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Risk of cardiovascular diseases after Hodgkin lymphoma treatment van Nimwegen, F.A.

2016

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van Nimwegen, F. A. (2016). Risk of cardiovascular diseases after Hodgkin lymphoma treatment.

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Background and epidemiology

,ŽĚŐŬŝŶůLJŵƉŚŽŵĂ;,>ͿŝƐĂŵĂůŝŐŶĂŶƚĚŝƐĞĂƐĞŽĨƚŚĞůLJŵƉŚĂƟĐƐLJƐƚĞŵ͘/ƚŝƐĐŚĂƌĂĐƚĞƌŝnjĞĚ ďLJƚŚĞĂďŶŽƌŵĂůŐƌŽǁƚŚŽĨůLJŵƉŚŽĐLJƚĞƐ͕ĨƵŶĐƟŽŶůŽƐƐŽĨůLJŵƉŚŽĐLJƚĞƐĂŶĚƚŚĞƉƌĞƐĞŶĐĞŽĨ ZĞĞĚͲ^ƚĞƌŶďĞƌŐĐĞůůƐ͘ZĞĞĚͲ^ƚĞƌŶďĞƌŐĐĞůůƐĂƌĞůĂƌŐĞĐĞůůƐĚĞƌŝǀĞĚĨƌŽŵͲůLJŵƉŚŽĐLJƚĞƐ͕ĂŶĚ ĂƌĞƚLJƉŝĐĂůůLJĂŶĚĞdžĐůƵƐŝǀĞůLJƐĞĞŶŝŶƉĂƟĞŶƚƐǁŝƚŚ,>͘,>ŐĞŶĞƌĂůůLJĂƌŝƐĞƐŝŶŽŶĞƉĞƌŝƉŚĞƌĂů ůLJŵƉŚŶŽĚĞ͕ĨƌĞƋƵĞŶƚůLJůŽĐĂƚĞĚĂďŽǀĞƚŚĞĚŝĂƉŚƌĂŐŵ͕ĂŶĚĐĂŶƐƉƌĞĂĚĨƵƌƚŚĞƌƚŚƌŽƵŐŚƚŚĞ ůLJŵƉŚĂƟĐƐLJƐƚĞŵ͕ďƵƚŵĂLJĂůƐŽĂīĞĐƚƚŚĞƐƉůĞĞŶ͕ůŝǀĞƌ͕ůƵŶŐƐŽƌďŽŶĞŵĂƌƌŽǁ1_{͘,>ĐĂŶďĞ} ĚŝǀŝĚĞĚŝŶƚŽƐĞǀĞƌĂůƐƵďƚLJƉĞƐ͘ůĂƐƐŝĐĂů,>ĂĐĐŽƵŶƚƐĨŽƌƚŚĞŵĂũŽƌŝƚLJŽĨŶĞǁ,>ĚŝĂŐŶŽƐĞƐ;ϵϱйͿ ĂŶĚĐŽŶƐŝƐƚƐŽĨŶŽĚƵůĂƌƐĐůĞƌŽƐŝŶŐ͕ŵŝdžĞĚĐĞůůƵůĂƌ͕ůLJŵƉŚŽĐLJƚĞͲƌŝĐŚĂŶĚůLJŵƉŚŽĐLJƚĞͲĚĞƉůĞƚĞĚ ƐƵďƚLJƉĞƐ͘dŚĞŶŽĚƵůĂƌůLJŵƉŚŽĐLJƚĞͲƉƌĞĚŽŵŝŶĂŶƚƐƵďƚLJƉĞŝƐĨĂŝƌůLJƌĂƌĞĂŶĚĂĐĐŽƵŶƚƐĨŽƌƚŚĞ ƌĞŵĂŝŶŝŶŐĮǀĞƉĞƌĐĞŶƚ͘dŚĞĞƟŽůŽŐLJŽĨ,>ƐƟůůƌĞŵĂŝŶƐƵŶĐůĞĂƌ͘/ŶĨĞĐƟŽŶǁŝƚŚƚŚĞƉƐƚĞŝŶͲ ĂƌƌǀŝƌƵƐŚĂƐďĞĞŶĂƐƐŽĐŝĂƚĞĚǁŝƚŚŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨ,>͕ĂƐĂďŽƵƚϯϬйŽĨ,>ƉĂƟĞŶƚƐĂƌĞ ƉƐƚĞŝŶͲĂƌƌǀŝƌƵƐĂŶƟŐĞŶƉŽƐŝƟǀĞ͕ďƵƚĞǀŝĚĞŶĐĞŝƐůĂĐŬŝŶŐƚŽƐƵƉƉŽƌƚĂĐĂƵƐĂůƌĞůĂƟŽŶƐŚŝƉ2, 3_. ǀĞƌLJ LJĞĂƌ͕ ĂďŽƵƚ ϰϬϬ ŶĞǁ ƉĂƟĞŶƚƐ ĂƌĞ ĚŝĂŐŶŽƐĞĚ ǁŝƚŚ ,> ŝŶ ƚŚĞ EĞƚŚĞƌůĂŶĚƐ4_{; the} ŝŶĐŝĚĞŶĐĞƌĂƚĞŚĂƐďĞĞŶƐƚĂďůĞŽǀĞƌƚŚĞƉĂƐƚĚĞĐĂĚĞƐ͘ŽŵƉĂƌĞĚƚŽƚŚĞƚŽƚĂůŶƵŵďĞƌŽĨŶĞǁ ĐĂŶĐĞƌƐĚŝĂŐŶŽƐĞĚĂŶŶƵĂůůLJ4_{͕,>ŝƐĂƌĞůĂƟǀĞůLJƌĂƌĞŵĂůŝŐŶĂŶĐLJ͕ƌĞƉƌĞƐĞŶƟŶŐĂƉƉƌŽdžŝŵĂƚĞůLJ}

