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ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

B r entuximab V edotin

nan nan

B r e n t ux im ab vedo ti n (S GN - 35, A d cetris) is a n ADC c on sisti ng o f t h e a nti -C D30 chim e ri c MAb cAC10 t h at is li nk e d t o t h ree t o fi v e m o lec u les o f t he mic ro t ubu l e - d i s r up ti ng agen t M ono met hy l a u ristati n E (MMAE) . MMA E is a h i gh l y po t en t de ri va ti ve o f do lastati n. Li nk a g e o f MMAE t o cAC 10 o cc ur s t h r ough a p r o t ease - c l e a v a b le li n te r . Bre n t ux ima b v e do ti n is a pprov e d f o r tr ea ti ng sys t e mic , c h em o t h era py -refract o r y a n a p lastic la r ge -cell l y m pho m as ( sA L C L) . It is als o a pp r ov e d t o treat p atie n ts wit h H od g kin l y m pho m a who have p r og r es se d after a n a u t o l ogou s stem cell tra n s p la n t (A SC T). P a ti en t s i ne li g i b l e f o r ASCT m u st h a v e faile d tw o p ri o r m u lti drug c h em o t he r apy r eg im ens. B r e ntux im ab vedo ti n r ece i v e d accelerate d a pp r ov al i n 20 1 1 b ase d i n pa r t on t h e resu lt s o f t wo phase II t rials . I n a m u ltice n ter trial c ondu cte d by Pr o et al ., 58 pa ti en t s w it h r e l ap se d o r refract o r y sALCL recei v e d br e n t ux im ab vedo ti n ( 1.8 m g p er k il og ram p er wee k ) , a nd 86 % o f p atie nts ac h ie v e d ob j ec ti ve r esponse. C o m p lete res pon ses o cc u rre d i n 57 % o f p atie n ts , w it h a m ed i an du r a ti on o f 13.2 m on t h s . A n a dd iti on al 17 p atien ts (29%) had pa rti a l r esponses. M e d ia n ov erall res pon se was 12.6 m on t h s . M o st c o mm on g r ade 3 and 4 adv erse e v e n ts (AE) were n e u tr op e n ia ( 21 %) , t hro m bocy t open i a ( 14 %) , an d p eri ph eral se n s o r y n e u r op at hy ( 12 %) . A simila r t r i a l , i n Hodgk i n l y m pho ma , was re po rte d by Y oun es et al

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

B r entuximab V edotin

nan nan

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

B r entuximab V edotin

nan nan

Patie n ts ( n = 102 ) t ha t had f a i l e d ASCT recei v e d b re n t ux ima b v e do ti n on t h e sam e schedu l e as li s t ed p re v i ou sl y a nd were assesse d f o r t h e ob jecti ve r es pon s e r a t e. I n t h i s se tti ng, 75 % o f p atie n ts h a d ob jecti v e res pon ses , w ith 34% b ei ng co m p l e t e r e mi ss i on s . T h e me d ia n du rati on o f c o m p lete r es pon s es was 20.5 m on t hs, and 31 p atie n ts were p r og ressi on free after a me d ia n f o ll ow - up o f 1.5 yea rs . P h ase III trials t o assess t h e kno w n ris k o f

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

B r entuximab V edotin

nan nan

n e urop a thy ( A ET H E RA ) and t o c on firm ov erall cli n ical b e n efit see n i n t he ph ase II tri a l s (E CH EL ON - 2, o r I d e n tifier N C T01712490 ) a r e ongo i ng.

CONC L USION

nan nan

CONC L USION

CONC L USION

nan nan

In t h e 35 yea r s s i nce Koh l e r and Milstei n first d e v el op e d t h e hyb ri do ma tec hno l ogy t ha t enab l ed an ti body - b ase d t h era p e u tics , t h e fiel d h as ma d e r ema rk a b l e p r og r ess. Nu m e r ou s a n ti body - b ase d m o lec u les are c u rre n tl y in cli n ical t ri a l s and m any m o r e a re i n d e v el op me n t . M u lti p le t h era p e u tic a n ti bod i es have a p r oven c li n ical b e n efit a nd h a v e b ee n lice n se d by t h e F DA. The t hough tf u l app li ca t ion o f a dv a n ces i n ca n cer b i o l ogy a nd a n ti body eng i nee ri ng sugges t t h at t h is p r og ress will c on ti nu e .

CONC L USION

nan nan

Lund J, T akahashi N, Pound JD, et al. Multiple interactions of IgG with its core oligosaccharide can modulate recognition by complement and human Fc gamma receptor I and influence the synthesis of its oligosaccharide chains. J Immunol 1996;157:4963–4969. Umana P , Jean-Mairet J, Moudry R, et al. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activit y . Nat Biotechnol 1999;17:176–180. W right A, Morrison SL. E f fect of glycosylation on antibody function: implications for genetic engineering. T r ends Biotechnol 1997;15:26–32. Ishida T , Joh T , Uike N, et al. Defucosylated anti-CCR4 monoclonal antibody (K W -0761) for relapsed adult T -cell leukemia-lymphoma: a multicenter phase II stud y . J Clin Oncol 2012;30:837– 842. Raghavan M, Bjorkman PJ. Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol 1996;12:181–220. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002;99:754–758. W eng WK, Levy R. T wo immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003;21:3940– 3947. Koene HR, Kleijer M, Algra J, et al. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood 1997;90: 1 109– 1 1 14. Gessner JE, Heiken H, T amm A, et al. The IgG Fc receptor famil y . Ann Hematol 1998;76:231–248. Keler T , Graziano R F , Mandal A, et al. Bispecific antibody-dependent cellular cytotoxicity of HER2/neu-overexpressing tumor cells by Fcgamma receptor type I-expressing e f fector cells. Cancer Res 1997;57:4008–4014. W einer LM, Holmes M, Richeson A, et al. Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. J Immunol 1993;151:2877–2886. Shalaby MR, Shepard HM, Presta L, et al. Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J Exp Med 1992;175:217–225. V alone FH, Kaufman P A, Guyre PM, et al. Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu. J Clin Oncol 1995;13:2281–2292. W einer LM, Clark JI, Davey M, et al. Phase I trial of 2B1, a bispecific monoclonal antibody ta r geting c-erbB-2 and FcgammaRIII. Cancer Res 1995;55:4586–4593. Liu MA, Kranz DM, Kurnick J T , et al. Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes. P r oc Natl Acad Sci U S A 1985;82: 8648–8652. Carter P . Bispecific human IgG by design. J Immunol Methods 2001;248:7–15. Mack M, Riethmuller G, Kufer P . A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicit y . P r oc Natl Acad Sci U S A 1995;92:7021– 7025. Ba r gou R, Leo E, Zugmaier G, et al. T umor regression in cancer patients by very low doses of a T cell-engaging antibod y . Science 2008;321:974–977. Fiedler W , Hönemann D, Ritter B, et al. Safety and pharmacology of the EpCAM/CD3-bispecific BiTE antibody MT 1 10 in patients with metastatic colorectal, gastric, and lung cance r . Eur J Cancer 2009;7:136–137.

CONC L USION

nan nan

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. T rastuzumab after adjuvant chemotherapy in HER2-positive breast cance r . N Engl J Med 2005;353:1659–1672. Romond EH, Perez EA, Bryant J, et al. T rastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cance r . N Engl J Med 2005;353:1673–1684. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29–36. Ewer MS, Gibbs HR, Swa f ford J, et al. Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicit y , syne r gistic or sequential stress, or surveillance artifact? Semin Oncol 1999;26:96– 101. Bang YJ, V an Cutsem E, Feyereislova A, et al. T rastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer ( T oGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687– 697. Gomez-Martin C, Plaza JC, Pazo-Cid R, et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J Clin Oncol 2013;10:4445–4452. Agus DB, Akita R W , Fox WD, et al. T a r geting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127–137. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cance r . N Engl J Med 2012;366:109– 1 19. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEO P A TRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 stud y . Lancet Oncol 2013;14:461–471. Gianni L, Pienkowski T , Im YH, et al. E f ficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammator y , or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:25–32. W aksal H W . Role of an anti-epidermal growth factor receptor in treating cance r . Cancer Metastasis Rev 1999;18:427–436. V an Cutsem ELI, D’haens G. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (metastatic CRC) treated with FOLFIRI with or without cetuximab: The C R YS T AL experience. Abstract 2. J Clin Oncol 2008;26:5s. Bokemeyer CBI, Hartmann J T . KRAS status and e f ficacy of first-line treatment of patients with metastatic colorectal (metastatic CRC) with FOLFOX with or without cetuximab: The OPUS experience. Abstract 4000. J Clin Oncol 2008;26:178s. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525– 1531. L ynch TJ, Patel T , Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010;28: 9 1 1–917. Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibod y , in metastatic colorectal cance r . Clin Colo r ectal Cancer 2006;6:29–31. Amado RG, W olf M, Peeters M, et al. W ild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cance r . J Clin Oncol 2008;26:1626–1634.

IN T RODUCTION

F r om Calipers and Rulers in L ymphoma to the Bidimensional W orld Health Organization Criteria

nan nan

F r om Calipers and Rulers in L ymphoma to the Bidimensional W orld Health Organization Criteria

ASSESSING RESPONSE

nan nan

ASSESSING RESPONSE

ASSESSING RESPONSE

RECIST 1.1

nan nan

RECIST 1.1

ASSESSING RESPONSE

RECIST 1.1

nan nan

Howeve r , a decade o f expe rie n ce wit h RECIST i d e n tifie d se v eral prob lem s w it h t he c rit e ri a, som e o f w h ic h c ou l d b e c o rrecte d. I n RECIS T 1.0, mi n im u m s i ze va ri ed be t w ee n 1 a nd 2 cm d e p e nd i ng on tec hn i qu e; in R E C I ST 1.1, a 1 - c m l es i on i s t h e mi n im u m meas u ra b le . I n RECIST 1.0, 10 lesi on s we r e t o be m easu r ed, 5 p er o r g a n ; RECIST 1.1 re du ce d t h at t o 5 lesi on s , 2 pe r o r gan. Response criteria i n RECIST 1.0 d i d no t a dd ress l y m ph nodes ; i n R E C IST 1.1, l y m ph nod es d ecreasi ng t o <1 cm i n t h eir s hor t a xis cou l d cons tit u t e a co m p lete res pon se . Disease p r og ressi on i n non ta r ge t d i sease was f u rt he r d efi n e d t o i nd icate t h at i n a dd iti on t o a 20 % i n c r ease i n t a r ge t l es i ons ove r t h e smallest s u m on st ud y , t h ere m u st b e a n a b s o l u te i nc r ease o f 5 mm , and t h at a n i n crease o f a si ng le non ta r g et lesi on s hou l d n o t tr u m p an ove r a ll di sease stat u s assessme n t b ase d on ta r g et lesi on s .

