RADIOTHERAPY AND CHEMOTHERAPY :RADIOTHERAPY AND CHEMOTHERAPY David Ponton Mercedes Gonzalez Beatriz Pelaez


OBJECTIVES :OBJECTIVES Explain what combined modality therapy is List the exploitable mechanism in combined therapy Define and explain therapeutic gain Explain the use of molecular targeting to enhance radiation response Discuss problems in the efficiency of combined modality trials List statistics involving combined modality treatment for head and neck cancer, lung cancer, gastrointestinal cancer and breast cancer Illustrate how a Gammaknife system works Describe how the cyberknife system works Compare the gammaknife and cyberknife systems


CHEMOTHERAPY :CHEMOTHERAPY Chemotherapy, refers to treatment of disease by chemicals that kill cells, specifically those of micro-organisms or cancer.


RADIOTHERAPY :RADIOTHERAPY Radiotherapy is the use of exact, carefully measured doses of radiation to treat disease


COMBINED THERAPY :COMBINED THERAPY All classes of chemotherapeutic agents have been used in combined modality involving one or more drugs plus radiotherapy The main aim is an improvement in local control and/or eradication of metastases Illustration showing herceptin antibody, which inhibits DNA repair


THERAPEUTIC GAIN :THERAPEUTIC GAIN In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone Any increase in toxicity from the combination should be taken into account


EXPLOITABLE MECHANISMS IN COMBINED RADIOTHERAPY AND CHEMOTHERAPY :EXPLOITABLE MECHANISMS IN COMBINED RADIOTHERAPY AND CHEMOTHERAPY Interactive: one modalities modifying the response of the other. Non-interactive: each modality exerting its own independent effect Enhancement of response: When the radiation dose-response curve is increase by the addition of chemotherapy Inhibition: When the radiation dose-response curve is decrease by the addition of chemotherapy Protection: Where the combination give less effect than radiation alone


SPATIAL CO-OPERATION :SPATIAL CO-OPERATION The use of radiotherapy and chemotherapy to target disease in different anatomical sites. The commonest situation is where radiation is used to treat the primary tumor and chemotherapy is added to deal with systematic spread


INDEPENDENT CELL KILL :INDEPENDENT CELL KILL If two modalities can both be given at full dose, then the tumor response (total cell kill) should be greater than that achieve with either agent alone The radiotherapy and chemotherapy should have no-overlapping toxicities The chemotherapy should not enhance normal- tissue damage within the radiation field


DEBULKING :DEBULKING This concept involves the use of several cycles of chemotherapy Smaller tumour will be easy to cure by radiotherapy The disadvantage of debulking schedules is that they involve a delay in starting radiotherapy


ENHANCED TUMOR RESPONSE :ENHANCED TUMOR RESPONSE There are several mechanisms, by which radiotherapy and chemotherapy may interact either: Directly: to give an alteration in the shape of the cell survival curve Indirectly: by killing subpopulations resistant to the other modality Several commonly used chemotherapy agents have been shown to inhibit the repair of radiation damage. cisplatin, bleomycin, adriamycin, and hydroxyurea. these drugs, like radiation, produce DNA damage which is manifest as DNA breaks


SEQUENSING OF CHEMOTHERAPY AND RADIOTHERAPY IN RELATION TO NORMAL-TISSUE TOXICITY :SEQUENSING OF CHEMOTHERAPY AND RADIOTHERAPY IN RELATION TO NORMAL-TISSUE TOXICITY Normal tissue damage after combined modality treatment is strongly influenced by the sequence and timing of the modalities Many commonly used drugs cause substantial increase in normal tissue radiation injury when the modalities are given in close sequence but not when they are separated in time


