Hodgkin Lymphoma
BACKGROUND
At what age does Hodgkin disease (HD) most commonly occur?
HD has a bimodal peak with peaks at age 15–30 yrs and age ≥55 yrs.
What are 2 broad histologic categories of HD? Which is more common?
Broad histologic categories of HD:
1. Classic (more common: 95%)
2. Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL: 5%)
What are the subtypes of classic HD, and which is most common in the U.S.?
Subtypes of classic HD:
1. Nodular sclerosing (most common in the U.S.)
2. Mixed cellularity
3. Lymphocyte depleted
4. Lymphocyte rich
What are the 2 most commonly involved LN regions at the initial Dx of HD?
Most commonly involved LN regions at initial Dx of HD:
1. Cervical chains (70% of pts)
2. Mediastinum (50% of pts)
90% of patients have contiguous nodes
Pts who present with mediastinal LAD are most likely to have which subtype of HD?
Pts who present with mediastinal LAD are most likely to have nodular sclerosing HD.
In classic HD, what is the most common pathologic feature and CD15, -30, -45, and –20 staining pattern?
Classic HD is characterized by Reed-Sternberg cells in an inflammatory background. In classic HD, tumors are typically CD15+ and -30+ but CD45– and -20–.
In NLPHL, what is the common pathologic feature and CD15, -30, -45, and –20 staining pattern?
NLPHL is characterized by lymphocyte-predominant cells, called “popcorn” cells. In NLPHL, tumors are typically CD15– and -30– but CD45+ and -20+ (i.e., the reverse of classic HD).
Which HD subtype has the best prognosis?
Lymphocyte-rich HD has the best prognosis.
Which HD subtype has the worst prognosis?
Lymphocyte-depleted HD has the worst prognosis.
Which HD subtype is associated with older age or HIV+ pts?
Lymphocyte-depleted HD is associated with older age and HIV+ pts.
Pts with which subtype of HD are at greatest risk of developing a subsequent non-Hodgkin lymphoma?
Pts with NLPHL are at greatest risk of developing a subsequent non-Hodgkin lymphoma.
What are the “B Sx” of lymphoma?
B Sx include:
1. Fevers >38°C (100.4 °F)
2. >10% body weight loss in 6 mos
3. Drenching night sweats
How is bulky mediastinal Dz commonly defined?
Bulky mediastinal Dz is commonly defined as a mass greater than one third of the intrathoracic diameter at T5-6 on an upright PA film.
How is bulky Dz defined outside of the mediastinum?
Outside of the mediastinum, bulky Dz is variably defined in clinical trials, but most often is any mass >10 cm.
WORKUP/STAGING
What kind of Bx is preferred for Dx of HD and why?
Excisional Bx is preferred for the Dx of lymphomas b/c it shows LN architecture.
What imaging studies are typically ordered as part of the workup of HD?
An integrated PET/CT is commonly used in the workup imaging for HD.
What lab work is required as part of the workup of HD?
The following labs have prognostic implications: ESR, CBC, albumin, and LDH. Labs necessary for Tx planning are BUN, Cr, and a pregnancy test in women of childbearing age.
What are common indications for a BM Bx in the workup of HD?
Common indications for a staging BM Bx:
1. B Sx
2. Stages III–IV
3. Bulky Dz
4. >2 sites
5. Recurrent Dz
How is HD staged?
HD is staged using the Ann Arbor system:
Stage I: involvement of 1 LN region or localized involvement of a single extralymphatic organ or site (IE)
Stage II: involvement of ≥2 LN regions on same side of diaphragm or localized involvement of a single associated extralymphatic organ or site and its regional LN with or without involvement of other LN regions on same side of diaphragm (IIE)
Stage III: involvement of LN regions on both sides of diaphragm that may also be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE)
Stage IV: multifocal involvement of ≥1 extralymphatic organ, with or without associated LN involvement, or isolated extralymphatic organ involvement with distant nodal involvement.
Note: Pts with B Sx are designated with a B, otherwise with an A. Pts with splenic involvement are designated with an S. Patients with bulky disease are designated with an X
Involvement of which sites is considered stage IV Dz?
Per the AJCC (7th edition, 2011), pts with involvement of the BM, liver, pleura, and CSF have stage IV Dz.
Name the 14 distinct LN regions as per the Rye classification.