ASSESSING RESPONSE

International W orking G r oup Criteria for L ymphoma

nan nan

International W orking G r oup Criteria for L ymphoma

ASSESSING RESPONSE

International W orking G r oup Criteria for L ymphoma

nan nan

Re v ise d gu i de li nes f o r l y m ph oma assessme n t were p r o m u l g ate d by t h e In te rn atio na l W o r k i ng G r oup (IWG) i n 2007 T h ese gu i d eli n es i n c orpor at ed 18 F-fl uo r odeoxyg l u c o se (FDG)-PET assessme n ts i n meta bo li ca ll y ac ti ve l y m phom as . Alt hough a CR re qu ires t h e c o m p lete d isa pp e a r ance o f de t ec t ab l e di sease , a po sttreatme n t resi du al mass is p e r mitte d if it i s nega ti ve on FDG-PET a nd was po siti v e at b aseli n e . F o r l y m pho m as t ha t a r e no t cons i s te n tl y FDG a v i d, o r if FDG a v i d it y is

ASSESSING RESPONSE

International W orking G r oup Criteria for L ymphoma

nan nan

unknown, a CR r equ ir es t ha t nod es >1.5 cm b ef o re t h era py re g ress t o <1.5 cm , a nd nodes t ha t we r e 1.1 t o 1.5 cm i n l ong a x is a nd >1.0 cm i n t h e s h or t a x is s hr i nk t o ≤1.0 c m i n sho rt a x is . T h e d efi n iti on o f PR resem b les t h e WHO c r it e ri a, i n t ha t a ≥50 % d ecrease i n t h e s u m o f t h e p r odu ct o f t h e d iamete rs i n up t o s i x noda l masses o r i n h e p atic o r s p le n ic nodu les m u s t be do c u me n t ed. A lt hough R E C I S T 1.1 no w i n cl ud es l y m ph nod e assessmen t, t h e IWG c rit e ri a r e m a i n t he as sessme n t met hod t yp icall y u se d i n l y m phoma cli n ical t ri a l s.

A L TERN A TE RESPONSE CRI TE RIA

nan nan

A L TERN A TE RESPONSE CRI TE RIA

A L TERN A TE RESPONSE CRI TE RIA

nan nan

Th e pr e v i ous exa m p l es r ep r e se n t attem p ts t o m o re acc u ratel y meas u re t u m or bu r den. E vo l v i ng im ag i ng tec hno l ogy e n a b li ng vo l u metric meas ur em en t s o f t u m o r m ass es ma y e v e n t u all y res o l v e s o me o f t h ese prob lem s, bu t e f f ec ti ve t he r ap e u tic a g e n ts are re qu ire d t o e n a b le v ali d ati on a nd u tili za ti on o f r esponse as sessme n t t oo ls . T h e lac k o f a n a g e n t t h at ca n me d iate subs t an ti a l t u m o r sh ri nk a g e und erlies t h e c on ce p t o f cli n ic a l b e nefit r es pon s e ( CBR ) as an endpo i n t i n p a n creatic ca n ce r . Cli n ical b e n efit wa s d e f i n e d as a co m b i na ti on o f im p r ov eme n t i n p ai n, p erf o rma n ce stat u s , a nd w ei gh t; t he assess m en t o f CB R s uppo rte d t h e U . S . F ood a nd Dr ug Ad mi n i s tr a ti on (F DA ) app r o val o f g emcita b i n e i n p a n creatic ca n ce r

A L TERN A TE RESPONSE CRI TE RIA

nan nan

A L TERN A TE RESPONSE CRI TE RIA

nan nan

Bette r th e r ap i es f o r panc r ea tic ca n cer t h at res u lt i n t u m o r s h ri nk a g e o r e r a d icat ion shou l d i nc l ude and t h e n ecli p se cli n ical b e n efit . Res ponse c rit e ri a m ay be s p ecific t o a p artic u lar d isease o r cli n ical setti ng. So m e d i seases by t he ir n at u re re qu ire s p ecific strate g ies f o r r es pon s e assess m en t .

A L TERN A TE RESPONSE CRI TE RIA

Severity- W eighted Assessment T ool Score in Cutaneous T -Cell L ymphoma

nan nan

Severity- W eighted Assessment T ool Score in Cutaneous T -Cell L ymphoma

A L TERN A TE RESPONSE CRI TE RIA

Pathologic Complete Response in Breast Cancer

nan nan

On e un i que r esponse endpo i n t is t h e assessme n t o f b reast ca n cer treate d i n t h e n e o adj uvan t se tti ng. T he pu r po se o f n e o a d j uv a n t t h era py is t o im p r ove s urv i v al , r ende r l oca ll y advan ce d ca n cer ame n a b le t o s u r g er y , o r t o ai d i n br east c onse r va ti on. I n t ha t set ti ng, t h e a b se n ce o f ca n cer cells i n resecte d br east tis sue has been used t o d efi n e a p at ho l og ic c o m p lete res pon se ( p CR) . Th e r ate o f pCR has been p r opo se d as a s u rr og ate e ndpo i n t f o r e v e n t-free s urv i v al (EFS) o r ove r a ll su r v i v al (OS) t o s uppo rt a pp r ov al o f n ew a g e nts or c o m b i na ti ons o f agen t s t es te d i n cli n ical trials . I n a poo le d a n al y sis o f 1 1,955 pa ti en t s en r o ll ed on 12 n e o a d j uv a n t trials , i nd i v i du al p atie n ts wit h p CR h a d im p r oved EFS and OS . H o we v e r , at t h e trial le v el , p CR rates d id no t c orr el a t e w it h EFS o r O S , a p r ob lem li k el y du e t o h eter og e n eit y o f br east c ance r sub t ypes a m ong t h e trials . Des p ite t h is , p CR rates were r ece n tl y used t o suppo rt t he app r ov al o f p ert u z u ma b a nd trast u z u ma b i n the n e o a d j uvan t se tti ng .

A L TERN A TE RESPONSE CRI TE RIA

Computed T omography-Based T umor Density

nan nan

Computed T omography-Based T umor Density

A L TERN A TE RESPONSE CRI TE RIA

FDG-PET

nan nan

A lt hough w i de l y used i n c li n ical p ractice , FDG-PET h as b ec o me p art o f sta nd a rd i zed r esponse c rit e ri a f o r cli n ical trials on l y i n l y m pho ma (see . I n so li d t u m o r s, FDG-PET ca n ai d i n t h e d etecti on o f n ew o r r ec urr e n t s it es o f d i sease, and ca n b e u se d as a n a d j un ct du ri ng assessme nts for d ise ase p r og r ess i on when u si ng RECIST criteria . Alt hough FDG up ta k e i s a powe rf u l d i agnos tic t oo l a nd its up ta k e reflects a t u m o r ’ s meta bo li c ac ti v it y , it has so m e limitati on s: S o me t u m o rs h a v e v aria b le F DG a v i d it y ; d i f f e r ences can occu r du e t o v ariati on s i n p atie n t acti v it y , ca rbohyd r a t e i n t ake, b l ood g l u c o se , a nd timi ng ; a nd t h ere are se v eral b e n i gn s ou r ces o f up t ake, i nc l ud i ng i n flammat o r y a nd po sts u r g ical sites . M u lti p l e m e t hods o f quan tit a ti ng FDG-PET a nd assessi ng res pon se h a v e

A L TERN A TE RESPONSE CRI TE RIA

FDG-PET

nan nan

b ee n proposed, bu t t o da t e t h ere is no c on se n s u s , p artic u larl y re g ar d i ng t he d e f i n iti on o f a m e t abo li c r espon se . Th e t wo m os t w i de l y used res pon se criteria — t h e E u r op ea n Or g a n isa tion for t h e R esea r ch and T r ea tm en t o f Ca n cer (EO R TC) criteria a nd PET Res pon se C rit e ri a i n S o li d T u m o rs (PERCIST) (see ) —h a v e been e v al u ate d i n spec ifi c d i sease t yp es , bu t un if y i ng FDG-PET res pon se crit e r ia r emai n s a cha ll enge i n an ti can cer d r ug d e v el op me n t . W e w ou l d no te t h at , as shown i n , a 30 % re du cti on i n t h e d iameter o f a s ph er e— t h e ma gn it ude o f change r equi re d t o sc o re a res pon se acc o r d i ng t o RECI ST —r e pr e sen t s a 65 % dec r ease i n vo l u me . If a n sta nd ar d ize d up ta k e v al u e (SUV) dec r ease i s d ir ec tl y equ ate d t o a vo l u me d ecrease , a re du cti on o f 25% t r a ns l a t es t o a 10 % r edu cti on i n d iamete r , a v al u e t h at li k el y c on stit utes an i nsu f fi c i en t r es p on se .