Words to be Familiar with :Words to be Familiar with Angiogenesis--the growth of new blood vessels from pre-existing blood vessels Adjuvant therapy - refers to additional treatment, usually given after surgery where all detectable disease has been removed Neoadjuvant therapy - given before the main treatment to reduce the size of the tumor so as to facilitate more effective surgery. ErbB-1 – (epidermal growth factor receptor) protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. COX: Cyclo-oxygenase, protein that acts as an enzyme to speed up the production of certain chemical messengers, called prostaglandins, within the stomach. Chemotherapy drugs used to treat various types of cancers: 5-FU (Fluorouracil) Cisplatin MMC (Mitomycin C) Carboplatin Etoposide


Molecular Targeting for Enhanced Radiation Response :Molecular Targeting for Enhanced Radiation Response A new development in cancer therapy is the increased understanding of cellular growth factors and signaling pathways for control of cell proliferation, differentiation, and angiogenesis The above mentioned pathways are activated in tumors or in inflammatory tissues but not in healthy or normal tissues – this offers potential for drug targeting


Epidermal Growth Factor Receptor :Epidermal Growth Factor Receptor Over-expression of ErbB correlates with an aggressive and radioresistant phenotype EGRF blocking antibodies have been developed that inhibit tumor proliferation and angiogenesis, which promotes apoptosis in cells over-expressing the receptor Antibodies blocking this receptor leads to growth arrest and radiosensitization in over-expressing cells


Molecular Targeting :Molecular Targeting COX enzymes are needed for synthesis of prostaglandins, which are implicated in the initiation and growth of tumors: COX-1 enzyme is expressed in all tissues. COX-2 is inducible and expressed in inflammatory and tumor tissue Inhibitors of COX-2 have been developed that are effective in preventing the growth of colonic polyps in patients COX-2 inhibitors also cause a marked increased in radiosensitivity of murine tumors, without any changes in radiosensitivity in healthy intestine


Perspecta Dome :Perspecta Dome Consists of a 20-inch dome that easily plugs into a PC to display full color and full motion MRI, x-ray, CT and nuclear medicine images in true 3D space


Problems In Efficiency of Combined Modality Trials :Problems In Efficiency of Combined Modality Trials There have been comparisons made between the outcome of combined modality treatments with retrospective trials where patients were treated with radiotherapy or surgery alone However, it is difficult to evaluate the therapeutic benefits between the comparisons There have been certain factors in the comparison of treatments that can be identified as bias


Factors Identified as Bias: :Factors Identified as Bias: Patient selection – only those patients who are fit to receive the relatively toxic combined modality schedules will be entered in the trial. Stage migration – improved diagnostic and detection methods such as CT or NMR scanning help to detect smaller amounts of metastatic disease and have the effect of shifting patients into higher stage categories The duration of follow-up – usually shorter in the new studies Small numbers of patients – In order to detect an improvement in survival of 15% with 90% confidence, about 300-400


Head and Neck Cancer :Head and Neck Cancer Chemotherapy with radiotherapy gave a larger increase in survival of 12.1% compared to the 3.7% survival benefit from just chemotherapy. An analysis of over 10,000 patients demonstrated a significant 5-year overall survival benefit of 4% in favor of combined modality The combination of concurrent chemotherapy and radiotherapy was more effective than a 10% increase in radiation dose


Lung Cancer :Lung Cancer In one trial where hyperfractionated radiotheraphy was given with concurrent carboplatin and etoposide there was a 42% improvement in 4-year recurrence-free survival versus 19% with just the hyperfractionated radiotherapy Alternating chemotherapy-radiotherapy schedules have produced some of the best results ever reported for this disease, with a 3-year survival of 26% -- some high incidents of severe toxicity have been reported in more recent studies


Gastrointestinal Cancer :Gastrointestinal Cancer Results of locally advanced oesophageal cancer, which demonstrated a large benefit for treatment with 5-FU, cisplatin and radiotheraphy versus a higher dose of radiotheraphy alone (27% versus 0% 5-year survival) Two trials for anal cancer demonstrated significant improvement in local control and colostomy-free survival for concurrent chemotherapy and radiotherapy versus radiotherapy alone