LN regions per the Rye classification:
1. Waldeyer ring
2. Occipital, cervical, preauricular, and supraclavicular
3. Infraclavicular
4. Axillary
5. Epitrochlear
6. Mediastinum
7. Right hilum
8. Left hilum
9. Para-aortic
10. Spleen
11. Mesenteric
12. Iliac
13. Inguinofemoral
14. Popliteal
Is involvement of the Waldeyer ring, thymus, or spleen considered extranodal?
No. Per the AJCC (7th edition, 2011), the Waldeyer ring, thymus, and spleen are not classified as extranodal sites.
What does the Waldeyer ring include?
The Waldeyer ring includes:
1. Pharyngeal tonsil (adenoids)
2. Palatine tonsil
3. Lingual tonsil (base of tongue)
What are unfavorable factors for early HD?
Risk factors used to stratify early-stage HD in clinical trials vary.
Unfavorable factors for early HD:
1. Age ≥50 yrs
2. Bulky Dz (at least one-third maximum thorax diameter by the German Hodgkin Study Group [GHSG] or >10 cm by Stanford or NCCN guidelines)
3. ≥4 sites (≥3 sites by GHSG)
4. ESR >50 if no B Sx or >30 if B Sx
5. Presence of extranodal sites
6. Mixed-cellularity or lymphocyte-depleted histology
What are unfavorable factors for advanced HD used in the International Prognostic Score (IPS)?
Unfavorable factors for advanced HD used in the IPS:
WBC ≥15 × 109 cells/L
Albumin <4 g/dL
Lymphocytes (ANC) <600 or < 8%
Stage IV
Hgb <10.5 g/dL
Age ≥45 yrs
Male
(Mnemonic: WALSH AM)
What % of pts with favorable early-stage HD have occult splenic involvement?
~30% of pts with favorable early-stage HD have occult splenic involvement. (Carde P et al., JCO 1993)
How many times are HD pts staged with PET/CT?
HD pts are typically staged with PET/CT at least twice, once as part of the workup and then again after initial chemo to assess response.
TREATMENT/PROGNOSIS
What are the 3 most common multiagent chemo regimens used for HD?
Most common chemo regimens used for HD:
1. ABVD
2. Stanford V
3. Dose-escalated BEACOPP
What agents are included in ABVD chemo for HD?
ABVD includes:
1. Adriamycin
2. Bleomycin
3. Vinblastine
4. Dacarbazine
What agents are included in the Stanford V regimen for HD?
There are 7 drugs in the Stanford V (MOPE-ABV):
1. Mechlorethamine
2. Oncovin (vincristine)
3. Prednisone
4. Etoposide
5. Adriamycin
6. Bleomycin
7. Vinblastine
The Stanford V regimen has reduced doses of mechlorethamine, Adr, and bleomycin compared with ABVD. Although ABVD is sometimes used without consolidation RT, the Stanford V regimen requires consolidation RT.
What agents are included in BEACOPP?
BEACOPP includes:
1. Bleomycin
2. Etoposide
3. Adriamycin
4. Cyclophosphamide
5. Oncovin (vincristine)
6. Procarbazine
7. Prednisone
Escalated-dose BEACOPP is typically used for advanced-stage HD with poor prognostic factors. It is more commonly used in Europe than in the U.S.
What is the common Tx strategy for stages I–II classic HD?
Chemotherapy followed by consolidation RT. Patients with favorable risk disease are generally treated with ABVD × 2 cycles followed by 20 Gy IFRT according to the HD10 study. Patients with unfavorable risk disease are generally treated with ABVD × 4 cycles followed by 30 Gy involved-field radiation therapy (IFRT) according to the HD11 study. Areas of residual disease are boosted to 30–36 Gy.
What are common Tx strategies for stages III–IV classic HD?
Common Tx strategies for stages III–IV classic HD:
1. ABVD × 6–8 cycles +/– IFRT to initial bulky Dz and/or residual PET+ sites at restaging
2. Stanford V + IFRT to initial bulky Dz and residual PET+ sites
3. Escalated-dose BEACOPP + IFRT to initial bulky Dz and residual PET+ sites
What is the Tx paradigm for stages I–II NLPHL?
Stages I–II NLPHL Tx paradigm: Tx is similar to Tx for a low-grade non-Hodgkin lymphoma. Stages I–II NLPHL can be treated with RT alone (regional-involved node radiotherapy is not appropriate if treated with RT alone) or chemo + IFRT (if B Sx are present).
