Principles of chemoradiations

The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies.

1. PRINCIPLES OF CHEMORADIATIONS Dr. Abani Kanta Nanda 2 nd year PG Student Dept. of Radiatherapy AH Regional Cancer Centre

2. Introduction Despite advances and refinements in cancer treatment and an emphasis toward early detection, the vast majority of human malignancies are not effectively treated. Knowledge of the complex nature of human cancer is increasing exponentially as modern molecular biology and genetics reveal potential targets to combat and perhaps some day prevent this dreadful disease. Yet, there is still a need to fully develop and optimize combined-modality cancer treatment to help patients who will not have the opportunity to benefit from the molecular biology revolution.

3. The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies. Local control of the primary tumor mass (which can often be achieved by high-dose radiation), combined with systemic chemotherapy to control metastatic disease, should provide effective means to combat such a highly complex disease. Moreover, the finding that many chemotherapy drugs enhance the effects of radiation provides even more impetus to integrate both modalities.

4. History In 1950 investigators began searching for chemical agents that might enhance the effects of radiation. In 1958 Heidelberger et al obtained “ potentiation of activity” by combining fluorouracil with radiation in a preclinical study in which they treated transplanted murine tumors with fluorouracil 20 mg/kg/day for 7 days and radiation doses of either 15 or 20 Gy . In 1970 s the results obtained with chemoradiotherapy at the Mayo Clinic on gastrointestinal cancers. In 1970 Nigro and colleagues used a combination of fluorouracil and mitomycin concurrent with radiation as neoadjuvant treatment in patients with cancer of the anal canal.

5. Biologic Considerations Therapeutic benefit requires differential properties on tumor and normal tissues. These include genetic instability of tumors compared with normal tissues differences in cell proliferation (particularly cell repopulation during fractionated radiation therapy) environmental factors such as hypoxia and acidity(which usually are confined to tumors).

6. Biological basis of Chemo-radiation Chemotherapy drugs reduces number of tumor cells by their cytotoxic activity. Renders tumor cells more susceptible to radiation therapy – Radio sensitization effect. By virtue of systemic activity of chemotherapy drugs, may act on distant metastasis. Chemo-radiation enhances radiation response which gives better control of local disease Enhancement Example Synergism 2+1=4 Additive 2+1=3 Subadditive 2+1=2.5 Interference 2+1=1.5 Antagonism 2+1=05 Nature of Radiation Enhancement

7. Chemotherapy may be given Neo-adjuvant/Induction CT Concurrent/Concomitant Adjuvant Used concurrently Advantage: Neither modality delayed Shorter treatment time Radiation enhancement Disadvantage: risk of increased toxicity Biological basis of Chemo-radiation

8. Goals in Combining CT with RT Increase patient survival by: Improving local-regional tumour control Decreasing or eliminating distant metastases Preserving organ or tissue integrity and function To have independent toxicity. To enhance tumour radio response.

9. Therapeutic Index or Therapeutic Ratio Is the ratio of the probability of tumor control to the probability of normal tissue toxicity. Typically, the ratio is calculated based on the 50% control rate of tumor tissue versus the 50% rate of normal tissue toxicity. These sigmoid-shaped curves determine estimated efficacy versus toxicity of treatment. The therapeutic index takes careful treatment planning to achieve maximal tumor cell destruction also spare normal tissue in hopes of preserving function. “The greater the separation of these two curves, the greater the therapeutic index.”

10. Four Strategies to improve Therapeutic Index Steel and Peckham classified into four groups: - A)Spatial cooperation B)Independent toxicity C)Enhancement of tumor response D)Protection of normal tissues

11. A) Spatial cooperation On the other hand, chemotherapeutic drugs are likely to be more effective in eliminating disseminated micrometastases Action of RT and CT drugs directed towards different anatomical sites No interaction between the two modalities Independent action of the two agents Eg - Localized tumors would be the domain of radiation therapy because large doses of radiation can be given. RT CT

12. B) Independent toxicity Combinations of radiation and drugs would be better tolerated if drugs were selected such that toxicities do not overlap with, or minimally add to, radiation-induced toxicities. Two modalities can both be given at full dose.

