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Hodgkins Lymphoma
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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. Introduction Hodgkin’s disease was initially described as an inflammatory disease (hence the term “disease”), but is clearly recognized and treated as a malignant lymphoma (hence the more accurate term Hodgkin’s lymphoma (HL) is used synonymously with Hodgkin’s disease). The management of Hodgkin’s lymphoma has evolved from extended-field radiation alone as the main therapy to a combined-modality approach with chemotherapy 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 Factors The 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 can be categorized as low (0–1), intermediate (2–3), or high (4–7) risk. 6
  7. 7. General guidelines for Hodgkin’s Lymphoma treatment 7
  8. 8. The current standard is the result of careful clinical trials 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 alone iii) 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 in demonstrating the high cure rate of a brief course of ABVD (four cycles) combined with involved-field radiation therapy in limited-stage Hodgkin’s lymphoma. Subsequently, multiple trials have explored the questions of how many cycles of ABVD are needed and what radiation dose is needed to maintain these outstanding results. 12
  13. 13. Among favorable patients without risk factors, the GHSG evaluated two versus four cycles of ABVD and 20 versus 30 Gy involved-field irradiation. The final results of this trial have not been published, but multiple presentations of the data to date have shown FFP rates in excess of 95% for all four treatment arms. Thus, for the approximately 35% of limited-stage patients with very favorable presentations, as few as two cycles of chemotherapy combined with low-dose involved-field irradiation is sufficient for cure. 13
  14. 14. For patients with unfavorable, limited-stage Hodgkin’s lymphoma the subjects of clinical trial inquiry have been chemotherapy combination, number of cycles of chemotherapy, and radiation dose. The H9U trial conducted by the EORTC-GELA demonstrated that the less toxic ABVD regimen was as effective as the BEACOPP regimen and that four cycles of treatment were sufficient. Similarly, the GHSG HD11 trial has shown no differences in outcome thus far between ABVD and BEACOPP in limited-stage patients with risk factors. 14
  15. 15. Randomized Clinical Trials in Limited-Stage Hodgkin’s Lymphoma 15
  16. 16. Randomized Clinical Trials in Limited-Stage Hodgkin’s Lymphoma 16
  17. 17. Following the ground-breaking demonstration of cure in advanced Hodgkin’s lymphoma with MOPP chemotherapy, a series of clinical trials was set in motion to identify the best chemotherapy regimen in advanced disease and to evaluate the role of radiation therapy in this setting. Based on historical development and the efficacy of ABVD in the relapsed setting, early trials pitted MOPP against ABVD and the alternating MOPP/ABVD regimen. 17
  18. 18. The early CALGB study determined that ABVD-containing combinations were superior. A second U.S. Intergroup trial comparing ABVD to the hybrid MOPP/ABV combination, concluded that the treatments were similarly efficacious but ABVD was less toxic. On the basis of these trials, ABVD was widely adopted as the standard chemotherapy for advanced Hodgkin’s lymphoma with an expected cure rate of about 70%. 18
  19. 19. Stanford V is a brief, 12-week chemotherapy regimen with minimal alkylating agent and lower cumulative doses of doxorubicin and bleomycin that was devised to explicitly address late effects of Hodgkin’s lymphoma treatment. The GHSG developed a novel chemotherapy combination, BEACOPP, which combines elements of COPP and ABVD with etoposide. The regimen was designed and tested in standard and escalated forms. 19
  20. 20. Randomized Clinical Trials in Advanced-Stage Hodgkin’s Lymphoma 20
  21. 21. Randomized Clinical Trials in Advanced-Stage Hodgkin’s Lymphoma 21
  22. 22. Secondary Therapy of Classical H L Fortunately, fewer patients with Hodgkin’s lymphoma currently progress after primary treatment. Those with advanced disease and a high IPS are at greatest risk. High-Dose Chemotherapy with either the CBV (cyclophosphamide, carmustine, etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) regimen followed by Autologous Stem Cell Transplantation has been the most successful approach . 22