A L TERN A TE RESPONSE CRI TE RIA

nan nan

A L TERN A TE RESPONSE CRI TE RIA

nan nan

In a dd iti on t o i ssues r ega r d i ng se n siti v it y a nd s p ecificit y , t h eir u se a nd

A L TERN A TE RESPONSE CRI TE RIA

nan nan

d e v el opmen t has a l so been h i nd ere d by t h e o fte n limite d efficac y o f t h e r a p ies; r esponse b i o m a r ke rs are o f little v al u e wit hou t h i gh l y e f fecti ve pr ima ry and sa l vage t he r ap i e s . F o r e x am p le , a rece n t cli n ical trial i nd ica tes t h at i n asymp t oma ti c pa ti en t s wit h ov aria n ca n cer w ho se on l y e v i d e n ce o f d isease p r og r ess i on i s an i so late d risi ng CA- 125, no t h i ng is g ai n e d by i n stit u ti ng tr ea tm en t be f o r e t he re is o t h er e v i d e n ce o f p r og ressi on . Ca nc er A nti ge n 125 ( CA - 125 ): Des p ite rec ogn ize d limitati on s , CA- 125 is w i de l y used. F o r exa m pl e , t h e G yn ec o l og ic Ca n cer I n terGr oup (G C IG ) c rit e ri a have evo lve d t o h el p d etermi n e w h et h er a p atie n t ’ s t u m o r has r esponded t o t h era p y . Res pon se is d efi n e d as a 50 % d ecli ne fr o m an e l eva t ed b aseli n e v al u e , w h ereas p r og ressi on is d efi ned as a doub li ng ove r t he nadi r o r t h e upp er limit o f no rmal . I n cli n ical pr acti ce, CA - 125 l eve l s a re f o ll o we d as p art o f sta nd ar d ma n a g eme n t , bu t m ak i ng c li n i ca l dec i s i on s on mar k er c h a ng es al on e is no t r ec o mm ended . P r o s ta t e -Sp ec ifi c A nti ge n (PSA): Similar iss u es h a v e c on fr on te d i nv es t i ga t o r s ca ri ng f o r pat ie n ts wit h p r o state ca n ce r . T h e PSA W o r k i ng Group 1 (P CWG1 ) gu i de lines , first pub lis h e d i n 1999, esta b lis h e d PS A c r ite r i a, pa rti cu l a rl y f o r us e i n p atie n ts wit h d isease t h at was d i f fic u lt to qu a n tif y T he r e f o ll owed a sec ond w o r k i ng g r oup (PCWG 2 ) t h at r ec o mm ended p l o tti ng t he p erce n t PSA c h a ng e f o r eac h p atie n t i n a w ate r f a ll p l o t so as t o avo i d creati ng a d ic ho t o m ou s v aria b le fr o m t h e c h a nges i n PS A P CWG 2 als o rec o mme nd e d k ee p i ng p atie n ts on tri al un til e v i dence o f a change i n cli n ical stat u s — eit h er s y m p t o matic o r r a d i og r aph i c p r og r ess i on. Th e latter a dd resse d c on cer n s wit h p atie n ts in who m PS A changes d i d n ot reflect cli n ical stat u s , p artic u larl y t ho se w ith t r a n si en t i nc r eases i n t he first 12 wee k s o f a n ew t h era p y . Hu m an C h or i o ni c G o n ado t r o pin (hCG) a nd a lph a fet o p r o tein (AFP ): Because t es ti cu l a r ca n cer is a h i gh l y c u ra b le d isease wit h v ali da t ed b i o m a r ke r s, ou t co me assessme n t h as f o c u se d on t h e ra p i d d etec t i on o f pa ti en t s whos e t u m o rs h a v e a poo r res pon se t o t h era p y . Beca use bo t h m a r ke r s hav e relati v el y s ho rt h alf-li v es —2 t o 3 d a y s f o r h C G a nd 5 t o 7 days f o r se r u m AFP — t h e rate o f d ecli n e ca n b e

A L TERN A TE RESPONSE CRI TE RIA

nan nan

d ete r mi ned. V a ri ous m e t hod s h a v e d em on strate d t h at a ra p i d d ecli n e or ea r l y no rm a li za ti on o f m a r k er le v els is i nd icati v e o f a good ou tc o me , w it hou t any one m e t hod a c h ie v i ng wi d es p rea d acce p ta n ce .

A L TERN A TE RESPONSE CRI TE RIA

nan nan

A L TERN A TE RESPONSE CRI TE RIA

nan nan

Non et he l ess, t he 2010 A merica n S o ciet y o f Cli n ical O n c o l ogy (ASC O ) gu i de li nes on se r u m t u m o r mar k ers c on cl ud e d t h ere was still i n s u f fici ent e v i d e nce t o r eco mm end ch a ng i ng t h era py s o lel y on t h e b asis o f a sl ow ma rke r dec li ne . R i s i ng l ev els after tw o c y cles o f t h era py ( ou tsi d e t he f i r st w eek o f tr ea tm en t when rises ca n b e du e t o t u m o r l y sis) ca n b e c on si de r ed an i nd i ca ti on t o c h a ng e t h e treatme n t p la n .

A L TERN A TE RESPONSE CRI TE RIA

Ci r culating T umor Cells and Ci r culating T umor DNA

nan nan

Ci r culating T umor Cells and Ci r culating T umor DNA

A L TERN A TE RESPONSE CRI TE RIA

Ci r culating T umor Cells and Ci r culating T umor DNA

nan nan

A L TERN A TE RESPONSE CRI TE RIA

Ci r culating T umor Cells and Ci r culating T umor DNA

nan nan

Wh et h e r t hese t es t s w ill u ltimatel y p r ov e t o b e m o re se n siti v e a nd acc u r ate t h a n t h e se r u m b i o m a r ke r s d isc u sse d p re v i ou sl y remai n s t o b e d etermi ned. Beca u se t a r ge t ed sequenc i ng ca n b e v er y se n siti v e , on e c on cer n is t h at f alse -pos iti ve c t DNA de t ec ti o n ma y o cc u r after treatme n t , o r i n termitte ntly i n t h e setti ng o f en l a r g i ng t u m o r masses . At t h e least , d etecti on o f CTCs a nd ct D N A i s advanc i ng ou r und ersta nd i ng o f ca n cer b i o l og y , as st ud ies r e v eal e v i dence o f m e t as t a ti c h eter og e n eit y , cl on al h eter og e n eit y , a nd eme r g e nce o f r es i s t ance m u t at i on s i n cli n ical sam p les .

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Overall Response Rate, Duration of Response, and Stable Disease

nan nan

Overall Response Rate, Duration of Response, and Stable Disease

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Overall Response Rate, Duration of Response, and Stable Disease

nan nan

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P r og r ession-F r ee Survival, T ime to P r og r ession, and T ime to T r eatment Failu r e

nan nan

P r og r ession-F r ee Survival, T ime to P r og r ession, and T ime to T r eatment Failu r e

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Overall Survival

nan nan

D e f i n e d as t he tim e fr o m r ando mizati on t o d eat h, OS h as b ee n c on si d ere d t h e go l d s t anda r d o f c li n i ca l t r ial e ndpo i n ts (see ) . I n p art , t h is is s o b eca use it i s una m b i guous and do es no t s u f fer fr o m i n ter p retati on b ias . An a dd iti ona l advan t age o f t h e s u r v i v al e ndpo i n t is t h at it ca n b ala n ce t h e e f f ect of t he r ap i es w it h h i gh t r eatme n t-relate d m o rtalit y e v e n if t u m o r c on t ro l is subs t an ti a ll y be tt e r w it h t h e n ew treatme n t . H o we v e r , s o me worr y t h at b eca use pa ti en t s m ay r ec ei v e m u lti p le li n es o f t h era py f o ll o wi ng t he cli n ical t ri a l , t he r esu lt s m ay b e c on f ound e d by t ho se s ub se qu e n t t h era p i es. Th e latt e r conce r n i s o ft en c it ed as t h e reas on w hy a n a dv a n ta g e i n

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Overall Survival

nan nan

PF S / TT P d i sappears when on e l ook s t o OS . B u t as a re v iew o f cli n ical t r ials c o nfirm s , t he m agn it ud e o f t h e d i f fere n ce do es no t d isa pp ea r , on l y t h e statisti ca l va li d it y ) . Wh e n eva l ua ti ng a r andom ize d c on tr o lle d trial , it is im po rta n t t h at t h e O S as we ll as t he PFS ana l ys es are alwa y s by i n te n ti on t o treat (ITT) . I n an ITT a n a lys i s, o ft en desc ri bed as on ce r ando mize d, a lw a ys ana lyze d , all p atie n ts a ss i gned t o a g r oup at t h e time o f ra ndo mizati on are a n al y ze d r e g a rd le ss o f wha t occu rr ed sub se qu e n tl y A n ITT a n al y sis a vo i d s t h e bias i n t rodu ce d by o mitti ng d r opou ts a nd non c o m p lia n t p atie n ts t h at ca n n e g a te r a ndo mi za ti on and ove r es tim a te cli n ical effecti v e n ess .

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Kaplan–Meier Plots

nan nan

In a t yp i ca l c li n i ca l tri a l , da t a are o fte n p rese n te d as a Ka p la n– Meier p l ots. In d isc re t e tim e i n t e r va l s, t he nu m b er o f p atie n ts i n eac h g r oup w ho are progr ess ion fr ee and a li ve (P F S a n al y sis) o r ali v e (OS a n al y sis) at t h e e nd of t h e i nte r va l a r e coun t ed an d d i v i d e d by t h e t o tal nu m b er o f p atie n ts i n t h at group a t t he beg i nn i ng o f t h e time i n ter v al . O n e e x cl ud es fr o m t h is calc u lati on pa ti en t s censo r ed f o r a reas on o t h er t h a n p r og ressi v e d isease o r d eat h du ri ng t he sa m e i n t e r va l . T h is h as t h e a dv a n ta g e t h at it all o ws on e to i n cl ud e censo r ed pa ti en t s i n es timates o f t h e p r ob a b ilit y o f PFS o r OS up to t h e po i n t when t hey we r e cen s o re d (i . e ., t h e y are e x cl ud e d on l y b e yond t he po i n t of censo ri ng ) . I n m os t cl i n ical trials , a fracti on o f p atie n ts are t yp icall y censo r ed. In c ons tr uc ti ng t he Kap l an– Meier p l o t , p r ob a b ilities are calc u late d f o r eac h i n t e r va l o f tim e. T he p r ob a b ilit y o f s u r v i v i ng p r og ressi on free o r being c oun te d as a su r v i vo r t o t he end o f a ny i n ter v al o f assessme n t is t h e p r o d uct of t h e probab iliti es o f su r v i v i ng i n all t h e p rece d i ng assessme n t i n ter v als m u lti p li ed by t he p r obab ilit y fo r t h e i n ter v al o f i n terest . O n e mi gh t as k t o wh at e x t en t t he t wo cu r ves i n eac h st udy d iffe r . O n e meas u re t h at is o f

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Kaplan–Meier Plots

nan nan

v al u e is t he m ed i an PFS o r O S — a v al u e calc u late d i n m o st st ud ies fr o m a K a p la n–Me i e r p l o t .