13. C) Enhancement of tumor response Interaction between drugs and radiation at the molecular, cellular, or pathophysiologic (micro-environmental, metabolic) level, resulting in an antitumor effect greater than would be expected on the basis of additive actions.

14. D) Protection of normal tissues This can be achieved through Technical improvements in radiation delivery. Administration of chemical or biologic agents that selectively or preferentially protect normal tissues against the damage by radiation or drugs. Amifostine (WR-2721) has been used in several clinical trials and has recently been used in a chemoradiation setting. Another new class of radioprotective agents, the nitroxides , are currently being studied preclinically .

15. Cyclophosphamide , Cyt Arab ., Chlorambucil , Methotrexate are effective radioprotective agents. Cyt Arab in morrow do not modify stem cell radiosensitivity Stimulate enhanced repopulation by surviving stem cells

16. Ideal Radio Sensitiser Acts selectively in tumors as opposed to normal tissues. “Gets” to tumor in adequate concentration to elicit radiation modification. Makes a radiation more effective to tumor by: Increasing radiation induced damage Increasing cytotoxic pathways(apoptosis) Inhibiting radiation repair Altering cell-cycle distribution to a radiosensitive phase Knowledge of appropriate timing of drug delivery and radiation treatment for maximal enhancement. Preferentially noncytotoxic ; however, if cytotoxic , exibits antitumor activity alone(primary and metastatic).

17. Ideal Radiation Protector Acts selectively in normal tissues as opposed to tumor . “Gets” to normal tissues in adequate concentration to elicit radiation modification. Is nontoxic. Makes a radiation dose less effective to normal tissues by: Decreasing radiation induced damage Scavenging free radicals Chemically repairing radicals induced by radiation Enhancing enzymatic radiation repair pathways Knowledge of appropriate timing of drug delivery and radiation treatment for maximal protection.

18. Mechanistic Considerations in Drug–Radiation Interactions Increasing Initial Radiation Damage Inhibition of Cellular Repair Cell Cycle Redistribution Counteracting Hypoxia-Associated Tumor Radioresistance Inhibition of Tumor Cell Repopulation Other Potential Interactions

19. 1.Increasing Initial Radiation Damage Radiation induces many different lesions in the DNA molecule, which is the critical target for radiation damage which causes cell death. The lesions consist of single-strand breaks (SSBs) double-strand breaks (DSBs) PRINCIPAL DAMAGE base damage DNA–DNA and DNA–protein cross-links etc.

20. So drugs that make DNA more susceptible radiation damage can be used concorently with Radiation . Eg .- halogenated pyrimidines { Iododeoxyuridine ( IdUrd ) in large unresectable sarcoma}

21. 2.Inhibition of Cellular Repair There are two types of repair after DNA get damaged SLDR ( sublethal damage repair)-increase in cell survival when the radiation dose is split into two fractions of radiation separated by a time interval. This time between two radiation fractions allows radiation-induced DSBs in DNA to rejoin and repair. PLDR (potentially lethal damage repair)-increase in cell survival as the result of post irradiation environmental conditions, which prevent cells from dividing for several hours. Preventing cells from division allows the completion of repair of DNA lesions that would have been lethal had DNA undergone replication within several hours after irradiation

22. Hence, drugs that interact with cellular repair mechanisms and inhibit repair can be used in CTRT, that may enhance cell or tissue response to radiation. Eg - halogenated pyrimidines Nucleoside analogs , such as gemcitabine

23. 3.Cell Cycle Redistribution Cells in the G2 and M cell cycle phases were approximately three times more sensitive to Radiation than cells in the S phase. The drugs that can block transition of cells through mitosis, with the result that cells accumulate in the radiosensitive G2 and M phases of the cell cycle Eg - Taxanes Elimination of the radioresistant S-phase cells by the chemotherapeutic agents. Eg - Nucleoside analogs , such as fludarabine or gemcitabine