  23. 23. To achieve maximal cytoreduction before transplantation the approach is to treat progressive and relapsing patients with secondary chemotherapy, most commonly the DHAP (cisplatin, high-dose cytarabine, dexamethasone), or ICE (ifosfamide, carboplatin, etoposide) regimen. Recently a new regimen, IGEV (ifosfamide, gemcitabine,etoposide, vinorelbine), has demonstrated excellent tolerability and efficacy in the second-line setting. 23
  24. 24. Complications of Chemotherapy Sterility was a major adverse effect of the MOPP regimen. ABVD does not seem to cause more than temporary cessation of menses in women and temporary oligospermia in men. In contrast, BEACOPP chemotherapy routinely sterilizes males and many young females. Semen preservation must take place before chemotherapy. 24
  25. 25. Early reports implicated the alkylating agents in MOPP chemotherapy in an increased risk of secondary acute myelocytic leukemia (AML) and myelodysplasia. ABVD chemotherapy does not seem to increase the risk of secondary AML above baseline. BEACOPP chemotherapy was accompanied by an increased risk of secondary AML. In this case, etoposide was also implicated. 25
  26. 26. Lung cancer is emerging as a leading cause of death in Hodgkin’s lymphoma patients. Relative risks increase with cumulative dose of alkylating agents and with increasing doses of radiation. The risk after chemotherapy is immediate, whereas there is a latency of about 5 years after radiation therapy. Importantly, the relative risk increases 20-fold with tobacco use, indicating that smoking cessation is absolutely imperative among Hodgkin’s lymphoma survivors. 26
  27. 27. Pulmonary toxicity related to bleomycin has been recognized to be both idiosyncratic and related to cumulative exposure. Bone toxicity in the form of osteoporosis may accompany prednisone use, particularly in the setting of gonadal failure. Osteonecrosis is an uncommon complication that occurs in the hips or shoulders in individuals exposed to high cumulative doses of prednisone, particularly with the addition 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 Region Arms position: Akimbo or at sides Upper 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, the border is placed at the ipsilateral transverse processes except when medial nodes close to the vertebral bodies are seen on the initial staging neck CT scan. For medial nodes the entire vertebral body is included. (b) When the SCL nodes are involved, the border should be placed at the contralateral transverse processes 33
  34. 34. Blocks: A posterior cervical cord block is required only if cord dose exceeds 40 Gy. Mid-neck calculations should be performed to determine the maximum cord dose, especially when the central axis is in the mediastinum. A laryngeal block should be used unless lymph nodes were present in that location. In that case the block should be added at 20 Gy. 34
  35. 35. Bilateral Cervical/Supraclavicular Region Both cervical and SCL regions should be treated as described in the preceding slide regardless of the extent of disease on each side. Posterior cervical cord and larynx blocks should be used. 35
  36. 36. Mediastinum Arms 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 Region Arms 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 Region Upper 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 axilla Mini-mantle: mantle without mediastinum, hila Modified 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 and teeth from the RT fields, and decreases the dose to the mandible 46
  47. 47. Borders: Lateral = beyond humeral heads; Inferior = bottom of diaphragm (T11/12); Superior = inferior mandible Blocks: 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. STLI TLI 49
  50. 50. Dose of Radiotherapy Combined Modality RT Dose Non-bulky disease (stage I-II) 20*-30 Gy (if treated with ABVD) 30Gy (if treated with Stanford V) Non-bulky disease (stage IB-IIB) and Bulky 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 30-36Gy Uninvolved regions 25-30Gy 51
  52. 52. Side Effects of Radiotherapy Side 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 prior chemotherapy, if any, and by the patient's age. 52
  53. 53. Most of the information that we use today to estimate risk of RT is derived from strategies that used radiation alone. The sizes of the fields and configuration, doses and technology have all drastically changed over the last decade. It is therefore probably misleading to judge current RT for lymphomas and inform patients solely on the basis of different past practice of using RT in treating lymphomas. 53
