Relation of Tumor Size, Lymph Node Status, and Survival in

Transcription

1 Reltion of Tumor Size, Lymph Node Sttus, nd Survivl in 24,74 Brest Cncer Cses CHRISTINE L. CARTER, PHD, MPH,* CAROL ALLEN, PHD,t AND DONALD E. HENSON, MD* Two of the most importnt prognostic indictors for brest cncer re tumor size nd extent of xillry lymph node involvement. Dt on 24,74 cses recorded in the Surveillnce, Epidemiology, nd End Results (SEER) Progrm of the Ntionl Cncer Institute were used to evlute the brest cncer survivl experience in representtive smple of women from the United Sttes. Acturil (life tble) methods were used to investigte the 5yer reltive survivl rtes in cses with known opertive/pthologic xillry lymph node sttus nd primry tumor dimeter. Survivl rtes vried from 45.5% for tumor dimeters equl to or greter thn 5 cm with positive xillry nodes to 96.3% for tumors less thn 2 cm nd with no involved nodes. The reltion between tumor size nd lymph node sttus ws investigted in detil. Tumor dimeter nd lymph node sttus were found to ct s independent but dditive prognostic indictors. As tumor size incresed, survivl decresed regrdless of lymph node sttus; nd s lymph node involvement incresed, survivl sttus lso decresed regrdless of tumor size. A liner reltion ws found between tumor dimeter nd the percent of cses with positive lymph node involvement. The results of our nlyses suggest tht disese progression to distnt sites does not occur exclusively vi the xillry lymph nodes, but rther tht lymph node sttus serves s n indictor of the tumor's bility to spred. Cncer 63:181187, UMEROUS STUDIES, done in mny countries, hve shown the vlue of using tumor size nd nodl sttus to estimte prognosis in brest cncer. 'I5 These observtions re so universlly ccepted s to form the bsis of the TNM stging tht is promulgted by the Americn Joint Committee on Cncer (AJCC) nd the Interntionl Union Aginst Cncer (UICC). This stging system uses three vribles: dimeter of the primry lesion (T), number of lymph nodes involved with the metsttic tumor (N), nd distnt metsttis (T). It is lso widely ccepted tht ge, rce, histologic type, hormonl receptor sttus, nd number of other significnt vribles my influence n individul's prognosis The reltion between tumor size, lymph node sttus nd outcome hs been qulittively known for mny yers. Fisher et l., in study of 2578 brest cncer ptients, found reltion between size, nodl sttus nd outcome bck in However, these uthors concluded tht size lone ws not s consequentil to the ptient's From the *Cncer Prevention Studies Brnch, nd $Community Oncology nd Rehbilittion Brnch, Division of Cncer Prevention nd Control, Ntionl Cncer Institute, Bethesd, Mrylnd;?Deprtment of Helth Services, Stte of Connecticut, Hrtford. 4ddress for reprint: Christine L. Crter, PhD, MPH, Ntionl Cncer Imtitute, Division of Cncer Prevention nd Control, Cncer Prevention Studies Brnch, Blir Bldg. 61, 9 Rockville Pike, Bethesd, MD ccepted for publiction July 11, survivl s were the other fctors.24 Vlguss et l. studied 716 ptients in 1978 nd noted tht survivl rtes were directly proportionl to the size of the primry tumor in node positive cses, but not in nodenegtive ptients.25 These uthors were not ble to quntittively relte size with nodl sttus nd survivl, owing in prt to reltively smll smple sizes nd in prt to the lck of popultion bsed comprison group. No effort ws mde to relte the number of positive nodes to the number of nodes exmined in these erlier studies. In limited series of ptients from the SEER progrm, Smrt nd coworkers in 1978 reported liner reltion between tumor size nd lymph node involvement.26 Since 1973, the Surveillnce, Epidemiology nd End Results (SEER) Progrm of the Ntionl Cncer Institute hs collected dt on the cncer survivl experience of nerly 1% of the generl popultion of the