24. 4.Counteracting Hypoxia-Associated Tumor Radioresistance Hypoxic cells are 2.5 to 3 times more resistant to radiation than well-oxygenated cells Hypoxic cell radiosensitiser - Destruction of tumor cells in well oxygenated areas leads to an increased oxygen supply to hypoxic regions, and hence reoxygenates hypoxic tumor cells. Massive loss of cells after chemotherapy lowers the interstitial pressure, which then allows the reopening of previously closed capillaries and the reestablishment of blood supply. It also causes tumor shrinkage so that previously hypoxic areas are closer to capillaries and thus accessible to oxygen. By eliminating oxygenated cells, more oxygen becomes available to cells that survived chemotherapy.

25. Eg - Taxanes Bioreductive drugs- these drugs accumulate in acidic environment, that is due to anaerobic metabolism in the hypoxic cells, lead to cell killing Eg - Tirapazamine

26. 5.Inhibition of Tumor Cell Repopulation The cell loss after each fraction of radiation during radiation therapy induces compensatory cell regeneration (repopulation). This increased rate of treatment induced cell proliferation is commonly termed “ accelerated repopulation”. Chemotherapeutic drugs, because of their cytotoxic or cytostatic activity, can reduce the rate of proliferation when given concurrently with radiation therapy, and hence increase the effectiveness of the treatment

27. 6.Other Potential Interactions Molecular Signaling Path ways:- Eg - Cetuximab , a EGFR inhibitor Targeting the Tumor Microenvironment:- Eg - Antiangiogenic agents Targeting cancer stem cells

28. Analyzing Drug-Radiation Interactions Clonogenic survival assay:- Measures all forms of cell death as well as prolonged or irreversible cell cycle arrest. Is the most encompassing method of measuring radiation cytotoxicity in vitro. Survival curves are generated by plating known quantities of cells, treating them with various doses of radiation and/or drug, and plotting the surviving fraction of colonies formed in a semilogarithmic fashion.

29. Modification in radiosensitization , therefore, is demonstrated in clonogenic survival curve data in which Dose of Radiation Surviving Fraction a downward or leftward shift implies a radiosensitizing interaction. an upward or rightward shift implies a radioprotective interaction

30. B) Steel and Peckham method:- Describes the construction of an “envelope of additivity ” for evaluating the interaction of two treatments using isobologram analysis. This envelope of additivity is constructed from cytotoxicity data by calculating a mode 1 curve that assumes that both agents have completely independent mechanisms of action as well as a mode 2 curve that assumes that the two agents have exactly the same mechanism of action

31. When combination therapy data points are plotted on the isobologram , they may fall between mode 1 and mode 2 (additive interaction; within the envelope) above mode 1 (infra-additive interaction) below mode 2 (supra-additive, or synergistic interaction). Graph of an isobologram for examining the interaction of radiation (RT) and a drug. Isoeffective doses of A (RT) and B (Drug) are indicated on the axes Mode 1 Mode 2

32. Enhancement Ratios Sensitizer enhancement ratio (SER):- Magnitude of the sensitizing effect of a drug for a given effect is given by the sensitizer enhancement ratio (SER): Radiation dose without sensitizer Radiation dose with sensitizer TheDose Modification Factor(DMF):- of a drug, is defined as the dose of radiation required to produce an effect without and with a drug If DMF = 1  No drug effect < 1 Protection > 1 Enhancement SER= DMF= Dose(radiation) Dose(Radiation + drug)

33. Drugs for Chemo-radiation Platinum based drugs: a) Cisplatin b) Carboplatin Antimicrotubules : a) Paclitaxel b) Docetaxel Antimetabolites : a)5 – Flurouracil b) Methotrexate c) Gemcitabine d) Capecitabine e) Pemetrexed Topoisomerase I inhibitors: a) Irinotecan b) Topotecan Alkylating agents a) Temozolamide Other a) Mitomycin b) Tirapazamine

