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.

Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma.

Breast carcinoma is the most common malignant disease among women and the second most lethal one. In search for a better understanding of the role of cellular mediators in the progression of this disease, we investigated the potential involvement of the CC chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) in breast carcinoma progression. To this end, RANTES expression was determined in breast tumor cell lines and in sections of breast carcinomas, followed by analysis of the incidence and intensity of its expression in different stages of the disease. Our study reveals that high and physiologically relevant levels of RANTES are constitutively produced by T47D and MCF-7 breast tumor cell lines. Analysis of RANTES expression in sections of breast carcinomas demonstrates a high incidence of RANTES expression in epithelial tumor cells; the chemokine was expressed in 74% of the sections. RANTES expression was rarely detected in normal duct epithelial cells or in epithelial cells that constitute benign breast lumps, which were located in proximity to tumor cells. High incidence and intensity of RANTES expression were detected in sections of most of the patients with stage II and stage III of the disease (expression was detected in 83 and 83.3%, respectively), whereas RANTES was expressed at a lower incidence and intensity in sections of patients with stage I of breast carcinoma (55% of the cases). Most importantly, the expression of RANTES was minimally detected in sections of patients diagnosed with benign breast disorders and of women that underwent reduction mammoplasty (15.4% of the cases). These results indicate that the expression of RANTES is directly correlated with a more advanced stage of disease, suggesting that RANTES may be involved in breast cancer progression. Moreover, it is possible that in patients diagnosed with benign breast disorders, RANTES expression may be indicative of an ongoing, but as yet undetectable, malignant process.

Radiation therapy of metastatic spinal cord compression. Multidisciplinary team diagnosis and treatment.

PURPOSE: To evaluate the effectiveness of a multidisciplinary approach to spinal cord compression (SCC) in accordance with prospective protocol, providing a uniform approach to diagnosis, decision making concerning optimal treatment modality in any particular case of SCC, treatment performance and evaluation of treatment results. The SCC patients treated by radiation therapy are described. MATERIALS AND METHODS: Patients with SCC were examined and treated by a multidisciplinary team consisting of a neurologist, radiologist, oncologist, orthopedic surgeon, and neurosurgeon. Seventy-nine patients for whom radiation was recommended received a 30 Gy radiation dose to a compression-causing mass and course of high dose dexamethasone. Three fractions of 5 Gy and 5 fractions 3 Gy each were delivered by Co60 or 8 MV photon beam in 12 days. Treatment outcome was essentially evaluated by ambulation capabilities which were considered to be the main problem of SCC. Changes in other neurologic motor, sensory and autonomic disturbances were also evaluated. RESULTS: Seventy-two percent of the patients were already non-ambulatory at diagnosis. The first symptom was motor deficiency in only 33% of them while in all other cases it was pain. Ambulation capability was the main prognosticator of treatment outcome; 90% of patients who were ambulatory before treatment remained so while 33% of the non-ambulatory patients regained their ability to walk. The grade of motor disturbance was also an important variable: among the non-ambulatory patients, 50% of the paretic but only 14% of the plegic ones became ambulatory. Overall, 51% of the study patients were ambulatory after undergoing radiation. The ambulatory state after treatment was the main predictor for survival. CONCLUSION: Close cooperation of a multidisciplinary team in diagnosis and treatment according to the above protocol enabled the achievement of good results of radiation treatment in SCC. Early diagnosis and early treatment should further enhance therapeutic outcome.

Primary intramedullary spinal melanoma: diagnostic and treatment problems.

A 76-year old female patient with 9 year history of right mastectomy for an infiltrating ductal breast cancer and no evidence of recurrent nor metastatic disease, was admitted due to pain in the lower thoracic area radiating bilaterally to the posterior aspect of the chest wall at the same level, difficulties in micturition, urinary hesitancy, and progressive weakness of the lower limbs. Primary intramedullary spinal tumor was demonstrated by a MRI study of the spine, partially resected, and found to be a malignant melanoma on pathological study. Postoperative irradiation and administration of dexamethasone did not improve the neurologic status.

Scalp cooling in the prevention of alopecia in patients receiving depilating chemotherapy.