What is the Tx paradigm for stages III–IV NLPHL?
Stages III–IV NLPHL Tx paradigm: observation, palliation (with chemo or RT), or definitive Tx with chemo +/- RT. If CD 20+, R-CHOP can be used as the chemotherapy regimen.
What are the commonly used RT doses in HD after initial chemo?
Sites without bulky Dz are typically treated to 30 Gy after chemo. Sites of initial bulky Dz are typically treated to 36 Gy after chemo.
Describe the evidence that suggests improved outcomes with CRT compared with RT alone in early-stage favorable HD.
In the 1990s, CRT vs. RT alone was evaluated in at least 4 major randomized trials:
1. EORTC H7 F (Noordijk EM et al., JCO 2006)
2. EORTC H8 F (Ferme C et al., NEJM 2007)
3. German HD7 (Engert A et al., JCO 2007)
4. SWOG S9133 (Press OW et al., JCO 2001)
Although the chemo and RT techniques varied in these studies, long-term relapse rates consistently favored the CRT arms. In EORTC H8 F, 10-yr OS was significantly improved with CRT (97% vs. 92%), but long-term OS was not significantly different in the other studies.
Summarize the evidence for and against the elimination of consolidative RT in pts who achieve a CR after chemo in HD.
The outcomes after chemo alone in early and advanced HD have been evaluated in at least 4 major RCTs:
1. EORTC GELA H9 F randomized favorable stages I–II HD pts with a CR after epirubicin/bleomycin/vinblastine/prednisone (EBVP) × 6 cycles to 36 Gy IFRT vs. 20 Gy IFRT vs. no RT. 4-yr EFS was similar between the 36 Gy and 20 Gy arms (87% vs. 84%, respectively) but was significantly lower in the no-IFRT arm (70%). (Noordijk EM et al., ASCO 2005 abstract)
2. EORTC H10 compared ABVD alone in pts who have a PET CR after 2 cycles vs. ABVD + INRT. Risk of early relapse in nonirradiated patients with stages I–II HD was significantly higher than in standard combined modality treated patients, even in this selected group of patients with an early negative PET. (Raemakers JM, JCO, 2014)
3. Laskar S et al. randomized a diverse cohort of pts in India (stages I–IV, +/– bulky Dz and/or B Sx, adults and children, all of whom had a CR after ABVD × 6 cycles) to IFRT or observation. A majority of pts had mixed cellularity histology (most common in India). IFRT improved 8-yr EFS (88% vs. 76%) and 8-yr OS (100% vs. 89%), especially in pts <15 yo, with B Sx, bulky Dz, and advanced stages. (JCO 2004)
4. NCI-Canada/ECOG randomized stages I–II nonbulky pts to ABVD × 4–6 cycles (4 if CR after 2nd cycle) vs. Sub-total nodal irradiation (STNI) to 35 Gy (+ ABVD × 2 cycles if unfavorable risk). STNI decreased 12-yr OS (87% vs. 94%) due to toxicity, but improved rates of freedom from disease progression (92% vs. 87%). (Meyer RM et al., NEJM 2012)
Summarize the evidence to support the use of IFRT instead of more extensive RT in HD pts receiving CRT.
At least 4 RCTs have compared IFRT to more extensive RT in HD pts receiving CRT:
1. Groupe Pierre-et-Marie-Curie (GPMC) (Zittoun R et al., JCO 1985)
2. German HD8 (Klimm B et al., Ann Oncol 2007)
3. Milan study (Bonadonna G et al., JCO 2004)
4. EORTC H8-U (Ferme C et al., NEJM 2007)
The 5–12-yr OS outcomes were similar in all of these studies, suggesting that more extensive RT than IFRT is not necessary.
Summarize the evidence to support the use of IFRT at 20 Gy after induction chemo in favorable stages I–II HD pts.
The use of <30 Gy in favorable stages I–II HD pts after initial chemo has been studied in at least 2 RCTs:
1. HD10 from the German Hodgkin Study Group randomized pts to 2 vs. 4 cycles of chemo followed by 20 Gy vs. 30 Gy IFRT (2 × 2 factorial design). 5-yr PFS, freedom from Tx failure, and OS were similar between the chemo comparison and the RT dose comparison. (Engert A et al., NEJM 2010)
2. EORTC GELA H9 F (see above)
Summarize the evidence to support consolidative RT after partial response or bulky disease in advanced stage disease.
