A retrospective study of earliest indicators of recurrence in patients on eastern cooperative oncology group adjuvant chemotherapy trials for breast cancer. A preliminary report

A retrospective study of earliest indicators of recurrence in patients on eastern cooperative oncology group adjuvant chemotherapy trials for breast cancer. A preliminary report
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  A zyxwv etrospective Study of Earliest Indicators of Recurrence in Patients on Eastern Cooperative Oncology Group djuvant Chemotherapy Trials for Breast Cancer A Preliminary Report zyx KISHAN J. PANDYA. MD,' ELEANOR T. MCFADDEN,t LESLIE A. KALISH,t DOUGLASS C. TORMEY, MD, PHD, SAMUEL G. TAYLOR zyxwvu V MD.5 AND GEOFFREY FALKSON, MD(I zyx A retrospective review of the Eastern Cooperative Oncology Group adjuvant chemotherapy studies EST 5177 and EST 6177 was performed in order to ascertain the first indicator of relapse in women with breast cancer and pathologically positive axillary lymph nodes. Of 856 evaluable patients, 208 have relapsed. In 175 patients who relapsed, the first indicator could be clearly identified: symptoms, 36 ; patient self-examination, 18.3 ; physical examination by the physician, 19.4 ; abnormal blood chemistries, 12 ; bone scans, 8 ; chest x-rays, 5.1 ; and mammograms, 1.1 . Although 74 of recurrences are therefore detected clinically, in a sizable proportion (26 ), the ancillary tests were the earliest indicators of relapse. The manner of detection was not influenced by nodal, estrogen receptor (ER), or menopausal status. These results suggest that the follow-up schedule currently employed by ECOG appears reasonable. Cuncer 55202-205. 1985. zyxwv HE CONCEPT that breast cancer with pathologically T positive axillary lymph nodes is a systemic disease from the outset is now well-established. Adjuvant che- motherapy has been shown to improve disease-free survi~al.~-~ espite this, a considerable number of pa- tients relapse. For this reason, patients receiving adjuvant chemotherapy after mastectomy on clinical trials are followed carefully during and after completion of their treatment so as to detect recurrence as early as possible, primarily for calculation of a precise disease-free interval, but also for initiation of other systemic therapy as indicated. In addition to history and physical examina- Presented in part at the 73rd Annual Meeting of the American Association for Cancer Research, St. Louis. Missouri, March 1982, and at the 5th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas. November 1982. From the Eastern Cooperative Oncology Group (Paul P. Carbone, MD, Chairman, CA2 I 15). Supported by Public Health Service grants from the NCI, NIH, and the Department of Health Education and Welfare. University of Rochester Cancer Center, Rochester, New York (CA23318). t Dana Farber Cancer Institute, Boston, Massachusetts (CA233 18). Wisconsin Clinical Cancer Center, Madison, Wisconsin (CA2 1076). Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois (CA25988-04). University of Pretoria, Pretoria. South Africa (CA21692). Address for reprints: Kishan J. Pandya, MD. St. Mary's Hospital, Accepted for publication December 19, 1983. 89 Genesee Street, Rochester. NY 146 I. tions, radionuclide bone scans, chest x-rays, and a number of laboratory tests are performed for follow-up of the patient. In this population of patients who have no clinical evidence of disease, the precise value of each of these methods of detection is not clear. We therefore undertook to study the method of detection of these recurrences so that a rational approach for the follow- up of patients with early breast cancer can be designed. This study was undertaken to identify retrospectively the earliest indicator of disease recurrence in patients with breast cancer treated on Eastern Cooperative On- cology Group ECOG) adjuvant studies. In addition, the possible interactions between tumor size, estrogen recep- tor ER), menopausal, and nodal status and the earliest indicator of recurrence were investigated. Patients and Methods Of 857 evaluable patients who entered ECOG adjuvant breast studies EST 5177 and EST 6177, 208 Fig. 1) had relapsed at the time of this analysis. The median duration of follow-up for all of the patients was 30 months range, 5-56 months). There were 74 relapses observed in the first year, 95 in the second year, and 39 in the third year. Of these 208 patients, 33 had incom- plete information with regard to the method of detection of recurrence 8 in the first year, 19 in the second year, 6 in the third year), leaving 175 patients for whom the earliest indicator of recurrence was ascertained retro- 202  No. zyxwvutsrqpo   EARLIEST NDICATORS F BREAST CANCER ECURRENCE zyx   Pandya et zyx l. 203 Stratify: Radical or modified Degree of nodal involvement radical (histologic) mastectomy with -10 weeks postoperatively - (A) zyxwvuts -3 positive positive nodes (B) >4 positive Estrogen receptor result (A) Positive (B) Negative MF X 12 cycles No adjuvant therapy2 (age z 65 FIG. 1 Schematic outline of EST 5 I77 and EST 6 177. C: cyclophosphamide 100 mg/m2 orally days I through I4 of each cycle: M: methotrexate 