Predicting recurrence in axillary-node negative breast cancer patients.

This study attempted to identify the risk groups in axillary node negative breast cancer patients using validated first-generation prognostic clinical and pathologic factors. An updated 10-year follow-up in 407 such patients treated by surgery alone at Roswell Park between 1976-1987 showed a 10-year recurrence rate (RR) of 19% (95% confidence interval +/- 5%). Predictors of outcome were, in order of strength: (1) Tumor size (p = 0.0006); RR at 10 years was 2% +/- 4 for tumors < or = 0.5 cm, 6% +/- 7 for tumors 0.6-1.0 cm, 16% +/- 9 for 1.1-2 cm, 29% +/- 12 for 2.1-5 cm, and 40% +/- 31 over 5 cm; (2) Histologic differentiation (p = 0.017); poorly differentiated/anaplastic (P/A) tumors had a greater RR (24% +/- 8) than well or moderately differentiated (W/M) tumors (13% +/- 8); (3) Age (p = 0.046); patients < 35 showed a RR of 28% +/- 20, pts 35-50, 22% +/- 10, and pts > 50,17% +/- 7 (p = 0.046). Cox Model analysis showed tumor size (4 groups) significant at < 0.0001, histologic differentiation (2 groups) significant at < 0.0005 after allowing for size, and age (+/- 50) significant at < 0.05 after allowing for size and differentiation. Combining these variables into subgroups enables selecting groups at various risks of recurrence. Groups with low risk are: (1) patients with tumor < or = 1 cm, W/M (0% RR), (2) patients with ductal carcinoma in situ with microinvasion (0% RR), and (3) patients with tumors < or = 1 cm, P/A (8% RR). In a suggestive finding in this last group, those over age 50 achieved a RR of 3% +/- 6, while those age 50 or less had RR 14% +/- 15. With the exception of this last group, all should be considered highly curable using loco-regional therapy alone, and might be spared the risks and costs of routine systemic adjuvant therapy. Groups with high risk are: (1) patients with tumors > 2 cm (RR 32% +/- 12), and (2) patients with tumors 1.1-2 cm, P/A (RR 21% +/- 14). These should receive adjuvant therapy. Groups with intermediate risk are patients with tumor 1.1-2 cm, W/M (RR 12% +/- 12). In a suggestive finding, those in this group over age 50 had a RR of 11% +/- 12, while those up to 50 had a RR of 17% +/- 30. These patients should be considered to be prime candidates for clinical trials.(ABSTRACT TRUNCATED AT 400 WORDS)

Should all patients with node-negative breast cancer receive adjuvant therapy? Identifying additional subsets of low-risk patients who are highly curable by surgery alone.

This study, which used combined first-generation prognostic factors (tumor size, histologic differentiation, and age) on 408 patients with axillary node-negative (ANN) breast cancer treated by surgery alone without systemic adjuvant therapy between 1976 and 1987 at the Roswell Park Cancer Institute, discerned four subsets of low-risk patients with a 7-year relapse rate of 6% or better. The first subset consisted of 48 patients (12% of the population) with tumors 1 cm or less in diameter that were well or moderately differentiated. These patients had a disease-free rate (DFR) of 100% (95% confidence interval [CI], 94% to 100%). The second subset consisted of 35 patients (9% of the population) with tumors less than or equal to 1 cm that were poorly differentiated or anaplastic. These patients older than 50 years of age had a DFR of 97% (95% CI, 91% to 100%). The third subset consisted of 36 patients (9% of the population) with tumors 1.1 to 2 cm that were well or moderately differentiated. These patients were older than 50 years of age and had a DFR of 94% (95% CI, 85% to 100%). The fourth subset consisted of 36 patients with ductal carcinoma in situ with microscopic invasion. These patients had a DFR of 100% (95% CI, 87% to 100%). Twenty-two of these patients, not in the other subsets mentioned, comprised 5% of the total population. These patients at low risk of recurrence, who comprise one third of the entire node-negative population, are highly curable by local therapy alone and may be spared the risks and costs of routine adjuvant systemic therapy (AST). Patients with tumors larger than 2 cm (152 patients; 37% of the population) are at high risk of recurrence (26% with a DFR of 74% [95% CI, 64% to 84%]) and should routinely receive systemic adjuvant therapy. Patients with tumors up to 2 cm who are not in the low-risk groups fall in a gray area (recurrence, 15% to 21%; DFR, 79% to 85%). For these groups, combining second-generation prognostic factors such as DNA ploidy, S-phase fraction, or cathepsin D should give the physician additional information to aid in making decisions regarding adjuvant therapy.