To assess any difference in the incidence of alopecia during treatment and of skull metastases during follow-up among breast cancer patients undergoing scalp cooling during chemotherapy and those treated at ambient temperatures. A series of 35 breast cancer patients receiving adjuvant chemotherapy were consecutively assigned either to a scalp cooling regimen (19 patients) or to an ambient temperature regimen (16 patients). Hypothermia was administered with electrically cooled caps (SCS II: Amit Technology, Jerusalem) for 1 h after treatment. A significant difference (P = 0.014) was detected in the incidence of alopoecia: 48% (9 patients) of those who had undergone cooling suffered alopoecia, while 81% (13 patients) of the group who had not undergone cooling lost scalp hair. Patient comfort levels were high. Follow-up (median time 14 months) has disclosed no scalp metastases. The implementation of routine scalp hypothermia as part of adjuvant chemotherapy treatment, especially in cancers without tendencies to bone metastases, should be seriously considered.

High dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation.

BACKGROUND: Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administration in humans has resulted in a life-threatening septic shock-like syndrome, and its use has been abandoned. The administration of high dose rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminated the systemic side effects and was shown to be very effective for metastatic melanoma confined to the limb. The purpose of the current study was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable in 10% of these patients despite aggressive conventional therapy. Limb preservation was the objective in this select group of candidates for amputation or mutilating surgery. METHODS: During a 36-month period, 35 patients with high grade soft tissue sarcoma underwent 41 ILPs with high dose rTNF-alpha (3-4 mg) and melphalan (1-1.5 mg/kg). There were 21 males and 14 females. The mean age was 48 years (range, 14-80 years). Histologic subtypes included malignant fibrous histiocytoma, synovial, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioid, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one patients presented with recurrent and 14 with very extensive primary tumors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candidates for amputation and 10 for extensive mutilating surgery. ILP was performed via the corresponding vessels proximal to the tumor. Six patients with partial response (PR) insufficient to render them resectable underwent a second ILP. With the exception of 4 of 9 patients with multifocal lesions and 1 who refused surgery, resection of the residual tumor or tumor bed or limb was performed 6-8 weeks after ILP. RESULTS: Marked tumor softening occurred within 48 hours, and in tumors protruding through the skin hemorrhagic necrosis was evident within 24 hours. The overall response rate was 91%. Thirteen patients (37%) had a complete response and 19 (54%) had a PR; in 5 of these patients > 90% necrosis of the tumor occurred. In 3 patients (8.5%), only minimal regression was observed (stabilization of disease). The rate of limb sparing was 85% (29 of 34 patients). CONCLUSIONS: The combination of high dose rTNF-alpha and melphalan given via ILP appears to be effective in patients with advanced soft tissue sarcoma confined to the limb, achieving a high response rate and limb preservation.

Detection of melanoma by monitoring the intracellular fluorescein fluorescence polarization changes in lymphocytes.

The effectiveness of detecting melanoma by measuring the intracellular fluorescein fluorescent polarization (IFFP) of patients' SCM (structuredness of the cytoplasmic matrix)-responding lymphocytes was examined. SCM-responding lymphocytes from 46 melanoma patients and 32 healthy volunteers were labeled with fluorescein diacetate and challenged with different stimuli, and the resulting polarization was determined. The polarizations (P) obtained upon stimulation with nothing (P-0), encephalitogenic factor (P-EF), phytohaemagglutinin (P-PHA), or melanoma antigen (P-MEL), and the ratios RR(ef) (P-EF/P-PHA) and RR(mel) (P-MEL/P-PHA) were lower for SCM-responding lymphocytes from the patients as a group than for those of the controls. The specificity and sensitivity of the IFFP tests (using cutoff values) to detect melanoma were 90.6 and 73.9%, respectively. The IFFP tests may facilitate the discrimination between melanoma patients and healthy subjects, and may be used in follow-up of patients with melanoma.

Palliative major amputation and quality of life in cancer patients.