United Sttes. This is ccomplished through the mintennce of nine SEER popultion bsed registries tht cover five sttes nd four metropolitn res (Connecticut, Hwii, Iow, New Mexico, Uth, Atlnt, Detroit, Sn FrnciscoOklnd, nd SettlePuget Sound). Cses in these ctchment res represent crosssection of cncer cses in the generl medicl prctice. The Seer smple is composed of 85% white nd pproximtely 8% blck, with 16% being less thn 5 yers old, 47% in the 5 to 69 yer ge rnge, nd 37% being 7 yers or older. In 1977, SEER registries begn to code tumor size nd lymph node sttus in form 181

2 182 CANCER Jnury Vol. 63 TABLE 1. Study Criteri for Brest Cncer Survivl Anlysis Cses dignosed between ,316 Excluded Study exclusions* 11,531 Cses with <8 lymph nodes exmined 18,481 Selected for study Pthologic lymph node sttus nd tumor size recorded 24,74 * Study exclusions: mle cses, cses with rce unknown, crcinoms in situ, no microscopic confirmtion, distnt metstsis t dignosis, brest cncer is not first primry, nd disese informtion ppers only on deth certificte. suitble for our nlysis. In this report, we hve used the SEER dt to nlyze the survivl experience of over 24, women newly dignosed with brest cncer between 1977 nd We investigted the quntittive reltion between size nd xillry lymph node sttus to brest cncer survivl in these women who were drwn from wide rnge of medicl prctice. Cse Selection nd Methods Dt from the SEER Progrm of the Ntionl Cncer Institute were used in the nlysis of brest cncer ptient survivl. Detils of the purposes, functions, nd procedures for SEER hve been published el~ewhere.~ A totl of 63,316 brest cncer cses dignosed between Jnury 1, 1977 nd December 31, 1982 nd under ctive followup until December 31, 1983 met our eligibility criteri (Tble 1) of microscopicly confirmed, first primry brest cncer in women. Of these cses, 24,74 hd recorded opertive/pthologic primry tumor dimeter nd t lest eight lymph nodes exmined nd were thus selected for extended nlysis. Selected cses included tumors recorded s microscopic in size while excluding those reported s diffuse since size ws not recorded. Cses tht were metsttic t the time of dignosis were excluded from nlysis, s were in situ crcinoms, the ltter constituted pproximtely 5% of ll cses. The survivl experience of these 24,74 cses ws nlyzed using the cturil (life Mble) method All survivl rtes reported re cumultive reltive rtes, obtined by djusting the observed survivl with the expected mortlity experience in generl popultion with the sme ge nd rce distribution. Reltive rtes thus reflect the number of cses tht re specificlly due to brest cncer s compred to deths from ll other cuses. In this report, we converted the 5yer reltive survivl rtes to percentges for ese in interprettion. Stright lines were fitted to the dte using the lest squres method of liner regression. For comprisons of slopes we used the Generl Liner Models (GLM) procedures of Sttisticl Anlysis System (SAS) to test the null hypothesis of homogeneity of slopes.3 Results Overll Chrcteristics nd Survivl Experience of Cses Infiltrting ductl cncers ccounted for 83.4% of the cses, with 7.4% lobulr nd the remining 9.3% distributed mong medullry, mucinous, comedo, tubulr, nd ppillry histologic types. We hve reported previously on the survivl of this cohort s function of tumor histologic type3 The overll reltive 5yer survivl rtes for the 24,74 cses in our nlytic cohort ws 81.7%. Cse distribution by tumor size nd lymph node sttus is summrized in Tble 2. We notice tht 57.6% of ll tumors in the smple were between 1. nd 2.9 cm in dimeter nd tht 54.4% of ll cses hd lymph nodes negtive for metsttic tumor t the time of surgery. Efect of Tumor Size nd Axillry Lymph Node Sttus on Survivl Figures 1A nd 1B illustrte the effect of tumor size nd lymph node sttus on 5yer survivl. As expected, TABLE 2. Distribution of Brest Cncer Cses by Size nd Lymph Node Sttus Lymph node sttus Dimeter (cm) Selected cses 13 Positive nodes 4+ Positive nodes < > (1.4) (4.) (28.2) (29.4) (17.5) (8.5) (1.9) (1) 269 (79.4) 791 (79.4) 4668 (66.8) 41 (55.1) 272 (47.9) 845 (4.) 89 (29.9) (54.4) 53 (15.6) 14 (14.1) 1574 (22.5) 1897 (26.1) 1185 (27.4) 549 (25.6) 63 (23.4) 619 (24.3) 17 (5.) (6.5) (1.6) 1375 (18.9) 172 (24.8) 727 (34.4) 1259 (46.7) 5257 (21.2)

