Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients.

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.

CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus cnf (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study.

A multicenter phase III randomized study compared the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer. The standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), was administered to 77 women. The experimental protocol, CNF (cyclophosphamide, mitoxantrone, 5-FU), in which mitoxantrone (Novantrone) replaced methotrexate, was given to 68 patients. Follow-up of the 145 patients by six participating hospitals showed no statistically significant difference (p = 0.6) between the two treatment regimens during a median follow-up of 4.5 years in terms of overall survival. There was, however, a significant advantage (p = 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF). Toxic side effects associated with CNF (particularly alopecia and myelotoxicity) were relatively more frequent but acceptable and did not lead to dose reduction. In light of its association with improved disease-free survival in this study, larger studies should be undertaken on the role of mitoxantrone as adjuvant treatment in stage II breast cancer.

Feasibility and low toxicity of early radiotherapy after high-dose chemotherapy and autologous stem cell transplantation for patients with high-risk stage II-III and locally advanced breast carcinoma.

BACKGROUND: This prospective trial examined the feasibility, toxicity, and effectiveness of early locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk American Joint Committee on Cancer (AJCC) Stage II-III and locally advanced breast carcinoma. METHODS: One hundred forty-seven consecutive patients with high-risk and locally advanced breast carcinoma were included in the current study. All patients received induction chemotherapy with a doxorubicin-based therapy, which was consolidated with high-dose cyclophosphamide, carboplatin, and thiotepa followed by autologous stem cell support. Within 50 days of the transplant, the patients were treated with locoregional radiotherapy that included the chest wall or breast, the axilla and supraclavicular area, and the internal mammary chain. The volume of lung included in the treatment volume was kept to a minimum. The central lung distance of the tangential fields ranged from 0.6-2.0 cm (mean, 1.1 cm). Tamoxifen was given based on receptor status. RESULTS: One hundred forty-six of 147 patients received the planned treatment. Only six patients had a delay in the initiation of radiotherapy, and another 16 patients had delays during radiotherapy. Leukocyte and platelet toxicities during radiotherapy were not life-threatening and blood counts thereafter returned to normal. Grade 2 (according to National Cancer Institute Common Toxicity Criteria) skin toxicity occurred in 22% of patients and Grade 3 skin toxicity occurred in 6% of patients. Radiation pneumonitis was reported to occur in 5 patients (< 4%). After a median follow-up of 36 months from diagnosis (range, 6-64 months), there were no long-term organ toxicity and no secondary malignancy reported. No treatment-related deaths were reported. Three patients (< 3%) developed locoregional recurrence. CONCLUSIONS: Locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation appears to be feasible and can be delivered safely within 10 weeks of transplantation. The short-term and long-term toxicity are reported to be low, with good local control.

Radiation pneumonitis complicating mediastinal radiotherapy postpneumonectomy.

Radiation pneumonitis is a well-characterized clinicopathological syndrome. The severity of radiation-induced lung injury correlates, among other factors, with the extent of lung volume incorporated within the field of radiation. The present article describes the cases of two patients with radiation pneumonitis following pneumonectomy and mediastinal radiotherapy. Postpneumonectomy pulmonary-mediastinal shift of the remaining lung towards the operated side, with inclusion of lung parenchyma within the "mediastinal" radiation portals, resulted in a substantial (albeit clinically unsuspected) radiation pneumonitis. Chest computed tomography in the postpneumonectomy patient may be helpful to evaluate the degree of pulmonary-mediastinal shift and optimization of the radiotherapy field.

Erythrocyte glutathione and tumour response to chemotherapy.

There is much evidence that tumour glutathione (GSH) concentration is an important factor in resistance to cancer chemotherapy. Since measurement of tumour GSH would require an invasive procedure in every patient, we have tried to find out whether GSH concentrations in peripheral-blood erythrocytes are related to the response to chemotherapy and thus whether they reflect those in tumour cells. Erythrocyte GSH concentrations were measured by spectrophotometry in peripheral blood from 28 patients with advanced breast cancer and 40 patients with other tumours before and after treatment with various conventional chemotherapeutic regimens. The mean pretreatment GSH concentration was lower in patients who showed a complete or partial response to chemotherapy than in those with stable or progressive disease in both the breast-cancer group (8.69 [95% confidence interval 5.99-11.39] vs 2.32 [1.23-3.41] mumol/g haemoglobin; p less than 0.01) and the group with other tumours (5.94 [4.14-7.74] vs 2.83 [1.71-3.95] mumol/g; p less than 0.01). The correlation of erythrocyte GSH concentration with response rate suggests that this measurement may be helpful in prediction of response to therapy.