Limb sparing surgery has replaced the amputation surgery in the treatment of limb sarcomas. Recurrent or persistent disease constitutes a major problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patient's quality of life. In this clinical set-up palliative amputation should be considered. Eighteen patients with soft-tissue or bone sarcomas and 3 patients with metastatic carcinoma underwent palliative major amputation. Hemipelvectomy was performed in 3 patients, hip disarticulation in 10, knee disarticulation or below-knee amputation in 3 patients, shoulder disarticulation in one patient and forequarter amputation in 4 patients. Local control of the disease and pain and improvement of the performance status were observed in 19 evaluable patients. The mobility was restored in 15 patients with lower limb surgery. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. To conclude, we have, found palliative major amputation surgery worth performing in low-performance status cancer patients with locally advanced disease.

Tamoxifen for disease-negative but MCA-positive breast cancer patients.

Increased levels of mucin-like carcinoma-associated antigen (MCA) in breast cancer patients with no evidence of disease following the treatment of the primary disease created a dilemma of 'to treat' or 'wait and see'. One might assume that early treatment of clinically undetectable disease on the basis of an elevated serum level of a sensitive and reliable tumor marker, may improve the treatment results, and even prolong the patient's survival. 'Wait and see' on acceptance of the notion that even early metastatic disease, still manifested only by uprising MCA levels, is incurable, and treatment should be kept in reserve for palliation of symptomatic disease. Sixty-one breast cancer patients with increasing MCA levels but without evidence of metastatic disease were randomized for tamoxifen 20 mg b.i.d. or to follow-up till relapse. The results for a median follow-up period of one year were encouraging. The non-treated patients experienced a significantly higher relapse rate (24.1%) than the tamoxifen-treated subjects (0%; p=0.012). The results for a median follow-up of 5 years were disappointing. The overall relapse rate was 22.2%. The relapse rate among the control patients was 25.8% while in the treatment arm it was 17.4% (p=0.46). The event-free survival and the pattern of relapse were similar in both arms. Tamoxifen may therefore be reserved for overt metastases, and not wasted on asymptomatic subclinical disease. It seems that there is no yield in terms of event-free survival for MCA measurements in breast cancer patients during the 5-year follow-up period.

Elevated breast cancer serum markers in otherwise healthy women.

A high value of mucin-like carcinoma associated antigen (MCA), CA-15.3 or H23, in a woman known to have a diagnosis of breast cancer, may reflect presence of disease. A low level in a breast cancer patient may be accepted for remission, but a false negative result cannot be excluded. On the other hand, a low level of serum tumor marker in the general population actually lacks any significance. However, what is the meaning of an elevated level of marker, known to have a relatively high sensitivity and specificity, in an otherwise healthy woman? Does it mean an occult breast cancer or a false positive? Sera samples were obtained from 155 consecutive, otherwise healthy women, who were referred for mammography, and assayed for tumor markers. MCA was elevated in 15-24% of patients with normal mammogram, depending on their ages. Lack of elevation of a second marker in most of the cases supported the assumption that the elevation of the MCA was insignificant. Elevation of H23 occurred more frequently in younger women than in the elders, but was not associated with elevation of a second marker. In the cases with abnormal mammogram due to histologically proven benign disorders, serum tumor markers were generally within the normal ranges. Our results pointed to the lack of diagnostic significance of an elevated level of serum tumor marker, as far as the mammogram was normal or benign, there was no history of cancer nor any other systemic disease (including malignancy), and a second tumor marker was within the normal range. The women with presently false positive marker level may, however, be followed, because of the possible risk for future development of breast cancer.

Amputation of the lower limb as palliative treatment for debilitating musculoskeletal cancer.

Limb sparing surgery has replaced amputation surgery for treating sarcomas of the lower limb in most cases. Wide resection followed by postoperative radiation therapy can achieve acceptable local control and survival rates in patients with bone and soft-tissue sarcomas of the lower limb. Recurrent or persistent disease constitutes a major oncological problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patient's quality of life. In this clinical set-up palliative amputation of the limb should be considered. Fourteen patients with soft-tissue or bone sarcomas underwent palliative major amputation. The procedures included: hemipelvectomy, hip disarticulation, knee disarticulation, above or below-knee amputation. Local control of the disease and pain, and improvement of the performance status were observed in 13 evaluable patients. The mobility was restored in 13/14 patients. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. We found palliative major amputation surgery worth-performing in low-performance status cancer patients with locally advanced disease of the lower limb.