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Hazard Ratios

nan nan

In c r easi ng l y , howeve r , haza rd rati o s are cite d i n p refere n ce t o t h e m o re t r a d iti ona l m easu r es o f e f fi ca c y s u c h as t h e me d ia n PFS a nd me d ia n OS . Ho weve r , because a haza r d ra ti o is a v a l u e t ha t ha s no d ime n si on s , it ha s very li m it ed va l ue, i n f orm i ng th e r e ad er on ly wit h r e ga r d t o t h e r eli ab ili ty and un if orm it y o f t he da t a. It do es no t qu a n tif y t h e ma gn it ud e o f t h e b e ne f it. A phy sici an and, espec i a ll y , a p atie n t wa n t t o kno w t h e ma gn it ud e o f t he b e n e f it ( i .e., t he ex t en t t o wh ic h a life will b e p r o l ong e d ) , no t w h at a d ime n si on l ess haza r d r a ti o i s. B y d efi n iti on, t h e ha z a r d r a ti o is a rati o of t h e ha z a r d ra t es . T he haza r d rate qu a n tifies t h e li k eli hood t h at a p atie n t w ill e xp e r ien ce a haza r dous even t o r a h azar d du ri ng a d efi n e d i n ter v al o f ob se rv ati on, and t h i s i s exp r e sse d as a rate o r p erce n t . F o r e x am p le , if dur i ng a g i ven pe ri od o f obse r v ati on 20 o f 100 p atie n ts recei v i ng a r e f e r e n c e o r con tr o l t he r apy exp erie n ce p r og ressi on o r d eat h, t h eir h azar d r ate dur in g t h i s i n t e r va l i s 0.2 ( 20 / 100 ) . If du ri ng t h is same i n ter v al , on l y 10 of t h e 100 pa ti en t s r ece i v i ng the e xp erime n tal t h era py e xp erie n ce progr ess ion o r dea t h, t he ir ha zar d rate is 0.1 ( 10 / 100 ) . I n t h is sim p le e x am p le, t he haza r d r a ti o f o r t h e i n ter v al , calc u late d as t h e r a ti o o f t h e ha z a r d rat es i s 0.5 ( 0.1 / 0.2 ) and i nd icates t h e li k eli hood o f e xp erie n ci ng a h aza rdous even t i s r educed by 50 % i n t h e e xp erime n tal arm . As c o mm only pr ese n te d, and as t h i s s im p l e e x am p le ill u strates , t h e l o wer t h e h azar d ra tio, t h e b ett e r t he expe rim en t a l t h era p y . T o d etermi n e w h et h er t h e h azar d rat io h as stati s ti ca l s i gn ifi cance, on e ca n ( 1 ) u se a l og -ra nk test t o s ho w t h at t he nu ll hypo t hes i s t ha t t he t wo treatme n ts lea d t o t h e same s u r v i v al prob a b iliti es i s w r ong, o r ( 2 ) u se a p arametric a pp r o ac h writi ng a re g ress ion m od el a nd fitti ng t he da t a t o t h e m od el s o t h at on e ca n esta b lis h t h e h azar d r ati o for t he who l e tri a l and it s statistical si gn ifica n ce . I n ma ny cases , t he C ox propo rti ona l haza r d m od el is u se d. Alt hough t h e i d eal h azar d rati o wou l d c ap t u r e t he d i f f e r en ti a l b e n efit t h r oughou t t h e p eri od o f st ud y , i n

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Hazard Ratios

nan nan

pr actice , t he ex tr e m es dep i c t ed i n a Ka p la n– Meier p l o t ma y no t b e a n al y ze d.

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Fo r est Plots

nan nan

In te r est i n de t e rmi n i ng whe t h er t h ere is h eter og e n eit y i n a treatme n t e f fe ct, s u c h t h at be tt e r ou t co m es occu r i n s o me s ubg r oup s , h as le d t o t h e u se o f F or est p l o t s t o d i sp l ay tr ea tm en t e f fects acr o ss s ubg r oup s . Alt hough sim ple i n c on cept , t hese p l o t s a r e sub ject t o err o r b eca u se s ubg r oup s are c o m posed of small e r nu m be r s and t he c o n fi d e n ce i n ter v als are t h eref o re wi d er t h a n t ho se for t he en tir e g r oup. T h e m o st c o mm on p rese n tati on i n cl ud es a v e r tical li ne a t t he no e ff ec t po i n t (e .g., a h azar d rati o o f 1.0 ) , wit h s y m bols of v a ry i ng s i ze r ep r esen ti ng the s ubg r oup s , eac h wit h its c on fi d e n ce i n ter val d e p icte d by a li ne t ha t s tr e t ch es fr o m t h e s y m bo l t o bo t h si d es (t h e s y m bol size is usua ll y p r opo rti ona l t o t h e size o f t h e s ubg r oup ) . If t h e c on fi d e n c e i n te rv al f o r a subg r oup c r osse s t h e no e f fect po i n t , t h is is c o mm on l y i n te rpr ete d ( no t necessa ril y co rrectl y ) as a lac k o f effect i n t h e s ubg r oup. T h e i n f orma ti on one seeks f r o m a F o r est p l o t is w h et h er t h e effect size f or d iffe r e n t subg r oups var i es s i gn ific an tly f r o m t h e m a i n effect , w h ic h is d eter m i ned by a t es t f or he t e r og e n eit y .

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Beyond Dichotomized Data

nan nan

Beyond Dichotomized Data

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Beyond Dichotomized Data

Quality of Life

nan nan

Th e ass ess m en t o f cance r pa tie n ts e n r o lle d on a cli n ical trial ca n b e sai d to c on sist o f t wo se t s o f endpo i n ts: ca n cer ou tc o mes a nd p atie n t ou tc o mes . Ca n ce r ou t co m es m easu r e t h e res pon se o f t h e t u m o r t o treatme n t , t h e dur ati on o f t he r esponse, t he s y m p t o m-free p eri od, a nd t h e earl y rec ogn it ion of r ela pse. I n con tr as t , pa ti en t ou tc o mes assess t h e b e n efit ac h ie v e d wit h a g i v e n t he r apy by m easu ri ng t h e i n crease i n s u r v i v al a nd t h e qu alit y o f lif e (QOL) be f o r e and a ft e r t he r ap y . U n f o rt un atel y , phy sicia n s te nd t o c on ce n t ra t e on cance r -r e l a t ed ou tc o mes , o fte n n e g lecti ng assessme n ts o f QOL. A lt hough a QO L asses sme n t i n cli n ical setti ng s is po ssi b le wit h

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Beyond Dichotomized Data

Quality of Life

nan nan

c urr e n tly ava il ab l e i ns tr u m en ts , t h ere m u st b e c on ti nu e d d e v el op me n t a nd r e f i n eme n t o f t hese i ns tr u m en ts . S u c h d e v el op me n t m u st f o c u s no t on l y on e x t r acti ng va l uab l e i n f o rm a tio n i n a n unb iase d ma nn e r , bu t als o a nd e qually im por ta n t , deve l op i ng an i ns t ru me n t t h at is u ser frie nd l y a nd will b e c o m p let ed i n a h i gh pe r cen t ag e o f e n c oun ters .

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Beyond Dichotomized Data

W aterfall Plots

nan nan

Th e a rb i t r a r y na t u r e o f t he 50% c u t o f f set by M o ertel a nd Ha n le y a nd its e vo l u ti on t o t he cu rr en t R E C IST t h res ho l d o f 30 % re du cti on i n t h e size o f t h e ma x im u m d i a m e t e r r a i ses v ali d qu eries as t o w hy 30 % is v al u a b le an d no t 29% o r 25 % . On t h i s backg r ound, waterfall p l o ts s u c h as t h e on e s hown i n have beco m e increasi ng l y popu lar b eca u se t h e y d e p ict t he b e n e f it o r l ack t he r eo f i n a ll pa tie n ts as a c on ti nuu m o f res pon se , rat h er t han a d ic ho t o mi zed r esponse r a t e W aterfall p l o ts ca n b e g e n erate d fr o m a ny qu a n titati ve assess m en t . If c tDNA o r t u m o r cells p r ov e t o b e as qu a n tita tive as hop e d, t he m ax im u m dec li n e c ou l d b e p l o tte d as a waterfall p l o t .

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Beyond Dichotomized Data

Growth Kinetics

nan nan

E f for ts t o quan tif y t u m o r k i n etic p arameters fr o m cli n ical d ata h a v e b ee n i nv esti g at ed i n r ecen t yea r s. Di f fere n t e qu ati on s h a v e b ee n a pp lie d t o d esc r i b e t he t wo - phase cu r ve b ase d on t u m o r size as ob ser v e d i n m o st s olid t u m or t r i a l s, whe r e t he r e i s first s h ri nk a g e f o ll o we d by re g r o wt h ( ) . Th ese mode l s show exponen tial t u m o r s h ri nk a g e after treatme n t , f o ll o w ed by t u m o r r eg r ow t h t ha t i s e it h er e xpon e n tial o r li n ear a nd h a v e b ee n s ho w n t o c orr elat e w it h O S and t o d iscrimi n ate effecti v e t h era p ies as well as i nd i v i du al pa ti en t s w it h i n tri a ls . A maj o r a dv a n ta g e is t h at m o re o f t he d ata a r e used, r e l a ti ve t o d i cho t o mize d res pon se assessme n t , a nd re g ress ion or growth r a t es can be de t e rmi n e d e v e n i n p atie n ts w ho are ce n s o re d i n a K a p la n–Me i e r ana l ys i s. E qua ti on s t h at m od el bo t h re g ressi on a nd g r o wt h r ates c on firm t he c li n i ca l i n t u iti on t h at resista n t d isease is eme r g i ng e v e n as

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Beyond Dichotomized Data

Growth Kinetics

nan nan

ov e r all tum o r vo l u m e i s r educ e d. F u rt h e r , “t h e strate gy o f st udy i ng t u m o r grow t h k i ne ti cs c ir cu m ven t s on e wea kn ess o f ‘ p r og ressi on criteria , ’ w h i ch is t h at t hey i nhe r en tl y d i cho t o mize a c o m p le x b i o l og ical p r o cess t h at ma y

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Beyond Dichotomized Data

nan nan

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Beyond Dichotomized Data

nan nan

time t o t he nad i r , and t he time t o p r og ressi on o r PFS , a nd t h ese are all ar e all d e p e nden t on t he g r ow t h r a te .