34. Cell cycle specific anticancer drugs G2 phase- Bleomycin Etoposide Teniposide M phase- Vinorelbine Vincristin Vinblastin Paclitaxel Docetaxel G1 phase- Steroids Asparaginase S phase- Antimetabolites Methotrexaate Flurouracil Cytarabine Fludarabine Cladribine Gemcitabine

35. Cell cycle nonspecific anticancer drugs Alkylating agents Chlorambucil Cyclophosphamide Busulfan Ifosfamide Mephelan Thiotepa Anthracycline antibiotics Doxorubicin Daunorubicin Idarubicin Other antibiotics Dactinomycin Mitomycin Mitoxantron Nitrosourea Carmustin Lomustin streptozocin Mislaneous Alkylator like agents Altretamine Caroplatin Cisplatin Dacarbazine Procarbazine

36. Mechanism of anticancer drugs Cisplatin , Carboplatin . Oxaliplatin - Cell cycle–nonspecific agent. Reacts with two different sites on DNA to produce cross-links (Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine) Inhibition of DNA synthesis and transcription. Cetuximab - Recombinant chimeric IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). Inhibition of critical mitogenic and anti-apoptotic signals involved in proliferation, growth, invasion/metastasis, angiogenesis.

37. 5 Flurouracil - Cell cycle–specific with activity in the S-phase. Inhibition of the target enzyme thymidylate synthase by the 5-FU metabolite, FdUMP which then gets misincorporated into DNA in the form of dUTP → inhibition of DNA synthesis and function. Paclitaxel , Docetaxel - Cell cycle–specific ( mitosis (M) phase ). High-affinity binding to microtubules enhances tubulin polymerization. Dynamic process of microtubule is inhibited → inhibition of mitosis and cell division.

38. Temozolamide - Nonclassic alkylating agent Cell cycle–nonspecific agent. Metabolic activation to the reactive compound MTIC is required for antitumor activity. Methylates guanine residues in DNA and inhibits DNA, RNA, and protein synthesis. Mitomycin C- Antitumor antibiotic Alkylating agent to cross-link DNA → inhibition of DNA synthesis and function. Bioreductive activation by NADPH cytochrome P450 reductase , and DT- diaphorase to oxygen free radical forms → inhibit DNA synthesis and function. Preferential activation in hypoxic tumor cells

39. Methotrexate - Cell cycle–specific antifolate analog ( S-phase) . Inhibition of dihydrofolate reductase (DHFR) resulting in depletion of critical reduced folates . Inhibition of de novo thymidylate synthesis and purine synthesis. Bevacizumab - Recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Binds to all isoforms of VEGF-α Inhibits formation of new blood vessels in primary tumor and metastatic tumors.

40. Vinorelbine , Vinblastin – Cell cycle–specific with activity in mitosis (M) phase. Inhibits tubulin polymerization, disrupting formation of microtubule assembly Capecitabine – Antimetabolite Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU). Capecitabine itself is inactive.

41. Indications for Chemo-radiation Head & Neck cancer Lung cancer-SCLC & NSCLC Carcinoma Cervix Carcinoma urinary bladder Carcinoma Anal Canal Carcinoma Esophagus Carcinoma Rectum Glioblastoma Multiforme Sarcoma

42. Over view of disease entities and indications in which concomitant Chemoradiotherapy is used:- Disease entities Indication and treatment Commonly used agents benefit Head and Neck cancer LAHNC- primary and adjuvant treatment Cisplatin , 5-FU, FHX (5-FU, Hydroxyurea , Radiation), Cetuximab Improved organ preservation and survival compared with radiation alone Non Small Cell Lung Cancer Stage IIIB, non-operable non-metastatic disease Cisplatin , Cisplatin / Etoposide , carboplatin / Paclitaxel , Curative approach in poor surgical candidate or IIIB disease Small Cell Lung Cancer Limited stage disease Cisplatin / Etoposide Curative in 20% patients Esophageal Cancer Locally advanced disease Cisplatin /5-FU Survival benefit, Increase cure rate, Organ preservation Upper Aerodigestive track cancer:-