  54. 54. Acute Effects Radiation, in general, may cause fatigue and areas of the irradiated skin may develop mild sun-exposure like dermatitis. The acute side effects of irradiating the full neck include mouth dryness, change in taste, and pharyngitis. These side effects are usually mild and transient. The main potential side effects of sub-diaphragmatic irradiation are loss of appetite, nausea, and increased bowel movements. These reactions are usually mild and can be minimized with standard antiemetic medications. 54
  55. 55. Irradiation of more than one field, particularly after chemotherapy, can cause myelosuppression, which may necessitate short treatment interruption and very rarely the administration of granulocyte-colony stimulating factor (G-CSF). 55
  56. 56. Early Side Effects Lhermitte's sign: <5% of patients may note an electric shock sensation radiating down the backs of both legs when the head is flexed (Lhermitte's sign) 6 weeks to 3 months after mantle-field RT. Possibly secondary to transient demyelinization of the spinal cord, Lhermitte's sign resolves spontaneously after a few months and is not associated with late or permanent spinal cord damage. 56
  57. 57. Pneumonitis and pericarditis: During the same period, radiation pneumonitis and/or acute pericarditis may occur in <5% of patients; these side effects occur more often in those who have extensive mediastinal disease. Both inflammatory processes have become rare with modern radiation techniques. 57
  58. 58. Late Side Effects Subclinical Hypothyroidism: Irradiation of the neck and/or upper mediastinal can induce subclinical hypothyroidism in approximately one-third of patients. This condition is detected by the elevation of the thyroid-stimulating hormone (TSH). Thyroid replacement with levothyroxine (T4) is recommended, even in asymptomatic patients, to prevent overt hypothyroidism and decrease the risk of benign thyroid nodules. 58
  59. 59. Infertility: Only irradiation of the pelvic field may have deleterious effects on fertility. In most patients, this problem can be avoided by appropriate gonadal shielding. In women, the ovaries can be moved into a shielded area laterally or inferomedially near the uterine cervix. Irradiation outside of the pelvis does not increase the risk of sterility. 59
  60. 60. Secondary Malignancies: Patients with HD who were cured with RT and/or chemotherapy, have an increased risk of secondary solid tumors (most commonly, lung, breast, and stomach cancers, as well as melanoma) and NHL, 10 or more years after treatment. Unlike MOPP and similar chemotherapy combinations, RT for HD is not leukemogenic. 60
  61. 61. Lung Cancer: Patients who are smokers should be strongly encouraged to quit the habit because the increase in lung cancer that occurs after irradiation or chemotherapy has been detected mostly in smokers. Effects on Bone and Muscle Growth: In children, high-dose irradiation will affect bone and muscle growth and may result in deformities. Current treatment programs for pediatric HD are chemotherapy based; RT is limited to low doses. 61
  62. 62. Coronary Artery Disease: An increased risk of coronary artery disease has been reported among patients who have received mediastinal irradiation. To reduce this hazard, patients should be monitored and advised about other established coronary disease 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 HL For women whose HL was successfully treated at a young age, the main long-term concern is the increased risk of breast cancer. The increase in risk of breast cancer is inversely related to the patient's age at HL treatment; no increased risk has been found in women irradiated after 30 years of age. It is also related to the radiation dose to the breast and the volume of breast tissue exposed. 63
  64. 64. Most breast exposure in the mantle era resulted from the radiation of the axillae, and to a lesser extent from wide mediastinal and hilar irradiation. During the last decade, reduction in field size has been the most important change in radiation therapy of HD. Reduction in the volume of exposed breast tissue together with dose reduction (from over 40 Gy to a dose in the range of 20-30 Gy) is likely to dramatically change the long-term risk profile of young male and female patients cured of HD. 64
  65. 65. thank you 65

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