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Beyond Dichotomized Data

nan nan

America ’ s Biopharmaceutical Research Companies. Medicines in Development for Cance r . PhRMA W eb site. Moertel CG, Hanley JA. The effect of measuring error on the results of therapeutic trials in advanced cance r . Cancer 1976;38:388–394. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207–214. Therasse P , Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European O r ganization for Research and T reatment of Cance r , National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205– 216. Eisenhauer EA, Therasse P , Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247. Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol 2004;57:358–365. W en P Y , Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963–1972. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004;15:257–260. W olchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412–7420. Quant EC, W en P Y . Response assessment in neuro-oncolog y . Curr Oncol Rep 20 1 1;13:50–56. Hawkins-Daarud A, Rockne RC, Anderson AR, et al. Modeling tumor-associated edema in gliomas during anti-angiogenic therapy and its impact on imageable tumo r . F r ont Oncol 2013;3:66. Fink J, Born D, Chamberlain MC. Pseudoprogression: relevance with respect to treatment of high-grade gliomas. Curr T r eat Options Oncol 20 1 1;12:240–252. Lin NU, Lee EQ, Aoyama H, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol 2013;14:e396–e406.

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Beyond Dichotomized Data

nan nan

Mabille M, V anel D, Albiter M, et al. Follow-up of hepatic and peritoneal metastases of gastrointestinal tumors (GIST) under Imatinib therapy requires di f ferent criteria of radiological evaluation (size is not everything!!!). Eur J Radiol 2009;69:204–208. Liu L, W ang W , Chen H, et al. EASL- and mRECIS T -evaluated responses to combination therapy of sorafenib with transarterial chemoembolization predict survival in patients with hepatocellular carcinoma. Clin Cancer Res 2014; 20:1623–1631. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586. Bernhard J, Dietrich D, Scheithauer W , et al. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial—SAKK 44/00-CECOG/ P AN.1.3.001. J Clin Oncol 2008;26:3695–3701. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–2413. Mann BS, Johnson JR, He K, et al. V orinostat for treatment of cutaneous manifestations of advanced primary cutaneous T -cell lymphoma. Clin Cancer Res 2007;13:2318–2322. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796–1804. Cortazar P , Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014 [Epub ahead of print]. Bardia A, Baselga J. Neoadjuvant therapy as a platform for drug development and approval in breast cance r . Clin Cancer Res 2013;19:6360–6370. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–1759. Schramm N, Englhart E, Schlemmer M, et al. T umor response and clinical outcome in metastatic gastrointestinal stromal tumors under sunitinib therapy: comparison of RECIS T , Choi and volumetric criteria. Eur J Radiol 2013;82:951–958. Dudeck O, Zeile M, Reichardt P , et al. Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib. Ann Oncol 20 1 1;22:1828–1833. Ronot M, Bouattour M, W assermann J, et al. Alternative response criteria (Choi, European Association for the Study of the Live r , and Modified Response Evaluation Criteria in Solid T umors [RECIST]) versus RECIST 1.1 in patients with advanced hepatocellular carcinoma treated with van der V eldt AA, Meijerink MR, van den Eertwegh AJ, et al. Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer 2010;102:803–809. W ahl RL, Jacene H, Kasamon Y , et al. From RECIST to PERCIS T : evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50:122S–150S.

DETER M INING O UTC OM E

Beyond Dichotomized Data

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Shankar LK, Ho f fman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med 2006;47:1059–1066. Y oung H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EO R TC recommendations. European O r ganization for Research and T reatment of Cancer (EO R TC) PET Study Group. Eur J Cancer 1999;35:1773–1782. Krame r -Marek G, Capala J. Can PET imaging facilitate optimization of cancer therapies? Curr Pharm Des 2012;18:2657–2669. Niederkohr RD, Greenspan BS, Prior JO, et al. Reporting guidance for oncologic 18F-FDG PET/CT imaging. J Nucl Med 2013;54:756–761. Liu Y , Litière S, de V ries EG, et al. The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: results of a survey in the oncology communit y . Eur J Cancer 2014;50:260–266. Rubin EH, Allen JD, Nowak JA, et al. Developing precision medicine in a global world. Clin Cancer Res 2014;20:1419–1427. Parkinson DR, McCormack R T , Keating SM. Evidence of clinical utility: an unmet need in molecular diagnostics for cancer patients. Clin Cancer Res 2014;20:1428–1444. Buyse M, Sa r gent DJ, Grothey A, et al. Biomarkers and surrogate end points—the challenge of statistical validation. Nat Rev Clin Oncol 2010;7:309–317. Karam AK, Karlan B Y . Ovarian cancer: the duplicity of CA125 measurement. Nat Rev Clin Oncol 2010;7:335–339. Rustin GJ, van der Bu r g ME, Gri f fin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EO R TC 55955): a randomised trial. Lancet 2010;376: 1 155– 1 163. V e r gote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Inte r group. J Natl Cancer Inst 2000;92:1534– 1535. Guppy AE, Rustin GJ. CA125 response: can it replace the traditional response criteria in ovarian cancer? Oncologist 2002;7:437–443. Rustin GJ, Quinn M, Thigpen T , et al. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96:487–488. Rustin GJ, V e r gote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Inte r group (GCIG). Int J Gynecol Cancer 20 1 1;21:419–423. Eisenhauer EA. Optimal assessment of response in ovarian cance r . Ann Oncol 20 1 1;22:viii49–viii51. Bubley GJ, Carducci M, Dahut W , et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen W orking Group. J Clin Oncol 1999;17:3461–3467. Scher HI, Halabi S, T annock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical T rials W orking Group. J Clin Oncol 2008;26: 1 148– 1 159. Mazumdar M, Bajorin D F , Bacik J, et al. Predicting outcome to chemotherapy in patients with germ cell tumors: the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therap y . J Clin Oncol 2001;19:2534–2541.

DETER M INING O UTC OM E

Beyond Dichotomized Data

Ca n ce r Pr even ti on and Sc r ee n i ng

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Ca n ce r Pr even ti on and Sc r ee n i ng

DETER M INING O UTC OM E

Beyond Dichotomized Data

T obacco Use a nd the C anc e r Pa t ient

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T obacco Use a nd the C anc e r Pa t ient

IN T RODUCTION

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T ob acc o i s co mm on l y desc ri b e d as t h e la r g est p re v e n ta b le ca u se o f ca n ce r . Ov e r 50 yea r s ago, t obacco w as i n creasi ng l y rec ogn ize d as t h e p rimar y ca u se of l ung cance r , w it h def i n iti v e rec ogn iti on f o r t ob acc o u se as a ca u sati ve f ac t o r i n t he se mi na l 1964 U . S . S u r g e on Ge n eral ’ s Re po rt (SGR) on Sm o ki ng and Hea lt h . Rec e n t e d iti on s o f t h e SGR h a v e d escri b e d t h e w i d es pr e ad adve r se hea lt h e f fects o f t ob acc o on a s p ectr u m o f d iseases , i n cl ud i ng as a causa ti ve agen t f o r a s p ectr u m o f ca n cers . T ob acc o u se is a n a dd ic t i on usua ll y i n iti a t ed i n you t h p ri o r t o t h e a g e o f 18 a nd is d ri v e n by t h e h i gh l y add i c ti ve d r ug, n i co ti n e . As relate d t o t h e ca n cer p atie n t , c on si d e rab l e wo r k has been condu cte d t o ass o ciate t ob acc o u se wit h t h e r isk of d e v el op i ng cance r and ho w t ob acc o cessati on ca n s ub sta n tiall y re du c e ca n ce r risks. Howeve r , t he r e is a relati v e p a u cit y o f e f f o rt t h at h as b ee n p ut for t h t o i den tif y t he e f f ec t s o f sm ok i ng on ou tc o mes f o r ca n cer p atie n ts o r t o esta b l ish m e t hods t o he l p c a n cer p atie n ts qu it sm ok i ng. F o rt un atel y , i n r ece n t y e a r s, t he im po rt ance o f t ob acc o u se by t h e ca n cer p atie n t h as b ee n i n c r easi ng l y r ecogn i zed as an im po rta n t h ealt h b e h a v i o r , i n cl ud i ng a N ati on a l Cance r I ns tit u t e ( N CI) – s pon s o re d c on fere n ce on t ob acc o u se i n 2010, a j o i n t sponso r ed NC I – America n Ass o ciati on o f Ca n cer Researc h (AA CR )–sponso r ed wo r kshop at t h e I n stit u te o f Me d ici n e i n 2012, a nd r ece n t reco mm enda ti ons by t h e AACR a nd t h e America n S o ciet y o f Cli n ical Onco l ogy ( A S CO ) t o a dd ress t ob acc o u se i n ca n cer p atie n ts . The

IN T RODUCTION

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r ece n tl y r e l eased 2014 S GR no w p r ov i d es s ub sta n tial e v i d e n ce b e h i nd t he e f f ects o f s m ok i ng by cance r p atie n ts wit h t h e f o ll o wi ng c on cl u si on s 1. In c ance r pa ti en t s and su r v i vo rs , t h e e v i d e n ce is s u fficie n t t o i n fer a ca u s a l r e l a ti onsh i p be t ween ci g arette sm ok i ng a nd a dv erse h ealt h ou tc o m es. Qu itti ng s m ok i ng im p r ov es t h e p r ogno sis o f ca n cer p atie nts. 2. In c ance r pa ti en t s and su r v i vo rs , t h e e v i d e n ce is s u fficie n t t o i n fer a ca u s a l r e l a ti onsh i p be t ween ci g arette sm ok i ng a nd i n crease d all-ca u s e m or talit y and cance r - spec ific m o rtalit y . 3. In c ance r pa ti en t s and su r v i vo rs , t h e e v i d e n ce is s u fficie n t t o i n fer a ca u s a l r e l a ti onsh i p be t ween ci g arette sm ok i ng a nd i n crease d ris k f o r sec ond p rim a r y cance r s kno w n t o b e ca u se d by ci g arette sm ok i ng, s uch as l ung cance r . 4. In ca nce r pa ti en t s and su r v i vo rs , t h e e v i d e n ce is s ugg esti v e bu t no t s u f f ici en t t o i n f e r a causa l relati on s h i p b etwee n ci g arette sm ok i ng a nd t h e r i sk o f r ecu rr ence, poor er res pon se t o treatme n t , a nd i n crease d t r eatm en t-r e l a t ed t ox i c it y . Th e ove r a ll ob j ec ti ve o f t hi s c h a p ter is t o d isc u ss t ob acc o u se by ca nce r p atie n ts , t he c li n i ca l e f f ec t s o f sm ok i ng i n ca n cer p atie n ts , met hod s t o a ddr ess t obacco use by cancer p atie n ts , a nd areas o f n ee d e d researc h.

