Steven H. Lin and Eli Glatstein
At what age does Hodgkin disease (HD) most commonly occur?
HD has a bimodal peak with peaks at age 25 yrs and age 60–70 yrs.
What are 2 broad histologic categories of HD? Which is more common?
Broad histologic categories of HD:
1. Classic (more common)
2. Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
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)
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 CD15, -30, -45, and -20 staining pattern?
In classic HD, tumors are typically CD15 and -30 positive but CD45 and -20 negative.
In NLPHL, what is the most common CD15, -30, -45, and -20 staining pattern?
In NLPHL, tumors are typically CD15 and -30 negative but CD45 and -20 positive (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
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 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 either any mass >5 cm or any mass >10 cm.
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:
1. Stage I: involvement of 1 LN region or localized involvement of a single extralymphatic organ or site (IE)
2. 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)
3. 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)
4. 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 without B Sx are designated with an A, otherwise with a B. Pts with splenic involvement are designated with an S.
Involvement of what sites is considered stage 4 Dz?
Per the AJCC (7th edition), 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
7. Right hilum
8. Left hilum
Is involvement of the Waldeyer ring and spleen considered extranodal?
No. Per the AJCC (7th edition), the Waldeyer ring 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
3. ≥4 sites
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:
1. WBC >15,000
2. Albumin <4
3. Lymphocytes <600
4. Stage IV
5. Hgb <10.5 g/dL
6. Age ≥45 yrs
(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)
Historically, what was included in a staging laparotomy for HD?
Historically, staging laparotomy typically included a liver Bx, splenectomy, and abdominal LN sampling.
What study showed that staging laparotomy was unnecessary given Tx with subtotal nodal irradiation (STNI) or CRT?
EORTC H6F showed that a staging laparotomy was unnecessary given Tx with STNI or CRT (Carde P et al., JCO 1993). The study randomized favorable stage I–II pts with supradiaphragmatic HD to laparotomy and Tx based on laparotomy results vs. clinical staging only and STNI. Freedom from progression (78%–83%) and OS (89%–93%) were similar at 6 yrs.
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.
What are the 3 most common multiagent chemo regimens used for HD?
Most common chemo regimens used for HD:
2. Stanford V
3. Dose-escalated BEACOPP
What agents are included in ABVD chemo for HD?
What agents are included in the Stanford V regimen for HD?
There are 7 drugs in the Stanford V (MOPE-ABV):
2. Oncovin (vincristine)
The Stanford V regimen has reduced doses of mechlor−ethamine, Adr, and bleomycin compared to ABVD. While ABVD is sometimes used without consolidation RT, the Stanford V regimen requires consolidation RT.
What agents are included in BEACOPP?
5. Oncovin (vincristine)
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 difference between involved-field radiation therapy (IFRT) vs. regional-field radiation therapy (RFRT) vs. involved nodal radiation therapy (INRT)?
IFRT covers the involved lymphoid region (defined by Rye classification). RFRT covers the involved regions + the immediately adjacent LN regions. INRT covers only the prechemo tumor volume. INRT is currently under investigation in RCTs.
What are common Tx strategies for stage I–IIA favorable classic HD?
Common Tx strategies for stage I–IIA favorable classic HD:
1. Chemo + planned IFRT
2. ABVD × 4 cycles +/− IFRT to residual PET+ sites at restaging
What are common Tx strategies for stage I–II unfavorable classic HD?
Common Tx strategies for stage I–II unfavorable classic HD:
1. Chemo + planned IFRT
2. ABVD × 6 cycles +/− IFRT to initial bulky Dz and/or residual PET+ sites at restaging
What are common Tx strategies for stage III–IV classic HD?
Common Tx strategies for stage 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 stage I–II NLPHL?
Stage I–II NLPHL Tx paradigm: Tx is similar to Tx for a low-grade non-Hodgkin lymphoma. Stage I–II NLPHL can be treated with RT alone (involved field or regional) or chemo + IFRT (if B Sx are present).
What is the Tx paradigm for stage III–IV NLPHL?
Stage III–IV NLPHL Tx paradigm: observation, palliation (with chemo or RT), or definitive Tx with chemo + / − RT.
