J. Rouesse

Reproducibility of a histopathologic grading system for adult soft tissue sarcoma

Tumor grade has been proposed as an essential factor in the staging of patients with soft tissue sarcomas. In a previous study, a histopathologic grading system using the evaluation of tumor differentiation, mitosis count, and tumor necrosis was described. The current study was conducted to test its reproducibility. The pathologic sections of 25 soft tissue sarcomas were submitted to a study group composed of 15 pathologists who had not been involved in the development of the grading system. The results were compared with those of a panel group. The crude proportion in agreement observed between the study group and the panel group was 81% for the evaluation of tumor necrosis, 74% for tumor differentiation, and 73% for the mitosis count. The crude proportion in agreement for the tumor grade was 75%, which was significantly better than the crude agreement rate of 61% for the diagnosis of histologic type (P = 0.001). A kappa statistical analysis, to check the possibility of chance‐related concordance, showed a proportion in agreement of 68%. A two‐way variance analysis showed that the homogeneity of the evaluation of tumor grade is impaired by tumor‐related and observer‐related factors. However, an improvement may be obtained by better training of pathologists. We conclude that the tumor grading system developed inside the French Federation of Cancer Centers, although perfectible, already provides reliable prognostic information and its use in prospective clinical studies may provide more information about its clinical usefulness. Cancer 58:306–309, 1986.

Cathepsin D: an independent prognostic factor for metastasis of breast cancer.

122 patients with primary breast cancer were followed-up for a median of 4.6 years after surgery. The concentration of cathepsin D in tumour cytosol was strongly related to both metastasis-free survival and disease-free survival and was independent of nine conventional prognostic indices. Cathepsin D assay may prove particularly useful in identifying women who, though without lymph node involvement at presentation, are at high risk of metastatic disease.

The importance of histologic grade in long-term prognosis of breast cancer: a study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy.

In a study of 1,010 patients with solitary, unilateral, nonmetastatic breast cancer, the histologic grade, assessed by a multifactorial analysis (Cox model) to study its significance with other prognostic factors, was found to be an important, independent factor. For 612 operable patients, two laboratory characteristics, the number of histologically positive nodes and the histologic grade, were the most valuable predictors. These two factors alone form a predictive index that may be an excellent and simple guide for the clinical decision of subsequent therapy. For 398 patients with inoperable breast cancer (ie, tumor greater than or equal to 7 cm, N2-3, inflammatory, skin fixation, and clinically rapidly growing forms), the histologic grade (performed on drill or cutting needle biopsy) was again a most important (and with inflammatory forms the most important) predictor of prognosis in these patients. Our data support that performing our modified histoprognostic grading of Scarff and Bloom is simple, reproducible, incurs no additional cost, may be carried out in the simplest histology laboratory, and finally, defines an important risk factor in all patients. It should be routine for all breast cancer specimens. Furthermore, studies of adjuvant therapy should stratify patients for this variable.

A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.

PURPOSE A randomized pilot study was undertaken to assess the acute and chronic toxicities of two short intensive chemotherapy regimens, and to evaluate the feasibility of conservative surgery in this setting. Additional aims were to determine the clinical and radiologic response and the degree of histologic necrosis after chemotherapy. With extension of the study, eventual accrual was sufficient to compare disease-free survival (DFS) and overall survival (OS). PATIENTS AND METHODS Between July 1983 and December 1986, the European Osteosarcoma Intergroup (EOI) entered 198 eligible patients with classic high-grade extremity osteosarcoma onto a randomized trial that compared doxorubicin (DOX) 25 mg/m2/d times three, intravenous (IV) bolus plus cisplatin (CDDP) 100 mg/m2, 24 hour infusion, every 3 weeks times six; the same combination was preceded 10 days earlier by high-dose methotrexate (HDMTX) 8 g/m2, 6-hour infusion, every 4.5 weeks times four. In the majority of patients (179), chemotherapy was commenced after biopsy; definitive surgery was scheduled at 9 weeks in both groups. RESULTS Toxicities for both regimens did not differ substantially from those that occurred in other trials of adjuvant chemotherapy in osteosarcoma. Local recurrence (9%) and surgical complications (18%) after conservative surgery were acceptable. With a median follow-up of 53 months, DFS at 5 years is superior (P = .02) for DOX/CDDP, 57% versus 41%, although OS, 64% versus 50%, is not different significantly (P = .10). In a subset of 66 patients for whom pathologic data on the resected specimen were available, DFS (P = .003) and OS (P = .008) were better for those who demonstrated > or = 90% necrosis. CONCLUSION A brief intensive chemotherapy regimen of DOX/CDDP has produced excellent long-term results, which are similar to those that have been achieved in cooperative group studies of longer, more complex multiagent chemotherapy, and provide the basis for a direct comparison in the next EOI study.

Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy.

We report the largest series of induction chemotherapy for inflammatory breast carcinoma (IBC). Results of two chemotherapy protocols with radiation therapy (RT) (170 patients) are compared with results with radiation alone (60 patients) in the treatment of this disease. From 1973 to 1975, 60 patients (control, group C) received RT (45 Gy and 20 to 30 Gy boost) and hormonal manipulation. From 1976 to 1980, 91 patients (group A) were treated with induction chemotherapy: Adriamycin (Adria Laboratories, Columbus, Ohio), vincristine, and methotrexate (AVM) and RT on a cyclical schedule; and maintenance chemotherapy: vincristine, cyclophosphamide, and 5-fluorouracil (5-FU) (VCF). From 1980 to 1982, 79 patients (group B) received induction chemotherapy, Adriamycin, vincristine, cyclophosphamide, methotrexate, and 5-FU (AVCMF) and RT on a cyclical schedule and VCF maintenance. Hormonal manipulation was performed in all groups. Disease-free survival at 4 years was 15% for group C, 32% for group A, and 54% for group B (P less than .005 group C v group A, less than .00001 group C v group B, and less than .01 group A v group B). Total survival at 4 years was 42% for group C, 53% for group A, and 74% for group B (P = .17 group C v group A, less than .00001 group C v group B, and less than .001 group A v group B). Clinical assessment of tumor aggressiveness, nodal status, type of chemotherapy administered, and early response to chemotherapy (by third course) were all prognostic factors. There is an important, highly statistically significant benefit in terms of both disease-free survival and total survival observed in patients treated with the addition of chemotherapy compared with radiation alone in IBC.

Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases

A retrospective study is reported of 120 consecutive cases of patients presenting with brain metastases as the primary sign of their malignancy. Primary site was found in 62 patients (53 while alive and 9 at postmortem examination) and remained unknown in 58. Lung was the most frequent primary site (45% of known sites), and digestive malignancies were surprisingly the second most frequent primary site (19% of known sites), whereas breast was found in less than 5%. When primary site was disclosed, in 85% it was after history, clinical exam, chest x‐ray, and pathologic findings. Survival was almost identical in both known and unknown primary sites: 54% versus 44% at 6 months, 20% versus 16% at 1 year, and 6% versus 5% at 2 years. It was concluded that extensive evaluations to identify primary sites do not appear to be rational in patients presenting with brain metastases.

Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease

Sixty-three evaluable patients with limited small cell lung carcinoma were entered into two pilot studies alternating 6 cycles of combination chemotherapy (Doxorubicin 40 mg/m2 d 1; VP16213 75 mg/m2 d 1, 2, 3; Cyclophosphamide 300 mg/m2 d 3, 4, 5, 6; and Methotrexate 400 mg/m2 d 2--plus folinic acid rescue--or Cis-Platinum 100 mg/m2 d 2) with 3 courses of mediastinal radiotherapy as induction treatment. The first course of radiotherapy started 10 days after the second cycle of chemotherapy; there was a 7 day rest between chemotherapy and radiotherapy courses. This 6 month induction treatment was followed by a maintenance chemotherapy. The total mediastinal radiation dose was increased from 4500 rad in the first study to 5500 rad in the second. Both protocols obtained a complete response (CR) rate of greater than 85% (with fiberoptic bronchoscopy and histological verification). Local control at 2 years was 61% in the first study and 82% in the second. Relapse-free survival at 2 years was 32 and 37%, respectively. Toxicity was acceptable. We conclude that our results justify further clinical research in alternating radiotherapy and chemotherapy schedules.