Ϭ͘ϰйŽĨĂůůŶĞǁŵĂůŝŐŶĂŶĐŝĞƐĚŝĂŐŶŽƐĞĚŝŶƚŚĞEĞƚŚĞƌůĂŶĚƐŝŶϮϬϭϰ4_{. However, it is the third}

ŵŽƐƚĐŽŵŵŽŶŵĂůŝŐŶĂŶĐLJĂŵŽŶŐĂĚŽůĞƐĐĞŶƚƐĂŶĚLJŽƵŶŐĂĚƵůƚƐ͖ƚŚĞŵĂũŽƌŝƚLJŽĨƉĂƟĞŶƚƐŝƐ ĂŐĞĚďĞƚǁĞĞŶϭϱĂŶĚϯϱLJĞĂƌƐĂƚĚŝĂŐŶŽƐŝƐ4, 5_{͘ĞĨŽƌĞƚŚĞϭϵϲϬƐ͕,>ǁĂƐĂŶŝŶĐƵƌĂďůĞĚŝƐĞĂƐĞ͘} ,ŽǁĞǀĞƌ͕ ŝŵƉƌŽǀĞŵĞŶƚƐ ŝŶ ƚƌĞĂƚŵĞŶƚ ŽƉƟŽŶƐ ƌĞƐƵůƚĞĚ ŝŶ ƚŚĞ ƉŽƐƐŝďŝůŝƚLJ ƚŽ ĐƵƌĞ ,>͕ ĂŶĚ ŶŽǁĂĚĂLJƐ͕ ,> ŝƐ ƚŚĞ ƉƌŽƚŽƚLJƉĞ ŽĨ Ă ĐƵƌĂďůĞ ŵĂůŝŐŶĂŶĐLJ͘ ƵƌƌĞŶƚůLJ͕ ŽǀĞƌĂůů ϭϬͲLJĞĂƌ ƐƵƌǀŝǀĂů ƌĂƚĞƐĞdžĐĞĞĚϴϬƉĞƌĐĞŶƚ4, 6-8_.