NEUR O BI OL OGY OF T OBACCO DEPENDENCE

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N ic o ti ne i s t he p rim a r y add i c ti v e c o m pon e n t o f t ob acc o t h at i n creases e x t r acel lu l a r concen tr a ti ons o f dop ami n e i n t h e nu cle u s acc u m b e n s a nd stim u lat es t he m eso lim b i c dop ami n er g ic s y stem , res u lti ng i n n ic o ti n e ’ s r e w a rd i ng e f f ec t expe ri enced by t ob acc o u sers . D op ami n e r g ic n e uro t r a ns mi ss i on m ay a l so be i nvo l v e d i n t h e assi gn me n t o f i n ce n ti v e salie n ce , o r s tim u l us f o r a p l ea s u re b ase d rewar d, t o t ob acc o u se – relate d e nv i ron m en t a l cue s t ha t ma y b ec o me c ond iti on e d rei n f o rcers o f t ob a cco u se b e hav i o r s. F o r exa m p l e, an i nd i v i du al w ho sm ok es w h ile d ri nk i ng t hei r

NEUR O BI OL OGY OF T OBACCO DEPENDENCE

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m orn i ng co f f ee m ay assoc i a t e c o f fee , o r e v e n ho l d i ng a c o f fee c up i n t h e i r h a nd, w it h t he r ewa r d fr o m smok i ng. T hu s , ci g arette sm ok i ng is d irectl y li nk e d t o ex t e r na l non t obacco - b ase d b e h a v i o ral stim u li . Acti v ati on o f t he nu cle u s accu m bens has f u rt h er b ee n im p licate d i n d r ug rei n stateme n t o r r ela p se I nd i v i dua l s who h a v e qu it t ob acc o u se f o r y ears h a v e restart ed a t ob acc o h ab it s im p l y by s itti ng n e x t t o a sm ok er a nd b ei ng e xpo se d t o sec ondhand s m oke. S ubs t an tial w o r k h as b ee n c ondu cte d on t h e a dd icti ve n at ur e o f t obacco and n i co ti ne, a nd rea d ers are referre d t o se v eral c o m pr e hens i ve r ev i ews on t h is t op ic .

T OBACCO U SE P R E V A LE NCE A ND TH E E V O L UTION OF T OBA C CO PR O DUCTS

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T OBACCO U SE P R E V A LE NCE A ND TH E E V O L UTION OF T OBA C CO PR O DUCTS

T OBACCO U SE P R E V A LE NCE A ND TH E E V O L UTION OF T OBA C CO PR O DUCTS

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M u c h o f t he d i scuss i on on t ob acc o u se e p i d emi o l ogy a nd carci nog e n esi s is pr ese n te d i n

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

T OBACCO U SE BY TH E CANCER P A TIENT

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

Th e pr e va l ence o f cu rr en t s m ok i ng am ong l ong -term a du lt ca n cer s u r v i vo r s a pp ea r s t o have dec li ned i n t h e p ast d eca d e , bu t d ata s ugg est h i gh er rat es of sm ok i ng a m ong cance r su r v i vo rs t h a n i n t h e g e n eral popu lati on .

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

Th ese da t a a r e o ft en b i ased by t h e fact t h at assessme n ts i n ca n cer p atie nts ma y no t i nc l ude cance r pa ti e nts w ho were c u rre n t sm ok ers at t h e time o f d eat h. A s a r esu lt , es tim a t es of sm ok i ng rates i n ca n cer s u r v i vo rs ma y be mislea d in g and m ay unde r es timate tr u e t ob acc o u se p atter n s f o r ca n cer p atie n ts . F u rt he rm o r e, a lt e r na ti v e t ob acc o p r odu cts are o fte n no t assesse d in ca n ce r p ati en t s. Da t a fr o m t h e C h il dhood Ca n cer S u r v i vo r St udy a nd t he 2009 Be hav i o r a l R i sk F ac t o r S u r v eilla n ce S y stem i nd icate t h at a pprox im a t e l y 3 % t o 8 % o f c a n cer s u r v i vo rs u se sm ok eless t ob acc o

T OBACCO U SE BY TH E CANCER P A TIENT

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T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

How e v e r , fi nd i ngs fr o m seve ral st ud ies i nd icate t h at ca n cer p atie n ts are r ece p ti ve t o s m ok i ng cessa ti o n i n ter v e n ti on s e v e n as t h e y c on ti nu e t o sm ok e . , A can ce r d i agnos i s can be u se d as a wi ndo w o f oppo rt un it y , o r te a c hable mom e n t , t o i n t e r vene and p r ov i d e assista n ce i n t h e qu itti ng p r o cess . A r ece n t st udy i n 12,000 cance r p atie n ts , i n cl ud i ng 2,700 p atie n ts w ho sm ok e d, cap it a li zed on t he t e ac h a b le m o me n t a nd d em on strate d t h at les s t h a n 3% o f pa ti en t s who we r e c on tacte d by t h e cessati on p r og ram reject ed t ob acc o c essa ti on ass i s t ance . H o we v e r , on l y 1.2 % o f p atie n ts w ho r ecei v e d a m a il ed i nv it a ti on pa rtici p ate d i n t h e p r og ram . T h is h i gh li gh ts t he i d ea t h a t pa ti en t s m ay be i n t e reste d i n qu itti ng, bu t met hod s s u c h as mai led t ob acc o c essa ti on i n f o rm a ti on ma y no t y iel d effecti v e p artici p ati on by ca n ce r p ati en t s. Once en r o ll ed, p atie n ts a nd cli n icia n s m u st realize t h at alt hough r e l apses i n t he gene ral popu lati on u s u all y o cc u r wit h i n 1 wee k o f cessati on, r e l apses i n cance r p atie n ts ma y b e d ela y e d du e t o ca n cer t r eatme n t – r e l a t ed va ri ab l es su c h as s u r g ical o r o t h er po sttreatme n t h eali ng .

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

T OBACCO U SE BY TH E CANCER P A TIENT

nan nan

C on se quen tl y , it i s im po rt an t t o c on ti nu e o f feri ng t ob acc o assessme n ts a nd cessati on suppo rt f o r cance r s ur v i vo rs h i p e f f o rts .

T OBACCO U SE BY TH E CANCER P A TIENT

Defining T obacco Use by the Cancer Patient

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Defining T obacco Use by the Cancer Patient

T OBACCO U SE BY TH E CANCER P A TIENT

Defining T obacco Use by the Cancer Patient

nan nan

In d eali ng w it h t obacco use b y ca n cer p atie n ts , it is im po rta n t t o no te t h a t v i r t u all y a ll o f t he ev i dence a ss o ciati ng t ob acc o wit h ca n cer treatme n t ou tc o m es dea l s w it h s m ok i ng. Few st ud ies re po rt ass o ciati on s b etwee n o t h e r for m s o f t obacco use ( e. g ., sm ok eless , ci g ars , ci g arill o s) a nd ou tc omes i n ca n cer pa ti en t s. F u rt he rm o re , t h e d efi n iti on o f sm ok i ng acr o ss pub lis hed st ud ies va ri es subs t an ti a ll y . I n st ud ies o f ca n cer p atie n ts , sm ok i ng h as b ee n d efi ned as cu rr en t ( e.g., s m ok i ng after d ia gno sis , at d ia gno sis , i n t he w ee k s be f o r e d i agnos i s, w it h in t h e 12 m on t h s p ri o r t o d ia gno sis , after d ia gno sis , w it h i n t he pas t 10 y ears) , f o rmer (e .g., rece n t , i n terme d iate- , o r l ong- te rm qu it f o r 1 m on t h, 3 m on t h, 6 m on t h, 12 m on t h, 2 y ears , 5 y ear s, 10 y ea r s ), neve r , qu itti ng a ft er d ia gno sis , a nd acc o r d i ng t o e xpo s u re (e .g., m u lti p le pack yea r cu t o f f s, B ri nk ma n i nd e x, y ears o f sm ok i ng, y ears o f sm ok i ng w it h i n a p r ede fi ned p eri od o f time s u c h as 5 y ears p ri o r t o d ia gno sis) . T hough t he nons ta nd ar d met hod o f a dd ressi ng t ob acc o u se i n ca n ce r p ati en t s has been obse r v e d i n se v eral re po rts , – t h ere are no c u rr ent sta nd a rd r eco mm enda ti ons f o r t h e d efi n iti on o f t ob acc o u se by a ny n ati onal o r g a n izati on. T he r e a r e f ou r p rimar y cate go ries f o r sm ok i ng stat u s: 1. N e ver s m o kin g i s t yp i ca l ly d efi n e d as h a v i ng sm ok e d less t h a n 100 ci g a re tt es i n a pe r son ’ s lifetime a nd no c u rre n t ci g arette u se . T h ese p atie n t s a r e gene r a ll y cons i d ere d as a refere n ce g r oup i n ma ny st ud ies . Cate go ri es 2 t h r ough 4 r equ ire t h at a p ers on h as sm ok e d at least 100 ci g a re tt es i n t he ir lif e tim e. 2. Fo rm er s m o kin g i s t yp i c all y d efi n e d as no c u rre n t ci g arette u se , u s u all y w it h i n t he pas t yea r . 3. R ecent s m o kin g ( o r r ecen t qu it) is g e n erall y d efi n e d as h a v i ng st opped sm o ki ng w it h i n t he r ecen t p ast , t yp icall y f o r a p eri od o f 1 wee k t o 1 y ea r . 4. C ur r e nt s m o kin g i s t yp i c all y d efi n e d as sm ok i ng on e o r m o re ci g a re tt es pe r day eve r y d a y o r s o me d a y s . E ver s m ok i ng i s a co m b i n ati on o f cate go ries 2 t h r ough 4 (i . e ., f o rme r , r ece n t , a nd cu rr en t s m oke r s ) t h at h as b ee n u se d t o re po rt n e g ati v e ass o ciat ions be t ween s m ok i ng a nd ca n cer ou tc o mes i n a nu m b er o f

T OBACCO U SE BY TH E CANCER P A TIENT

Defining T obacco Use by the Cancer Patient

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st ud ies De fi n i ng s m ok i ng acc o r d i ng t o ever sm ok i ng stat u s limits t he a b ilit y t o i n t e r p r e t t he e f f ec t s o f c u rre n t sm ok i ng on a cli n ical ou tc o me , and no t h i ng can be done t o add r es s a p ri o r t ob acc o u se h ist o r y . H o we v e r , d e f i n i ng exposu r e acco r d i ng t o c u r r e n t sm ok i ng stat u s all o ws f o r t h e a n al y sis o f po t en ti a ll y r eve r s i b le effects as well as f o r t h e po te n tial im p lem en t a ti on o f s m ok i ng ce ssati on t o p re v e n t t h e a dv erse ou tc o mes of sm ok i ng on cance r pa ti en t s. T h e p rimar y f o c u s f o r t h e remai nd er o f t h is c h a p te r will be on cur r en t s m ok i ng a nd will i n cl ud e a d isc u ssi on o f met hod s t o add r ess t obacco u se wit h t h e ca n cer p atie n t t h r ough acc u rate assessme n t s and s tr uc t u r ed t ob acc o cessati on s uppo rt .