Ductal carcinoma in situ with microinvasion. A curable entity using surgery alone without need for adjuvant therapy.

Of 408 negative axillary node (NAN) patients surgically treated at Roswell Park Cancer Institute (Buffalo, NY, 1976 through 1987), 36 (8.8%) presented with ductal carcinoma in situ with microinvasion (DCISM). In more than 50% of the patients (20/36) the disease was detected solely by mammography (microcalcifications and/or radiological density less than 1.5 cm). Thirty-three patients underwent modified radical mastectomy; three had wide excision +/- axillary dissection. Residual disease after excisional biopsy was found in 22 of 33 mastectomy specimens (67%): 11 (33%) pure ductal carcinoma in situ, five (15%) DCISM, and six (18%) frankly invasive. Of the 22 incidents of residual disease, 50% (11) were multicentric (one third of all specimens). These findings imply a high likelihood of residual cancer after excisional biopsy in these patients. All patients were free of disease for a mean follow-up of 57 months (range, 16 to 137). These findings indicate that DCISM is an entirely curable disease when treated by mastectomy alone, without the need for adjuvant therapy, regardless of the status of other prognostic factors such as tumor size, histologic differentiation, age, or steroid receptor status.

Node-negative minimal invasive breast cancer patients are not candidates for routine systemic adjuvant therapy.

Ninety-one patients with invasive breast carcinoma with a diameter of 1 cm or less and histologically negative axillary nodes were treated between 1976 and 1986 with radical surgery alone (67), or with conservative surgery (24). Cases were analyzed in relation to tumor size, steroid receptors, histologic and nuclear grade, age, and type of therapy, none of which showed a significant relationship to relapse or survival. There were 22% well-differentiated, 20% moderately differentiated, and 56% poorly differentiated or anaplastic tumors. Estimated disease-free survival (DFS) for this group was 91% at 7 years, and overall survival 96% for the same period. There were five relapses (all among poorly differentiated tumors) and three deaths unrelated to breast cancer. With the three deaths censored, 100% of the well-differentiated and moderately differentiated tumors were disease-free at 7 years versus 91% for poorly differentiated and anaplastic tumors (P = 0.076). These data suggest that node-negative patients with minimal invasive breast cancer are highly curable by primary surgical therapy alone, and the authors believe that these patients are not appropriate candidates for adjuvant therapy until such time as subgroups at high risk of recurrence can be identified.

Differential response to chemotherapy in metastatic breast cancer in relation to estrogen receptor level. Results of a prospective randomized study.

The predictive value of estrogen receptor (ER) level for response to chemotherapy was studied in 182 patients with metastatic breast cancer in a prospective study. Patients were stratified according to ER status and dominant site of disease and randomized to one of three regimens: cyclophosphamide, 5-Fluorouracil, and prednisone (CFP) versus CFP, methotrexate, and vincristine (CFPMV) versus doxorubicin and cyclophosphamide (AC). There was no significant differences in all response categories (P = 0.21), was taken as a predictor for response to chemotherapy, there was no significant difference in overall response (P = 0.61) between ER+ (62/108, 57%) and ER- patients (31/49, 63%). However, there was a significant trend toward a higher degree of response in ER- patients (more complete response [CR] nine of 49, 18%, and fewer failures six of 49, 12%) than in ER+ (less CR seven of 108, 7%, and more failures 37/108, 34%) (P = 0.006). Patients with higher measured levels of ER showed worse response (Kendall's tau C, P = 0.026). This trend for ER- patients to have better response than ER+ patients was generally consistent, regardless of the predominant site of metastases or chemotherapy regimen (P = 0.04 for CFP; P = 0.08 for CFPMV; and P = 0.20 for AC). The advantage of a better response for ER- patients was nullified by an earlier relapse which was reflected in longer duration of remission, time to treatment failure, and survival in favor of ER+ patients (12.3 months versus 7.3 months remission duration, 18.7 months versus 13.6 months survival in partial responders). These data suggest that ER- patients respond to a higher extent to chemotherapy but relapse sooner than ER+ patients, suggesting a more rapid growth for ER- tumors. In patients with ER- tumors and poorer prognosis on conventional chemotherapy, new trials of intensive consolidation after response should be considered.

