Surgical and adjuvant radiation therapy of resectable retroperitoneal soft tissue sarcomas in adults.

Primary soft tissue sarcoma of the retroperitoneum is a rare disease. A series of 11 evaluable adult patients with retroperitoneal soft tissue sarcomas is reported. These patients were treated with complete surgery and adjuvant radiation therapy (total dose from 50 to 64 Gy) using an 18 MeV linear accelerator. After a median follow-up of 48 months (range, 6-84), 4 patients had a local-regional recurrence, 3 had distant metastases, and 4 died of progressive disease. Four-year estimated disease-free survival was 54.5% and overall survival was 70%. Treatment was well tolerated by most patients: 7 patients experienced moderate gastrointestinal toxicity, mainly nausea and diarrhea, during radiotherapy; 2 cases had weight loss > 15% at the end of the therapy; and chronic ileitis was observed in 2 cases. We conclude that adjuvant radiotherapy seems to reduce the incidence of local-regional recurrences in these patients. No radiation-induced irreversible injury was observed, but one young woman had amenorrhea after radiotherapy. Controlled clinical trials are warranted to define the role and effectiveness of adjuvant radiotherapy and/or chemotherapy in retroperitoneal soft tissue sarcomas.

Synchronous radiotherapy and chemotherapy with cisplatin in the management of locally advanced or recurrent head and neck cancer.

A synergism between cisplatin and radiotherapy has been demonstrated in in vitro and in vivo studies. To improve the locoregional control of disease and the survival rate in patients affected by locally advanced or recurrent squamous cell carcinoma of the head and neck, we planned a Phase II study of concurrent radiotherapy, 2 Gy for 5 days every week for a total dose of 60-70 Gy with cisplatin 80 mg/m2 every 21 days for 2 or 3 doses (on days 1, 21, 42). Fifty-one patients were entered in the study; 48 were evaluable for response and toxicity; 18 (37.5%) had untreated Stage III disease; 25 (52%) had Stage IV disease; 5 (10.5%) had recurrent disease. The complete response rate in Stage III-IV patients was 63% (27 of 43) with 95% confidence limits from 48 to 77% (+/- 14.5%). In the group of five patients with recurrent disease, only one (20%) achieved a complete response. In patients with Stage III-IV disease, a significantly higher complete response rate was observed for those younger than 58.5 years (p = 0.05). The overall estimated 1- and 2-year survival was 59% and 37%, respectively, and a significantly better survival was observed in complete responders compared to partial responses or patients with stable disease (p = 0.037). Disease-free survival was 46% and 36% at 1 and 2 years, respectively. Distant failure occurred only in 12.5% of the patients. Overall, the treatment was well tolerated, and only three patients refused to complete the planned therapy. Gastrointestinal and hematological toxicity were the most common side effects. Data from present trial were compared with that of 50 patients with comparable characteristics treated with radiotherapy alone from 1985 to 1987 as a historical control. The complete response rate, the disease-free survival, and the overall survival appear to be better in the patients treated with chemoradiotherapy. It was concluded that the combination of chemoradiotherapy in patients with Stage III-IV head and neck squamous cell carcinoma is an effective and safe treatment with an apparent better locoregional control than radiotherapy alone. Survival results need to be evaluated in a Phase III randomized trial.

Phase I study of escalating dose mitoxantrone in combination with alpha-2-interferon in patients with advanced solid tumors.

