Hodgkin’s Lymphoma


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Different modalities of treatment in Hodgkin Lymphoma

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Hodgkin’s Lymphoma

  1. 1. HODGKIN’S LYMPHOMA CHEMOTHERAPY RADIOTHERAPY DR ARNAB BOSE Dept. of Radiotherapy NRS Medical College, Kolkata 1
  2. 2. IntroductionHodgkin’s disease was initially described as an inflammatorydisease (hence the term “disease”), but is clearlyrecognized and treated as a malignant lymphoma (hence themore accurate term Hodgkin’s lymphoma (HL) is usedsynonymously with Hodgkin’s disease).The management of Hodgkin’s lymphoma has evolved fromextended-field radiation alone as the main therapy to acombined-modality approach withchemotherapy and radiation, or chemotherapy alone. 2
  3. 3. WHO classification (2008) 3
  4. 4. Staging 4
  5. 5. Treatment Groups in Early Stage 5
  6. 6. Adverse Prognostic FactorsThe International Prognostic Score (IPS) is based on seven factors:three clinical and four laboratory values .Patients are given a score of from 0 to 7, and disease canbe categorized as low (0–1), intermediate (2–3), or high (4–7) risk. 6
  7. 7. General guidelines forHodgkin’s Lymphoma treatment 7
  8. 8. The current standard is the result of careful clinicaltrials that demonstrated three principles:i) ABVD is the preferred chemotherapy based on both efficacy and safety,ii) combined-modality therapy (chemotherapy + radiation therapy) is superior to wide-field radiation therapy aloneiii) there is no advantage of wide-field radiation therapy over involved-field radiation therapy when given in combination with chemotherapy. 8
  9. 9. Combination Chemotherapy Regimens 9
  10. 10. 10
  11. 11. 11
  12. 12. The Milan trial was among the first and most influential indemonstrating the high cure rate of a brief course of ABVD(four cycles) combined with involved-field radiation therapyin limited-stage Hodgkin’s lymphoma.Subsequently, multiple trials have explored the questions ofhow many cycles of ABVD are needed and what radiationdose is needed to maintain these outstanding results. 12
  13. 13. Among favorable patients without risk factors, the GHSGevaluated two versus four cycles of ABVD and 20 versus30 Gy involved-field irradiation.The final results of this trial have not been published, butmultiple presentations of the data to date have shown FFPrates in excess of 95% for all four treatment arms.Thus, for the approximately 35% of limited-stage patientswith very favorable presentations, as few as two cycles ofchemotherapy combined with low-dose involved-fieldirradiation is sufficient for cure. 13
  14. 14. For patients with unfavorable, limited-stage Hodgkin’slymphoma the subjects of clinical trial inquiry have beenchemotherapy combination, number of cycles ofchemotherapy, and radiation dose.The H9U trial conducted by the EORTC-GELAdemonstrated that the less toxic ABVD regimen was aseffective as the BEACOPP regimen and that four cycles oftreatment were sufficient.Similarly, the GHSG HD11 trial has shown no differencesin outcome thus far between ABVD and BEACOPP inlimited-stage patients with risk factors. 14
  15. 15. Randomized Clinical Trials inLimited-Stage Hodgkin’s Lymphoma 15
  16. 16. Randomized Clinical Trials inLimited-Stage Hodgkin’s Lymphoma 16
  17. 17. Following the ground-breaking demonstration of cure inadvanced Hodgkin’s lymphoma with MOPP chemotherapy,a series of clinical trials was set in motion to identify thebest chemotherapy regimen in advanced disease and toevaluate the role of radiation therapy in this setting.Based on historical development and the efficacy of ABVDin the relapsed setting, early trials pitted MOPP againstABVD and the alternating MOPP/ABVD regimen. 17
  18. 18. The early CALGB study determined that ABVD-containingcombinations were superior.A second U.S. Intergroup trial comparing ABVD to thehybrid MOPP/ABV combination, concluded that thetreatments were similarly efficacious but ABVD was lesstoxic.On the basis of these trials, ABVD was widely adopted asthe standard chemotherapy for advanced Hodgkin’slymphoma with an expected cure rate of about 70%. 18
