Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination.

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Metastatic angiosarcoma of the kidney: a case report with treatment approach and review of the literature.

Angiosarcomas are rare soft tissue malignancies. Typically they originate from the skin of the scalp or face, whereas visceral sarcomas are very rare. We report the case of a 67-year-old man affected by a large angiosarcoma of the kidney. After surgical removal, a rapid peritoneal, visceral and cutaneous diffusion developed. Palliative chemotherapy, based on anthracycline and ifosfamide, which are normally used to treat all other high-grade spindle cell sarcomas, was totally inactive. On the basis of these results and of the biological characteristics of these rare neoplasms it is mandatory to develop other therapeutic approaches. Antiangiogenetic agents are of interest for this disease due to the peculiar origin of the cells of these sarcomas.

Phase I and clinical pharmacological evaluation of aphidicolin glycinate.

The toxicity profile and the pharmacokinetics of aphidicolin glycinate, a water-soluble analogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion for 5 consecutive days, every 3 weeks (daily x 5 study); in the second study, which was planned on the basis of the pharmacokinetic information obtained in the previous study, the drug was given by 24-hour continuous infusion. Treatment was repeated every 3 weeks. In the daily x 5 study, the daily dose was escalated from 12 mg/m2 to the maximum tolerated dose of 2250 mg/m2. Local toxicity was dose limiting. Elimination half-life was 2 +/- 0.2 hours (mean +/- SE) with aphidicolin being undetectable 6-8 hours after the end of the infusion. In the 24-hour continuous-infusion study, the dose was escalated from 435 mg/m2 to the maximum tolerated dose of 4500 mg/m2. Local toxicity was dose limiting, while other toxic effects were absent. The experimentally determined concentrations at the steady state were in agreement with those predicted on the basis of the available pharmacokinetic data. The targeted concentration at the steady state of 3 micrograms/mL was achieved at doses greater than or equal to 3000 mg/m2. Twenty-four-hour continuous infusion is the recommended schedule for clinical evaluations of aphidicolin glycinate as the synchronizing agent or in combination with cisplatin.

Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of 4'-epidoxorubicin (EPI) in combination with full dose of ifosfamide (IFO) when granulocyte-macrophage colony-stimulating factor (GM-CSF) was used, to estimate its clinical efficacy, and to evaluate the mobilization of hematopoietic progenitors. PATIENTS AND METHODS: Previously untreated advanced patients were treated with fixed doses of IFO at 1.8 g/m2/d for 5 days and escalating doses of EPI. The starting dose level of EPI was 50 mg/m2 bolus on days 1 and 2; subsequent levels were 60 mg/m2 and 70 mg/ m2 given on days 1 and 2. GM-CSF (5 micrograms/kg/d) was administered from days +6 to +19. Clinical evaluation of response was performed after three consecutive cycles. Mobilization of hematopoietic progenitors was evaluated as day 14 CFU-GM after the first cycle only. RESULTS: Overall, six, 18, and 13 assessable patients were entered onto each EPI dose level, respectively. The first and the second EPI level were considered feasible. Conversely, at the third level, only six of 13 patients [46%] tolerated full EPI doses at the scheduled time. Therefore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1%, respectively. Overall, 20 of 37 patients (54%) obtained an objective response. The response rates for the three EPI dose levels were significantly different [17%, 33%, and 100%, respectively; test for trend, P < .001]. Considering only lung metastases, the overall response rate was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI level, when both GM-CSF and IL-3 were used as in vitro-stimulating factors. CONCLUSION: The third EPI level (70 mg/m2 on days 1 and 2) is the MTD of this program, since it was administered, without dose reduction or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting with regard to response rate (13 of 13 objective responses) and in mobilization of the hematopoietic progenitors.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

Randomized crossover antiemetic study in cisplatin-treated patients. Comparison between high-dose i.v. metoclopramide and high-dose i.v. dexamethasone.