3 I PROGNOSTIC FACTORS FOR BREAST CANCER * Crter et l A B I 2 8 h 3 v) I E u 6 <2cm C crn >5cm M NO NODAL INVOLVEMENT C. 13 POSITIVE NODES 4+ POSITIVE NODES ~ ,,, bth incresed primry tumor dimeter nd incresed lymph node involvement hve negtive influence on percent of reltive survivl. From the figure, it is pprnt th,zt cses with four or more positive lymph nodes hve thle poorest survivl experience, regrdless of tumor size. The reltion between these two prognostic indictors nd their mutul effect on survivl is given in Tble 3 nd shown grphiclly in Figure 2. As the dimeter of the primry tumor increses from less thn 2 cm to 5 cm or more, the 5yer survivl declines from 96.3% to 82.2% for nodenegtive cses. The effect of lymph node invcllvement is shown by the decline in survivl within ech size ctegory with incresed lymph node involvement. For exmple, for the tumors less thn 2 cm, survivl decreses from 96.3% for nodenegtive cses to 87.4% for those with one to three positive xillry nodes, nd to 66.% for cses with four or more positive nodes. For tumors 2 to 4.9 cm in dimeter, survivl decreses from 89.4% for node negtive ptients to 79.9% for ptients with one to three positive nodes, nd to 58.7% for ptients with four or more positive nodes. Bsed on dt presented in Figure 2, both tumor size nd nodl sttus pper to hve n independent dverse effect on survivl. Figure 3 shows the quntittive reltion between size, lymph node sttus, nd survivl for cncers rnging in size from less thn.5 cm in dimeter to those equl to or greter thn 5. cm. The reltion between size nd survivl t 5 yers is liner regrdless of lymph node sttus. For nodenegtive ptients, the dverse effects of size on survivl is less thn tht for nodepositive ptients. For ptients with positive nodes, the effect of size on survivl is similr whether one to three nodes or four or more nodes re involved. The verticl difference between the lines in Figure 3 represents the dverse effects of nodl sttus on survivl for tumors of the sme size. There is smll subset of tumors (those.5.9 cm, with four or more positive nodes [N = 82, Tble 41) for which the liner reltion described between tumor size nd survivl does not hold. Probbility of Lymph Node Involvement In Figure 4, the probbility of lymph node involvement (defined s the percentge of cses with one or more pos TABLE 3. FiveYer Brest Cncer Survivl Rtes by Tumor Size nd Lymph Node Sttus Reltive Size survivl LN Sttus (%) 12. cm 13 Pos nodes 4+ Pos nodes 25 cm 13 Pos nodes 4+ Pos nodes >5. cm 13 Pos nodes 4+ Pos nodes LN: lymph node; Pos: positive

4 1 NO NODAL INVOLVEMENT 13 POSITIVE NODES lm 4+ POSITIVE NODES 1 CANCER Jnury Vol. 63 Discussion Figure 6 summrizes the cse distribution by size nd lymph node sttus, nd the survivl experience of 24,74 women dignosed with primry brest cncer between Jnury 2, 1977 nd December 31, The mrkedly poorer survivl of women with four or more xillry lymph nodes positive (2 1 % of this cohort) is evident for ll tumor sizes. This is especilly striking when one contrsts the survivl rtes for tumors less thn 2 cm; those with no positive nodes or only one to three nodes involved hve 77% to 99% reltive survivl to 5 yers, wheres those with four or more positive nodes hve mximum 64% survivl. Since ptients from ll ges nd rces were used in this study, the dt represent the verge over the entire