Breast Cancer :Breast Cancer Post-mastectomy radiotherapy reduces the risk of local recurrence from about 30% to 10% A study of over 1,700 patients demonstrated that radiotherapy combined with postoperative chemotherapy further reduces loco-regional recurrence, which indicates an improved 10-year survival by 54%


Breast Cancer :Breast Cancer Adjuvant hormone therapy gives a significant increase in long-term survival, with a 25% reduction in the death hazard ratio The best results were women who received both adjuvant chemotherapy and hormone therapy, with a 35% reduction in the death hazard ratio


Cancer of the Cervix :Cancer of the Cervix Study in 1999 shows significant survival advantage for concurrent chemo and radiotherapy with 30-50% reduction in risk of death compared to radiotherapy alone Concomitant chemo and radiotherapy is now standard for bulky cervical cancer


Bladder Cancer :Bladder Cancer Survival rates for locally advanced bladder cancer are poor Standard treatment is cystectomy with or without radiotherapy Newer studies done in 1999 In Testing Photodynamic therapy (PDT) is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells.


Future Perspectives :Future Perspectives There are currently over 6000 clinical studies being done on the use of chemotherapy and radiotherapy on different areas of the body Conjugation of cytotoxic drugs to tumor seeking carriers Antibodies are being developed which can block the signaling pathways involved in tumor cell proliferation, differentiation, and angiogenesis Cytostatic chemotherapy is also being researched in conjunction with radiotherapy


Radiotherapy the “old way” :Radiotherapy the “old way”


Gamma Knifehead only :Gamma Knifehead only


Gamma Knife :Gamma Knife Able to focus radiation directly, and very precisely, on the target in the brain without affecting surrounding healthy tissue No incision or blood, and minimal risk of complications Use of 3D computer-aided planning guide the dose to the target


Gamma Knife :Gamma Knife Up to 201 sources of cobalt-60 loaded within the unit Thousands of radiation beams can be generated from these sources with a level of accuracy of more than 0.3mm So accurate, the full dose of radiation can be delivered during a single session


Leksell Gamma Knife :Leksell Gamma Knife


Procedure :Procedure 4 stages of gamma knife surgery Attaching the frame Imaging Treatment planning Treatment


Cyber knife system :Cyber knife system


Components of the Cyber Knife System :Components of the Cyber Knife System RoboCouch Patient Positioning System–Robotically aligns patients precisely with 6 degrees of freedom, reducing patient setup times and enabling faster treatments X-ray Sources–The low-energy X-ray sources generate orthogonal diagnostic X-ray images to determine the location of bony landmarks, implanted fiducials or soft tissue targets throughout the entire treatment. Image Detectors–The flush mounted detectors capture high-resolution anatomical images throughout the treatment. These live images are continually compared to previously captured DRR’s to determine real-time patient positioning and target location Robotic Manipulator–The high precision robotic manipulator capable of delivering repeatable sub-millimeter accuracy, positions the linear accelerator in almost any direction Linear Accelerator–This compact, light weight 6MV X-band linear accelerator precisely delivers highly collimated beams of radiation MultiPlan Treatment Planning System–intuitive workflow-based workstation designed for radiosurgery, enables the creation of plans that have excellent conformality and coverage with steep dose gradients.


Capabilities :Capabilities Synchrony® Respiratory Tracking System–Continuously synchronizes beam delivery to the motion of the tumor, allowing clinicians to significantly reduce margins while eliminating the need for gating or breath-holding techniques. Xsight™ Spine Tracking System–Eliminates the need for surgical implantation of fiducials by using the bony anatomy of the spine to automatically locate and track tumors, making radiosurgery less invasive along the spinal column. Xsight™ Lung Tracking System–Tracks the movement of lung tumors directly, without fiducials, with precision, reliability and self-adjusting repeatability. Xchange™ Robotic Collimator Changer–Automatically exchanges collimators robotically, maintaining highly conformal treatments delivered more efficiently. 4D Treatment Optimization and Planning System–Takes into account not only the movement of the target but also the movement and deformation of the surrounding tissue.