In vitro and preclinical in vivo data have shown a synergistic antitumor activity between alpha-interferon and some antiproliferative agents. A phase I study of the concurrent administration of interferon-alpha 2 and mitoxantrone was initiated, to determine the maximum tolerated dose of mitoxantrone given i.v. every 3 weeks in escalating doses combined with a fixed dose of s.c. interferon alpha 2 (6 x 10(6) IU three times per week 3), in patients with advanced solid tumors resistant to conventional chemotherapy. At least three evaluable patients were entered in each dose level of mitoxantrone starting at 4 mg/m2, with no escalations allowed in the same patient. Twenty-seven patients received a total of 101 cycles and five dose-levels were explored (4-6-8-10-12 mg/m2 of mitoxantrone). The dose-limiting toxicities were leukopenia and granulocytopenia at 12 mg/m2 of mitoxantrone, at which dose hematological toxicity occurred in greater than 50% of cases, with one patient presenting grade 4 leuko-granulocytopenia. No severe thrombocytopenia occurred. In the majority of patients transient hepatic enzyme elevations and a flu-like syndrome due to interferon alpha 2 were observed in all dose-levels explored. These observations suggest that the hepatotoxic effects of interferon alpha 2 do not emphasize mitoxantrone side-effects if given simultaneously. When mitoxantrone is administered with 6 x 10(6) IU of interferon alpha 2, the recommended dose for future phase II studies is 10 mg/m2/weeks 3 with escalation up to 12 mg/m2 in selected patients if such a combination is well tolerated in terms of myelosuppression. Regarding therapeutic activity, four out of 25 (16%) cases evaluable for response achieved a partial response.(ABSTRACT TRUNCATED AT 250 WORDS)

Conservative surgery and irradiation (QUART) in the treatment of 243 stage I-II breast cancer patients.

From 1980 to 1987, 243 evaluable patients with pT1, pT2 (less than 3 centimeters in diameter), N0, M0, invasive breast cancer were treated with "quadrantectomy" with axillary dissection followed by electron beam radiation therapy (QUART) at the St. Bortolo Hospital, Vicenza. Stage II patients received adjuvant chemotherapy (CMF) if preperimenopausal or hormonotherapy (tamoxifen) if postmenopausal. The median follow-up was 54 months (26 to 116 months). The 4.5-year overall survival (OS) and disease-free survival (DFS) were respectively 91% and 85%; the 10-year actuarially estimated OS and DFS was 77%. Thirty-three patients relapsed, 11 of whom had local recurrence, and 23 developed distant metastases. A significantly longer OS and DFS were observed in stage I versus stage II (p = 0.0008) and in pT1 versus pT2 (p = 0.001) tumors. No difference was found regarding menopausal status and histotype. The local control of disease was very high (95.5%), with a significantly higher local recurrence rate in premenopausal women compared to postmenopausal (10/117 versus 1/126; p = 0.009). Tumor size did not influence the frequency of local recurrence. No major complications occurred but a significantly higher rate of reversible radiation-pneumonitis occurred in patients treated with higher energies of electrons (17 to 20 MeV) compared with lower (6 to 13 MeV) (33/177 versus 7/66; p less than 0.05). Cosmetic results were judged as excellent in 20%, satisfactory in 68%, unsatisfactory in 6% and not evaluable in 6% of cases. We conclude first, that small pT2 breast carcinomas may also be safely treated with QUART, second, that the electron beam is a radiotherapeutic technique able to produce a good cosmetic result and to assure a satisfactory local control and, finally, that the use of tamoxifen in postmenopausal stage II breast carcinomas is safe and easy to combine with radiotherapy in the conservative management of early breast cancer due to the lower toxic effects, compared to those observed in premenopausal women treated with chemotherapy.

Splenic irradiation in chronic lymphocytic leukemia.

52 patients with CLL, presenting primarily with splenomegaly, stage II-IV according to the Rai stage system, were treated with a regime of low-dose splenic irradiation (SI) between January, 1979 and December 1987. The treatment modality consisted of 1 Gy, from 1 to 10 doses, given at weekly intervals. The median given dose was 700 cGy (100-1000). CHR occurred in 23/52 (44%), PR in 20/52 (38%) and no response (NR) in 9/52 (17%) of the patients. The median duration of remission was 9 months (range 3-24), 15 and 7 months for patients achieving CHR and PR, respectively. At relapse, 14 patients received a second course of SI by the same modalities: 2 of them obtained a second CHR, 9 a PR and 3 NR. The median duration of remission was 4 months. In conclusion, SI represents a suitable therapy for CLL patients presenting primarily with splenomegaly. The low rate of response and the short remission duration after the second treatment suggest that SI should be combined either with splenectomy or with other therapeutic approaches.

Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinical trial.