group. Within the group, however, re subsets tht hve incresing or decresing survivl experiences for the sme tumor size nd nodl sttus. An nlysis of the effects of ge nd rce on the prognostic indictors investigted in this study will be reported seprtely. Our dt on the role of tumor size in predicting xillry metstsis confirm nd extend the results of surveys by the Americn College of surgeon^^^,^^ which showed tht 1 < >5 FIG. 2. Fiveyer reltive survivl of brest cncer s function of both tumor dimeter nd lymph node sttus. itive nodes for ech size) is plotted ginst the dimeter of the primry tumor. The reltion between the tumor dimeter nd the probbility of nodl involvement in ll tumor sizes ppers liner for the rnge of tumor sizes shown. For ptients with cncers 5 cm or greter, % re expected to hve t lest one node involved. The reltion of tumor size to number of lymph nodes involved is shown in Figure 5. In our dt, the point t which the two curves for one to three positive nodes versus four or more positive nodes intersect (t tumor size of pproximtely 3 cm) defines two groups of ptients. Among the cncers tht re less thn 3 cm tht hve metstsized to xillry nodes, there is greter probbility of the ptients hving only one to three positive nodes rther thn four or more positive nodes. In cncers greter thn 3 cm, however, the probbility of finding ptients with 4 or more positive nodes continues to increse. However, beyond 3 cm, incresing tumor size does not increse the probbility of finding cses with one to three positive nodes. 1 5 CC 3! 5 CC UJ n M NO NODAL INVOLVEMENT M 13 POSITIVE NODES M 4+ POSITIVE NODES I I I I I I I < FIG. 3. Reltion of tumor dimeter nd lymph node sttus to 5yer reltive survivl. Slopes for one to three ( ) nd for four or more (A A) positive nodes re not significntly different (P <.5).

5 I PROGNOSTIC FACTORS FOR BREAST CANCER Crter et l yer survivl decresed s the tumor size nd the probbility of xillry metstsis incresed. We notice, for exmlple, tht even for tumors less thn 1 cm, positive nodl sttus is found in pproximtely 2% of our cses. This hs been reported previ~usly. ~ Moreover, we hve shown (Fig. 3) tht in both nodenegtive nd nodepositive ptients, the contribution of tumor size to mortlity is linier function of tumor dimeter. The effect of size is greter for nodepositive ptients thn for nodenegtive ptients. This differs from the report by Vllguss et 1.* who found no reltion between survivl nd tumor size in nodenegtive women, nd Fisher et LZ4 who found direct reltion between survivl nd size only in women with four or more positive nodes. Our results lso indicte tht both size nd lymph node sttus re independent prognostic indictors, since sur TABLE 4. FiveYer Brest Cncer Survivl Rtes for Seven Tumor Sizes nd Three Ctegories of Lymph Node Involvement Reltive Size survivl LN sttus ( /.I <.5 cm Pos nodes Pos nodes cm Pos nodes Pos nodes cm Pos nodes Pos nodes cm Pos nodes Pos nodes I cm Pos nodes Pos nodes cm pos nodes Pos nodes >5. cm Pos nodes Pos nodes N: lymph node; Pos: positive. < DIAMETER (crn) PRIMARY TUMOR FIG. 4. Percent positive xillry lymph nodes s function of primry tumor dimeter. viv1 declines with incresing size when nodl sttus is held constnt, nd survivl declines when nodl sttus increses nd size is held constnt. It seems likely, however, tht both nodl sttus nd survivl re reflections of the sme biologicl process, i.e., the bility of the tumor to spred either loclly or to distnt sites. Furthermore, our dt show tht consistent reltion exists between the vribles of tumor size nd the probbility of nodl metstsis (Fig. 4). Smrt et l., in review of 8587 ptients recorded in the SEER progrm in 1975, showed liner reltion between size of the primry tumor nd lymph node involvement.26 Hence, we suggest tht the metsttic potentil evolves s the