Treatment

/Ŷ ϭϵϲϰ͕ ƚŚĞ ƵƌŽƉĞĂŶ KƌŐĂŶŝnjĂƟŽŶ ĨŽƌ ZĞƐĞĂƌĐŚ ĂŶĚ dƌĞĂƚŵĞŶƚ ĨŽƌ ĂŶĐĞƌ ;KZdͿ >LJŵƉŚŽŵĂ ŐƌŽƵƉ ŝŶƚƌŽĚƵĐĞĚ ƚŚĞ ĮƌƐƚ ŽĨ Ă ƐĞƌŝĞƐ ŽĨ ƌĂŶĚŽŵŝnjĞĚ ƚƌŝĂůƐ ;,ϭͲ,ϭϬͿ ǁŚŝĐŚ ĞǀĂůƵĂƚĞĚƚŚĞĞīĞĐƟǀĞŶĞƐƐŽĨĚŝīĞƌĞŶƚƚƌĞĂƚŵĞŶƚƌĞŐŝŵĞŶƐ7, 9-17_{. Since then, treatment for}

;ϴϴйͿƚŚĂŶƉĂƟĞŶƚƐƚƌĞĂƚĞĚǁŝƚŚDKWWŝŶĐŽŵďŝŶĂƟŽŶǁŝƚŚŵĂŶƚůĞĮĞůĚŝƌƌĂĚŝĂƟŽŶ;ϳϲйͿ͘ ůƚŚŽƵŐŚƐƵƌǀŝǀĂůĚŝĚŶŽƚĂƉƉĞĂƌƚŽĚŝīĞƌ;ϵϭйǀĞƌƐƵƐϴϱй͕ƌĞƐƉĞĐƟǀĞůLJͿ10_{, the ABVD regimen}

1

Ɛ Ye ar Coun try ^/Zƚƌ Ğ Ăƚ ŵĞŶ ƚŐƌ ŽƵƉ Ɛ Cum Inc RR/HR 1998 ^ǁŝƚnj ĞƌůĂŶĚ D ĞĚŝĂƐ ƟŶĂůZ d͗ϯ͘Ϭ;ϵϱй/͗Ϭ͘ϲͲϴ͘ϴͿ DĞĚŝĂƐ ƟŶĂůZ dн d͗ ϲ͘ϯ;ϵϱй/͗Ϯ͘ϬͲϭϰ͘ϲͿ -s 1999 EĞƚŚĞƌůĂŶĚƐ -ϮϬͲ LJĞ Ăƌ͗Ϯϭ͘Ϯй;ϵϱй/͗ϭϱͲϯϬͿ

CHD higher than median dose: 1.3 ;ϵϱй/͗Ϭ͘ϲͲϮ͘ϳͿ VHD higher than median dose: 1.1 ;ϵϱй/͗Ϭ͘ϰͲϮ͘ϲͿ