[Extraskeletal Ewing's sarcoma].

5 patients diagnosed as having extraskeletal Ewing's sarcoma have been referred to our adult oncology unit since 1980. All were men, ranging in age from 18-57 (mean 32 years). The primary tumor was located on the trunk in 4 and in an extremity in 1. Wide tumor excision was feasible in only 2. 3 died within 27 months and 2 are alive, 13 and 67 months, respectively, following diagnosis. This study demonstrates the highly aggressive nature of extraskeletal Ewing's sarcoma and the need for early diagnosis and efficient chemotherapy.

Neoadjuvant chemotherapy in early-stage and locally advanced small bulk squamous cell carcinoma of the oral cavity and oropharynx.

Thirty patients with Stages I, II and III squamous cell carcinoma of the oral cavity and oropharynx (6, 12 and 12 patients, respectively) were entered into a combined modality protocol using preoperative chemotherapy, followed by resection with or without radical neck dissection and radiotherapy. None of the patients received prior treatment and all had good performance status. Primary sites included alveolar ridge (in nine patients), buccal mucosa (in eight), tongue (in six), floor of mouth (in five), and hard palate and tonsillar fossa in one each. Chemotherapy was given as a neoadjuvant debulking procedure using two courses of the Price-Hill regimen (5FU, methotrexate with citrovorum rescue, vincristine, bleomycin, and hydrocortisone) followed in 10 to 14 days by local resection for Stage I-II patients and radical neck dissection plus radiotherapy for Stage III patients. Response to chemotherapy alone was observed in 70% (21 of 30), with 17% (5 of 30) complete responders. Responses were seen in 100% of Stage I, 75% of Stage II, and 50% of Stage III patients. Age greater than 80 years was a poor prognostic indicator. Both men and women responded equally well. Of the 25 patients not entering CR with chemotherapy, a further 75% (11 of 15) did so after local resection and 50% (5 of 10) after local resection, radical neck dissection, and radiotherapy. Overall salvage rate post chemotherapy was 64% (16 of 25). All five patients in CR with chemotherapy alone are alive at a median follow-up time of greater than or equal to 43 months; full survival data are discussed. Toxicity was minimal and did not affect change in treatment course in any patient. These results show that further investigations on the use of neoadjuvant chemotherapy in early-stage and locally advanced squamous cell carcinoma of the oral cavity and oropharynx are indicated.

Prophylactic oophorectomy in premenopausal women with stage II breast carcinoma.

Prophylactic oophorectomy, as an additional treatment for stage II breast cancer, is controversial. In a retrospective study, a group of 37 premenopausal women with stage II infiltrating duct carcinoma and one to three positive axillary lymph node involvement after modified radical mastectomy and bilateral oophorectomy were compared to a matched group of 34 women treated by modified radical mastectomy only. Prophylactic oophorectomy prolonged the disease free interval significantly as compared to the control group. However, it did not prolong survival. This raises the question whether the prolongation of survival achieved by late oophorectomy in women with advanced breast cancer is preferable to an improvement in quality of life resulting from longer disease free intervals.

Reduced thoracic vertebrae metastases following post mastectomy parasternal irradiation.

A retrospective study of 118 women with breast cancer metastatic to bone is presented. All had originally received post mastectomy adjuvant radiation therapy for Stage II (T2 N0, T2 N1, T1 N1) infiltrating duct carcinoma of breast. Sixty-two women (group A) received a parasternal portal and 56 women (group B) did not. There was significantly less metastatic involvement of the mid-dorsal vertebrae D5-6-7-8, 13% in group A compared to 60% in group B. The mean time to diagnosis of metastatic disease was 33 months (group A) and 36 months (group B). The dose of radiation to the vertebrae through which the parasternal beam exited was estimated at between 1000-1600 rad over three to four weeks. This observation may have significant implications for the management of high risk operable breast cancer.