1. Aleman et al. randomized those with stages III–IV HD who achieved a CR after 4 or 6 cycles of MOPP-ABV to IFRT or observation. Patients with PR after 6 cycles received IFRT to 30 Gy with a 4–10 Gy boost. Rates of EFS and OS in patient with PR + IFRT were similar to those of patients in CR. In patients with CR, there was no difference in 8-yr EFS (observation, 77% vs. IFRT, 73%) or 8-yr OS (observation, 85% vs. IFRT, 78%). (IJROBP 2007)
2. HD12 randomized patients to 2 BEACOPP regimens and patients with initial bulky disease or partial response to chemotherapy to consolidative RT to 30 Gy vs. no consolidative RT. RT improved FFTF in patients with residual disease after chemotherapy but not in patients with initially bulky disease with a complete response. (Borchmann P, JCO 2011)
What are the historic fields used to treat HD?
The mantle field is a classic comprehensive field including major nodal regions above the diaphragm. Total lymphoid irradiation (TLI) treats a mantle field and “inverted Y” to include the para-aortic lymph nodes, pelvic lymph nodes, and spleen. Subtotal lymphoid irradiation (STLI) excludes the pelvic lymph nodes.
What is the difference between IFRT vs. regional-field radiation therapy (RFRT) vs. involved nodal radiation therapy (INRT) vs. involved site radiation therapy (ISRT)?
IFRT covers the involved lymphoid region (defined by Rye classification and delineated by Yahalom et al. [Ann Oncol 2002]). RFRT covers the involved regions + the immediately adjacent LN regions. INRT and ISRT cover only the prechemo tumor volume and are currently under investigation. INRT relies on ideal prechemotherapy imaging with PET/CT in the treatment planning position, while ISRT is used when ideal prechemotherapy imaging is not available. For this reason, the CTV cannot be reduced to the same extent as with INRT; therefore, clinical judgment is used along with imaging to create a larger CTV in order to accommodate these uncertainties. (Specht L et al., IJROBP, 2013)
Describe the IFRT borders for the cervical/supraclavicular region
Upper: 1–2 cm above mastoid
Lower: 2 cm below clavicle
Lateral: Include medial two-thirds of clavicle
Medial: Ipsilateral transverse process (if (+) supraclavicular fossa (SCV), extend to contralateral transverse process and block larynx)
Describe the IFRT borders for the mediastinal region
Upper: C5-C6
Lower: 5 cm below carina or 2 cm below prechemo border
Lateral: postchemo volume with 1.5-cm margin. Hilum to be included with 1 cm margin (1.5-cm margin if involved)
Describe the IFRT borders for the axillary region.
Upper: C5-C6
Lower: tip of scapula or 2 cm below the lowest axillary node
Medial: Ipsilateral cervical transverse process
Lateral: Flash axilla
Describe the IFRT borders for the abdominal region
Upper: Top of T11 and at least 2 cm above prechemo volume
Lower: Bottom of L4 and at least 2 cm below prechemo volume
Lateral: transverse process or at least 2 cm from postchemo volume
Describe the IFRT borders for the pelvic region
Upper: Middle of sacroiliac joint
Lower: 5 cm below the lesser trochanter
Lateral: Greater trochanter and 2 cm lateral to prechemo volume
Medial: Obturator foramen and at least 2 cm medial to prechemo volume
Describe INRT.
INRT relies on ideal prechemotherapy imaging. The prechemotherapy PET/CT is fused with the postchemotherapy radiation planning CT. The prechemotherapy GTV (based on prechemotherapy CT and PET imaging) is drawn. The CTV is then created by modifying the prechemotherapy GTV based on the postchemotherapy CT scan to respect normal structures that were never involved by lymphoma. For details regarding INRT as well as ISRT, see Specht L et al. (IJROBP 2013)
TOXICITY
In pts treated for HD, what is the RR for a 2nd solid malignancy after 30 yrs?
In pts who survive >5 yrs, the overall RR is 2–3 for a solid malignancy after 30 yrs compared to the general population. (Hodgson DC et al., JCO 2007)
Which type of secondary cancer occurs sooner after HD Tx: leukemias or solid malignancies?
Leukemias tend to occur <5 yrs after Tx, whereas solid malignancies typically occur >7 yrs after Tx.
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