Osteosarcoma--the winds of change.

The occurrence of pulmonary metastases in patients suffering from primary classic osteogenic sarcoma is compared among two groups of patients treated according to different protocols at Groote Schuur Hospital. A group of 28 patients treated by radiation and delayed amputation (before the end of 1974) is compared with 12 patients managed by immediate ablation and adjuvant chemotherapy with vincristine, high-dose methotrexate and leucovorin rescue, and adriamycin (after 1974). The incidence of pulmonary metastases at 12 months was significantly lower in the latter group.     

Vinblastine and methotrexate for advanced bladder cancer

Fifty-seven patients with advanced measurable urothelial tract cancer, 52 of whom had an adequate trial, were treated weekly with 3 to 4 mg. per m.2 vinblastine and 30 to 40 mg. per m.2 methotrexate. Of 3 patients with unidimensional parameters 2 showed improvement lasting 16 and 27 months, which was documented by serial cystoscopic examinations. An additional 2 patients had measurable disease that could have been encompassed in a preoperative radiotherapy field. Both patients are free of disease at more than 12 and 14 months, respectively. Of the 47 patients with bidimensionally measurable parameters 19 (40 per cent) achieved a complete or partial remission lasting a median of 8 months, with a range of 1 to 24 months. Of 25 patients with intra-abdominal or pelvic disease 7 achieved a complete or partial remission and 5 also had a minor remission. Of note, 18 of 38 patients who had received no prior chemotherapy achieved a remission versus 1 of 9 who had been treated previously (p equals 0.06). Responders frequently obtained another remission with subsequent chemotherapy (4 of 9 versus 0 of 16, p equals 0.03). Responders lived 14 months versus 8 months for nonresponders (p equals 0.02). Four responders had brain metastases compared to none of 28 nonresponders. The combination of vinblastine and methotrexate is a well tolerated, effective outpatient regimen for patients with urothelial tract cancers.     

Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis.

Between 1977 and 1988, 67 patients underwent surgical removal of residual metastatic deposits following an aggressive chemotherapy regimen (cisplatin, vincristine, methotrexate and bleomycin alternating with etoposide, actinomycin D and cyclophosphamide) for disseminated germ cell tumours of the testis (stage IIB or above). Ninety-one surgical procedures were performed. There were 63 (69 per cent) retroperitoneal lymph node dissections, 16 (18 per cent) thoracotomies, three (3 per cent) hepatic resections, three (3 per cent) craniotomies, five (5 per cent) delayed orchidectomies and one anterolateral decompression of the vertebral column. Nine (13 per cent) patients required a repeat retroperitoneal node dissection and one patient needed a repeat thoracotomy to remove recurrent metastatic deposits during the period of follow-up. Multivisceral resections and vascular reconstruction procedures were required in 20 (30 per cent) patients undergoing retroperitoneal node dissection. Fifty-five (82 per cent) patients remain in complete remission with a mean follow-up period of 49.6 months (range 2-121 months). Nine (13 per cent) patients died with metastatic disease between 2 months to 4 years after operation. There were three deaths in the perioperative period (4 per cent). The histology of the resected metastases revealed undifferentiated active tumour in 20 (30 per cent) patients, differentiated mature teratoma in 29 (43 per cent) patients and fibrosis/necrosis in 18 (27 per cent) patients. Twelve (60 per cent) patients with undifferentiated elements and 15 patients (60 per cent) with raised preoperative tumour markers (poor prognostic categories) are in complete remission. Cytoreductive surgery in patients with metastatic germ cell tumours offers the best chance of remission following chemotherapy even in poor prognostic group categories.     

Neoadjuvant chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) or cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 69 cases of locally advanced (stage IIIb) breast cancer.

Sixty nine patients with a median age of 45 years, 62.3 per cent of whom were premenopausal, with locally advanced breast cancer (T 4, N 0-3, M 0; Stage IIIb) were treated with 3 cycles of either neoadjuvant cyclophosphamide, doxorubicin and 5-fluorouracil, being the CAF group: 36 patients, or cyclophosphamide, methotrexate and 5-fluorouracil, being the CMF group: 33 patients. Patients achieving complete response or with residual disease of less than 2 cm in diameter received radical radiotherapy while those with more residual disease underwent radical mastectomy. Nine cycles of adjuvant chemotherapy were administered. Complete responses and disease control by radiotherapy with complete breast preservation were more frequently observed after CAF than CMF, being 25 per cent vs 3 per cent (p = 0.025) and 48.5 per cent vs 12 per cent (p = 0.002), respectively. Overall response rates, adverse effects, disease control following radiotherapy/surgery, local relapses and metastases were similar for both regimes. Relapsing patients were young, with a median age of 38 years, 68.4 per cent of relapses occurred at metastatic sites and 42 per cent of relapses occurred during adjuvant chemotherapy. This study suggests that in locally advanced breast cancer, a greater proportion of patients can be rendered disease free after neoadjuvant CAF and radiotherapy compared to neoadjuvant CMF and radiotherapy.     