40 mg/m’ IV day 1 and 8 of each cycle; F: 5-fluorouracil 600 mg/m2 IV day I and 8 of each cycle; P: prednisone 40 mg/m2 orally days 1 through 14 of each cycle; T: tamoxifen 1 mg orally twice daily, continuous. spectively. The study parameters required for both studies are identical and are shown in Table 1. In this review, the following parameters were defined for use as indi- cators of recurrence: symptoms, self-examination by the patient, physical examination by the physician, blood chemistries (lactate dehydrogenase [LDH], serum glu- tamic oxalacetic transaminase [SGOT], serum glutamic pyruvic transaminase [SGPT], alkaline phosphatase, bil- irubin), radionuclide bone scan, chest x-ray, and mam- mogram. Dejnit ions Sites of treatment failure for both adjuvant studies were designated as follows: 1. Local; Evidence of tumor in all soft tissues of the ipsilateral chest wall and operative scar. 2. Regional; Evidence of tumor in the internal mam- mary, supraclavicular and/or ipsilateral axillary nodes, as well as the soft tissue of the axilla. 3. Distant Evidence of tumor in all areas except those described above. The combined Modalities Working Group criteria (De- partment of Health, Education and Welfare Document No. 77-1 192) were used for documenting treatment failure. Statistical Analysis The analysis of first indicators of recurrence and differences over time of recurrence and the impact of various prognostic factors on the method of detection was camed out by using a two-sided Fisher’s exact test6 Results Table 2 shows the type of recurrence and its method of detection. The history was the most important means of detecting recurrence, detecting a total of 54.390 (36% symptomatic recurrences; 18.3% by patient self-exami- nation). An additional 19.4% of the patients were de- tected by physical examination by the physician, com- prising a total of 73.7% of all patients. As would be expected, virtually all of the locoregional recurrences (95.7%) were detected by these means. However, the TABM Study Parameters Required Before Day I of Day 8 of Every Every Every therapy cycle cycle 3 mo 6 mo 12 mo ~~ History and physical examination X X HGB or HCT X X Leukocyte count X X* X* Platelet Count X X* X* BUN or serum Creat, glucose X Bilirubin X x, zyx   Alkaline phosphatase X x. SGOT or SGPT zyxwvutsrq   x, Serum calcium X x. Bone scan$ X X Xeromammogram or X X Hematologic studies Chemistries Xt Xt X-ray and scan examination Chest (PA and lateral) mam m ogra m X X§- 5 Estrogen binding X Prior to drugs administration. t Blood glucose determination required on days 1 and 8 of cycles I, Bone scans are required; if scan is positive, x-rays of suspicious Optional one oblique view every 12 mo. X: 0-1 yr; : 1-5 yr; HGB: hemoglobin; HCT: hematocrit; BUN: blood urea nitrogen; Creat: creatinine; SOT: erum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase; PA: pos- 2, and 3. areas zyxwvutsrqp us be performed. teroanterior.  204 CANCER zyxwvu anuary 1 1985 Vol. 55 z TABLE . First Indicator and Type of Recurrence Symptoms Patient PE Physician PE Chemistries Chest x-rays Bone scans Mammogram recurrence (n)* zyxwvutsrqpo o. Percent No. Percent No. Percent No. Percent No. Percent No. Percent No. Percent Type of zyxwvutsrqp  ~ ~ Locoregional (69) 10 14.5 30 43.5 26 37.7 3 4.3 0 0 00 0 0 Other soft tissue 10) 1 10.0 3 30.0 4 40.0 0 0 0 0 Bone (66) 43 65.2 2 3.0 zyxwvut   1 5 8 12.1 0 0 I2 18.2 0 0 Viscera (44) 19 43.2 0 0 3 6.8 14 31.8 9 20.5 0 0 0 All cases (175) 63 36.0 32 18.3 34 19.4 21 12.0 9 5.1 14 80 2 1 1 2 20.0 Some patients may have more than one type of recurrence. detection rate by this method starts to decline with other types of recurrences: other soft tissue, 80 ; bone, 69.7 ; and viscera, 50 . The ancillary tests show their usefulness s indicators of these types of recurrences: chemistries, 12.1 of osseous and 31.8 of hepatic recurrences; chest x-rays, 20.5 of asymptomatic pulmonary recur- rences; bone scans, 18.2 of asymptomatic osseous recurrences; and mammograms, 20 of other soft tissue recurrences. Table 3 shows the relationship between the first indicator of recurrence and the year of recurrence. Of the 175 patients, 142 (81.1 ) elapsed during the first 2 years. Although most symptomatic recurrences were seen in the first 2 years (23 versus 21 versus 19), the year with the highest percentage of symptomatic recur- rence (57.6 ) was the third year (P = 0.01). It is inter- esting to note that the bone scans appear to have detected recurrences only in the first 2 years. This, howevet, is not statistically significant (P = 0.06), and longer observation is necessary since only one third of the patients have completed their first 3 years of fol- Table 4 shows the analysis of first indicators versus tumor size, nodal, menopausal, and ER status. The method of detection does not appear to be influenced significantly by these factors, even though ER- patients had a significantly higher incidence of locoregional and visceral recurrence, and postmenopausal women had a significantly higher incidence of osseous recurrence.' Similarly, tumor size and nodal status do not appear to have any influence on the indicators of recurrence, even though patients with tumors of >3 cm have a higher incidence of locoregional recurrence and those with four low-up. PE: physical examination. positive nodes have a significantly higher incidence of recurrence of all types (locoregional, osseous, and vis- ~eral).