Plasma selenium levels in patients with advanced upper gastrointestinal cancer.

Plasma selenium levels were determined at various intervals during hospitalization of 71 patients with upper gastrointestinal and other malignancies. These patients often require frequent nutritional as well as surgical or medical intervention. Attempts were made to identify, evaluate, and compensate for numerous confounding variables at each of the 374 plasma selenium determinations. Selenium levels in stable patients who were neither receiving aggressive antineoplastic therapy, nor septic, nor taking corticosteroids and who had no clinically significant metabolic imbalance were then separately analyzed. In 55 stable patients selenium levels were 28% lower than those found in 20 normal controls (mean 61.8 micrograms/L, P less than 0.0005). An analysis of all the readings showed that selenium levels were substantially decreased by recent radiotherapy or sepsis, by regional tumor spread and increased tumor burden, and by intravenous and/or enteral hyperalimentation and intravenous lipids. In contrast to these findings, levels were relatively higher in patients with an adequate oral diet or with a lesser tumor burden. The comparison between selenium levels in stable and in aggressively treated or septic patients supports the importance of the relationship of nutrition to selenium levels in cancer patients.

Prognosis after resection of non-small cell lung cancer of the right middle lobe.

In a previous study at Roswell Park Memorial Institute, it was noted that in patients whose resected non-small-cell lung cancer had originated in the right middle lobe, the prognosis was much worse than when it had originated in any other lobe. A review of a longer period and exclusion of patients who might introduce a bias resulted in a group of 18 patients whose fate was compared to the findings reported in other comparable series. Three out of those are alive at 8-96 months after operation. Five-year survival was 22% (30% counting only survivors of the operations). These findings indicate that the results of surgery for non-small-cell carcinoma of the right middle lobe fall within the lower range of lung cancer generally.

A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer.

Two intensive chemotherapy regimens CFPMV (Cytoxan [cyclophosphamide], 5-fluorouracil, prednisone, methotrexate, vincristine) and CA (Cytoxan, Adriamycin [doxorubicin]) were tested against a moderate regimen, CFP, in a prospective three-arm, randomized study with crossover when relapse or failure occurred, in order to assess whether the response, duration of remission, and survival can be altered by using more intensive regimens as first-line or as rescue therapy. All three regimens were equally effective as initial chemotherapy: CFP 26/46 (57%); CFPMV 31/48 (65%) and CA 26/47 (55%) (P = 0.61) with the least toxicity for the CFP regimen. Median duration of remission were 9.5, 11, and 9 months, respectively. Complete responses were almost identical in all three regimens: 4/46 (9%); 6/48 (12%) and 5/47 (11%) (P = 0.94). CFPMV was an effective regimen as second-line therapy: 11/33 (33%) or third-line therapy: 7/21 (33%). The CA regimen was equally effective as second-line therapy: 8/25 (32%), suggesting that intensive regimens provide an effective rescue therapy, as well in previous responders as in nonresponders. Initial intensive regimens have not substantially altered long-term survival in the whole group of treated patients, Arm II (CFPMV----CA----CFP) 17.6 months; Arm III (CA----CFP----CFPMV) 12.3 months when compared with initial moderate regimens Arm I (CFP----CFPMV----CA) 16.6 months (P = 0.24). The same lack of difference in survival was noticed in responder patients in each arm: Arm II 19.0 months; Arm III 16.0 months versus Arm I 22.0 months (P = 0.13). Our data suggest that a moderate regimen is as effective as more intense regimens for induction therapy in metastatic breast cancer, with less toxicity, preserving the opportunity for an effective rescue therapy with intensive regimens in second or third-line chemotherapy.

Chemotherapy induces regression of brain metastases in breast carcinoma.