Preoperative induction chemotherapy in the treatment of locally advanced soft tissue sarcomas

Evidence that supports the use of systemic, presurgical induction chemotherapy to render soft tissue sarcomas resectable or to minimize the extent of surgical excision is presented. Induction chemotherapy was administered in 34 cases of nonmetastatic soft tissue sarcomas. All patients had large tumors for which only mutilating surgery, if any, was possible. In 21 patients, a combination of Adriamycin (doxorubicin), cyclophosphamide, cisplatin, vindesine, and DTIC (DCPAV) produced two complete remissions (CR) and 6 partial remissions (PR). A combination of cyclophosphamide, vincristine, Adriamycin, and DTIC (CYVADIC) produced three PR in eight patients, and a combination of Adriamycin and ifosfamide (AI) produced two PR in five patients. After two to seven cycles of chemotherapy, 24 patients underwent surgery. In 19, gross tumor excision was performed; 12 proved to be microscopically fully resected. Disease in two patients entered CR with chemotherapy alone, but surgery was performed in both patients as well. Irradiation was administered in ten patients to produce or insure CR (eight cases of residual disease postoperatively), and in two patients with unresectable disease. Four patients with disease in CR after surgery also received radiation due to the initial massive tumor size. The Kaplan‐Meier survival curves at 2 years showed 18% total survival in the patients in whom CR of disease was not achieved, and 80% survival in patients with disease in CR. Of the 22 patients with disease in CR (by all means), disease‐free survival was 1 to 44 months (mean, 13.7). Disease currently remains in CR in ten patients with a mean follow‐up of 13.6 months (3 to 34 months from end of therapy). Ten patients had a local recurrence following a CR after 3 to 44 months (mean, 15.3 months).

Sequential cytopunctures during preoperative chemotherapy for primary breast carcinoma. II. DNA flow cytometry changes during chemotherapy, tumor regression, and short‐term follow‐up

Between May 1986 and May 1987, 35 primary noninflammatory breast carcinomas (T3N0‐N1M0) were studied by means of DNA flow cytometry (FCM‐DNA) before and after each of three courses of preoperative chemotherapy (doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5‐fluorouracil) to assess initial nuclear DNA content, initial S‐phase fraction (SPF), and the impact of chemotherapy on these parameters. Correlations were sought with objective regression and short‐term follow‐up. Four sequential cytopunctures were performed for cytologic examination and FCM‐DNA analyses. Ten tumors were diploid and 25 aneuploid. No significant changes in FCM‐DNA parameters during chemotherapy were observed in diploid tumors, and no regression was seen in nine of the ten cases. Among the 25 aneuploid tumors, 10 showed changes in DNA content and/or kinetic parameters. A significant correlation was observed between objective regression and initial FCM‐DNA content (P = 0.008), initial SPF (P = 0.004), and changes in FCM‐DNA patterns observed during chemotherapy (P = 0.00005). During the follow‐up period (range, 27 to 41 months), 13 patients had relapses. Patients with aneuploid tumors were more likely to have relapses (n = 11) than patients with diploid tumors (n = 2), and patients with high SPF were more likely to have relapses than patients with low SPF, but the differences were not significant. Similarly, changes in FCM‐DNA parameters were observed more often in patients who had relapses, but, again, the difference was not significant. In 5 of the 13 patients who had relapses, FCM‐DNA analyses were performed on cytopunctures of the recurrences: patterns were identical to those observed before treatment even when the primary tumor regressed or showed changes in FCM‐DNA parameters during chemotherapy.

Sequential cytopunctures during preoperative chemotherapy for primary breast carcinoma. Cytomorphologic changes, initial tumor ploidy, and tumor regression

Thirty‐five patients with large but operable breast carcinoma (T3, N0‐N1, M0) received before surgery three cycles of preoperative Adriamycin (doxorubicin), vincristine, cyclophosphamide, methotrexate, 5‐fluorouracil (AVCMF) chemotherapy (CT). All patients had sequential cytopunctures for both cytologic examination and flow cytometric DNA analysis (FCM): one before treatment and the three others after each cycle of CT. At cytologic examination, 20 carcinomas showed CT‐induced cytomorphologic changes. These changes in malignant cells were also evaluated on histologic sections after surgery. A significant relationship was found between cytomorphologic changes in cytopunctures and in the corresponding tumor tissue. The lobular carcinomas did not reveal changes either on cytologic or on histologic study. At FCM analysis before treatment, ten carcinomas were diploid and 25 were nondiploid. When initial tumor ploidy was compared to cytomorphologic changes, none of the diploid carcinomas showed changes. An objective tumor regression was observed in 12 of 20 tumors with cytomorphologic changes and in four of 15 tumors without changes on cytologic examination. But, a significant relationship appeared only when cellular changes were evaluated on histologic analysis. When tumor regression was compared to ploidy before treatment, the rate of objective regression was significantly higher in nondiploid tumors (15/25) than in diploid tumors (one of ten). From these findings, initial tumor diploidy could be a predictor of tumor chemoresistance, whereas cytomorphologic changes during chemotherapy could be an indicator of tumor cell chemosensitivity.