Forty-nine patients with advanced breast cancer who had failed from first-line cyclophosphamide, methotrexate, and 5-fluorouracil (CMF regimen) chemotherapy, were randomized to treatment with either epirubicin (Epi) or doxorubicin (Dox) at a dose of 20 mg/m2 given intravenously (i.v.) weekly to compare the efficacy and toxicity of these two anthracyclines given in such a schedule. Of 43 evaluable patients 36% (eight of 22) treated with Epi and 38% (eight of 21) treated with Dox achieved a complete plus partial response rate (95% confidence limits 16-56% +/- 20% and 18-58% +/- 20%, respectively). Patients who obtained a major therapeutic response to previous CMF exhibited a significantly higher response rate with both the drugs: seven of eight (87.5%) compared with one of 13 (8%); p less than 0.05 for Epi and six of seven (86%) compared with two of 15 (13%); p less than 0.05 for Dox. The median duration of response was 4.5 months with Epi compared with 7 months with Dox, and the median survival of the two groups of patients were superimposable (12 months with Epi versus 11 months with Dox). The median cumulative dose was 220 mg/m2 (range 160-620) and 240 mg/m2 (range 160-860) for Epi and Dox, respectively. Gastrointestinal and hematological toxicities were moderate for both the drugs, with fewer episodes of nausea and vomiting, stomatitis, and leukopenia following Epi administration. A very low incidence of alopecia was recorded for both the drugs. Regarding cardiac evaluation, no significant differences were evident; however, the only case that developed symptomatic congestive heart failure was in the Dox arm, after a cumulative dose of 820 mg/m2 at 11.5 months. Epi given weekly at low doses preserves efficacy in the treatment of patients with advanced breast cancer, and given at equimolar doses, has a slightly better therapeutic index than the parent compound.

Simultaneous cis-platinum and radiotherapy in inoperable or locally advanced squamous cell carcinoma of the head and neck.

A synergism between cis-platinum (CDDP) and radiotherapy (RT) has been demonstrated both in culture systems and in clinical studies. On the above basis, we planned, in patients with locally advanced or unresectable squamous cell carcinoma of the head and neck, a concomitant treatment with CDDP 80 mg/m2 i.v. every 3 weeks for three doses (days 1, 21 and 42) and RT in the primary and in the neck nodes bilaterally, for a total dose of 60-70 Gy. Thirty-five untreated patients with poor prognosis unresectable stage II and stages III-IV disease were entered in the study and 32 were evaluable. Complete response (CR) rate was 75% (24/32) with 95% confidence limits from 60 to 90% (+/- 15%): 8 cases (25%) achieved a partial response, for an overall response rate of 100%. A significantly higher CR rate and a longer survival rate was observed in patients with good performance status (PS = 90-100) and stages II-III. The overall estimated 2-year survival is 46%; 59% for patients who obtained a CR versus 0% for those who achieved only a partial response. Overall the treatment was well tolerated and gastrointestinal and hematologic toxicities were the most common side effects. In conclusion, the combination of CDDP plus RT is a very effective and safe treatment and we recommend such an approach in head and neck squamous cell carcinoma, particularly in those patients with good PS and with unresectable stage II or stage III disease.

Radiotherapeutic treatment for breast cancer choroidal metastases.

A series of 14 eyes (11 patients) with choroidal metastases from breast cancer were reported. The lesions were classified into three grades according to the severity and extent of involvement. Eleven eyes (9 patients) were treated by radiotherapy with two opposed lateral fields using a 4 MeV linear accelerator. The contralateral eye received a prophylactic irradiation. An average dose of 42 Gy was delivered (range, 30-50). Results of radiotherapy were the following: 5 CR and 2 PR in grade II (9 eyes) and 2 PR in grade III (2 eyes). We conclude that radiotherapy is useful to control choroidal metastases of breast cancer. No contralateral metachronous involvement was found. Quality of life of responders showed a marked improvement. Radiation-induced injury was not seen.

Immunocytochemical determination of epidermal growth factor receptor with monoclonal EGFR1 antibody in primary breast cancer patients.