This study improves treatment options and ultimately survival by using systemic chemotherapy in brain metastases from breast carcinoma, since most of these patients have disseminated disease and a dismal prognosis when treated by conventional brain irradiation alone. One hundred consecutive patients with symptomatic brain metastases documented by radionuclide and/or computerized tomography scan were treated with systemic chemotherapy. Fifty of 100 patients demonstrated an objective response of brain metastases which was similar for extracranial metastases. There were 10 complete responders (CR), 40 partial responders (PR), 9 stable, and 41 nonresponders. Median duration of remission was 10+ months for CR and 7 months for PR (range, 2-72 months). Primary chemotherapy of brain metastases yielded responses in 27 of 52 patients (52%) treated with Cytoxan (cyclophosphamide) (C), 5-fluorouracil (F) and prednisone (P); 19 of 35 (54%) receiving CFP-methotrexate (M) and vincristine (V); 3 of 7 (43%) treated with MVP, and 1 of 6 (17%) receiving Cytoxan plus Adriamycin (doxorubicin) (CA). Thirteen of 35 patients (37%) who subsequently had relapse of brain metastases were retreated successfully with secondary chemotherapy. The median survival for CR and PR was 39.5 months and 10.5 months, respectively, in contrast with nonresponder patients who had a median survival of 1.5 months. Thirty-one percent of all treated patients survived more than 12 months. These findings suggest that the chemotherapeutic agents used penetrate the blood-brain barrier inducing regression of brain metastases. This approach offers a significant benefit by simultaneously controlling extracranial disease, improving the response and prolonging survival.

Prostatic cancer. Treated at a categorical center, 1980-1983.

This report covers the experience from 537 patients with prostatic cancer seen at Roswell Park Memorial Institute (RPMI) from 1980 through 1983. This is a look at experiences in the early 1980s and is a continuation of the series covering the decades of the 1950s, 1960s, and 1970s. Referrals continue to dominate the series (85% of cases) but are now only slightly younger (65 years) than in-house diagnoses (66 years), of which one third were diagnosed at autopsy. Survival rates in this series, although limited in follow-up, were similar at two years to those in the 1970s and in the extensive series collected by the survey of the American College of Surgeons. Multiple primary tumors were observed in 22 per cent of this series, most frequently involving the bladder in addition to the prostate. Treatments continue to involve chemotherapy earlier in the course of disease as part of a succession of therapeutic modalities that include transurethral resection of prostate (TURP) or prostatectomy, lymph node dissection, external irradiation, castration, and hormones.

Oral contraceptive use has no adverse effect on the prognosis of breast cancer.

This study evaluates the possible effect of OC use on the prognosis of established breast cancer. Three hundred forty-seven patients with primary invasive breast carcinoma age 50 and under treated from 1971 to 1981 are included in this study. There were 112 OC Users (U) and 235 Non-Users (NU). Separate retrospective analysis were done for a group of 154 patients (59 U and 95 NU) under age 35 (Group A) and for 193 patients (53 U and 140 NU) age 35 to 50 (Group B), in order to pay particular attention to relationship of duration, recency and latency of OC usage. Both subsets of U and NU presented similar clinical characteristics regarding menstrual, reproductive, family history, histology, receptor status. Users presented with a similar extent of disease as Non-Users. No significant differences were found between U and NU in disease-free interval (Gr A p = .41; Gr B p = .81), metastatic period (Gr A p = .66; Gr B p = .41) or survival (Gr A p = .54; Gr B p = .79), either alone or when adjusted for extent of node involvement. Users of less than two years (78 patients) had a similar survival (Gr A = .54; Gr B p = .36) as those of longer duration (33 patients). Recent OC users within a year of diagnosis had a similar survival as other users who stopped the pills more than one year (Gr A p = .86; Gr B p = .14). No significant differences were noticed in survival between the patients who began the use 10 years or more before diagnosis from those beginning more recently (Gr A p = .82; Gr B p = .69). Our data suggests no adverse effect of OC on the outcome of breast cancer, regardless the duration of use, latency or recency period.

Chemotherapy followed by lung resection in inoperable non-small cell lung carcinomas due to locally far-advanced disease.