ZŝƐŬĨĂĐƚŽƌƐĨŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐ

/ƚ ŚĂƐ ůŽŶŐ ďĞĞŶ ŬŶŽǁŶ ƚŚĂƚ ƚŚĞ ƌŝƐŬ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞƐ ŝŶ ƚŚĞ ŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ ŝƐ ƐƚƌŽŶŐůLJ ŝŶŇƵĞŶĐĞĚ ďLJ ƚŚĞ ƉƌĞƐĞŶĐĞ ŽĨ ƐĞǀĞƌĂů ƌŝƐŬ ĨĂĐƚŽƌƐ͕ ƐƵĐŚ ĂƐ ŚLJƉĞƌƚĞŶƐŝŽŶ͕ ŚLJƉĞƌĐŚŽůĞƐƚĞƌŽůĞŵŝĂ͕ŽďĞƐŝƚLJĂŶĚƐŵŽŬŝŶŐ96, 97_{͘dŽĚĂƚĞ͕ŝƚŝƐƵŶŬŶŽǁŶƚŽǁŚŝĐŚĞdžƚĞŶƚƚŚŝƐ} ŝƐ ĂůƐŽ ƚŚĞ ĐĂƐĞ ĨŽƌ ,> ƐƵƌǀŝǀŽƌƐ ƚƌĞĂƚĞĚ ǁŝƚŚ ĐĂƌĚŝŽƚŽdžŝĐ ƚƌĞĂƚŵĞŶƚƐ͕ ĂŶĚ ǁŚĞƚŚĞƌ ƚŚĞƌĞ ĂƌĞ ŝŶƚĞƌĂĐƟŽŶƐ ďĞƚǁĞĞŶ ĞƐƚĂďůŝƐŚĞĚ s ƌŝƐŬ ĨĂĐƚŽƌƐ ĂŶĚ ƚŚĞƐĞ ƚƌĞĂƚŵĞŶƚƐ͘ /ƚ ŚĂƐ ďĞĞŶ ƉƌĞǀŝŽƵƐůLJ ƐŚŽǁŶ ƚŚĂƚ ,> ƐƵƌǀŝǀŽƌƐ ǁŚŽ ƐŵŽŬĞĚ ĚƵƌŝŶŐ ƚƌĞĂƚŵĞŶƚ ǁŝƚŚ ƌĂĚŝŽƚŚĞƌĂƉLJ ƚŽ ƚŚĞ ĐŚĞƐƚ ŚĂĚ Ă ƐŝŐŶŝĮĐĂŶƚůLJ ŝŶĐƌĞĂƐĞĚ ƌŝƐŬ ƚŽ ĚĞǀĞůŽƉ ƌĂĚŝĂƟŽŶͲĂƐƐŽĐŝĂƚĞĚ ůƵŶŐ ĐĂŶĐĞƌ ĂƐ ƐƵďƐĞƋƵĞŶƚŵĂůŝŐŶĂŶĐLJĐŽŵƉĂƌĞĚǁŝƚŚƉĂƟĞŶƚƐǁŚŽĚŝĚŶŽƚƐŵŽŬĞ57, 98_{͘tŚĞƚŚĞƌƚŚĞƌĞŝƐĂůƐŽ} ĂŶŝŶƚĞƌĂĐƟŽŶďĞƚǁĞĞŶƌĂĚŝŽƚŚĞƌĂƉLJĂŶĚƐŵŽŬŝŶŐǁŝƚŚƌĞŐĂƌĚƚŽƚŚĞƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞƐƌĞŵĂŝŶƐƵŶĐůĞĂƌ͘ /Ŷ ĐŚŝůĚŚŽŽĚ ĐĂŶĐĞƌ ƐƵƌǀŝǀŽƌ ƐƚƵĚŝĞƐ ŝƚ ŚĂƐ ƌĞĐĞŶƚůLJ ďĞĞŶ ƐŚŽǁŶ ƚŚĂƚ ƉĂƟĞŶƚƐ ǁŚŽ ƌĞĐĞŝǀĞĚƌĂĚŝŽƚŚĞƌĂƉLJƚŽƚŚĞĂďĚŽŵĞŶŚĂĚĂŶŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨĚĞǀĞůŽƉŝŶŐĚŝĂďĞƚĞƐŵĞůůŝƚƵƐ͕ ĐŽŵƉĂƌĞĚ ǁŝƚŚ ƐƵƌǀŝǀŽƌƐ ǁŚŽ ĚŝĚ ŶŽƚ ƌĞĐĞŝǀĞ ĂďĚŽŵŝŶĂů ƌĂĚŝŽƚŚĞƌĂƉLJ99, 100_{͘ Ɛ ĚŝĂďĞƚĞƐ}

ŵĞůůŝƚƵƐŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚŝŶĐƌĞĂƐĞĚŵŽƌďŝĚŝƚLJĂŶĚŽǀĞƌĂůůŵŽƌƚĂůŝƚLJ101, 102_{, and increases the}