Epidermal growth factor (EGF) has been shown to be important in regulating the growth of breast cancer cells in vivo because of its mitogenic action on some breast cancer cell lines in vitro. Immunocytochemical analysis of EGF receptor (EGFr) was carried out on frozen sections in 134 primary breast cancer patients. Overall 68 of 134 (51%) of the tumors were EGFr positive. There was no correlation between EGFr positivity and menopausal status. Regarding the histopathological features, no significant correlations were observed between EGFr expression and tumor size, grading and lymph nodes status. Estrogen (ER) and progesterone (PgR) receptors were detected by an immunocytochemical assay and an equal distribution of EGFr was found regarding steroid hormonal receptors expression. Finally, there was only a positive trend between the proliferative activity of the tumors, as measured by Ki-67 antibody, and the amount of EGFr. Our results suggest the presence of a subclass of breast tumors, characterized by the absence of ER and/or PgR and the presence of EGFr, whose growth appears to be mediated by autocrine growth factors rather than by steroid hormones. The overall picture is that of an independent relationship between EGFr expression and the known prognostic factors in breast cancer.

Characterization of node-negative breast cancer by clinico-pathologic and biologic factors.

About 30% of node-negative breast cancer (NNBC) patients relapse and about 20-25% die after local treatment. This is a heterogenous disease and at present no single factor completely distinguishes those patients destined to have a recurrence and to die, for whom an adjuvant treatment seems indicated. With the objective of subdividing NNBC into different prognostic groups, we studied the expression and relationship of eight factors related both to the clinico-pathologic characteristics and to the tumor biology in 78 consecutive patients: menopausal status, tumor size, grading (G), intratumoral vascular invasion (IVI) steroid hormonal receptors, proliferative rate and epidermal growth factor receptor (EGFr) expression. The frequencies of the risk factors examined were: pre- or perimenopausal status in 29.5%, tumor size greater than 2 cm (pT2) in 28%, GIII in 45%, IVI in 13% estrogen receptor (ER)-negative in 43% and progesterone receptor (PgR)-negative in 60%. There were 23% high proliferating (Ki-67 antibody greater than 20%) and 54% EGFr positive tumors. The distribution of the above risk factors in each tumor were: no factor in 4%; one in 15%; two in 30%; three in 23%; four in 14%; five in 8%; six in 2%; seven in 4% and no case had the sum of all the factors. The mean distribution value was of two per case. Twenty-eight percent of patients had more than the sum of four factors. A significant correlation was observed among: premenopausal status with G III (61% vs 45% in postmenopausal status; p less than 0.05), premenopausal status with ER-negative tumors (65 vs 29% in postmenopasual; p less than 0.05) and between the lack of expression of the two hormonal receptors (overall agreement of 77; p less than 0.05). The prognostic value of these findings needs to be verified with an adequate follow-up.

Correlation of growth fraction by Ki-67 immunohistochemistry with histologic factors and hormone receptors in operable breast carcinoma.

Breast cancer tissue samples obtained from 147 Stage I and II patients were tested with the monoclonal antibody Ki-67 and avidin-biotin-peroxidase complex in frozen sections. The percentage of cells with nuclear staining ranged from 5% to 65%. The frequency of Ki-67 positivity was classified in five groups: 0% (45/147 = 31%); 5-9% (38/147 = 26%); 10-19% (15/147 = 10%); 20-39% (24/147 = 16%) and greater than or equal to 40% (25/147 = 17%). The mean value was 20%, median 18% with standard deviation of 14.5%. A significant positive correlation was observed between the presence of high Ki-67 nuclear staining rate with pathological tumor size (p = 0.003), histologic grading (p = 0.04), and axillary lymph node metastases (p = 0.009). An inverse significant correlation was found between Ki-67 and estrogen receptor expression (p less than 0.001). No correlation was observed with progesterone receptor expression or menopausal status. The overall picture is of an inverse relationship between high growth fraction determined with Ki-67 antibody and tumor differentiation parameters. These correlations confirm those already reported by thymidine labeling index and flow cytometry methods. The proliferative rate determined with Ki-67 antibody may provide information regarding cell kinetics of breast carcinoma, potentially useful in identifying patients with a different clinical course in order to improve the therapeutic approach, by a rapid, practical and easily performed immunohistochemical method.

[Advanced stages of rectosigmoid cancer. The role of postoperative radiotherapy]. / Stadi avanzati del cancro del sigma-retto. Ruolo della radioterapia postoperatoria.

