Radiation Therapy for CTCL- Then and Now

 Radiation Therapy  Radiation in CTCL  Radiation in the 70’s-90’s  Radiation today  Assumptions: background, staging and overall treatment sequencing have been discussed

 Radiation =Energy travelling through space  Generated by a machine or from a radioactive source  Waves or Particles  Biological effect on tissue at the level of DNA  Rapidly dividing cells are the most sensitive  Can control how deep it penetrates by adjusting the energy

 1895 Discovery of x-rays by Wilhelm Conrad Roentgen  1899 First reported patient cured by radiation therapy  The skin is the 2 nd most common extranodal site of lymphoma after the gastrointestinal tract  Jean Louis Marc Alibert coined the term Mycosis Fungoides in By 1870 it was recognized as a progressive cutaneous lymphoid disorder.

Radiation was used as early as 1902 to treat CTCL Total Skin Electron Beam (TSEB) technique was developed by Stanford University in 1958 By the end of the 1970’s, Hamilton Regional Cancer Centre was the only Centre in Ontario offering TSEB Hamilton has treated nearly 1000 pts with TSEB 2006 dedicated dermatologist retired, Hamilton joined with Princess Margaret Hospital, Odette Cancer Centre and Women’s College Hospital to form Provincial CTCL group

 First Roentgen ray tubes deliver energy 40 – 70 KV  KV  Introduction of radium teletherapy in 1915

 To deliver a precisely measured dose of radiation to a defined tumour volume with minimal damage to the surrounding normal tissues.  ? How to do that when the “target” is the entire skin surface?  CT scans/MRIs and precision radiation techniques do not help

Kim et al J. Clin. Invest. 115:

Need to cover the entire skin surface – patients must be naked for treatment. 3 positions front and back designed to expose all skin areas – need to assess skin folds.

 Response in field generally upwards of 90%  Responses measured by fading of rash and more importantly reduction in symptoms  Duration of response for local therapy is dependant on biology and whether other therapies given ( re seeding)  TSEB as primary modality has response rates upwards of 75% and duration of response in early stage measured in years, in later stages generally months  Hard to determine accurately as rarely given as solo modality of treatment

Predominately skin – includes both the general skin and the structures of the skin – hair follicles, nails and sweat glands. Tend to start the third or fourth week of treatment. Skin may become erythematous, scaly/flaky and pruritus may occur. Open areas may occur especially in skin folds, hands and feet – potential for skin infection. Hair loss begins in 3 rd week. Can lose all or part of body hair. Generally grows back 2 –4 months post treatment. May come back a different colour or texture. Fingernails and toenails stop growing because of TSEB. Nail loss is possible. Growth is suspended for 2 – 6 weeks. As new nails grow, old nails become a bit thicker and may feel loose.

 Refinement of TSEB technique  Optimal Dose defined  Most could tolerate 4-6 week course with shielding and breaks  Few therapies other than radiation  Chemo for other hematological malignancies had transient benefit with lots of toxicity  Effective skin clearing for most patients  Single institution experiences

 Lots of long term toxicity from radiation  Few comparative studies  Most patients recurred with longer follow up  Early clearance did not appear to prevent later stages –biological destiny  Localized treatment in early stages or to ‘de bulk” thick plaques or tumours had equal long term outcomes  Results from studies of “Add on” treatment inconsistent in supporting longer responses  Chemo or IFN after radiation

 Development of new biological agents to tackle the root cause of CTCL  Observation that low doses of radiation for local areas as effective as higher doses  EORTC GUIDELINES 2004  RT is a skin directed therapy  “save it til you need it approach”  Body can only take so much radiation, used in sequence with other therapies quality of skin/life overall better  Better able to target radiation

 Stage-based.  Skin-directed therapy usually starting point and component of all therapies.  Stage 1A/B and 2A:  Topical Corticosteroids.  Topical Retinoids.  Topical imiquimod.  Light therapy (UVB; PUVA).  Total skin electron beam (TSEB).  Light + systemic  (oral retinoid + PUVA)  (Interferon + PUVA)

 Stage 2B and higher:  Phototherapy and TSEB as adjuncts.  Local electron beam to tumours.  Oral retinoids.  Interferon.  Histone deacetylase inhibitors.  Methotrexate.  Extracorporeal photophoresis (if circulating clone).  Pruritus is a significant component of this disease:  Menthol, camphor.  Sedating antihistamines.  Gabapentin, mirtazapine.

 Early stage spot radiation  5-20 treatments  Spot radiation early on for bulky or symptomatic sites  1-5 treatments  Save TSEB for progression if other therapies stop working  Lower dose/less cumbersome positioning for older patients who have trouble with usual TSEB technique

 people treated per year with TSEBT  20+ treated with spot radiation  Short term control rates in excess of 80%  Average duration of response 18 months  20% may have long term ( years) remission  Mostly early stage disease

 Debra Gallinger  PERC  Odette Hematology  UHN ECP unit  Patients