1

ŽƵƌůĂƌŐĞĐŽŚŽƌƚ͕ŝŶǀĞƐƟŐĂƟŶŐƌŝƐŬĨĂĐƚŽƌƐĨŽƌĐŽƌŽŶĂƌLJŚĞĂƌƚĚŝƐĞĂƐĞĂŌĞƌ,>͕ǁŝƚŚƉĂƌƟĐƵůĂƌ ĨŽĐƵƐŽŶƚŚĞƌĂĚŝĂƟŽŶĚŽƐĞƚŽƚŚĞŚĞĂƌƚ͘^ƵďƐƟƚƵƚĞdͲƉůĂŶŶĞĚƌĂĚŝĂƟŽŶĚŽƐŝŵĞƚƌLJǁĂƐƵƐĞĚ ƚŽĚĞƚĞƌŵŝŶĞƚŚĞŵĞĂŶŚĞĂƌƚĚŽƐĞŝŶĂƐƚƵĚLJĞǀĂůƵĂƟŶŐƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƚƌĞĂƚŵĞŶƚ ĂŶĚƌŝƐŬŽĨŚĞĂƌƚĨĂŝůƵƌĞ͕ǁŚŝĐŚŝƐƉƌĞƐĞŶƚĞĚŝŶchapter 5. dŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞƐ ŝƐ ŶŽƚ ƐŽůĞůLJ ĚĞƉĞŶĚĞŶƚ ŽŶ ƌŝƐŬ ĨĂĐƚŽƌƐ ƌĞůĂƚĞĚƚŽ,>ƚƌĞĂƚŵĞŶƚ͘^ŵŽŬŝŶŐ͕ŽďĞƐŝƚLJ͕ŚLJƉĞƌƚĞŶƐŝŽŶ͕ŚLJƉĞƌĐŚŽůĞƐƚĞƌŽůĞŵŝĂĂŶĚĚŝĂďĞƚĞƐ ŵĞůůŝƚƵƐŚĂǀĞďĞĞŶĂƐƐŽĐŝĂƚĞĚǁŝƚŚŝŶĐƌĞĂƐĞĚƌŝƐŬƐŽĨĚĞǀĞůŽƉŝŶŐĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐŝŶ ƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͘/ƚŝƐ͕ŚŽǁĞǀĞƌ͕ƵŶĐůĞĂƌǁŚĞƚŚĞƌ,>ƚƌĞĂƚŵĞŶƚŝŶĐƌĞĂƐĞƐƚŚĞƌŝƐŬŽĨ ƚŚĞƐĞ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƌŝƐŬ ĨĂĐƚŽƌƐ͕ ƚŚĞƌĞďLJ ŝŶĐƌĞĂƐŝŶŐ ƚŚĞ ƌŝƐŬŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞƐ͘ /Ŷ chapter 6ǁĞƌĞƉŽƌƚŽŶĂƐƚƵĚLJŝŶǀĞƐƟŐĂƟŶŐƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƌĂĚŝĂƟŽŶĚŽƐĞƚŽƚŚĞ ƉĂŶĐƌĞĂƐĂŶĚƚŚĞƌŝƐŬŽĨĚŝĂďĞƚĞƐŵĞůůŝƚƵƐĂŌĞƌƚƌĞĂƚŵĞŶƚĨŽƌ,ŽĚŐŬŝŶůLJŵƉŚŽŵĂ͘/ŶƚĞƌĂĐƟŽŶƐ ďĞƚǁĞĞŶĞƐƚĂďůŝƐŚĞĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƌŝƐŬĨĂĐƚŽƌƐĂŶĚƚƌĞĂƚŵĞŶƚͲƌĞůĂƚĞĚƌŝƐŬĨĂĐƚŽƌƐĂƌĞ ĞǀĂůƵĂƚĞĚŝŶchapter 4 and chapter 5.