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

nan nan

Ca n ce r tr ea tm en t i s gene r a ll y d efi n e d acc o r d i ng t o d isease site , sta g e , t r eatme n t t ype ( e.g., su r ge r y , c h em o t h era py [CT] , ra d i o t h era py [ R T] , o r b i o l og ic t he r apy ) , and p rim a r y treatme n t ob jecti v e , s u c h as c u re o r p alliati on. A co m p r ehens i ve d isc u ssi on o f t h e effects o f sm ok i ng on ca nce r p atie n ts is beyond t he scope o f a si ng le c h a p te r , bu t t h e 2014 SGR p r ov i des a n e x cell en t ev i dence base, con cl ud i ng t h at “t h e e v i d e n ce is s u f ficie n t t o i nf e r a c ausa l r e l a ti onsh i p be t w ee n ci g arette sm ok i ng a nd a dv erse h ealt h ou tc o m es. Ove r a ll , app r ox imatel y 75 % t o 80 % o f st ud ies i n t h e SGR d em on st ra t ed a nega ti ve asso ciati on b etwee n sm ok i ng a nd ou tc o me , with a pprox im a t e l y 65 % t o 70 % of st ud ies d em on strati ng statisticall y si gn ifi cant n e g ati v e assoc i a ti ons. T h i s chap ter will p r ov i d e a n ill u strati v e re v iew o f st ud ies t ha t de m ons tr a t e t he adv erse effects o f t ob acc o acr o ss d isease sit es a nd t r ea t m en t m oda liti es ( e.g., s u r g er y , C T , R T) , a nd e f fects will b e d isc u sse d ac r oss t he ca t ego ries o f m o rt a lit y , r ec u r r e n ce and c an ce r - r el ated mo rt a lit y , t ox i c it y , and r i sk o f a sec ond p rim a ry c an ce r . E v i d e n ce f o r t he b e n e f its o f s m ok i ng cessa ti on will als o b e p rese n te d wit h i n eac h secti on.

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Overall Mortality

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The Effect of Smoking on Overall Mortality

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Overall Mortality

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Overall Mortality

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Overall Mortality

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Nu m e r ous s t ud i es have de m on strate d t h at c u rre n t sm ok i ng i n creases ov e r all m o rt a lit y as co m pa r ed wit h f o rmer a nd n e v er sm ok ers c o m b i ned. , T h e a dv erse e f fects o f sm ok i ng c o m p are d with for me r and neve r s m oke r s not on l y reflect t h e n e g ati v e effects o f sm ok i ng on m or talit y as a who l e, bu t a ls o d em on strate t h at t h e e f fects o f sm ok i ng a r e r e v e r si b l e. Cu rr en t s m ok i ng i n crease d m o rtalit y ris k as c o m p are d wit h p atie n ts w ho qu it w it h i n t he ye a o r 1 t o 3 m on t h s p ri o r t o d ia gno sis .

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Overall Mortality

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

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Th e pr i ma r y ob j ec ti ve o f can cer t h era py is t o c u re ca n cer a nd p re v e n t r ec urr e nce. Howeve r , s m ok i ng h as b ee n s ho w n t o i n crease ca n cer r ec urr e nce and cance r -r e l a t ed m o rtalit y . Acr o ss a b r o a d s p ectr u m o f ca n c e r p atie n ts , cu rr en t s m ok i ng i nc r e ase d ca n cer m o rtalit y as c o m p are d wit h for me r and neve r s m oke r s . C u rre n t sm ok i ng h as b ee n s ho w n t o i n creas e

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

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ca n ce r m o rt a lit y i n pa ti en t s wi t h h ea d a nd n ec k ca n ce r b reast ca n ce r gas tr o i n t es ti na l can cers , p r o state ca n ce r ,

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

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gyn ec o l og i c cance r s , a nd l ung ca n ce r Ca n cer rec u rre n ce , wh et h e r l oca l o r m e t as t a ti c, i s a k e y d ri v er b e h i nd ca n cer-relate d m o rtali t y . Se v e r al s t ud i es de m ons tr a t e t h at c u rre n t sm ok i ng i n creases t h e ris k o f r ec urr e nce and dec r eases r espon se acr o ss m u lti p le d isease sites . ,

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer Recur r ence and Cance r -Related Mortality

nan nan

Th e e f f e c t s o f s m ok i ng on i n creasi ng rec u rre n ce o r ca n ce r -relate d m o rta lity h a v e als o been r epo rt ed i n se veral relati v el y rare ca n cers . I n a r ema rk a b l e r epo rt o f pa ti en t s w it h rec u rre n t h ea d a nd n ec k ca n cers treate d w it h sal vage su r ge r y , con ti nu e d sm ok i ng after sal v a g e treatme n t c on ti nu e d t o i n c r e ase t he ri sk o f ye t anoth er rec u rre n ce by 42 % . T h e stri k i ng n atur e of t h is l as t s t udy h i gh li gh t s t h e c on ti nu e d ris k s e v e n i n rec u rre n t ca n cer p atie n ts a nd t he r es ili ence w it h w h ic h s o me ca n cer p atie n ts will c on ti nue to sm ok e . Th e e f f ec t s o f s m ok i ng a r e als o no te d i n p remali gn a n t lesi on s . I n p atie n ts wit h h i gh - g r ade vu l v ar i n trae p it h elial n e op lasia , c u rre n t sm ok i n g i n c r ease d t he ri sk o f pe r s i s t en t d isease after t h era py by 30 -f o l d . I n a pro s p ecti ve tri a l o f p r oges t e r on e t o treat cer v ical i n trae p it h elial n e op lasia ( C IN), c u rr en t s m ok i ng i nc r e ase d t h e ris k o f p r og ressi on as c o m p are d wi th for me r and neve r s m oke r s co m b i n e d . A p r o s p ecti v e trial o f 516 l o w- gr a d e cer v i ca l i n tr aep it he li a l ne op lasia p atie n ts d em on strate d t h at c u rre nt sm ok i ng dec r eased r esponse by 36 % , alt hough a similar effect was als o no te d i n f o rm e r s m oke r s . A s no t ed w it h ove r a ll m o r t alit y , se v eral st ud ies d em on strate d t h at t h e e f f ects o f cu rr en t s m ok i ng a re w o rse t h a n t h e e f fects o f f o rmer sm ok i ng and t h at t h e e f fects o f sm ok i ng ma y b e ac u te ly r e v e r si b l e. S eve r a l s t ud i es a l so d em on strate t h at c u rre n t sm ok i ng i n crea ses r ec urr e nce o r cance r m o rt a lit y , w h ereas f o rmer sm ok i ng h as no si gn ifica nt e f f ect . , – T h e ac u tel y re v ersi b le e f fects o f sm ok i ng wer e s hown by B r ow m an e t a l . w ho d em on strate d t h at c on ti nu e d sm ok i ng i n c r ease d t he ri sk o f cance r -r e late d m o rtalit y by 23 % as c o m p are d wit h p atie n ts w ho qu it w it h i n 12 w ee k s o f starti ng R T . I n 284 c o l o rectal ca n c e r p atie n ts , s m ok i ng a t t he fir s t po st op erati v e v isit i n crease d t h e ris k o f ca nce r

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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The Effect of Smoking on Cancer T r eatment T oxicity

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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D isc u ssi on o f t he e f f ec t s o f smok i ng on ca n cer treatme n t t ox icit y is h i ghly d e p e nd e n t upon d i sease s it e, treatme n t m od alit y (e .g., s u r g er y , C T , R T) , a nd timi ng of t ox i c it y . Ac r oss d i s ease sites a nd treatme n ts , c u rre n t sm ok i ng has b ee n s hown t o i nc r ease co m p licati on s fr o m s u r g er y pu lm on ar y c o m p lic a ti ons , t ox i c it y fr o m R T , – m u c o sitis , ho s p italizati on

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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a nd v as o m o t o r sy m p t o m s O n e o f t h e la r g est rece n t st ud ies i n ov er 20,000 gas tr o i n t es ti na l , pu lm on ar y , a nd u r o l og ic p atie n ts d em on strates th at for me r o r cu rr en t s m ok i ng i n crease d t h e ris k o f s u r g ical site i n fecti on, pu lm ona r y co m p li ca ti ons, o r 30 - d a y m o rtalit y i n a site-s p ecific ma nn e r .