43. continued:- Disease entities Indication and treatment Commonly used agents benefit Rectal cancer Neoadjuvant 5-FU Improved sphincter preservation, Decrease in local and distal failure Anal cancer Mainstay of curative treatment 5-FU, Mitomycin C Improved organ preservation Gastric cancer Adjuvant Cisplatin , 5-FU Some data indicate survival benefit Pancreatic cancer Adjuvant, Unresectable locoregionally advanced cancer 5-FU Improved locoregional control, Possibly a survival benefit cholangiocarcinoma Adjuvant, Unresectable locoregionally advanced cancer 5-FU Some data indicate survival benefit Gastrointestinal malignancies:-

44. Continued:- Disease entities Indication and treatment Commonly used agents benefit Cervical cancer Primary modality Cisplatin , 5-FU, Hydroxyurea Improved local and distal control, Organ preservation Bladder cancer Primary modality Cisplatin Improved local control Disease entities Indication and treatment Commonly used agents benefit Glioblastoma Adjuvant Temozolamide Survival benefit Sarcoma Neoadjuvant Doxorubicin Downstaging , Improved organ preservation Gynecological and genito -urinary cancers:- Other cancers:-

45. Head and Neck cancer:- Chemoradiotherapy versus radiotherapy in patients with locally advanced nasopharyngeal cancer : phase III randomized 147 patients Concurrent chemo- Rt : Cisplatin (100mg/m²) on day 1, 22, 43 {3 weekly} in + RT (70Gy/35#) followed by Adjuvant chemotherapy: Cisplatin (80mg/m²) on day1 and 5FU(1gm/m²)on day1-4 {3 weekly} 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemo- Rt group was 76% (P < .001) 5year overal survival-37 vs 67% INTERGROUP STUDY 0099

46. EORTC -22931 & RTOG-9501 for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers ( oral cavity, oropharynx , larynx or hypopharynx ). Both studies compared the addition of concomitant relatively high doses of cisplatin 100mg/m² on d₁(on days 1, 22, and 43) { 3weekly } to radiotherapy vs radiotherapy alone . Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CCRT was significant in both trials. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors.

47. EORTC RTOG MARGIN + ECE 2 POSITIVE NODES STAGE III-IV PNI+ LVSI+ LEVEL 4 or 5 in OC,OP ELEGIBILITY CRITERIA

48. Study by Chan et al. In the Intergroup 0099 trial- Only 63% completed all three cycles of concurrent chemotherapy Only 55% were able to receive all three courses of adjuvant therapy. As a result, weekly CDDP has been adopted by many institutions, especially for patients with poor nutritional status. In a phase III trial comparing CRT versus RT alone in 350 patients with locally advanced disease, Chan et al . Demonstrated good efficacy and tolerability for a regimen consisting of weekly CDDP (40 mg/m2). 70% of patients in the CRT arm received at least four cycles of CDDP, and CRT was associated with a statistically significant survival benefit after adjusting for age and disease stage.

49. GORTEC 94-01 trial 226 patient Phase III multicenter, randomized trial comparing radiotherapy alone Arm A- 70 Gy in 35 fractions Arm B- concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil). The 5-year overall survival rate- 22% in Arm B and 16% in Arm A (p = 0.05). The 5-year locoregional control rate- 48% in Arm B and 25% in Arm A (p = 0.002). 

50. Clinical Trials in ca cervix

51. NCI Clinical alert February 23, 1999 “based on significant improvement in both progression free survival and overall survival when cisplatin -based chemotherapy was given concurrently with radiotherapy” Strong consideration should be given to the incorporation of concurrent cisplatin based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.”

52. Clinical Trials in Anal canal

53. Clinical Trials in Esophagus

54. summary CCRT increases patient survival by: Improving local-regional tumour control Decreasing or eliminating distant metastases Preserving organ or tissue integrity and function To have independent toxicity. To enhance tumour radio response Amifostin is the only radioprotector clinically proved to use with radiotherapy. A number of cell cycle specific and nonspecific chemotherapeutic drugs are there, whose mechanism of action should be well understood, so that there timing of administration with radiation could be determined to give maximum result.

55. Thank you