This prospective, randomized, nonblind study comparing the antiemetic effectiveness of high-dose IV metoclopramide and high-dose IV dexamethasone was performed in 78 advanced cancer patients. Chemotherapeutic treatment consisted in cisplatin at a high-dose (120 mg/m2) (HD-CDDP) and at a low-dose (LD-CDDP), either alone (60 mg/m2) or in combination with other chemotherapeutic agents (50 mg/m2). The evaluation of the effectiveness of antiemetic therapy was based on three parameters: prevention of vomiting ("major protection"), number of emetic episodes, and subjective preference. Out of 78 study patients, 67 were evaluable. Overall, metoclopramide proved to be statistically superior to dexamethasone in preventing vomiting (P less than 0.005), in reducing the median/mean number of emetic episodes (P less than 0.001/0.001), and in subjective preference (P less than 0.01). The results divided between HD-CDDP and LD-CDDP groups were also in favor of metoclopramide for reduction of the median/mean number of emetic episodes (P less than 0.001/0.001 for the HD-CDDP group and P less than 0.001/0.005 for the LD-CDDP group) and in subjective preference (P less than 0.001 and P less than 0.001 for the HD- and LD-CDDP groups, respectively). No statistical differences were noted when LD-CDDP was used in monochemotherapy, whereas when LD-CDDP was used in combination chemotherapy, statistical differences in favor of metoclopramide were noted again for the median/mean number of emetic episodes (P less than 0.01/0.05) and for subjective preference (P less than 0.01), even though the effectiveness of both antiemetic agents was greatly reduced. The evaluation of previously untreated patients reflected the overall results: for the HD-CDDP group all three parameters demonstrated statistical significance in favor of metoclopramide; for the LD-CDDP group, of all three parameters, prevention of vomiting (major protection) was the only one for which there was no significant difference. Mild sedation was the only side effect of metoclopramide. No extrapyramidal reactions were noted during this trial, but concomitant orphenadrine treatment was given. Dexamethasone was always well tolerated. In conclusion, high-dose IV metoclopramide demonstrated its superiority over high-dose IV dexamethasone in all subsets of our population except the LD-CDDP monochemotherapy group, in which the two antiemetics were found to be equivalent in effect.

Prognostic factors in soft tissue sarcomas: a study of 395 patients.

AIMS: The aim of this study was to report prognostic factors, end-points of local recurrence, distant recurrence, post-metastasis survival, and overall survival in a cohort of patients with soft tissue sarcomas. METHODS: We analysed a database of 395 patients affected by primary soft tissue sarcomas of various primary sites, treated and followed up at the Centro di Riferimento Oncologico, Aviano, Italy from January 1985 to January 1997. RESULTS: Grade, size, stage, surgical margins, distant metastasis, age, sex, performance status, and haemoglobin value were significant for overall survival. Histology, grade, stage, and surgical margins were significant for local recurrence. Grade, size, and stage, were significant for distant recurrence; and surgical margin was significant variable for post-metastasis survival. CONCLUSIONS: Grade, size, and TNM stage (UICC/AJCC) have stronger prognostic significance for overall survival and distant recurrence than for local relapse. Positive surgical margins are the main predictors for local relapse. Age was the most consistent adverse independent prognostic factor for survival.

A phase II study of AMSA in head and neck cancer.

AMSA was given to 22 evaluable patients with advanced head and neck cancer with measurable lesions. The starting dose was 90-120 mg/m2 by i.v. infusion over 45 min every 3 weeks. The dose of AMSA was escalated by 30 mg/m2 in absence of bone marrow toxicity. At least two cycles were given prior to the evaluation of response. Only one patient with oropharyngeal cancer achieved a partial response, lasting for 20 weeks. Toxicity was mild and mainly hematological. We conclude that AMSA given at this dose and schedule has little activity in head and neck cancer.

Phase II study of five-day continuous infusion of vinblastine in patients with metastatic renal-cell carcinoma.

Vinblastine 5-day continuous infusion in metastatic renal-cell carcinoma was evaluated in a Phase II trial. The dosage varied from 1.4 to 1.6 mg/m2/day every 3 weeks according to previous treatment and performance status (PS). From September 1983 to January 1986, 25 consecutive patients entered the study; 21 were evaluable for response and 23 were evaluable for toxicity. The median number of cycles administered was three (range, one to six). One complete response (liver) lasting 5 months, one partial response (lung) lasting 3 months, 12 cases of stable disease, and seven progressions were noted. Toxicity (WHO criteria) was relevant and mainly hematological: one treatment-related death occurred. Vinblastine continuous infusion did not demonstrate significant antineoplastic activity against metastatic renal-cell carcinoma.

Intraoperative radiation therapy for retroperitoneal soft tissue sarcomas.