ZĞĨĞƌĞŶĐĞƐ

1. >ƵŬĞƐZ:͘ƌŝƚĞƌŝĂĨŽƌŝŶǀŽůǀĞŵĞŶƚŽĨůLJŵƉŚŶŽĚĞ͕ďŽŶĞŵĂƌƌŽǁ͕ƐƉůĞĞŶ͕ĂŶĚůŝǀĞƌŝŶ,ŽĚŐŬŝŶ͛Ɛ disease. ĂŶĐĞƌZĞƐ͘Nov 1971;31(11):1755-1767. 2. :ĂƌƌĞƩZ&͕^ƚĂƌŬ'>͕tŚŝƚĞ:͕ĞƚĂů͘/ŵƉĂĐƚŽĨƚƵŵŽƌƉƐƚĞŝŶͲĂƌƌǀŝƌƵƐƐƚĂƚƵƐŽŶƉƌĞƐĞŶƟŶŐĨĞĂƚƵƌĞƐ ĂŶĚŽƵƚĐŽŵĞŝŶĂŐĞͲĚĞĮŶĞĚƐƵďŐƌŽƵƉƐŽĨƉĂƟĞŶƚƐǁŝƚŚĐůĂƐƐŝĐ,ŽĚŐŬŝŶůLJŵƉŚŽŵĂ͗ĂƉŽƉƵůĂƟŽŶͲ ďĂƐĞĚƐƚƵĚLJ͘ůŽŽĚ͘Oct 1 2005;106(7):2444-2451. 3. :ĂƌƌĞƩ Z&͘ dŚĞ ZŽůĞ ŽĨ sŝƌƵƐĞƐ ŝŶ ƚŚĞ 'ĞŶĞƐŝƐ ŽĨ ,ŽĚŐŬŝŶ ůLJŵƉŚŽŵĂ͘ /Ŷ͗ ŶŐĞƌƚ ͕ zŽƵŶĞƐ ͕ eds. ,ŽĚŐŬŝŶůLJŵƉŚŽŵĂͲŽŵƉƌĞŚĞŶƐŝǀĞKǀĞƌǀŝĞǁ͘ϮŶĚĞĚ͗^ƉƌŝŶŐĞƌ/ŶƚĞƌŶĂƟŽŶĂůWƵďůŝƐŚŝŶŐ͖ 2015. 4. /<E>͘ƵƚĐŚĂŶĐĞƌ&ŝŐƵƌĞƐ͘ŚƩƉ͗ͬͬǁǁǁ͘ĐŝũĨĞƌƐŽǀĞƌŬĂŶŬĞƌ͘Ŷů͘ĐĐĞƐƐĞĚ:ƵŶĞϭϱƚŚϮϬϭϱ͕ϮϬϭϱ͘ 5. 'ůĂƐĞƌ ^>͕ ŚĂŶŐ d͕ ůĂƌŬĞ ͕ <ĞĞŐĂŶ d,͘ ƉŝĚĞŵŝŽůŽŐLJ ŽĨ ,ŽĚŐŬŝŶ ůLJŵƉŚŽŵ͘ /Ŷ͗ ŶŐĞƌƚ ͕ zŽƵŶĞƐ͕ĞĚƐ͘,ŽĚŐŬŝŶůLJŵƉŚŽŵĂͲŽŵƉƌĞŚĞŶƐŝǀĞKǀĞƌǀŝĞǁ͘ϮŶĚĞĚ͗^ƉƌŝŶŐĞƌ/ŶƚĞƌŶĂƟŽŶĂů WƵďůŝƐŚŝŶŐ͖ϮϬϭϱ͘ 6. <ůŝŵŵ͕'ŽĞƌŐĞŶ,͕&ƵĐŚƐD͕ĞƚĂů͘/ŵƉĂĐƚŽĨƌŝƐŬĨĂĐƚŽƌƐŽŶŽƵƚĐŽŵĞƐŝŶĞĂƌůLJͲƐƚĂŐĞ,ŽĚŐŬŝŶ͛Ɛ ůLJŵƉŚŽŵĂ͗ ĂŶ ĂŶĂůLJƐŝƐ ŽĨ ŝŶƚĞƌŶĂƟŽŶĂů ƐƚĂŐŝŶŐ ĚĞĮŶŝƟŽŶƐ͘ŶŶ KŶĐŽů͘ Dec 2013;24(12):3070-3076. 7. &ĞƌŵĞ ͕ ŐŚďĂůŝ ,͕ DĞĞƌǁĂůĚƚ :,͕ Ğƚ Ăů͘ ŚĞŵŽƚŚĞƌĂƉLJ ƉůƵƐ ŝŶǀŽůǀĞĚͲĮĞůĚ ƌĂĚŝĂƟŽŶ ŝŶ ĞĂƌůLJͲ ƐƚĂŐĞ,ŽĚŐŬŝŶ͛ƐĚŝƐĞĂƐĞ͘EŶŐů:DĞĚ͘Nov 8 2007;357(19):1916-1927. 8. ZĂĞŵĂĞŬĞƌƐ :͕ ƵƌŐĞƌƐ D͕ ,ĞŶƌLJͲŵĂƌ D͕ Ğƚ Ăů͘ WĂƟĞŶƚƐ ǁŝƚŚƐƚĂŐĞ ///ͬ/s ,ŽĚŐŬŝŶ͛Ɛ ĚŝƐĞĂƐĞŝŶ ƉĂƌƟĂů ƌĞŵŝƐƐŝŽŶ ĂŌĞƌ DKWWͬs ĐŚĞŵŽƚŚĞƌĂƉLJ ŚĂǀĞ ĞdžĐĞůůĞŶƚ ƉƌŽŐŶŽƐŝƐ ĂŌĞƌ ĂĚĚŝƟŽŶĂů ŝŶǀŽůǀĞĚͲĮĞůĚ ƌĂĚŝŽƚŚĞƌĂƉLJ͗ ŝŶƚĞƌŝŵ ƌĞƐƵůƚƐ ĨƌŽŵ ƚŚĞ ŽŶŐŽŝŶŐ KZdͲ>' ĂŶĚ 'WD ƉŚĂƐĞ /// ƚƌŝĂů͘dŚĞKZd>LJŵƉŚŽŵĂŽŽƉĞƌĂƟǀĞ'ƌŽƵƉĂŶĚ'ƌŽƵƉĞWŝĞƌƌĞͲĞƚͲDĂƌŝĞͲƵƌŝĞ͘ŶŶKŶĐŽů͘ ϭϵϵϳ͖ϴ^ƵƉƉůϭ͗ϭϭϭͲϭϭϰ͘ 9. ĂƌĚĞW͕ƵƌŐĞƌƐ:D͕,ĞŶƌLJͲŵĂƌD͕ĞƚĂů͘ůŝŶŝĐĂůƐƚĂŐĞƐ/ĂŶĚ//,ŽĚŐŬŝŶ͛ƐĚŝƐĞĂƐĞ͗ĂƐƉĞĐŝĮĐĂůůLJ ƚĂŝůŽƌĞĚƚŚĞƌĂƉLJĂĐĐŽƌĚŝŶŐƚŽƉƌŽŐŶŽƐƟĐĨĂĐƚŽƌƐ͘:ůŝŶKŶĐŽů͘&Ğďϭϵϴϴ͖ϲ;ϮͿ͗ϮϯϵͲϮϱϮ͘ 10. ĂƌĚĞW͕,ĂŐĞŶďĞĞŬ͕,ĂLJĂƚD͕ĞƚĂů͘ůŝŶŝĐĂůƐƚĂŐŝŶŐǀĞƌƐƵƐůĂƉĂƌŽƚŽŵLJĂŶĚĐŽŵďŝŶĞĚŵŽĚĂůŝƚLJ ǁŝƚŚDKWWǀĞƌƐƵƐsŝŶĞĂƌůLJͲƐƚĂŐĞ,ŽĚŐŬŝŶ͛ƐĚŝƐĞĂƐĞ͗ƚŚĞ,ϲƚǁŝŶƌĂŶĚŽŵŝnjĞĚƚƌŝĂůƐĨƌŽŵƚŚĞ ƵƌŽƉĞĂŶKƌŐĂŶŝnjĂƟŽŶĨŽƌZĞƐĞĂƌĐŚĂŶĚdƌĞĂƚŵĞŶƚŽĨĂŶĐĞƌ>LJŵƉŚŽŵĂŽŽƉĞƌĂƟǀĞ'ƌŽƵƉ͘J ůŝŶKŶĐŽů͘Nov 1993;11(11):2258-2272. 11. ĂƌĚĞ W͕ ,ĂLJĂƚ D͕ ŽƐƐĞƚ :D͕ Ğƚ Ăů͘ ŽŵƉĂƌŝƐŽŶ ŽĨ ƚŽƚĂů ŶŽĚĂů ŝƌƌĂĚŝĂƟŽŶ ǀĞƌƐƵƐ ĐŽŵďŝŶĞĚ ƐĞƋƵĞŶĐĞŽĨŵĂŶƚůĞŝƌƌĂĚŝĂƟŽŶǁŝƚŚŵĞĐŚůŽƌĞƚŚĂŵŝŶĞ͕ǀŝŶĐƌŝƐƟŶĞ͕ƉƌŽĐĂƌďĂnjŝŶĞ͕ĂŶĚƉƌĞĚŶŝƐŽŶĞ ŝŶĐůŝŶŝĐĂůƐƚĂŐĞƐ/ĂŶĚ//,ŽĚŐŬŝŶ͛ƐĚŝƐĞĂƐĞ͗ĞdžƉĞƌŝĞŶĐĞŽĨƚŚĞƵƌŽƉĞĂŶKƌŐĂŶŝnjĂƟŽŶĨŽƌZĞƐĞĂƌĐŚ and Treatment of Cancer. E/DŽŶŽŐƌ͘1988(6):303-310.