Adjuvant chemotherapy of bladder cancer: a preliminary report

Adjuvant combination chemotherapy with cyclophosphamide, doxorubicin and cisplatin was administered to 36 patients after cystectomy for bladder cancer. Therapy was tolerated well except for 1 patient who suffered a fatal chemotherapy complication. Indications for adjuvant chemotherapy included vascular invasion of the primary tumor, perivesicular tumor involvement, invasion of adjacent pelvic viscera (vagina and prostate) and nodal metastases. There were 53 concurrently treated patients who did not receive adjuvant chemotherapy despite similar unfavorable pathological indications (high risk control group). Survival rates (61 and 73 per cent, respectively) were not significantly different for those patients treated with adjuvant chemotherapy and an additional group of 158 patients who underwent cystectomy during the study period but who had no adverse pathological findings (low risk control group). Survival rates differed significantly between the low risk (73 per cent) and high risk (38 per cent) control groups (p less than 0.001). Patients with unfavorable histological findings who received adjuvant chemotherapy had a significant survival advantage over the high risk control groups (61 versus 38 per cent, p equals 0.03). These data confirm the predictive value of post-cystectomy pathological findings and suggest that adjuvant chemotherapy with cyclophosphamide, doxorubicin and cisplatin not only prolongs the survival free of disease for patients at high risk for recurrence but it also may ultimately increase the cure fraction of such patients.     

Neoadjuvant chemotherapy with cyclophosphamide,doxorubicin and 5-fluorouracil (CAF) or cyclophosphamide,methotrexate and 5-fluorouracil (CMF) in 69 cases of locally advanced (stage IIIb) breast cancer

Sixty nine patients with a median age of 45 years, 62.3 per cent of whom were premenopausal, with locally advanced breast cancer (T 4, N 0–3, M 0; Stage IIIb) were treated with 3 cycles of either neoadjuvant cyclophosphamide, doxorubicin and 5-fluorouracil, being the CAF group: 36 patients, or cyclophosphamide, methotrexate and 5-fluorouracil, being the CMF group: 33 patients. Patients achieving complete response or with residual disease of <2 cm in diameter received radical radiotherapy while those with more residual disease underwent radical mastectomy. Nine cycles of adjuvant chemotherapy were administered. Complete responses and disease control by radiotherapy with complete breast preservation were more frequently observed after CAF than CMF, being 25 per centvs 3 per cent (p=0.025) and 48.5 per centvs 12 per cent (p=0.002), respectively. Overall response rates, adverse effects, disease control following radiotherapy/ surgery, local relapses and metastases were similar for both regimes. Relapsing patients were young, with a median age of 38 years, 68.4 per cent of relapses occurred at metastatic sites and 42 per cent of relapses occurred during adjuvant chemotherapy. This study suggests that in locally advanced breast cancer, a greater proportion of patients can be rendered disease free after neoadjuvant CAF and radiotherapy compared to neoadjuvant CMF and radiotherapy.     

Small cell carcinoma: combined approach to treatment.

Fifty-six patients with untreated small cell carcinoma of the bronchus were treated with three courses of chemotherapy (cyclophosphamide, vincristine, and procarbazine and methotrexate) and assessed for response. Thirty-one patients (55.4%) were classified as responders; they were given a course of radiotherapy and were then randomly allocated to continued cyclical chemotherapy or not further chemotherapy until relapse. Non-responders to chemotherapy were treated with radiotherapy or palliatively. The median survival was 10.5 months in responders and 6 months in non-responders (P less than 0.01). The one-year survival in responders was 42%. There was no statistical difference in survival between patients treated with continued chemotherapy and those treated at relapse. Sixty-nine per cent of patients experienced no side effects from chemotherapy. Three indicators of non-response to chemotherapy were identified--exercise tolerance at diagnosis, macroscopic liver metastases, and inappropriate ADH secretion.     