Treatment of retroperitoneal soft tissue sarcomas is a difficult clinical problem. Despite the improvement in resection rates in the most recent surgical series, local control still remains the main problem because of the high incidence of local recurrences after surgery. Postoperative radiation therapy has not been always successful because of dose-tolerance of surrounding normal structures, which prevent the delivery of adequate doses of radiation. To overcome this limitations, new therapeutic approaches including external-beam radiation and intraoperative radiation therapy (IORT) have been evaluated at some Institutions. The results of IORT with or without external-beam radiation are reviewed and our experience with preoperative radiation and IORT is reported. As treatment of retroperitoneal sarcomas has evolved into combined modalities including preoperative radiation, maximum surgical resection and IORT, a possible improvement in local control rates has been achieved. However, locoregional failures and the incidence of distant metastases remain a challenge, emphasising the need for further improvement in local and distant treatment. The new phase II trial, activated within the Italian Sarcoma Group, with preoperative concurrent chemo-radiation therapy and IORT is presented.

Dysphonia as an unusual toxic event of oxaliplatin-based chemotherapy.

Oxaliplatin is a new, third-generation platinum complex. It has a good safety profile characterized by low hematological-gastrointestinal toxicity. No significant nephro-ototoxicity has been observed. Acute peripheral neuropathy is a common event affecting, as grade 1 or 2, 85-95% of patients. Recently, data on dysphonia toxicity, after the administration of oxaliplatin, has been reported in literature. This toxicity with acute onset can be misunderstood if not carefully looked for. However, it is self-limiting and a non-permanent (grade 1-2) neurotoxic phenomenon, which impairs transiently the quality of life of a percentage of oxaliplatin-treated patients. We report our experience in consecutive patients affected by advanced colorectal cancer treated with oxaliplatin-based chemotherapy. Overall, we observed 13 (16%) cases of dysphonia out of 81 consecutive patients treated with oxaliplatin-based chemotherapy. This toxic effect was self-limiting and all patients recovered rapidly. Nonetheless, a deeper understanding of this phenomenon is essential to give correct information to the patients.

Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas.

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m2) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.

Cisplatin and mitomycin C in advanced chemotherapy-refractory breast cancer.

A combination of platinum (100 mg/m2 in a 24-h continuous i.v. infusion) and mitomycin C (10 mg/m2 i.v. push at the end of the cisplatin infusion) was administered in 20 patients with advanced breast cancer refractory to conventional treatments (CMF and anthracycline-containing regimens, hormonal therapies). The response rate was 20% (4/20), including one complete response of lung metastases which lasted 12 months. Median duration of partial responses was 4 months. Major toxicity was gastrointestinal and it was superimposable to that observed with other cisplatin-containing regimens. A marked and prolonged asthenia was reported in 6/20 patients (30%), and the regimen's compliance was poor. We conclude that at these doses and schedule, the cisplatin and mitomycin C combination has a limited efficacy in advanced breast cancer patients, and its use is not recommended in pretreated patients.

Ovarian cancer: ten-year experience in a community hospital.

We reviewed 187 patients with epithelial ovarian cancer treated, from 1975 to 1985, at the Division of Radiotherapy and Medical Oncology, Pordenone General Hospital, Italy. It seemed of interest to report an experience carried out in a community hospital in a consecutive unselected series of patients affected by ovarian cancer. Survival time was evaluated from the day of the primary surgical approach to the end of the study (March 1985). The aim of the study was to confirm in our patient population the importance of some already recognised prognostic factors that influence survival (age, stage, histology, grade, type of surgery and residuum). We also analyzed the effect of the treatment variables chemotherapy and radiotherapy on survival. The general pattern of prognostic factors appears to be in agreement with reports in the literature. In our experience, residual disease and stage were the main important prognostic factors; grade and histology had a secondary relevance, and age did not seem to be a prognostic factor in our population. New chemotherapy regimens and/or radiotherapy did not appear to improve survival. In fact, comparison of the results obtained from 1975-1979 and from 1980-1985 (when more aggressive surgery and cisplatin-containing regimens were employed) showed no statistically significant difference in survival rate. Our data suggest that patients at an early stage can receive a satisfactory quality of care in a general hospital with oncology facilities, provided the surgeon and the pathologist are experienced in ovarian cancer. Patients at stage III but completely surgically resected can also be adequately treated. Patients with advanced disease, considering the lack of established efficacious treatments, should be referred to specialized centers, where new drugs or experimental strategies can be tested.

Retrospective analysis of the CYVADIC regimen in advanced soft tissue sarcomas.

