power point presentation of Clinical evaluation of strabismus
Hodgkin’s Lymphoma
1. HODGKIN’S LYMPHOMA
CHEMOTHERAPY
RADIOTHERAPY
DR ARNAB BOSE
Dept. of Radiotherapy
NRS Medical College, Kolkata
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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
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.
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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.
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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. 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. 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
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.
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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%.
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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.
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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 .
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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)
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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
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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
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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