  19. 19. Stanford V is a brief, 12-week chemotherapy regimen withminimal alkylating agent and lower cumulative doses ofdoxorubicin and bleomycin that was devised to explicitlyaddress late effects of Hodgkin’s lymphoma treatment.The GHSG developed a novel chemotherapy combination,BEACOPP, which combines elements of COPP and ABVD withetoposide. The regimen was designed and tested in standardand escalated forms. 19
  20. 20. Randomized Clinical Trials inAdvanced-Stage Hodgkin’s Lymphoma 20
  21. 21. Randomized Clinical Trials inAdvanced-Stage Hodgkin’s Lymphoma 21
  22. 22. Secondary Therapy of Classical H LFortunately, fewer patients with Hodgkin’s lymphomacurrently progress after primary treatment. Those withadvanced disease and a high IPS are at greatest risk.High-Dose Chemotherapy with either theCBV (cyclophosphamide, carmustine, etoposide) orBEAM (carmustine, etoposide, cytarabine, melphalan)regimen followed by Autologous Stem Cell Transplantationhas been the most successful approach . 22
  23. 23. To achieve maximal cytoreduction before transplantationthe approach is to treat progressive and relapsing patientswith secondary chemotherapy,most commonly theDHAP (cisplatin, high-dose cytarabine, dexamethasone), orICE (ifosfamide, carboplatin, etoposide) regimen.Recently a new regimen,IGEV (ifosfamide, gemcitabine,etoposide, vinorelbine),has demonstrated excellent tolerability and efficacy in thesecond-line setting. 23
  24. 24. Complications of ChemotherapySterility was a major adverse effect of the MOPP regimen.ABVD does not seem to cause more than temporarycessation of menses in women and temporary oligospermiain men.In contrast, BEACOPP chemotherapy routinely sterilizesmales and many young females. Semen preservation musttake place before chemotherapy. 24
  25. 25. Early reports implicated the alkylating agents in MOPPchemotherapy in an increased risk of secondary acutemyelocytic leukemia (AML) and myelodysplasia.ABVD chemotherapy does not seem to increase the risk ofsecondary AML above baseline.BEACOPP chemotherapy was accompanied by an increasedrisk of secondary AML. In this case, etoposide was alsoimplicated. 25
  26. 26. Lung cancer is emerging as a leading cause of death inHodgkin’s lymphoma patients. Relative risks increase withcumulative dose of alkylating agents and with increasingdoses of radiation.The risk after chemotherapy is immediate, whereas there isa latency of about 5 years after radiation therapy.Importantly, the relative risk increases 20-fold withtobacco use, indicating that smoking cessation is absolutelyimperative among Hodgkin’s lymphoma survivors. 26
  27. 27. Pulmonary toxicity related to bleomycin has beenrecognized to be both idiosyncratic and related tocumulative exposure.Bone toxicity in the form of osteoporosis may accompanyprednisone use, particularly in the setting of gonadalfailure. Osteonecrosis is an uncommon complication thatoccurs in the hips or shoulders in individuals exposed tohigh cumulative doses of prednisone, particularly with theaddition of high-dose radiation therapy. 27
  28. 28. LYMPH NODAL REGIONS Lymph Nodal Groups 28
  29. 29. Radiotherapy Fields 29
  30. 30. Radiotherapy Fields 30
  31. 31. Fields for I F R T 31
  32. 32. Unilateral Cervical/Supraclavicular RegionArms position: Akimbo or at sidesUpper Border: 1 to 2 cm above the lower tip of the mastoid process and midpoint through the chin.Lower Border: 2 cm below the bottom of the clavicle.Lateral Border: To include the medial two-thirds of the clavicle. 32
  33. 33. Medial Border: (a) If the SCL nodes are not involved, theborder is placed at the ipsilateral transverse processesexcept when medial nodes close to the vertebral bodies areseen on the initial staging neck CT scan. For medial nodesthe entire vertebral body is included. (b) When the SCL nodes are involved, theborder should be placed at the contralateral transverseprocesses 33
  34. 34. Blocks: A posterior cervical cord block is required only ifcord dose exceeds 40 Gy. Mid-neck calculations should be performed todetermine the maximum cord dose, especiallywhen the central axis is in the mediastinum. A laryngeal block should be used unless lymph nodeswere present in that location. In that case the block shouldbe added at 20 Gy. 34