We performed a retrospective review of our data obtained with the original CYVADIC regimen in 31 consecutive patients with advanced soft tissue sarcomas. The treatment consisted of cyclophosphamide 500 mg/m2 i.v. from day 1, vincristine 1.5 mg/m2 in days 1 and 5, doxorubicin 50 mg/m2 i.v. on day 1, and dAcarbazine 250 mg/m2 i.v. from days 1 to 5, repeated every 3 weeks. An objective response was observed in 11/31 patients (35.5%). There were 2 complete remissions (6.5%) lasting 23 and 2 months respectively and 9 partial responses (median duration 7 months, range 1-23). No change was observed in 14 patients, and 6 patients showed progression after a median of 2 cycles of chemotherapy. Toxicity was similar to that already described with this regimen, with alopecia, nausea, vomiting and myelosuppression being the most important side effects. In particular, the median WBC nadir was 1,900/mm3 (range 400-3,600/mm3) whereas the platelet nadir was 181,000/mm3 (range 80,000-358,000/mm3); no patient developed congestive heart failure, and no treatment related death was observed. Still today, after 10 years of use, the CYVADIC regimen is very widely employed as a standard treatment for recurrent or metastatic soft tissue sarcomas, although the original positive results have been confirmed only by a few authors. In our retrospective analysis of a totally unselected population of patients, we too observed a lower activity which is, however, according to a recent review, similar to the mean value of responses obtained in the whole population of treated patients reported in the literature.

Non-platinum-containing combination chemotherapy for stage III-IV head and neck squamous carcinoma.

From May 1980 to November 1981, 51 consecutive patients with locally advanced, recurrent or metastatic head and neck squamous carcinoma were treated with 2 successive outpatient chemotherapeutic regimens including adriamycin, cyclophosphamide, vincristine, bleomycin, methotrexate and 5-fluorouracil with or without mitomycin-C. A 34% objective response rate was obtained with acceptable toxicity and good patient compliance. The presence of mitomycin-C did not influence response rate. Median survival was 9 months.

Clinical and immunological evaluation of 5 cases of mycosis fungoides in advanced stages.

Five patients with mycosis fungoides, hospitalized in the Division of Radiotherapy and Medical Oncology of the Ospedale Civile, Pordenone, from January 1975 to December 1978, were studied and treated as non-Hodgkin lymphomas. All patients had evidence of disseminated disease: 3 with bone marrow infiltration, 1 with splenic involvement and 1 with lymph node involvement. Three patients were treated with CVP, resulting in 2 complete remissions that lasted 18 months and 1 PR greater than 50% maintained for 7 months. One patient was treated with ABVD with a PR greater than 50% maintained for 10 months. The last patient was treated with prednisone and then with CV, but expired from pulmonary embolism after 1 cycle. Lymphocyte function, using E and EAC rosette and PHA, was evaluated before therapy in all patients: in the 2 patients who obtained a CR, an improvement in T-lymphocyte function was noted after therapy. The chromosome pattern of peripheral blood lymphocytes was altered before therapy in only one patient. Even if the follow-up period is still relatively brief, the duration of the 2 complete remissions must be stressed. In addition, a strict correlation between T-lymphocyte function and response to therapy was revealed in our study.

Medical treatment of metastatic renal cell carcinoma.

Thirty five patients with metastatic RCC were observed over a 57 months period in our Division of Radiotherapy and Medical Oncology, and 30 are evaluable for this analysis. MPA was selected as primary treatment agent in 23 patients, VLB singly, in combination with MPA or in combination with CCNU was used in 1.4 and 2 patients. With MPA the TR rate was 3/23 (1 CR and 2 PR). Duration of response for the patient with CR was 6 months whereas for the patients with PR was 21 and 14 months respectively. 4 additional patients showed NC. With VLB-MPA the TR rate was 1/+ (1 PR). Duration of PR was 3 months. The median duration of survival for the 11 patients with CR, PR and NC was 14 months whereas for the 19 patients with NR was 7 months (p < 0.01). TES and TAM showed no or minimal activity as second treatment agents.

Tamoxifen therapy in postmenopausal advanced breast cancer: efficacy at the primary tumor site in 46 evaluable patients.

Forty-six evaluable postmenopausal patients with locally advanced, inoperable T3-T4 breast carcinoma were treated with tamoxifen 10-20 mg twice daily for a period at least 6 weeks. Eight patients (17%) had an objective response at the primary tumor site after 6 weeks of treatment. Improvement of response with a further single tamoxifen therapy was observed in 7 patients, resulting in an overall objective response in 14 of 46 (30%). Median duration of response was 8 months (range 2-24). No response was obtained in the 5 patients with inflammatory signs. Toxicity of treatment was minimal. Medial survival was 10 months (responders 17.5, non-responders 9). Tamoxifen seems to be safe and effective treatment for locally advanced breast cancer without inflammatory signs in postmenopausal women.