Hodgkin Lymphoma

Disclaimer

This manual is not a substitute for consultation with an appropriate specialist.
The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

1. Diagnosis

Revised 12 April 2013

The diagnosis of Hodgkin lymphoma is based on the recognition of Reed-Sternberg cells and/or Hodgkin cells in an appropriate cellular background in tissue sections from a lymph node or extra-lymphatic organ, such as the bone marrow, lung or bone. Fine needle aspiration biopsy is not adequate for the diagnosis of Hodgkin lymphoma. Open biopsy is required because of the need to establish progress to Hodgkin lymphoma and should be distinguished from it (see lymphoma-like conditions).

2. Staging

Definition of Stages

The staging system for Hodgkin lymphoma used at BCCA is based on clinical staging according to the Ann Arbor system with the additions of a definition of bulky disease. Staging laparotomy is not required.

Stage	Involvement
1	Single lymph node region (1) or one extralymphatic site (1E).
2	Two or more lymph node regions, same side of the diaphragm (2) or local extralymphatic extension plus one or more lymph node regions same side of the diaphragm (2E).
3	Lymph node regions on both sides of the diaphragm (3) which may be accompanied by local extralymphatic extension (3E).
4	Diffuse involvement of one or more extralymphatic organs or sites.

Symptoms

A	= no B symptoms
B	= presence of at least one of these
	1)	unexplained weight loss > 10% baseline during 6 months prior to staging
	2)	recurrent unexplained fever > 38^oC
	3)	recurrent night sweats

Bulky tumour is defined as a single mass of tumour tissue 10 cm or larger in largest diameter.

Mandatory Staging Procedures

Pathology review
All patients should receive the immunizations recommended in Appendix III
Complete history and physical examination including rectal and gynecological examinations
Complete blood count.
Serum creatinine, alkaline phosphatase, lactate dehydrogenase, bilirubin, calcium, AST, albumin (usually most easily obtained by ordering a serum protein electrophoresis)
Chest radiograph, PA and lateral views
CT scan of neck, thorax, abdomen and pelvis
PET/CT scan
Hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis C antibody

Certain tests are required only in special circumstances.

Test	Presentation/Condition
Bone marrow biopsy and aspiration	B symptoms or WBC < 4.0 x 10⁹/L or Hgb < 120 g/L (women), 130 g/L (men) or Platelets < 125 x 10⁹/L
ENT examination	Stage 1A or 2A disease with upper cervical lymph node involvement (supra-hyoid)

Assessment of the Liver

Only well defined non-cystic space-occupying lesions documented by CT scan or sonogram can be accepted as unequivocal evidence of liver involvement. Abnormal liver function tests with or without hepatomegaly are not firm evidence of liver involvement.

Assessment of the Spleen

Patients with sonographic or CT scan evidence of discrete non-cystic lesions in the spleen are considered to have extensive splenic involvement for treatment planning. Patients with minimal enlargement of the spleen (enlarged by scan but not palpable or only the tip palpable) are not considered to have splenic involvement.

3. Treatment

Optimal treatment of Hodgkin lymphoma depends on the histologic stage of the disease. The following table summarizes the recommended treatment according to these factors using an algorithm depending on information determined from the recommended staging procedures above. Patients who do not have a complete response to the primary treatment noted in this table should be discussed with a medical or radiation oncologist.

Definitions

Involved Node Radiotherapy (INRT)

Adopted mainly from Campbell’s papers on “INRT<5cm” = pre- and post-chemo involved lymph nodes (within post-chemo anatomical limits) + 1.5-5cm to field edge[1] or to PTV[2], [3]

CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
- o cranio-caudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
Mediastinal Area[4], [5]
- Length of CTV = length of mediastinal mass or LN(s) before chemo
- Width of CTV = width of mediastinal mass or LN(s) after chemo
- The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

Residual Disease Radiotherapy (RDRT)

CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
- cranio-caudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
- Do not include any pre-chemo involved LN region that is far away from the residual disease
PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
Mediastinal Area[4], [5]
- Length of CTV = length of mediastinal mass or LN(s) before chemo
- Width of CTV = width of mediastinal mass or LN(s) after chemo
- The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

References

[1] B. A. Campbell et al., “Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size,” Journal of Clinical Oncology, vol. 26, no. 32, pp. 5170–5174, Oct. 2008.

[2] B. A. Campbell et al., “Long-term outcomes for patients with limited stage follicular lymphoma,” Cancer, vol. 116, no. 16, pp. 3797–3806, May. 2010.

[3] B. A. Campbell, J. M. Connors, R. D. Gascoyne, W. J. Morris, T. Pickles, and L. H. Sehn, “Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy,” Cancer, vol. 118, no. 17, pp. 4156–4165, Jan. 2012.

[4] T. Girinsky, “Radiotherapy Recommendations for Patients with Early Stage Hodgkin's Lymphoma: Involved Node Radiation Therapy (INRT),” pp. 1–9, Mar. 2008.

[5] T. Girinsky et al., “The conundrum of hodgkin lymphoma nodes: To be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines,” Radiotherapy and Oncology, vol. 88, no. 2, pp. 202–210, Aug. 2008.

[6] P. J. Hoskin, P. Díez, M. Williams, H. Lucraft, and M. Bayne, “Recommendations for the Use of Radiotherapy in Nodal Lymphoma,” Clinical Oncology, vol. 25, no. 1, pp. 49–58, Jan. 2013.