  35. 35. Bilateral Cervical/Supraclavicular RegionBoth cervical and SCL regions shouldbe treated as described in thepreceding slide regardless of theextent of disease on each side.Posterior cervical cord and larynxblocks should be used. 35
  36. 36. MediastinumArms position: Akimbo or at sides. The arms-up position is optional if the axillary nodes are involved.Upper Border: C5-6 interspace. If SCL nodes are also involved, the upper border should be placed at the top of the larynx. 36
  37. 37. Lower Border: The lower of: (a) 5 cm below the carina or (b) 2 cm below the pre-chemotherapy inferior border.Lateral Border: The post-chemotherapy volume with 1.5 cm margin.Hilar Area: To be included with 1 cm margin unless initially involved, in which case the margin should be 1.5 cm. 37
  38. 38. Axillary RegionArms position: Arms akimbo or arms up.Upper Border: C5-6 interspace.Lower Border: The lower of the two: (a) the tip of the scapula or (b) 2 cm below the lowest axillary node.Medial Border: Ipsilateral cervical transverse process. Include the vertebral bodies only if the SCL are involved.Lateral Border: Flash axilla. 38
  39. 39. 39
  40. 40. Abdomen (Para-Aortic Nodes)Upper Border: Top of T11 and at least 2 cm above pre-chemotherapy volume.Lower Border: Bottom of L4 and at least 2 cm below pre-chemotherapy volume.Lateral Borders: The edge of the transverse processes and at least 2 cm from the post-chemotherapy volume. 40
  41. 41. Inguinal/Femoral/External Iliac RegionUpper Border: Middle of the sacroiliac joint.Lower Border: 5 cm below the lesser trochanter.Lateral Border: The greater trochanter and 2 cm lateral to initially involved nodes. 41
  42. 42. Medial Border: Medial border of the obturator foramen with at least 2 cm medial to involved nodes. If common iliac nodes are involved the field should extend to the L4-5 interspace and at least 2 cm above the initially involved nodal border. 42
  43. 43. 43
  44. 44. Mantle:bilateral cervical,SCV, infraclavicular,mediastinal, hilar,and axillaMini-mantle:mantle withoutmediastinum, hilaModified mantle:mantle without axilla mini mantle modified mantle 44
  45. 45. Mantle Field
  46. 46. Simulate with Arms - up (to pull axillary LN from chest to allow for more lung blocking) or Arms akimbo (to shield humeral heads and minimize tissue in SCV folds) Head extended this ensures the exclusion of the oral cavity andteeth from the RT fields, and decreases the dose to themandible 46
  47. 47. Borders: Lateral = beyond humeral heads; Inferior = bottom of diaphragm (T11/12); Superior = inferior mandibleBlocks: Larynx on AP field Humeral heads on AP and PA fields PA cord block (if dose >40 Gy) Lung block at top of fourth rib to cover IC LN If pericardial or mediastinal extension, include entire heart to 15 Gy, then block apex of heart. After 30 Gy, block heart beyond 5 cm inferior to carina (unless residual disease) 47
  48. 48. Inverted Y Field
  49. 49. STLITLI 49
  50. 50. Dose of RadiotherapyCombined Modality RT DoseNon-bulky disease (stage I-II) 20*-30 Gy (if treated with ABVD) 30Gy (if treated with Stanford V)Non-bulky disease (stage IB-IIB) andBulky and Non-bulky disease (stage III-IV) 30-36 Gy if treated with BEACOPP*A dose of 20Gy following ABVD x 2 is sufficient if the patient has non bulky stage I-IIA disease with ESR <50, no extra lymphatic lesions, and only one or two lymph node regions involved 50
  51. 51. Bulky disease sites (all stages) 30-36 Gy (if treated with ABVD) 36Gy (if treated with Stanford V)RT Alone Doses (uncommon except for NLPHL)Involved regions 30-36GyUninvolved regions 25-30Gy 51
  52. 52. Side Effects of RadiotherapySide effects of RT depend on the irradiated volume, the dose administered, and the technique employed.They are also influenced by the extent and type of priorchemotherapy, if any, andby the patients age. 52
  53. 53. Most of the information that we use today to estimate riskof RT is derived from strategies that used radiation alone.The sizes of the fields and configuration, doses andtechnology have all drastically changed over the lastdecade.It is therefore probably misleading to judgecurrent RT for lymphomas and inform patients solely on thebasis of different past practice of using RT in treatinglymphomas. 53