Postsurgical adjuvant treatment of malignant melanoma patients by the thymic factor thymostimulin.

37 patients with cutaneous malignant melanoma (MM) were randomized, after surgical removal of tumor, to either no further treatment or to adjuvant treatment by the thymic factor thymostimulin (TS; Tp-1 Serono). 26 patients were with primary (stage I) MM (tumor thickness greater than 1.25 mm), and 11 patients with local or regional disease spread (stage II MM). Randomization was done separately for each disease stage. Life table analysis of the results indicates that significantly (p less than 0.01) more patients were free of disease at one year on study if treated by TS than if left untreated. Probability of survival was also better (p = 0.05) in the TS-treated group at 15 months on study. No side effects, toxic or allergic, were observed under TS treatment.

Prophylactic low-dose post-operative orthovoltage radiotherapy in stage II breast cancer.

Between the years 1974 and the beginning of 1977, 199 patients with stage II infiltrating duct carcinoma of the breast were treated with post-operative radiation, using a 250 kVp X-ray machine. Three treatment schedules were used consisting of 22, 26.2 and 29.6 Gy (2200, 2620 and 2960 rad) total tumour dose, calculated at 2 cm depth, with 5, 3 and 3 fractions a week respectively. The frequency of local recurrences, mainly in the chest wall, were 20.3%, 8.3% and 8.1% respectively. The latter two frequencies were not different from those reported for the commonly used high dose treatments of 45-60 Gy (4500-6000 rad) delivered either as given doses or tumour doses. An approximate 70% five year survival rate was similar in the three groups and does not differ from results observed with high doses. Low dose treatment is advantageous, because it has fewer complications and it can be delivered in a smaller number of sessions, making it more convenient to the patient, without loss of efficacy. The results presented of the low dose treatment may reflect the existence of an optimal dose level of radiation.

Adjuvant therapy for Dukes C adenocarcinoma of colon.

Forty-two patients with adenocarcinoma of the colon, who received surgery between 1975 and 1978 and were to found to have pericolonic fat infiltration and lymph node metastases, were analyzed for disease free period and overall survival. Twenty-one patients had received post-operative X ray therapy, and post-X ray therapy intravenous 5-Fluorouracil adjuvant therapy. Twenty-one patients, matched by age, sex, ethnic origin and site of disease were untreated. The 5 year survival rate for the treated group was 65% compared with 36% for the control group (P greater than 0.2). At 5 years 55% of the treated group were disease free but only 12% of the control group remained disease free (P = 0.04). The significance of this work needs to be established by a randomized and prospectively controlled clinical trial.

Computerized tomography in ovarian cancer.

Sixteen women suffering from ovarian cancer were staged by clinical and pathological means and concomitantly scanned by computed tomographic means. Computed tomography (CT) was found accurate in nine patients. The staging of the disease was upgraded in three patients following the CT examination. CT examination in four patients was equivocal or failed to detect the true extent of the disease. It was not possible to accurately assess the true nature of the pelvic mass on CT following a partial debulking pelvic procedure, as the remnant pelvic bed tissue could be misinterpreted as recurrent cancer. Small peritoneal cancer seedings were not detected on CT. CT scanning despite certain limitations is a valuable noninvasive adjunct in the assessment of carcinoma of the ovary and its response to treatment.

Modification of the response of mouse skin to x-irradiation by a polar solvent, N,N-dimethylformamide.

The modification of the response of mouse skin to either single or split (24 hrs) graded doses of X rays by topically applied N,N-dimethylformamide (DMF) was investigated. DMF was applied daily for 5 days prior to irradiation. At a radiation dose level producing dry desquamation, DMF enhanced the X ray response by a factor of 1.3. Also, at the same level of response, the fraction of X ray dose repaired in 24 hours was 0.57, whereas for the DMF-treated and irradiated skin, this factor was 0.41, indicating a reduction of about 28% in subeffective damage repair. The times of maximal involvement of the skin reactions were not different in the X ray plus DMF treated mice versus mice receiving x-irradiation only. The data indicate that DMF is able to modify intrinsic radiation sensitivity of mouse skin epithelial cells, possibly through a reduction in the magnitude of the shoulder region of the survival curve.