Combination chemotherapy with cisplatin and methotrexate in advanced transitional cell cancer of the bladder

We studied 53 patients with bidimensionally measurable metastases of transitional cell cancer of the bladder who were treated with a planned regimen of 70 mg. per m. cisplatin intravenously on day 1, and 40 mg. per m. methotrexate intravenously on days 8 and 15 every 3 weeks. The toxicity of this regimen, with agranulocytosis and mucositis as the most important side effects, was so severe that only 17 per cent of the patients actually received the protocol regimen without modification. Six patients were ineligible and 47 were evaluable for toxicity, including 43 who were evaluable for response. The response to treatment was assessed after each second treatment cycle. A complete response was achieved in 10 patients (23 per cent) and a partial response was achieved in 10 (23 per cent). The median duration of response was 64 weeks for patients with a complete response and 23 weeks for those with a partial response, while the median duration of survival was 81 and 37 weeks, respectively. The aforementioned regimen with allowance of routine leucovorin rescue is tested as preoperative chemotherapy in patients with stages T3 to T4 nonmetastatic bladder cancer.     

Adjuvant chemotherapy in non-seminomatous testis cancer: "mini-VAB" regimen: long-term followup

Since 40 to 50 per cent (range 20 to 80 per cent) of patients with stage II non-seminomatous germ cell tumors of the testis suffer relapse after orchiectomy and retroperitoneal lymph node dissection, relatively non-toxic adjuvant chemotherapy (consisting of vinblastine, actinomycin D, bleomycin and chlorambucil) was given to 62 patients after lymphadenectomy. Of these patients 82 per cent remained free of disease with a 4-year median followup and 18 per cent had relapse. Retrospective analysis reveals that no patient (0 of 33) with stage IIA and 38 per cent (11 of 29) with stage IIB disease had relapse. Patients with histologic evidence of extranodal extension of disease (N3 category) had the highest relapse rate (62 per cent). Based on our experience we recommend that patients with resected stage IIB disease, particularly those with extranodal extension of tumor, receive aggressive adjuvant chemotherapy.     

Tuberculous spondylitis in adults

We treated 107 adults with spinal tuberculosis. The average age was 41.8 years (range, sixteen to seventy-five years). Diagnosis was difficult: bone scans were negative in 35 per cent; gallium scans, negative in 70 per cent; and results of tuberculin skin tests, negative in 14 per cent. Five neurologically impaired patients had no discernible bone lesions when they were first seen but were found to have either intradural or extradural tuberculomas or tuberculous arachnoiditis. Our indications for a spinal operation were neurological impairment, spinal instability, or failure of medical management, and an operation was required in fifty-three of the 107 patients. Anterior decompression and fusion was the surgical procedure of choice. Ninety-four per cent of neurologically impaired patients recovered normal neurological function after anterior decompression; 79 per cent, after non-surgical treatment; and 55 per cent, after laminectomy. Neurological recovery and relief of pain occurred more rapidly in the surgically treated group. Kyphosis did not worsen in any patient, whether treated medically or surgically. There were no organisms that were resistant to isoniazid, rifampin, or ethambutol, and there was neither progression nor reactivation of disease after twelve months of adequate chemotherapy.     

Osteogenic sarcoma. A study of one hundred and thirty cases.

One hundred and thirty patients with osteogenic sarcoma were studied clinically, roentgenographically, and pathologically. Prognosis by each of ten factors was analyzed with the Wilcoxon test. The test yielded p smaller than 0.05 in a comparison between the survival curves of patients fifteen years old or younger and that of patients over fifteen, but other comparisons did not yield p smaller than 0.05. The actual five-year survival rate was 25.5 per cent (twenty-six of 102 patients who had radical surgery). Our therapeutic regimen for osteogenic sarcoma at the present time consists of regional perfusion, amputation, bronchial artery infusion, and systemic administration of anticancer agents.     

Adjuvant chemotherapy for malignant fibrous histiocytoma in the femur and tibia

Between 1974 and 1982, twelve patients with malignant fibrous histiocytoma of the femur and tibia were treated by excision and adjuvant chemotherapy. During the same time-period, eighteen patients were treated by excision alone. The disease-free survival rate among the former was 59 per cent (seven of twelve). There was only one survival in the latter group.     

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum for advanced germ cell testis tumors: Brazilian experience

Disseminated germ cell testicular cancer proved to be highly sensitive to platinum-containing chemotherapy regimens. We present data concerning the treatment of advanced seminoma and nonseminomatous tumors in a developing country. We treated 30 patients with advanced germ cell testis tumors with 3 or 4 cycles of vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum. Surgical resection of residual masses was done 30 days after completion of chemotherapy in 18 patients. The histology of the primary tumor was seminoma in 13 patients and nonseminomatous tumors in 17. Toxicity was mild and no treatment-related deaths occurred. All 13 patients (100 per cent) with seminoma and 12 of 17 patients (71 per cent) with nonseminomatous tumors had a complete response to chemotherapy, and 1 of 17 patients was free of disease after a debulking operation and additional chemotherapy. A total of 3 patients with seminoma and 2 with nonseminomatous tumors had recurrences 5 to 8 months after an initial complete response and received additional chemotherapy (VP-16 regimen) with or without radiotherapy. Complete clinical response was achieved in 4 of 5 patients. Median followup was 24 months (range 8 to 38 months) in the 13 patients with seminoma and 28 months (range 9 to 58 months) in those with nonseminomatous tumors, and 13 (100 per cent) and 12 (71 per cent), respectively, are alive without evidence of disease. These data suggest that the protocol of vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum is highly effective and minimally toxic in the treatment of disseminated germ cell testicular cancer, inducing an 83 per cent long-lasting clinical remission. Seminomas seem to be equally or even more sensitive than nonseminomatous tumors to this platinum-containing chemotherapy regimen. Recurrence after initial complete response can be treated successfully with regimens containing VP-16.     

No adjuvant chemotherapy in selected patients with pathologic stage II nonseminomatous germ cell tumors of the testis

In a previous report on patients with resected stage II nonseminomatous germinal cell testis tumors the findings of retroperitoneal metastases larger than 5 cm., macroscopic extranodal spread and tumor invasion into retroperitoneal veins (pathologic stage IIC) almost invariably were associated with relapse and poor survival in the absence of adjuvant chemotherapy, while postoperative cisplatin, vinblastine and bleomycin therapy was effective in preventing relapses in all cases. From February 1980 to January 1982, 40 consecutive patients underwent retroperitoneal lymphadenectomy for stage II disease. Only patients with pathologically assessed stage IIC cancer received 4 cycles of adjuvant cisplatin, vinblastine and bleomycin, while those with pathologic stages IIA and IIB disease, with or without microscopic extracapsular extension of the tumor, received no further therapy and were followed carefully at monthly intervals. After a median followup of 26 months or more relapses were noted in none of the 14 treated patients compared to 9 of 26 untreated patients (35 per cent). Of the latter 9 patients 8 (89 per cent) had continuous complete remission after salvage therapy and 39 of 40 patients (97.5 per cent) currently are free of disease. No difference was observed in the relapse rate and survival between patients with stages IIA and IIB disease. We conclude that patients with pathologic stages IIA and IIB disease can be treated safely only at the time of relapse, while the usefulness of adjuvant chemotherapy has been confirmed in those with stage IIC cancer.     

Recurrent dislocation of the patella. Relation of treatment to osteoarthritis.

Eighty-one knees surgically treated and twenty-six conservatively treated for recurrent dislocation of the patella in seventy-eight patients were studied. The average follow-up on the surgically treated knees was eight years and on the conservatively treated knees, sixteen years. In the non-surgical group dislocations tended to become less frequent with advancing age and there was very little evidence of osteoarthritis. After the sixty-nine tibial tubercle transfers there was a 20 per cent recurrence rate; further procedures were often needed, and the incidence of late osteoarthritis was disturbingly high. After the twelve soft-tissue corrections without movement of the tibial tubercle, dislocation recurred in three, but late osteoarthritis was not seen.     

Total resection of distal femur or proximal tibia for bone tumours. Autogenous bone grafts and arthrodesis in twenty-six cases.

Resection of the distal femur or proximal tibia en bloc has been performed on twenty-six patients with primary bone tumours. The gap was filled with autogenous bone grafts stabilised with a long intramedullary nail, thus arthrodesing the knee. In two cases temporary stabilisation with a Küntscher rod and acrylic cement was adopted because of adjuvant chemotherapy. Union was achieved in twenty-four cases (92 per cent). Infection was the main and practically the only major complication, occurring in five (19 per cent) of the cases: it healed with union in three, healed with non-union in one, and led to an above-knee amputation in the fifth case. Follow-up has been from one to eight years with an average of four years.     

Bypass operation for advanced esophageal cancer--an analysis of 93 cases

From 1973 to 1987, 235 patients with esophageal squamous cell carcinoma were treated at Hiroshima University. Of these patients, 121 (51.5 per cent) were submitted to esophagectomy, 93 (39.6 per cent) to bypass surgery and 21 (8.9 per cent) to either exploratory or no surgery. In this report, the 93 cases who underwent bypass surgery were analysed. Ten patients died within thirty days after their operation (10.8 per cent) and there were 33 cases of hospital death (35.5 per cent). Following the bypass surgery, 49 (59.0 per cent) cases were able to tolerate over 50 per cent of their normal oral intake and 22 cases (26.5 per cent) were able to tolerate between 25 per cent and 50 per cent. For twelve cases (14.6 per cent), however, oral ingestion proved impossible up until the time of death due to such complications as leakage. The overall survival rates were 44.3 per cent at 6 months, 12.7 per cent at 1 year and 2.8 per cent at 5 years, respectively. Two cases survived for over 5 years. Hyperthermia was applied in combination with chemotherapy from 1981, however, no case survived for over one year without radiation therapy. Recently, radiation plus hyperthermia is being performed in combination with immunochemotherapy.     

Bypass operation for advanced esophageal cancer —An analysis of 93 cases—

From 1973 to 1987, 235 patients with esophageal squamous cell carcinoma were treated at Hiroshima University. Of these patients, 121 (51.5 per cent) were submitted to esophagectomy, 93 (39.6 per cent) to bypass surgery and 21 (8.9 per cent) to either exploratory or no surgery. In this report, the 93 cases who underwent bypass surgery were analysed. Ten patients died within thirty days after their operation (10.8 per cent) and there were 33 cases of hospital death (35.5 per cent). Following the bypass surgery, 49 (59.0 per cent) cases were able to tolerate over 50 per cent of their normal oral intake and 22 cases (26.5 per cent) were able to tolerate between 25 per cent and 50 per cent. For twelve cases (14.6 per cent), however, oral ingestion proved impossible up until the time of death due to such complications as leakage. The overall survival rates were 44.3 per cent at 6 months, 12.7 per cent at 1 year and 2.8 per cent at 5 years, respectively. Two cases survived for over 5 years. Hyperthermia was applied in combination with chemotherapy from 1981, however, no case survived for over one year without radiation therapy. Recently, radiation plus hyperthermia is being performed in combination with immunochemotherapy.     

Testicular cancer: prognostic implications of vascular invasion

In a retrospective study the primary tumors of 33 patients with seminomas and 53 with nonseminomatous germ cell tumors were re-evaluated for vascular invasion. The significance of vascular invasion was analyzed in respect to the appearance of visceral metastases and the effect of adjuvant chemotherapy. Vascular invasion was demonstrated in 27 per cent of the patients with seminomas and 53 per cent with nonseminomatous germ cell testis tumors, while visceral metastases appeared in 9 and 32 per cent, respectively. Without adjuvant chemotherapy all 13 patients with nonseminomatous germ cell testis tumors and vascular invasion had metastases, compared to only 3 of 13 without vascular invasion (p less than 0.0005). Of 9 patients with seminoma and vascular invasion 3 had tumor progression, compared to 1 of 24 without vascular invasion (p greater than 0.05). With adjuvant chemotherapy only 1 of 15 patients (7 per cent) with nonseminomatous germ cell testis tumors and vascular invasion had metastases, compared to 100 per cent of 13 without this treatment. No significant correlation was noted between pT stage versus vascular invasion and pT stage versus tumor progression. The results demonstrate the importance of vascular invasion in the staging of and choice of treatment for early nonseminomatous germ cell testis tumors.     

Superficial bladder tumors (stage pTa, grades 1 and 2): the importance of recurrence pattern following initial resection

We treated 414 new patients with stage pTa, grades 1 and 2 bladder tumors by transurethral resection between 1970 and 1982. All of the patients with grade 3 or previous upper tract tumors, or who had been treated at some stage with intravesical chemotherapy were excluded. Followup for 5 or more years was available in 188 of the patients. There was a low increase in T stage (6 per cent). Of the patients followed for 5 or more years 46 per cent remained free of tumor. Only 16 per cent of the patients had multiple tumors at presentation and 20 per cent had tumors of 10 gm. or more. These factors were associated with a worse prognosis. Patients free of tumor at 3 months had an 80 per cent chance of having no further recurrences and this rate remained the same up to 2 years from the start of the disease. Patients with a recurrence at 3 months were much less likely to remain free of tumor, and had a higher chance of recurrence at every future visit.