In patients with advanced rectosigmoid adenocarcinoma treated with radical surgery alone, loco-regional relapse rate is quite high (29%-60%). When postoperative radiotherapy is performed, loco-regional relapse rate sharply falls to 7%-15%. A series of 42 patients, stage B2, C1 and C2, is presented. All patients were treated with radical surgery and postoperative radiotherapy. Only two loco-regional relapses were found (5%). Overall actuarial survival at 5 years is 76% for B2, and 46% for C1 and C2. The authors conclude that adjuvant postoperative radiotherapy is useful in reducing loco-regional relapses, whereas survival seems to be improved only for stage B2 patients.

[Small size breast cancer conservative surgical therapy and subsequent radiotherapy]. / Il cancro mammario di piccole dimensioni: terapia chirurgica conservativa e successiva radioterapia.

From february 1980 to december 1985, 115 breast carcinomas were treated with QU.A.RT. with limited surgery and following radiotherapy. Median age was 51 years (range 25 to 75). Surgical approach was quadrantectomy with axillary nodes dissection. Irradiation of residual breast was performed by an anterior high energy electron beam. 50 Gy in 25 fractions was the minimal dose to whole breast. In pN+ patients systemic adjuvant therapy was done. Local control was obtained in 111 cases. Local recurrence appeared in 4: 1 menopausal pT1 pNO and 3 premenopausal (1 pT1 pNO and 2 pT1 pN+) at respectively 31, 19, 22 months from diagnosis. Distant metastases appeared in 10 patients. 7 died for cancer and 3 are still alive. Cosmetic results were scored as good in 52, better than mastectomy in 26, unsatisfactory in 3, and not stated in 34. Our results are comparable to those of other Centers. Youth, axillary metastases and delay between surgery and radiotherapy appears to influence the risk of recurrence also in our series.

Long-term survival in response to combined chemotherapy and radiotherapy in laryngeal small cell carcinoma.

Fourteen patients with small cell carcinoma of the larynx are studied. This represents the largest series, from a single institution, reported in the literature. This neoplasm is usually highly aggressive and the prognosis very poor, but, in our experience, combined chemo- and radiotherapy can significantly improve the clinical course of the disease. Three of six patients who received this combined modality treatment are still clinically disease-free more than six years after the initial diagnosis.

Treatment of early stage Hodgkin's disease with radiation therapy plus short-cycle (3 MOPP) adjuvant chemotherapy.

Eighty-four consecutive, previously untreated patients with stage I, II A-B and IIIA Hodgkin's disease were treated with combined modality therapy including subtotal or total nodal irradiation, followed by three cycles of MOPP. MOPP was administered before radiotherapy in patients with systemic symptoms or with bulky disease. Seventy-six of 84 patients (90.5%) achieved complete remission, and 8 died from disease progression after a variable period of incomplete remission. Three of 76 (3.9%) relapsed, and 2 of them have been subsequently salvaged. Up to the present time, 70 patients are alive, without evidence of disease; 9 have died from Hodgkin's disease, 2 from acute non-lymphoblastic leukemia, and 3 from intercurrent causes. No death occurred from acute toxicity due to chemotherapy. Actuarial overall survival is 82.3% and freedom from relapse is 81.8% after 48 months' median observation (range: 12-111 months). No significant difference in survival and freedom from relapse has been observed with respect to age, sex, stage, presence or absence of unfavorable prognostic factors. The role of adjuvant chemotherapy and its use in a reduced number of cycles in early stage Hodgkin's disease are discussed.

Treatment of 49 unrandomized patients with advanced Hodgkin's disease.

Forty-nine patients with previously untreated advanced Hodgkin's disease were treated in our Institution between 1973 and 1981. Treatment modalities of these patients were reviewed, and they were divided into 3 groups according to the treatment employed: 13 patients received MOPP only, 22 patients received MOPP plus involved field radiotherapy, and 14 received alternating MOPP/ABVD chemotherapy. The response rates for the 3 groups were respectively 38.5%, 63.6% and 78.6%. A longer follow-up is needed to assess a significant difference in survival curves. The advantages of adjuvant radiotherapy and alternating non-cross-resistant drugs in advanced Hodgkin's disease are discussed.