tumor grows, nd tht nodl sttus simply reflects the bility of the tumor to spred. However, the evolution of this metsttic potentil is not the sme in ll tumors. Nonetheless, it is this reltion between tumor size, nodl sttus, nd survivl tht mkes the TNM stging system work; otherwise there would be no consistent correltion between nodl sttus, distnt metstsis, nd prognosis. We conclude from the dt tht cncers re more likely to spred directly from the brest to distnt sites, with the xillry nodes representing locl site which serves s n indictor for the tendency to metstsize. Cliniclly, nerly 25% of ptients who re node negtive t the time of surgery eventully develop distnt metstisis. Presumbly, in these ptients, the tumor hs spred by other routes to

6 186 CANCER Jnury Vol. 63 z 8ol U 13 POSITIVE NODES M 4+ POSITIVE NODES P I I I I I < > FIG. 5. Reltion of tumor dimeter to percent involvement of one to three versus four or more positive lymph nodes. distnt sites. Regrdless of the mechnism of metstsis, nodl sttus remins the single most importnt indictor for prognosis. 5 w n NO NODAL 2 INVOLVEMENT 154%) 13 POS. NODES 125%) 5 YEAR SURVIVAL 1%) POS. NODES 121%) RG. 6. Distribution of 24,74 brest cncer cses by tumor size nd lymph nodes sttus. Shding indictes 5yer reltive survivl for ech ctegory. Finlly, becuse of our lrge smple size, we were ble to identify subset of smll but highly virulent tumors tht hve metstisized to four or more nodes by the time of dignosis. These cses hve 5yer survivl rte of only 54% to 59% compred with 94% to 95% survivl rte seen in ptients with the sme tumor size, but with only one to three nodes involved. This group (N = 99, Tble 5) seems to be n exception to the rule tht the metsttic potentil evolves s the tumor develops. For this smll subset of tumors, the metsttic potentil is clerly expressed erly in the course of the disese. It would be of interest to compre these smll, gressive tumors to the intervl cncers found in screening progrms. These results show the benefit of using stge s n effective guide to tretment. For exmple, our dt indicte tht ptients with cncers 1. to 1.9 cm in size with one to three positive nodes hve pproximtely the sme 5 yer survivl experience s ptients with much lrger cncers (3.3.9 cm) nd negtive nodes. Our results, bsed on 24,74 cses drwn from the generl medicl prctice, confirm tht the TNM stging system for brest cncer is useful for estimting prognosis. Nonetheless, other prognostic fctors exist, such s differentition nd nucler grde, tht lso should be considered in individul ptient mngement. Tumor size nd nodl sttus, the bsis for the TNM system, re prcticl prmeters for estimting prognosis. As erly detection increses the number of smller tumors found, nd s more ptients re treted by segmentl resection, the ssessment of regionl lymph nodes will become less importnt cliniclly. REFERENCES 1. Adir F, Berg J, Jow, Robbins G. Longterm followup of brest cncer ptients: The 3yer report. Cncer 1974; 33: Foster R, Costnz M. Brest self exmintion prctices nd brest cncer survivl. Cncer 1984; 53: Dly MB, Clrk CM, McLoure WL. Brest cncer prognosis in mixed CucsionHispnic popultion. J Ntl Cncer Inst 1974; 4: Frcchi AA, Robinson D, Lyspi A, Greenwll MJ, Kinne DW, Groshen S. Survivl in bilterl brest cncer. Cncer 1985; 55: Pscul MR, Rodriguez M, Zys A, Moreno L, Lge A. Fctors ssocited with prognosis in humn brest cncer: 11. Mutivrite strtifiction nlysis. Neoplsm 1983; 3(4): Hrtveit F, Thoresen S, Mehle BO. Prognostic evlution in nodepositive brest crcinom: Stge versus growth rte. Br J Surg 1984; 71: Ketterhgen JP, Quckenbush SR, Hushlter RA. Tumor histology s prognostic determinnt in crcinom of the brest. Surg Gynecol Obstet 1984; 158: Coulson PB, Thornthwite JT, Woolley TW, Sugrbker EV, Seckinger D. Prognostic indictors including DNA hitogrm type, receptor content, nd stging relted to humn brest cncer ptient survivl. Cncer Res 1984; 44: Peterson AHG, Zuck VP, Szfrn, Lees AW, Hnson J. Influence nd significnce of certin prognostic fctors on survivl in brest cncer. Eur J Cncer Clin Oncoll982; 18: Crter D, Pipkin RD, Sheprd RH, Elkins RC, Abbey H. Rel