Cyber knife advantages :Cyber knife advantages Treats tumors anywhere in the body Continuously tracks, detects and corrects for tumor and patient movement throughout the treatment Delivers treatments with sub-millimeter accuracy, minimizing damage to surrounding healthy tissue Utilizes the skeletal structure of the body as a reference, eliminating the need for bone fiducials or invasive frames typically used with traditional radiosurgery systems An option for inoperable or surgically complex tumors Successfully treats patients in single or multiple fractions Provides linac maneuverability and access and coverage for any tumor volume Boasts a patient-centric design providing a relaxed treatment experience Enables superior flexibility in treatment planning: forward or inverse treatment planning isocentric or non-isocentric treatment plans simultaneous treatment of multiple tumors Allows for the flexible scheduling of treatments Attracts a new patient population to a physician's practice


Ultimate Showdown :Ultimate Showdown Gamma Knife 201 source cobalt unit designed exclusively for non-invasive brain surgery Radiologic accuracy better than 0.3mm Rigid immobilization to prevent head movement using a lightweight stereotactic head frame fixed to the outer skull. Provides exact MR and CT correlation from planning to treatment delivery in 3D. Treatment delivered during one session Target position is confirmed 10 times per second CyberKnife Single source linear accelerator with robotic arm to compensate for patient movement during treatment 1 mm accuracy; dose outside the target area is 2-6x greater than with GK Non-rigid immobilization reduces head movement by using a face mask that is shrink-wrapped to the table The CK is inherently less accurate since the positioning is optically guided, not head-frame based. Provides relative MR and CT correlation from planning to treatment delivery in 3D. Single or multiple treatments, possibly over a period of days Target position confirmed once every 10 seconds


Proton therapy :Proton therapy Due to their relatively enormous mass, protons scatter less easily in the tissue and there is very little lateral dispersion All protons of a given energy have a certain range; no proton penetrates beyond that distance The dosage to tissue is maximum just over the last few millimeters of the particle’s range; this maximum is called the Bragg Peak. This depth depends on the energy to which the particles were accelerated by the proton accelerator, which can be adjusted to the maximum rating of the accelerator It is therefore possible to focus the cell damage due to the proton beam at the very depth in the tissues where the tumor is situated: tissues situated before the Bragg peak receive some reduced dose tissues situated after the peak receive none


Proton therapy :Proton therapy Interesting for its ability to accurately target and kill tumors, both near the surface and deep seated within the body, while minimizing damage to the surrounding tissue Favored for treating certain kinds of tumors where conventional X-ray radiotherapy would damage surrounding radio-sensitive tissues to an unacceptable level(pediatric patients, choroidal malignant melanomas) Proton therapy, however, needs heavy equipment - weighing into the hundreds of tons(cyclotron)


Summary :Summary Combined modality therapy uses all classes of chemotherapeutic agents combined involving one or more drugs plus radiotherapy The main aim is an improvement in local control and/or eradication of metastases In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone The first step in identifying exploitable mechanisms for combined modality therapy is to define whether the modalities are: Interactive: one modalities modifying the response of the other. Non-interactive: each modality exerting its own independent effect


Summary :Summary The increased understanding of cellular growth factors and signaling pathways for control of cell proliferation, differentiation, and angiogenesis offers potential for drug targeting It is difficult to evaluate the therapeutic benefits between the comparisons, because there are certain factors in the comparison of treatments that can be identified as bias The use of chemotherapy along with radiotherapy improves the survival rate for those who suffer from head and neck caner, lung cancer, gastrointestinal cancer, and breast cancer. The old style of therapy works, but it isn’t the best The Gamma Knife is only for radiotherapy to the head and has cobalt sources The Cyber Knife is for anywhere on the body and uses a linear accelerator The Gamma Knife is more accurate than the Cyber Knife Proton therapy is even less damaging than the Cyber Knife or the Gamma Knife


