liniar accelerator’s have a skin-sparing effect, with the maximum dose deposited at depth.sparing effect, with the maximum dose deposited at depth.

Direct and indirect damage of DNA in cells particularDirect and indirect damage of DNA in cells particularlly double-y double-strand breaks, is belived to be dominant form of radiation-indiced strand breaks, is belived to be dominant form of radiation-indiced cell kill; RT causes diverse cellular responses that induce cell kill; RT causes diverse cellular responses that induce molecular mechanisms for DNA damage reapir, cell cycle arrest, molecular mechanisms for DNA damage reapir, cell cycle arrest, and cell death.and cell death.

The The radradiosensitivity of cells change as they progress through iosensitivity of cells change as they progress through different stages of cell cycle; cells are most radiosensitivity in G2 different stages of cell cycle; cells are most radiosensitivity in G2 and M phases.and M phases. The response of cells to radiation is highly oxigen The response of cells to radiation is highly oxigen dependent an effect expresed by oxigen enhancement ratio dependent an effect expresed by oxigen enhancement ratio (OER).(OER).

Radiation therapy - Radiation therapy - ssummary of key pointsummary of key points (II) (II)

New modalities in radiation therapyNew modalities in radiation therapy:: - - brahytherapybrahytherapy delivers extremely high-dose delivers extremely high-dose

radiationradiation - - systemic targeted radionuclide therapysystemic targeted radionuclide therapy has has

been a significant advance in the treatment of been a significant advance in the treatment of hematologic malignancies and is being hematologic malignancies and is being investigated for the treatament of solid cancers.investigated for the treatament of solid cancers.

- - intensity-modulated radiation therapy ( IMRT)intensity-modulated radiation therapy ( IMRT) uses multiple radiation beam intensities to try to uses multiple radiation beam intensities to try to improve the therapeutic ratio.improve the therapeutic ratio.

- - proton therapyproton therapy has radiobiologic advantages has radiobiologic advantages over photon therapy, and it may be used to deliver over photon therapy, and it may be used to deliver high doses of radiation to tumors in close high doses of radiation to tumors in close proximity to normal structures.proximity to normal structures.