From 1977, 29 patients with inoperable non-small cell lung carcinoma due to locally far-advanced disease underwent lung resection after receiving two to eight courses of chemotherapy. After the surgery was performed, three additional courses of chemotherapy were given. The overall median survival from onset of the chemotherapy was 30.5 months; postoperatively, it was 24.5 months (five patients survived greater than 5 years). Postoperative mortality was 10.3%. The overall survival results compare favorably with those obtained with radiation therapy.

Oral contraceptives and prognosis of breast cancer in women aged 35 to 50.

Among 193 breast cancer patients aged 35-50 years, there was no appreciable difference in the extent of disease at diagnosis between 53 oral contraceptive (OC) users and 140 OC non-users. There was no overall significant difference between OC users and non-users for either the disease-free interval (P = .81), metastatic period (P = .41), or survival (P = .79), either alone or when adjusted for stage or family history. The survival rate of OC users of more than 2 years was similar to the survival rate of those of shorter duration (P = .36). Patients who began the use of OC 10 years or more before diagnosis showed no statistical difference from those beginning more recently (P = .69). Recent OC users within a year of diagnosis had a survival rate similar to that of other users who stopped the pills at least 1 year prior to diagnosis (P = .14). Our data suggest no adverse effects of OC use on the prognosis of breast cancer, regardless of duration of use, latency or recency period.

Influence of oral contraceptives on the prognosis of breast cancer in young women.

The possible effect of oral contraceptive (OC) use on the prognosis of established breast cancer was investigated in 154 young women aged 35 and younger. No significant differences were found between the study group of 59 OC users, and the control group of 95 nonusers in age, parity and gravidity, family history of breast cancer, benign breast disease, morphology, or surgical therapy. No appreciable differences were found between OC users and nonusers in extent of disease at presentation (P = 0.78), histologic features of tumor (P = 0.83), or axillary node involvement (P = 0.88). No significant or even suggestive differences were found between users and nonusers in disease-free interval (P = 0.41), metastatic period (P = 0.66), or survival (P = 0.54), respectively, either alone or when adjusted for extent of node involvement, duration of OC use, or other risk factors. In this study no evidence was found that the use of OC has any harmful or beneficial effect on evolution and survival of breast cancer.

Lumpectomy for mammary carcinoma. A retrospective analysis of 40 presumptive candidates from a surgical series.

This presumptive study concerns the value of lumpectomy as a curative procedure for minimal breast carcinoma, defined as an operable cancer no larger than 2 cm in diameter, with no palpable axillary lymph nodes, and, in peripherally located lesions, no Paget's disease. From 199 surgically treated mammary cancer patients, 40 cases met the minimal criteria. Thirty-eight of the minimal breast carcinoma patients had a radical mastectomy and two had a supraradical procedure. The pathology findings and survival data were analyzed in these minimal carcinoma cases, and it was calculated that lumpectomy alone would have left cancer cells in 48% of the patients because of regional lymph node involvement by cancer, extension of cells from a peripheral cancer to the nipple ducts, or presence of a second carcinoma in the breast. However, the estimated 30-year cure rate in these radical surgically treated patients was 86%.

Accuracy of basic cancer patient data: results from an extensive recoding survey.

The accuracy of data coded from the medical records of 985 patients from 22 major U.S. cancer centers was checked by recoding during 1978-81. The 29 items covered demographics, diagnosis, and therapy. Original codes were compared to recodes, and disagreements were classified as major or minor. The highest rate of major disagreements, 23%, was for stage of disease, followed by 10% for histology and 7% for site. Major disagreement rates for most other items were under 7%. Only 3% of a large sample of major disagreements involved justifiable differences in interpretation; the others were due to errors in the use of records. Major disagreement rates varied by a factor of 10 across sites, 4 across centers, and 2 across stage of disease. For several items the code "unknown" was overused and led to disagreements. A new procedure is presented for analysis of disagreement rates. The results from this procedure can guide training effort to improve coding accuracy.

Cyclic alternating combination chemotherapy for small cell lung cancer.