7 I PROGNOSTIC FACTORS FOR BREAST CANCER Crter et l. 187 tionship of necrosis nd tumor border to lymph node metstses nd 1yer survivl in crcinom of the brest. Am J Surg Pthol 1978; 2: I I. Blmey RW, Dvies CJ, Elston CW, Johnson J, Hybittle JL, Mynrd PV. Prognostic fctors in brest cncer: The formtion of prognostic index. Clin Oncol 1979; 5: I:!. Rosen PP, Sigo PE, Brun DW, Wethers E, DePlo A. Predictors of rc:currence in Stge I (TINOM,) brest crcinom. Ann Surg 1981; 193: 1525, 13. Wllgren A, Silfverswrd C, Eklund G. Prognostic fctors in mmmry crcinom. Act Rdio1 Ther Phys Biol 1976; 15:l Atkinson EN, Brown BW, Montgue ED. Tumor volume, nodl sttus, nd metstsis in brest cncer in women. J Ntl Cncer Inst 1986; 76: I I!;. Freedmn LS, Edwrds DN, McConnell EM, Downhm DY. Histologicl grde nd other prognostic fctors in reltion to survivl of ptients with brest cncer. Br J Cncer 1979; 4: Lge A, Rodriguez M, Pscul MR, Diz JW, Fernndez L. Fctors ssocited with prognosis in humn brest cncer: I. Predictors for rte of evolution nd relpse. Neoplsm 1983; 3(4): Schefer G, Rosen PR, Lesser ML, Kinne DW, Bettie EJ Jr. Brest crcinom in elderly women: Pthology, prognosis, nd survivl. Pthol Annu 1984; 17: Young JL Jr, Ries LG, Pollck ES. Cncer ptient survivl mong ethnic groups in the United Sttes. J Ntl Cncer Inst 1984; 73: Fentimn IS, Cuzick J, Millis RR, Hywrd JL. Which ptients re cured of brest cncer? Br Med J 1984; 289: Hcene K, Desplces A, Brunet M, Lidereu R, Bourguignt A, Oglosbine J. Competetive prognostic vlue of clinicopthologic nd bioirnmunologic fctors in primry brest cncer. Cncer 1986; 57: Sutherlnd CM, Mther FJ. Longterm survivl nd prognostic fctclrs in ptients with regionl brest cncer. Cncer 1985; 55: Ntionl Institutes of Helth Consensus Development Conference Sttement: Adjuvnt chemotherpy for brest cncer, Sept. 91 1, ; C 36: Brown BW, Adkinson EN, Brtoszynski R, Thompson JR, Montgue ED. Estimtion of humn tumor growth rte from distribution of tumor size t detection. J Ntl Cncer Inst 1984; 72: Fisher B, Slck NH, Biss ID. Cncer of the brest: Size of neoplsm nd prognosis. Cncer 1969; 24: Vlguss P, Bondonn G, Veronesi. Ptterns of relpse nd survivl following rdicl mstectomy: Anlysis of 716 consecutive ptients. Cncer 1978; 41:1l71l Smrt CR, Myers MH, Gloeckler LA. Implictions from SEER dt on brest cncer mngement. Cncer 1978; 41: Ries LG, Pollck ES, Young JL Jr. Cncer ptient survivl: Surveillnce, epidemiology nd end results progrm, J Ntl Cncer Inst 1983; 7: Ederer F, Axtell LM, Cutler SJ. The reltive survivl rte: A sttisticl methodology. Ntl Cncer Inst Monogr 1962; 6:lOl Cutler SJ, Ederer F. Mximum utiliztion ofthe life tble method in nlyzing survivl. J Chronic Dis 1958; 8: SAS Institute, Inc. SAS User s Guide: Sttistics. Cry, NC: SAS Institute, Inc., 1982; Crter CL, Allen C, Henson D. Fiveyer survivl of brest cncer by histology, tumor size nd extent of xillry lymph node involvement. Proc 14th Int Cncer Congress 1986; Americn College of Surgeons Commission on Cncer. Finl Report on LongTerm Ptient Cre Evlution for Crcinom of the Femle Brest, Chicgo: Americn College of Surgeons Commission on Cncer 1979; Americn College of Surgeons Commision on Cncer. LongTerm nd ShortTerm Surveys of Ptterns of Cre of Femle Brest in Americn College of Surgeons Approved Cncer Progrms, 1982; Nemoto T, Vn J, Bedwni RN, Bker HW, McGregor FH, Murphy GP. Mngement nd survivl of femle brest cncer: Results of ntionl survey by the Americn College of Surgeons. Cncer 198; 45: