A. Ferraro

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47‐month follow‐up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease‐free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewings sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewings sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

Aneurysmal Bone Cyst and Giant Cell Tumor of the Foot

From 1950 to 1994, 257 cases of benign bone tumors of the foot were treated at the Bone Tumor Center of the Rizzoli Institute. Aneurysmal bone cysts (ABC) and giant cell tumors (GCT) are rare and often they are misdiagnosed. To define the clinical and radiographic features useful for diagnosis, x-rays of 24 ABCs and 21 GCTs of the foot were reviewed. Adding our series to the cases reported in the literature, the only important clinical data that emerged was the average age of patients affected by ABC and GCT (15 and 27 years, respectively). ABCs localized in small tarsal bones were rare (6%), whereas 19% of GCTs were found in this site. The eccentric, round shape of a lytic lesion was more characteristic of GCT. An aggressive pattern of radiographic bone destruction was observed more frequently in GCT than in ABC (P = 0.01). Septation was seen in both tumors. Typical of ABC was a sharp and trabeculated margin, whereas GCT had an ill-defined edge with normal cancellous bone (P = 0.007). The growth of ABCs often expanded the cortex, while GCTs eroded, thinned, and broke the cortical bone (P = 0.001). A saucerized cortex was observed only in ABCs. A bony shell was more characteristic of ABC than of GCT (P = 0.002). Pathologic fractures (67%) and joint involvement, evaluated by computed tomography and magnetic resonance imaging (83%), were more frequent in GCTs, whereas fluid levels were more frequently observed in ABCs (47%). The majority of the tumors were stage 2, but GCTs represented 70% of stage 3 aggressive lesions.

Influence of chemotherapy on perioperative complications in limb salvage surgery for bone tumors.

From 1970 to 1986, 304 patients underwent limb salvage resections for 271 malignant and 33 benign tumors of the extremities. Reconstruction was with a prosthesis or nonbiologic spacer. Nonmechanical complications were analyzed to determine the influence of the site and method of reconstruction and the use of chemotherapy on their incidence and severity. There were 82 shoulder resections, 53 proximal femur resections, and 169 knee resections. No chemotherapy was used in 115 patients; neoadjuvant therapy was used in 128 patients and adjuvant therapy was used in 61. There were 120 complications. The most common complication was infection (36 of 304 patients; 11.8%), which led to amputation in eight patients. Resections about the knee led to more complications than the other sites, particularly if reconstructed with a large cement spacer. Patients who did not receive any chemotherapy had a 25.2% (29 of 115) incidence of complications and those who received adjuvant treatment had a 32.8% (20 of 61) incidence. This compares with a 55.4% (71 of 128) incidence in the neoadjuvant group. After neoadjuvant chemotherapy, reconstruction with an uncemented prosthesis led to the fewest complications.

Tumor response assessment by modified Choi criteria in localized high-risk soft tissue sarcoma treated with chemotherapy.

The objective of this study was to compare the prognostic relevance of Response Evaluation Criteria in Solid Tumors (RECIST) versus Choi criteria for the assessment of response in patients with high‐risk soft tissue sarcoma of the extremities or trunk wall who received preoperative chemotherapy with or without radiotherapy in a phase 3 trial.

The effect of quadriceps excision on functional results after distal femoral resection and prosthetic replacement of bone tumors

Although resection and reconstruction with a prosthesis is an accepted form of treatment for tumors of the distal femur, minimal effort has been made to correlate the functional result with the degree of adjacent muscle excision. From 1983 to 1986, 65 patients had distal femoral resection and prosthetic reconstruction. Ten patients had only the vastus intermedius excised (Group A), 30 patients had excision of the vastus intermedius plus either the vastus medialis or lateralis (Group B), nine patients had only the rectus femoris spared (Group C), and 16 patients had the entire quadriceps excised or conversion of the previous arthrodesis (Group D). Based on the rating system of the Musculoskeletal Tumor Society, satisfactory results were obtained in 70% of Group A patients (30% excellent and 40% good), with no poor results. In group B, 80% had good or excellent results and 7% poor results. In Group C, 78% of the patients had good results but no excellent results, whereas Group D had only 50% satisfactory results. The parameters that most often led to functional impairment were restricted motion and inadequate extensor powers. Muscle transfers, however, (flexors to extensors) were effective only in Group C patients. With proper technique and prosthetic design, satisfactory results can be achieved after distal femoral resection and prosthetic reconstruction, even after extensive quadriceps excision.

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.

Complications and surgical indications in 144 cases of nonmetastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy

From September 1986 to December 1989, 144 patients with osteosarcoma of the extremities were treated with combined surgery and neoadjuvant chemotherapy. The disease-free survival was 79% for good responders (necrosis greater than 90%) and 72% for poor responders (necrosis less than 90%), and the local recurrence rate was low. Improvement in long-term prognosis and the increase of limb-sparing surgery determine a higher rate of immediate and late complications. Most of the complications were observed in limb-salvage procedures; 63% of these procedures presented one or more complications. In nine rotationsplasties, there were four complications, and in 13 amputations no complications were observed. Therefore, 55% of patients were affected by surgical complications. Twenty-eight complications were considered minor (not requiring surgery), whereas 77 complications were major. Functional results, evaluated according to Ennekings new system, were higher than 50% in two thirds of the limb-salvage procedures. Complications in limb-salvage procedures are more influenced by the type of reconstruction than by the surgical procedure used. Probably the most troublesome consequence of surgical complications in osteosarcoma is the deviation or delay in administering postoperative chemotherapy, which jeopardizes survival.

Proximal tibial resections and reconstructions: clinical outcome of 225 patients.

Previous studies reported variable outcome of proximal tibial resections and reconstructions. Therefore, we evaluated the survival, Musculoskeletal Tumor Society (MSTS) function, and complications of patients and reconstructions in this location.

No advantages in the addition of ifosfamide and VP-16 to the standard four-drug regimen in the maintenance phase of neoadjuvant chemotherapy of Ewing's sarcoma of bone : results of two sequential studies

Between January 1988 and December 1990, 74 patients with localized Ewings sarcoma of bone were treated with a new protocol that consisted of an initial 6-week period of chemotherapy with vincristine (VCR), adriamycin (ADM) and cyclophosphamide (EDX) followed by local therapy and additional chemotherapy with the same drugs previously indicated plus ifosfamide and VP-16. The rationale for the addition of ifosfamide and VP-16 to the four drugs of the standard chemotherapy of this tumor was that this drug combination was previously very effective in the treatment of metastases from Ewings sarcoma even in patients who did not respond to cyclophosphamide. As local treatment all patients were offered surgery, when feasible (70 cases). Forty-three patients accepted and 27 refused. These patients, as the 4 patients in whom surgery was not considered feasible, were treated with radiation therapy alone (50-60 Gy). In the remaining patients amputation was performed in 4 cases, rotationplasty in 3 and resection in 36. Where conservative surgery was marginal or intralesional (30 cases), radiotherapy at lower doses (40-45 Gy) was also delivered. At a mean follow-up of 3.5 years (2-7), 43 patients (58%) remained continuously disease-free and 31 relapsed (29 with metastases and 2 with both metastases and local recurrences). These results do not differ from those obtained at our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol in which only VCR, ADM, EDX and dactinomycin (DAC) were used (3-year continuously disease-free survival (CDFS) respectively of 54% and 55%). Despite the fact that these results came from a nonrandomized study, the Authors conclude that the addition of ifosfamide and VP-16 to the four-drug standard regimen did not improve the outcome of the patients with Ewings sarcoma of bone which remains a lethal disease in about 50% of the cases. These findings stress the need to find more effective chemotherapeutic regimens for the associated treatment of this tumor.