Sixty-two patients with small cell carcinoma of lung received cyclic alternating non-cross-resistant combination chemotherapy. Radiation to the chest was given to all the patients. Patients were given a course of VP16, adriamycin and vincristine (VAV) followed by radiation (3,000 rads) to the chest and then a second course of VAV. Three weeks later, a course of cytoxan, CCNU, and methotrexate (CCM) was given (6 weeks). Subsequently, the treatment was cycled between two courses of VAV (6 weeks) and one course of CCM (6 weeks). Overall objective response rate of 73%, with 45% complete response, was noted. Overall median survival was 50 weeks, with 83 weeks for complete responders. Median survival for patients with regional disease was 58 weeks compared to 40 weeks for extensive disease. All the patients headed for complete response did so prior to receiving CCM. These results were not superior to conventional combination chemotherapy regimens.

Metastatic patterns in patients with carcinomas of the lower esophagus and upper rectum.

The frequency of metastatic involvement of eight target organs was examined in people dying as a consequence of squamous cell carcinomas of the lower third of the esophagus or adenocarcinomas of the upper third of the rectum. In both groups, there was a stronger association of metastatic incidence in the target organs with organ blood flow per gram in patients with liver metastases than without. The results suggest that this association, which is consistent with the 'mechanical' hypothesis of metastatic pattern, is only seen in people with advanced disease and that in the others temporal limitations imposed by death or cure prevent full development of the pattern. The data suggest that in accord with the 'cascade' theory, cancer cells must first form metastases in the liver, that cells from these metastases not the primary cancer, then form metastases in the lungs; cancer cells from the lung metastases then subsequently disseminate with a trend towards an arterial pattern. Data from animal experiments suggest that owing to the inefficiency of the metastatic process in terms of cancer cells, this sequential process is slow relative to tumor development and that this time base affects expression of metastatic pattern. This proposed scheme for metastatic pattern development provides evidence in favor of Ewing's 'mechanical' hypothesis for two histologic types of cancer, each growing in one designated primary site. It does not exclude a role for 'seed and soil' effects in these and other cancers.

Central nervous system metastasis from breast carcinoma. Autopsy study.

Central nervous system (CNS) metastasis was noted in 309 patients of 1044 autopsy cases of breast carcinoma. The brain was involved in 193 cases, and cranial dura in 167 cases. In 82 cases, the cranial dura was the sole site of CNS involvement. Metastasis to the leptomeninges was found in 59 cases, and to the spinal cord and dura in 32 cases. Metastases to the infratentorial portion of the brain was almost as frequent as to the cerebrum. Forty-two percent of the brain metastasis were single lesions, which is similar to the frequency of solitary metastasis to the brain from malignant tumors as a whole. CNS metastasis occurred more frequently in younger patients than older patients, and the clinical course of these patients was shorter than for those patients without CNS metastasis. CNS metastasis developed in the late stage of the disease, and often was not recognized clinically. Only 31% of the cases were clinically diagnosed or suspected before death. A median survival of these patients after clinical diagnosis of CNS metastasis was 33 days. However, a significant improvement was noted in the clinical diagnosis and median survival in the latter half of the study period. Eleven patients lived for more than 1 year after diagnosis of CNS metastasis. Only 14% of the 309 patients died from CNS failure.

A novel method of assessing completeness of tumor registration.

A random sampling method of measuring the completeness of registration of cancer patients was tested at a university referral hospital. The target population consisted of all inpatients and nonprivate outpatients with in situ or invasive malignancies. The medical records of a random sample of all hospital records active in the last five years were reviewed to determine their reportability and inclusion in the tumor registry (Method A). Traditional casefinding assessment methods were also employed by conducting a complete review of four commonly used hospital sources for a short time period (Method B). The primary purpose of the study was methodologic; namely, to test the feasibility of Method A and to characterize it relative to the more traditional Method B. The estimated missed case rates using Methods A and B (3% and 5%, respectively) are not directly comparable because not all outpatient information is recorded in the medical record. It is concluded that as a means of completeness assessment, Method A can be feasible, cost effective, and useful in other institutions provided certain conditions are met: (1) an appropriate random sample of the target population can be obtained; (2) all relevant information is available in a unit medical record; (3) the reviewer is fully aware of the reportability criteria.