Postoperative irradiation combined with chemotherapy for high-risk rectal cancer patients.

In a prospective open-study we evaluated the combination of radiation therapy and adjuvant 5-FU plus levamisole in controlling Modified Astler-Coller (MAC) B2 or C rectal cancer following a curative-intended surgery. Sixty-four consecutive rectal cancer patients were treated by adjuvant radiation therapy (Linac 8 MV, 50-50.4 Gy to an isocentric pelvis brick volume in 5 fractions per week each of 1.8-2 Gy), and 12 monthly courses of 5-fluorouracil (375 mg/m(2)/day for 5 consecutive days) plus levamisole (50 mg t.i.d. for 3 days). Within a median follow-up period of 36 months, 19 patients (29.6%) experienced relapses. The 3-year-DFS of MAC B2 patients was 82%, compared with 60% in MAC C. Early radiation treatment was not associated with a higher proportion of relapses, while late radiation therapy initiation was associated with a significantly higher proportion of relapses. Early radiation therapy, not later than following the 2nd to 4th course of chemotherapy, is associated with the more acceptable proportion of relapses.

Melanoma-associated hypopigmentation: where are the antibodies?

Antibodies to the B16 melanoma cell line and to tyrosinase have been recently defined in our laboratory in sera of patients with vitiligo, melanoma, melanoma-associated hypopigmentation (MAH), and in healthy subjects. The antibody titers in each subject were measured by enzyme-linked immunosorbent assay, were compared with the mean optical density (OD) of the control group, and were expressed as relative OD. The titers of anti-B16 antibodies (relative OD +/- standard error) were 1.000 (0.058) in the controls, 1.025 (0.077) in patients with metastatic melanoma, 0.5862 (0.15) in MAH, 1.377 in surgery-induced MAH, 1.087 in vaccination with anti-idiotypic antibodies, and 2.098 (0.15) in autoimmune vitiligo. The titers in vitiligo were significantly higher (p < 0.0001) than in MAH or in healthy controls. Antityrosinase antibodies were found in titers of 1.000 (0.1024) in the controls, 1.516 (0.225) in metastatic melanoma, 1.027 (0.180) in MAH, 1.075 in surgery-induced MAH, 2.308 in vaccination-induced MAH, and 4.536 in vitiligo. Differences were found between vitiligo and MAH (p = 0.008), surgery-induced MAH (p = 0.009), vaccination-induced MAH (p = 0.059), and healthy subjects (p < 0.0001). The results of this study point to the cross-antigenicity between melanocytes and melanoma cells, and to participation of antibodies against melanoma-associated membrane antigens in the mechanism leading to the development of MAH in patients with melanoma.

Prognostic importance of advanced age in aggressive non-Hodgkin's malignant lymphoma.

The importance of age as a prognostic factor in aggressive non-Hodgkin's malignant lymphoma (NHL) remains controversial. It is not clear whether age is an independent factor, reflecting the limited physiologic reserves of the patient, and leading in any treatment conditions to the poorer treatment outcome. This study was aimed at assessing the influence of age on treatment results in NHL patients. Therefore, the records of 40 patients with histologically confirmed NHL of intermediate and high-grade malignancy, according to the Working Formulation, who were treated by Adriamycin-containing chemotherapy, were retrospectively reviewed. There were 25 patients above 60 years of age and 15 patients below this age. Myelotoxicity was observed in 60% of the patients in the younger and in 48% patients in the older age group. The median time to dose-limiting toxicity, average percentage of projected dose intensity for all drugs, and percentage of projected dose intensity did not differ significantly in the two groups. Complete remissions (CR) were obtained in 67 and 64% of the younger and older groups, respectively. Progressive disease was observed during the treatment in 20% of the patients in each age group. Median survival was 36.5 and 32 months in the younger and older group, respectively. In conclusion, age alone is not an absolute predictor of survival of treated elderly patients with aggressive NHL. Dose rate, tolerance of treatment and achievement of CR are additional important prognostic factors. Dose intensity should not be automatically reduced at the beginning of the treatment, especially now that growth factors are available.

[Isolated limb perfusion with tumor necrosis factor for malignancies of the limbs].