What are commonly used RT doses in HD after initial chemo?
Sites without bulky Dz are typically treated 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 to 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 H7F (Noordijk EM et al., JCO 2006)
2. EORTC H8F (Ferme C et al., NEJM 2007)
3. German HD7 (Engert A et al., JCO 2007)
4. SWOG S9133 (Press OW et al., JCO 2001)
While the chemo and RT techniques varied in these studies, long-term relapse rates consistently favored the CRT arms. In EORTC H8F, 10-yr OS was significantly improved with CRT, 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 3 major RCTs:
1. NCI-Canada/ECOG randomized unfavorable stage I–II nonbulky pts to ABVD × 4–6 cycles (4 if CR after 2nd cycle) vs. ABVD × 2 cycles + STNI. 5-yr freedom from progression favored the CRT arm (88% vs. 95%), but OS was not significantly different (95% ABVD alone vs. 92% CRT) (Meyer RM et al., JCO 2005). The authors suggested that lack of OS benefit was due to increased toxicity of the combined modality arm and that a difference favoring ABVD alone may be seen in the long term, given the known late RT toxicity profile.
2. Laskar et al. randomized a diverse cohort of pts in India (stage 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)
3. Aleman et al. randomized stage III–IV HD who achieved a CR after 4 or 6 cycles of MOPP-ABV to IFRT or observation. Pts who had a CR after 2 cycles rcv 4 cycles, and those who had a CR after 4 cycles rcv 6 cycles. There was no difference in 8-yr EFS (observation, 77% vs. IFRT, 73%) or 8-yr OS (observation, 85% vs. IFRT, 78%). (IJROBP 2007)
4. EORTC H10 is an ongoing trial comparing ABVD alone in pts who have a PET CR after 2 cycles vs. ABVD + INRT.
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 HD 8 (Klimm B et al., Ann Oncol 2007)
3. Milan study (Banadonna 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 stage I–II HD pts.
The use of <30 Gy in favorable stage I–II HD pts after initial chemo has been studied in at least 2 RCTs:
1. HD 10 from the German Hodgkin Study Group randomized pts to 2 vs. 4 cycles of chemo → 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 H9F randomized favorable stage 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 abstract 2005)
Summarize the evidence that suggests consolidative RT is more important in pts treated with Stanford V chemo compared to ABVD chemo.
2 RCTs have compared ABVD and Stanford V regimens for HD:
1. Gobbi et al. compared ABVD vs. Standford V (vs. a 3rd regimen). RT was not mandatory and was used in only 66% of the Stanford V arm and 62% of the ABVD arm. 5-yr FFS significantly favored ABVD (78% vs. 54%). (JCO 2005)
2. Hoskin et al. randomized unfavorable stage I–II and stage III–IV HD pts to ABVD- or Stanford V–based regimens. Initially, IFRT was required to a site initially >5 cm, though in the latter part of the study, RT was optional for the ABVD arm. Ultimately, 53% in the ABVD arm and 73% in the Stanford V arm rcv IFRT. Despite the higher rate of consolidative RT, 5-yr PFS (ABVD, 76%; Stanford V, 74%) and OS (ABVD, 90%; Stanford V, 92%) were not significantly different. (JCO 2009)
Describe a mantle field.
A mantle field is a classic comprehensive field including major nodal regions above the diaphragm (inf border: T10-11).
Describe a mini-mantle field.
A mini-mantle field is a mantle without mediastinal, hilar, and neck nodal regions.
Describe a modified mantle.
A modified mantle is a mantle without axillae and neck nodal regions.
What is covered in total lymphoid irradiation (TLI)?
TLI includes a mantle field → an inverted Y field (para-aortic and pelvic nodes) and spleen field.
How is STLI different from TLI?
STLI excludes iliac and inguinal regions.
At what dose should the larynx be blocked in a mantle field?
Consider blocking through entire RT course, unless there is midplane Dz. Otherwise, consider blocking after ~20 Gy.
What is the subcarinal block in a mantle field used to block? After what dose is it used?
The subcarinal block in a mantle field is used to block the heart. Consider blocking after 15 Gy in pts who have a CR after initial chemo, otherwise after 30 Gy.
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.