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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Th e e f f e c t s o f cu rr en t s m ok i n g were m o st si gn ifica n t f o r pu lm on ar y c o m p lic a ti ons whe r e f o rm e r s m ok i ng h a d a lesser o r non si gn ifica n t e f fe ct. In 13,46 9 l ung cance r pa ti en t s treate d wit h s u r g er y , c u rre n t sm ok i ng i n c r ease d t he ri sk o f pos t ope r a ti v e d eat h wit h no i n crease d ris k i n f o rmer sm ok e r s Cu rr en t s m ok i ng i n crease d t h e ris k o f c o m p licati on s , m o r b i dit y , or r e op er a ti on f o ll ow i ng esoph a g ect o m y , p a n createct o m y , o r c o l o rectal s u r g e r y . A s t udy o f 836 p r o state ca n cer p atie n ts treate d wit h R T d em on st ra t ed t ha t cu rr en t s mo k i ng i n crease d a bdo mi n al cram p s , rectal u r g e n c y , d i a rr hea, i nco m p l e t e em p t y i ng, a nd s udd e n em p t y i ng b etwee n

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Cancer T r eatment T oxicity

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t wo- a nd n i ne -f o l d , w it h s i m ilar e f fects no te d i n 3,489 cer v ical ca n cer p atie n ts w ho s m oked m o r e t h a n 1 p ac k p er d a y (PPD) . Se v e ra l s t ud i es have de m on strate d t h at t h e effects o f sm ok i ng on ca nce r t r eatme n t t ox i c it y a r e r eve r s i b le . St opp i ng sm ok i ng wit h i n 3 wee k s o f s u r g e ry r educed wound hea li ng c o m p licati on s i n es oph a g eal ca n cer p ati ents t r eate d w it h su r ge r y and r econ str u cti on . I n 393 T 1 lar yng eal ca n cer p atie n ts t r ea t ed w it h R T , qu itt ing sm ok i ng after d ia gno sis re du ce d lar yngeal c o m p lic a ti ons as co m pa r ed w it h c on ti nu e d sm ok i ng . I n a la r g e st udy o f 7,990 l ung cance r pa ti en t s fr o m t h e S o ciet y o f T ho racic S u r g e on s Data b a se, c urr e n t s m ok i ng i nc r eased t h e ris k o f pu lm on ar y c o m p licati on s by 80 % and ho s p ital m o rt a lit y 3.5 -f o l d . H o we v e r , sm ok i ng cessati on f o r 2 wee k s elimi n at ed t he ri sks f o r pu lm on ar y c o m p licati on s , a nd cessati on f o r 1 m onth elimi n at ed ri sks f o r hosp it a l m o rtalit y . V a po rci y a n et al als o s ho we d t hat c urr e n t s m ok i ng i nc r eased t h e ris k o f pu lm on ar y c o m p licati on s 2.7 -f o l d as c o m p a red w it h s m ok i ng cess ati on f o r at least 1 m on t h p ri o r t o s u r g er y . I n a st r i k i ng exa m p l e o f t he po t ent iall y re v ersi b le effects o f sm ok i ng i n 205 h ea d a nd neck cance r pa ti en t s treate d wit h R T 43 % o f sm ok i ng p atie nts t r eate d i n t he m o r n i ng expe rie n ce d Gra d e 3+ m u c o sitis c o m p are d wit h 72 % of sm oke r s tr ea t ed i n t he a ft ernoon ( p = 0.04 ) . T h ese d ata s ugg est t h at r e du ci ng s m ok i ng ove r n i gh t m a y y iel d a cli n ical b e n efit i n re du ce d t ox i cit y . Wh e r ea s a ll t ox i c it y m ay no t be ac u tel y re v erse d, t h ese e n c ou ra g i ng d at a s how t h at pa ti en t s can m ake c li n icall y mea n i ng f u l im p r ov eme n ts i n t h eir h ealt h an d o r cance r tr ea tm en t wit h i n a s ho rt time frame by qu itti ng sm ok i ng.

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Risk of Second Primary Cancer

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The Effect of Smoking on Risk of Second Primary Cancer

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Risk of Second Primary Cancer

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Se v e r al s t ud i es have r epo rt ed t h e e f fects o f sm ok i ng on t h e ris k o f d e v el oping a second p rim a r y ca n ce r . Par k et al . re po rte d on ov er 14,000 male ca nce r pa ti en t s and de m on strate d t h at c u rre n t sm ok i ng i n crease d t he r is k of deve l op i ng a second t ob acc o -relate d p rimar y ca n cer tw o f o l d, wit h no i n c r e ased ri sk i n f o rm e r s m ok ers . A h i gh er ris k was ob ser v e d i n i n head a nd n ec k cance r pa ti en t s who sm ok e d m o re t h a n 10 ci g arettes p er d a y , with

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Risk of Second Primary Cancer

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no i n c r e ased ri sk i n li gh t e r s m ok ers . Ki no s h ita et al . s ho we d a n 82 % i n c r ease d ri sk o f deve l op i ng a sec ond p rimar y i n g astric ca n cer p atie n ts who a r e cu rr en t s m oke r s w it h no i n crease d ris k i n f o rmer sm ok ers . I n t he ph ase III r ando mi zed tri a l o f is o treti no i n f o r t h e p re v e n ti on o f a sec ond pr ima ry t u m o r i n 1,190 head and n ec k ca n cer p atie n ts , c u rre n t sm ok i ng i n c r ease d t he ri sk o f a second p rimar y by 2.2 -f o l d wit h a non si gn ifica n t t r e nd of 1.6 -f o l d i n f o rm e r s m ok ers . N o ta b l y , 39 % o f p atie n ts w ho r e por te d qu itti ng w it h i n t he p re v i ou s y ear were b i o c h emicall y c on firme d sm ok e r s As a r esu lt , t hese d ata c o llecti v el y s ugg est t h at s o me o f t h e i n c r ease d ri sk m ay be b i ased by c on ti nu e d sm ok i ng i n p atie n ts w ho d e ny sm ok i ng by se lf-r epo rt . Th e e f f ec t s o f s m ok i ng on t h e ris k o f a sec ond p rimar y ca n cer are als o no te d i n non t obacco -r e l a t ed can cers a nd i n l ong -term s u r v i vo rs . I n 835 br east c ance r pa ti en t s, s m ok in g i n crease d t h e ris k f o r t h e d e v el op me n t of l ung met as t ases a ft e r b r eas t c a n cer by m o re t h a n t h reef o l d . F o r d et al

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

The Effect of Smoking on Risk of Second Primary Cancer

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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Human Papilloma V irus, Epidermal G r owth Factor Recepto r , Anaplastic L ymphoma Kinase, P r ogrammed Cell Death P r otein 1, and Smoking

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Human Papilloma V irus, Epidermal G r owth Factor Recepto r , Anaplastic L ymphoma Kinase, P r ogrammed Cell Death P r otein 1, and Smoking

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Human Papilloma V irus, Epidermal G r owth Factor Recepto r , Anaplastic L ymphoma Kinase, P r ogrammed Cell Death P r otein 1, and Smoking

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D ata ove r t he pas t decade has s ho w n t h at h ea d a nd n ec k ca n cers t h at are hu ma n pap ill o m a v ir us ( H P V ) po siti v e are kno w n t o h a v e a n im p r ov e d progno si s as co m pa r ed w it h HP V - n e g ati v e t u m o rs . Patie n ts w ho h a v e H P V -po siti ve t u m o r s t yp i ca ll y h a v e i n crease d p16 e xp ressi on a nd o fte n r es pond be tt e r t o conven ti ona l ca n cer t h era p y , i n cl ud i ng R T a nd C T . Man y H P V -po siti ve pa ti en t s a r e nev er sm ok ers o r h a v e a li gh ter sm ok i ng h ist o r y . How e v e r , s m ok i ng was an i nd e p e nd e n t a dv erse ris k fact o r f o r bo t h ov er all a nd ca nce r -r e l a t ed m o rt a lit y w it h a 1 % i n crease i n ris k p er p ac k - y ear sm ok e d. Cu rr en t s m ok i ng i n crease d ca n cer m o rtalit y a pp r ox imatel y f i v e fo l d even i n p16 - pos iti ve p atie n ts treate d wit h s u r g er y . Sm ok i ng al so i n c r ease d t he ri sk o f deve l op i ng sec ond p rimar y ca n cer i n bo t h HP V - po siti v e and H P V - nega ti ve pat ie n ts . As a c on se qu e n ce , t h e p rese n ce o f H P V does no t appea r t o negat e t h e a dv erse e f fects o f sm ok i ng.

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Human Papilloma V irus, Epidermal G r owth Factor Recepto r , Anaplastic L ymphoma Kinase, P r ogrammed Cell Death P r otein 1, and Smoking

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A si m il a r e f f ec t i s no t ed i n l ung ca n cer p atie n ts wit h e p i d ermal g r o w th f act or r ec ep t o r (E G F R )-m u t a t ed o r a n a p lastic l y m pho ma k i n ase (ALK)-m u tate d t u m o r s. As w it h H P V - po siti v e h ea d a nd n ec k ca n cer p atie n ts , l ung ca n ce r p ati en t s who a r e li gh t o r n e v er sm ok ers h a v e a h i gh er rate o f EG F R- po siti v e t u m o r s t ha t m ay r espond t o b i o l og ic t h era py u si ng EGFR t y r o si ne– k i n ase i nh i b it o r s. A t t h i s tim e, m o st i n f o rmati on re g ar d i ng EGFR- b ase d t h e r a py f o r l ung cance r r epo rts on t h e e f fects o f e v er sm ok i ng d em on st ra ti ng t ha t eve r s m ok ers h a v e a d ecrease d res pon se t o EGFR t h e r a p y . E a rl y , l a r ge, r ando mize d trials d em on strate t h at T arce v a (erl o ti nib ) a nd Ir ess a ( ge fiti n i b ) p r ov i de s u r v i v al a nd t u m o r c on tr o l b e n efits s p eci f ic a ll y i n neve r s m oke r s A v er y similar p atter n is no te d f o r A LK - po siti v e pa ti en t s w it h a m uch h i gh er i n ci d e n ce i n n e v er sm ok ers a nd h i gh r es pon s e r a t e t o t he A L K k i n ase i nh i b it o r criz o ti n i b . Pai k et al h a v e d esc r i b e d t he im po rt ance o f dr i v er m u tati on s i n EGFR , ALK , a nd KRA S d em on st ra ti ng t ha t s m oke r s hav e a h i gh er p re pond era n ce f o r K-ras d ri v e rs, wh e r eas nons m oke r s t end t o h a v e EGFR o r ALK d ri v er m u tati on s . I n g e n e r al , pa ti en t s who a r e s m ok ers ma y b e b est ser v e d wit h c onv e n ti on al ca n ce r tr ea tm en t s r a t he r t han th ese b i o l og ic t h era p ies , bu t ra ndo mize d c on t ro ll ed tri a l s con firmi ng t h is s ugg esti on are lac k i ng at t h is time . A lt hough t he r e a r e essen ti a ll y no b i o l og ic t h era p ies t h at h a v e s ho w n to h a v e a be tt e r r esponse i n s m ok ers , t h ere are e x citi ng d ata p rese n te d at t he 2013 Eu r opean CanCe r O r gan izati on (ECCO) a nnu al c on fere n ce , s ugg esti ng t ha t an ti –p r og r a m m e d cell d eat h p r o tei n 1 (PD- 1 ) –b ase d t h e r a p ies m ay have a be tt e r res pon se rate i n sm ok ers . T h ese v er y pr elimi n ar y da t a have ye t t o be re p licate d o r e xp a nd e d i n t o ra ndo mize d t r ials , bu t if expanded tri a l s p r ov e e f fecti v e , t h e y ma y re p rese n t on e o f t he on l y ca nce r tr ea tm en t s t ha t ma y s p ecificall y b e n efit sm ok ers .