12. ŽƐƐĞƚ :D͕ ,ĞŶƌLJͲŵĂƌ D͕ DĞĞƌǁĂůĚƚ :,͕ Ğƚ Ăů͘ dŚĞ KZd ƚƌŝĂůƐ ĨŽƌ ůŝŵŝƚĞĚ ƐƚĂŐĞ ,ŽĚŐŬŝŶ͛Ɛ ĚŝƐĞĂƐĞ͘dŚĞKZd>LJŵƉŚŽŵĂŽŽƉĞƌĂƟǀĞ'ƌŽƵƉ͘Ƶƌ:ĂŶĐĞƌ͘1992;28a(11):1847-1850. 13. ŐŚďĂůŝ,͕ZĂĞŵĂĞŬĞƌƐ:͕ĂƌĚĞW͘dŚĞKZdƐƚƌĂƚĞŐLJŝŶƚŚĞƚƌĞĂƚŵĞŶƚŽĨ,ŽĚŐŬŝŶ͛ƐůLJŵƉŚŽŵĂ͘ Ƶƌ:,ĂĞŵĂƚŽů^ƵƉƉů͘:ƵůϮϬϬϱ;ϲϲͿ͗ϭϯϱͲϭϰϬ͘ 14. EŽŽƌĚŝũŬ D͕ ĂƌĚĞ W͕ ƵƉŽƵLJ E͕ Ğƚ Ăů͘ ŽŵďŝŶĞĚͲŵŽĚĂůŝƚLJ ƚŚĞƌĂƉLJ ĨŽƌ ĐůŝŶŝĐĂů ƐƚĂŐĞ / Žƌ // ,ŽĚŐŬŝŶ͛ƐůLJŵƉŚŽŵĂ͗ůŽŶŐͲƚĞƌŵƌĞƐƵůƚƐŽĨƚŚĞƵƌŽƉĞĂŶKƌŐĂŶŝƐĂƟŽŶĨŽƌZĞƐĞĂƌĐŚĂŶĚdƌĞĂƚŵĞŶƚ ŽĨĂŶĐĞƌ,ϳƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚƚƌŝĂůƐ͘:ůŝŶKŶĐŽů͘:ƵůϭϮϬϬϲ͖Ϯϰ;ϭϵͿ͗ϯϭϮϴͲϯϭϯϱ͘