QUESTIONS :QUESTIONS In combined therapy only one kind of chemotherapeutic agent is used in combined modality involving only one drug plus radiotherapy When is a therapeutic gain achieved? Interactive modality is when each modality is exerting its own independent effect Smaller tumors will be easy to cure by radiotherapy, why? Chemotherapy may also influence the radiation response indirectly? Many commonly used drugs cause substantial increase in normal tissue radiation injury? 7. What is angiogenesis? The growth of new blood vessels from pre-existing blood vessel 8. Why is it important to have an increased understanding of cellular growth factors and signaling pathways for control of cell proliferation, differentiation, and angiogenesis? Those pathways are activated in tumors or inflammatory tissue which offers the potential for drug targeting the tumors 9. Antibodies blocking the EGRF, leads to growth arrest and ____________ in over expressing tumor cells. a. radioresistance b. radiosensitization c. apoptosis 10. True or False It is quite simple to evaluate the comparison between combined modality treatments and treatments of just radiotherapy or surgery alone.


Slide 55:11. List two factor that are bias in the evaluation of therapeutic benefits in the comparison between treatments. patient selection - duration of follow up stage migration - small number of patients 12. Alternating chemotherapy – radiotherapy schedules have produced some of the best results ever reported for those who suffer from lung cancer. 13. Post-mastectomy radiotherapy reduces the risk of local recurrence from about 30% to _____. 10% 14. Combining radiotherapy with chemotherapy does nothing for cervical cancer? T/F 15. The gamma knife is designed for radiotherapy to the _______? 16. List three differences between the gamma knife and the cyber knife 17. List these in the order of their ascending accuracy and multi-port therapy gamma knife proton therapy cyber knife


Slide 56:18. List these starting with the least amount of peripheral radiation to healthy tissue multi-port therapy gamma knife proton therapy cyber knife 19. Proton therapy is not a widely used cancer therapy, why is this? 20. Explain how proton therapy works


ANSWERS :ANSWERS False/All classes of chemotherapeutic agents have been used in combined modality clinical trials involving one or more drugs plus radiotherapy A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone False/Interactive: one modalities modifying the response of the other True/smaller tumour will be easy to cure by radiotherapy because of reduced cell number. True/indirectly by killing subpopulations resistant to the other modality True/ Many commonly used drugs cause substantial increase in normal tissue radiation injury when the modalities are given in close sequence The growth of new blood vessels from pre-existing blood vessel Those pathways are activated in tumors or inflammatory tissue which offers the potential for drug targeting the tumors B False


Slide 58:11. Patient selection, stage migration, duration of follow-up, small number of patients 12. True 13. 10% 14. T 15. Head 16. Refer to slides 17. multi-port therapy cyber knife gamma knife proton therapy 18. proton therapy gamma knife cyber knife multi-port therapy 19. needs heavy equipment - weighing into the hundreds of tons and it is expensive 20. Depth charge analogy


REFERENCES :REFERENCES Bartelink, Harry. "The Combination of radiotherapy and chemotherapy." Basic Clinical Radiobiology. Edited. G. Gordon Steel. London: Arnold, 2002. McKay, Judith, and Nancee Hirano. The Chemotherapy and Radiation Therapy Survivor's Guide, 2nd ed. Oakland, CA: New Harbinger Publications, 1998. Radiation Combined With EGFR Signal Inhibitors: Head and Neck Cancer Focus .  Seminars in Radiation Oncology , Volume 16 , Issue 1   Pages 38 - 44 P . Harari , S . Huang "Understanding Cancer." National Cancer Institute. 2008. U.S. National Institutes of Health. 17 Oct 2008 .