~ ynchronous multiple types of recurrences (e.g., locoregional and bone) were seen in only 1690 of all patients at first relapse and tended to occur in patients with four positive lymph nodes. Discussion Our study shows that 54.3 of the recurrences were detected by history (symptoms, 36 ; patient self-exam- ination, 18.3 ) and physical examination detected an additional 19.470, for a total of 73.7 . The ancillary tests were the earliest indicators of recurrence for the remaining 26.3 of the patients. These findings are at variance with a report by Winchester zy l a1.' in which 9 1 of the recurrences were symptomatic, although in their series radionuclide scans were obtained only when the patient was symptomatic, and routine blood chem- istries were not performed. In their study 17 patients with recurrence from a more closely followed group of I12 patients who received adjuvant chemotherapy were also included. It is interesting to note that 6 of the 17 patients were asymptomatic, 4 of whom were detected by physical examination by a physician, 1 by abnormal blood chemistries, and by chest x-ray. This pattern of detection is somewhat closer to that of the current study. Valagussa et af.' have reported that 77.7 of their recurrences were detected by history and physical examination, a finding that is similar to ours. Their finding of asymptomatic detection of pulmonary lesions is also similar to ours, but is at variance with the report by Winchester el a1.' Our results are also similar to those reported by Cantwell er a/. wherein 85.6 were TABLE . First Indicator by Year of Recurrence Phys or patient Chest x-ray or Symptoms PE Chemistries Bone scan mammogram All cases Year of recurrence No. Percent No. Percent No. Percent No. Percent No. Percent No. Percent I st 23 34.8 27 25.8 6 9. 5 7.6 5 7.6 66 100 2nd 21 27.6 29 38.2 12 15.8 10 11.8 5 6.6 76 100 3rd 19 57.6 10 30.3 3 9.1 0 0.0 I 3 O 33 100 P = 0.01 P = 0 06 PE: physical examination; Phys: physician.  No. zyxwvutsrqpo   EARLIEST NDICATORS F BREAST CANCER ECURRENCE Pandya et al. z 205 TABLE . First Indicator of Recurrence zyxwvu ersus Prognostic Factors zyx   Symptoms Patient PE Physician Chemistries Chest x-ray Bone scan Mammogram Prognostic factors (n). No. Percent No. Percent No. Percent No. Percent No. Percent No. Percent No. Percent Nodal 1-3 status 4+ ER status Pos Neg zyxwvutsrqpo   umor wet <3 >3 Menopause Premenopausal status Postmenopausal (57) 19 33.3 13 22.8 II zyxw 118) 44 37.3 19 16.1 23 (79) 33 41.8 II 13.9 I2 (96) 30 31.3 21 21.9 22 (59) 20 33.9 9 15.3 10 114) 41 36.0 23 20.2 24 (100) 40 40.0 18 18.0 18 (75) 23 30.7 14 18.7 16 19.3 3 19.5 18 15.2 8 22.9 13 16.9 8 21.1 I3 18.0 12 21.3 9 Some patients may have more than one type of recurrence. PE. physical examination: ER: estrogen receptor: Pos: positive; Neg: negative. detected by history and physical examination, I I .9 by bone scans, and 2.3% by chest x-rays. They did not use abnormal blood chemistries as a separate indicator of recurrence, although 77.7% of patients with recurrence were noted to have abnormal values of carcinoembryonic antigen (CEA), alkaline phosphatase, or erythrocyte sedimentation rate ESR). Serial CEA and ESR deter- minations were not obtained in our study, even though CEA may reflect tumor burden, *'* and may be of some value in following early disease as reported by Falkson et al. The practice of obtaining routine follow-up bone scans in an asymptomatic patient remains controver- ~iaI.'~-'~ outine bone scans were not performed in the studies reported by Winchester et al. and Valagussa et d n our study, 18.2% of all osseous recurrences were detected by routine bone scans in asymptomatic patients, without any concommittant abnormalities in blood chemistries. We believe that bone scans may be useful, and further studies are needed before a definitive state- ment can be made. Although we find that there is a significantly higher frequency of locoregional and visceral recurrence in patients with ER- tumors and of osseous recurrence in postmenopausal patients, we have observed no influence of these factors on the indicators of recurrence. The tumor size or nodal status also did not have any influence on the indicators of recurrence. Again, these results are similar to those of Valagussa et d ut contrary to those reported by Scanlon et zyxwv 1. ~ In conclusion, we believe that although a definitive statement cannot yet be made on the optimal follow-up schedule for postmastectomy patients receiving adjuvant chemotherapy, the schedule currently employed by the ECOG appears reasonable. We plan to conduct a similar review at a later date to confirm our initial observations and hope to be able to make more definitive recom- mendations on the follow-up schedule at that time. REFERENCES I Henderson IC, Canellos GP. Cancer of the breast: The past decade. 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