  54. 54. Acute EffectsRadiation, in general, may cause fatigue and areas of theirradiated skin may develop mild sun-exposure likedermatitis.The acute side effects of irradiating the full neck includemouth dryness, change in taste, and pharyngitis. These sideeffects are usually mild and transient.The main potential side effects of sub-diaphragmaticirradiation are loss of appetite, nausea, and increased bowelmovements. These reactions are usually mild and can beminimized with standard antiemetic medications. 54
  55. 55. Irradiation of more than one field, particularly afterchemotherapy, can cause myelosuppression, which may necessitate short treatment interruption andvery rarely the administration of granulocyte-colonystimulating factor (G-CSF). 55
  56. 56. Early Side EffectsLhermittes sign: <5% of patients may note an electricshock sensation radiating down the backs of both legs whenthe head is flexed (Lhermittes sign) 6 weeks to 3 monthsafter mantle-field RT. Possibly secondary to transientdemyelinization of the spinal cord, Lhermittes signresolves spontaneously after a few months and is notassociated with late or permanent spinal cord damage. 56
  57. 57. Pneumonitis and pericarditis: During the same period,radiation pneumonitis and/or acute pericarditis mayoccur in <5% of patients; these side effects occur moreoften in those who have extensive mediastinal disease. Both inflammatory processes havebecome rare with modern radiation techniques. 57
  58. 58. Late Side EffectsSubclinical Hypothyroidism: Irradiation of the neck and/orupper mediastinal can induce subclinical hypothyroidism inapproximately one-third of patients. This condition is detected by the elevation ofthe thyroid-stimulating hormone (TSH). Thyroidreplacement with levothyroxine (T4) is recommended, evenin asymptomatic patients, to prevent overt hypothyroidismand decrease the risk of benign thyroid nodules. 58
  59. 59. Infertility: Only irradiation of the pelvic field may havedeleterious effects on fertility. In most patients, this problem can be avoidedby appropriate gonadal shielding. In women, the ovaries can be moved into ashielded area laterally or inferomedially near the uterinecervix. Irradiation outside of the pelvis does notincrease the risk of sterility. 59
  60. 60. Secondary Malignancies: Patients with HD who were curedwith RT and/or chemotherapy, have an increased risk ofsecondary solid tumors (most commonly, lung, breast, andstomach cancers, as well as melanoma) and NHL, 10 or moreyears after treatment. Unlike MOPP and similar chemotherapycombinations, RT for HD is not leukemogenic. 60
  61. 61. Lung Cancer: Patients who are smokers should be stronglyencouraged to quit the habit because the increase in lungcancer that occurs after irradiation or chemotherapy hasbeen detected mostly in smokers.Effects on Bone and Muscle Growth: In children, high-doseirradiation will affect bone and muscle growth and mayresult in deformities. Current treatment programs forpediatric HD are chemotherapy based; RT is limited to lowdoses. 61
  62. 62. Coronary Artery Disease: An increased risk of coronaryartery disease has been reported among patientswho have received mediastinal irradiation. To reduce this hazard, patients should bemonitored and advised about other established coronarydisease risk factors, such as smoking, hyperlipidemia,hypertension, and poor dietary and exercise habits. 62
  63. 63. Breast Cancer as a long term sequelae of Radiotherapy in HLFor women whose HL was successfully treated at a youngage, the main long-term concern is the increased risk ofbreast cancer.The increase in risk of breast cancer is inversely related tothe patients age at HL treatment; no increased risk hasbeen found in women irradiated after 30 years of age.It is also related to the radiation dose to the breast andthe volume of breast tissue exposed. 63
  64. 64. Most breast exposure in the mantle era resulted from theradiation of the axillae, and to a lesser extent from widemediastinal and hilar irradiation.During the last decade, reduction in field size has been themost important change in radiation therapy of HD.Reduction in the volume of exposed breast tissue togetherwith dose reduction (from over 40 Gy to a dose in the rangeof 20-30 Gy) is likely to dramatically change the long-termrisk profile of young male and female patients cured of HD. 64
  65. 65. thank you 65