Standard and Experimental Treatment - Overview

The standard treatment of early stage Hodgkin lymphoma at BCCA is two cycles of chemotherapy followed by assessment with PET scan. If the PET scan is negative treatment should be concluded with two more cycles of chemotherapy. If the PET scan is positive treatment should be concluded with residual disease radiation therapy.
Standard chemotherapy of advanced Hodgkin lymphoma at BCCA is ABVD. This type of chemotherapy has been shown to be the best available in large prospective randomized trials. (Canellos, NEJM, 1992;327:1478; Duggan, J Clin Oncol 2003;21:607.)
High risk disease. Criteria which can identify patients with high risk advanced Hodgkin lymphoma are available (Hansenclever, New Engl J Med, 1998;339: 1506-14). Each of the following factors has an equivalent negative impact on survival.

Age	>45 years
Gender	male
Stage	IV
Hemoglobin	<105 g/L
Albumin, serum	<40 g/L
WBC	>15.0 x 10⁹/L
Lymphocytes	count <0.6 x 10⁹/L or percent <8% of WBC

When three or more of these factors are present at diagnosis (high risk), risk of treatment failure is high and the likelihood of cure with ABVD alone is only about 70%. Therefore, patients less than 66 years of age with advanced Hodgkin lymphoma and four or more of these factors should be offered treatment with experimental treatment on a clinical trial if available. Please check with one of the chemotherapists associated with the Lymphoma Tumour Group for information about which such clinical trials are available.

Standard Treatment - Specific Details

Stage	Bulk*	Risk Factors**	Age (y)	Treatment
1A, 1B or 2A	low	0-7	any	CT***x 2 then PET scan if PET neg -> CT x 2 more cycles if PET pos -> INRT
1A, 1B or 2A	high	0-7*****	any	CTx6 then CT scan and marrow biopsy if originally positive If CR, no further treatment If otherwise in CR but residual mass > 2 cm do PET scan If PET neg, no further treatment If PET pos and encompassable in a reasonable radiation volume-> RDRT If PET pos and not encompassable in a reasonable radiation volume-> close observation or biopsy to direct further treatment on proof of persistent lymphoma
2B 3A or 3B 4A or 4B	any	0-7*****	any

* Bulk: low = no tumour mass >10 cm; high = any single tumour mass > = 10 cm (note: round to nearest whole cm, e.g. 9.5 cm = 10 cm but 9.4 cm = 9 cm)
** Risk defined using the prognostic index described above in section 2.3.2.3
*** CT=chemotherapy, ABVD
**** RDRT=residual disease radiation therapy
***** If 4 or more risk factors present consider enrolment on clinical trial, if available

4. Follow-Up

Most patients with Hodgkin lymphoma, especially those below the age of 65 years at diagnosis, can be cured with the treatments described in this section. Most cured patients experience minimal long-term toxicity from the treatments, however, certain predictable and occasional rare and unpredictable late effects may occur and require preventive measures and/or recognition and treatment.

The following late effects of Hodgkin lymphoma or its treatment should be considered when patients are reviewed in follow-up.

Risk/Problem	Incidence/Response
Relapse	10% to 30% of patients relapse depending on stage and bulk of presentation. Careful attention should be directed to lymph node sites, especially if previously involved with disease.
Dental caries	Neck or oropharyngeal irradiation may cause decreased salivation. Patients should have careful dental care follow-up and should make their dentist aware of the previous irradiation.
Hypothyroidism	After external beam thyroid irradiation to doses sufficient to cure Hodgkin lymphoma at least 50% of patients will eventually become hypothyroid. Also, there is an increased risk of secondary thyroid carcinoma after irradiation. All patients whose TSH level becomes elevated should be treated with life-long thyroxine replacement in doses sufficient to suppress TSH levels to low normal for two purposes: to maintain euthyroidism and to minimize the risk of thyroid carcinoma by reducing overstimulation with endogenous TSH.
Infertility	ABVD is not known to cause any permanent gonadal toxicity based on longterm follow-up of thousands of patients. Direct or scatter radiation to gonadal tissue may cause infertility, amenorrhea or premature menopause but this seldom occurs with the fields used for the treatment of Hodgkin lymphoma. Thus, with the current chemotherapy regimens and radiation fields used, most patients will not develop these problems. In general, after treatment, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer.
Secondary neoplasms	Although uncommon, certain secondary neoplasms occur with increased frequency in patients who have been treated for Hodgkin lymphoma. These include acute myelogenous leukemia, thyroid, breast, lung and upper gastrointestinal carcinoma and melanoma and cervical carcinoma-in-situ. It is appropriate to screen for these neoplasms for the rest of the patient's life because they may have a lengthy induction period.

The following minimum follow-up tests and examinations should be performed on all patients after treatment of Hodgkin lymphoma. Visits should be every 3 months for 2 years, then every 6 months for 3 years, then annual. Patients should be strongly encouraged to perform careful breast and skin examination on a regular basis. Immunizations should be updated as recommended in Appendix III.

Interval	Test
Every visit	Lymph node, abdominal, thyroid, and skin examination CBC, alkaline phosphatase
Every visit for 2 years then every other visit	Chest radiograph
Annually	TSH level (only if the thyroid was irradiated) Mammography for women beginning 10 years after diagnosis of Hodgkin lymphoma or at age 40 years, whichever comes first Pap smear Influenza immunization (Appendix III)