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97. tŝůƐŽŶWt͕͛ŐŽƐƟŶŽZ͕>ĞǀLJ͕ĞůĂŶŐĞƌD͕^ŝůďĞƌƐŚĂƚnj,͕<ĂŶŶĞůt͘WƌĞĚŝĐƟŽŶŽĨĐŽƌŽŶĂƌLJ ŚĞĂƌƚĚŝƐĞĂƐĞƵƐŝŶŐƌŝƐŬĨĂĐƚŽƌĐĂƚĞŐŽƌŝĞƐ͘ŝƌĐƵůĂƟŽŶ͘DĂLJϭϮϭϵϵϴ͖ϵϳ;ϭϴͿ͗ϭϴϯϳͲϭϴϰϳ͘

98. >ŽƌŝŐĂŶW͕ZĂĚĨŽƌĚ:͕,ŽǁĞůů͕dŚĂƚĐŚĞƌE͘>ƵŶŐĐĂŶĐĞƌĂŌĞƌƚƌĞĂƚŵĞŶƚĨŽƌ,ŽĚŐŬŝŶ͛ƐůLJŵƉŚŽŵĂ͗ ĂƐLJƐƚĞŵĂƟĐƌĞǀŝĞǁ͘>ĂŶĐĞƚKŶĐŽů͘Oct 2005;6(10):773-779.