Tumor necrosis factor (TNF) induces rapid necrosis in a variety of experimental neoplasms. However, its clinical application is limited by life-threatening systemic toxicity. Isolated limb perfusion (ILP) enables administration of large doses of TNF and cytotoxic drugs directly to the affected limb, avoiding systemic toxicity. We describe our experience in 20 consecutive patients (10 with melanoma and 10 with soft tissue sarcoma) treated with high-dose TNF and melphalan via ILP. ILP was performed via the external iliac (10 cases), femoral (2), popliteal (5) or brachial (3) vessels. Patients received 3-4 mg TNF to an upper, and 1-1.5 mg/kg to a lower extremity. Isolation efficiency was determined by injection of radiolabelled albumin. The procedure was successful in all 20 patients. Local complications included wound infection in 6 cases and hematoma in 2. 1 patient developed sepsis secondary to extensive necrosis of a large, secondarily infected tumor. The first 6 patients who underwent high-flow perfusion experienced systemic side-effects, mainly hypotension. These side-effects were eliminated when low-flow perfusion was introduced. The response rate was 100%. In the sarcoma group, 5/10 had complete response, and 5 partial response. Amputation or mutilating surgery was avoided in 9/10. Of the 10 with melanoma, 7 had complete, and 3 partial response. We conclude that administration of TNF via ILP is a safe and effective modality for treating advanced neoplasms of the limbs.

Regional perfusion with hemofiltration (chemofiltration) for the treatment of patients with regionally advanced cancer.

BACKGROUND: Regionally advanced cancer is a common, often unresolved problem. Effective local control with chemotherapy is limited by the toxicity following systemic administration. Chemofiltration (CF) is a form of regional perfusion that enables the administration of cytotoxic drugs into one body area while limiting systemic toxicity. The drug is infused into the artery supplying the involved area. The venous effluent of the same organ is pumped out into a hemofiltration unit at a high flow rate. The drug is then filtered away and the blood returned to systemic circulation. METHODS: Forty-one patients underwent 45 CF. Twenty-four patients had CF of the pelvis for advanced rectal carcinoma (10), malignant melanoma (6), and cancers of the uterine cervix (3), ovary (2), vulva (1), endometrium (1), and anus (1). Seventeen patients underwent CF of the liver for metastatic colon (10), breast (4), pancreas (1), ovary (1), and unknown primary (1) cancer. 5-fluorouracil (1 g/m2) and mitomycin-C (30 mg/m2); cisplatinum (200 mg/m2) alone or combined with bleomycin (50 mg/m2) and mitomycin-C (20 mg/m2); or melphalan (1 mg/kg) were the combinations used. RESULTS: Generally the procedure was well tolerated. Complications included transient leukopenia (18), paralytic ileus (2), hair loss (2), renal failure (1). Two patients died within 40 days following CF. Of 36 evaluable patients, 16 (44%) had partial response, 14 (38%) had stable disease, and 6 (18%) had disease progression. A decrease of at least 30% in carcinoembryonic antigen levels occurred in 12 of 24 patients (50%). Median time to progression was 7 months. Ten of 13 patients (77%) achieved good symptomatic palliation. CONCLUSIONS: The results of CF in our study are not superior to alternative methods of drug delivery to the liver and pelvis. However, considering that previous systemic chemotherapy had failed two-thirds of the patients, some benefit may be attributed to this regional delivery modality. Furthermore, pelvic CF afforded very significant symptomatic relief which was definitely superior to other methods.

Adaptation of the cellscan technique for the SCM test in breast cancer.

The value of the SCM (Structuredness of Cytoplasmic Matrix) cancer test, a procedure based on the detection of differences in lymphocyte activation in the presence and absence of cancer, has remained controversial, with inconsistent results having been reported among investigators. The Cellscan, a high-precision static cytometer system, has been designed to perform the SCM test; the apparatus facilitates the polarisation measurements and can examine cells which have been separated by simpler procedures than were originally described. In this study, using methods and diagnostic criteria adapted for the Cellscan system in a hospital environment, the SCM test correctly classified over 90% (76/80) of patients with breast cancer and differentiated over 90% (72/73) of individuals without cancer.