Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.     

Systemic therapy of low malignancy non-Hodgkin lymphomas

Substantial progress has been achieved in eludicating the molecular mechanisms of malignant transformation, in establishing therapeutic standards and in evaluating innovative treatment strategies in patients with low grade Non-Hodgkin's Lymphoma. Correlation of genetic aberrations and immunologic marker profiles to histopathological entities and the clinical course has lead to a new transatlantic lymphoma classification. Today, application of 6-8 courses of moderately intensive induction polychemotherapy induces partial or complete remissions in 80% of patients in stage III or IV. Longterm maintenance therapy with interferon alpha significantly prolongs progression free survival. Current multicenter trials evaluate the curative potential of high-dose chemotherapy with autologous stem cell transplantation. Recently, several new approaches including new cytostatic drugs, immunotherapy with monoclonal antibodies and gene therapy with antisense oligonucleotides have been developed and have achieved remissions in pretreated patients. In the future, intensification of chemotherapy and the new treatment options may offer the potential for cure in patients with low malignant Non-Hodgkins Lymphoma.     

Fludarabine. An update of its pharmacology and use in the treatment of haematological malignancies

Fludarabine is an antineoplastic agent which has been studied in patients with a variety of lymphoproliferative malignancies. Clinical evidence from comparative studies in chronic lymphocytic leukaemia (CLL) suggests that fludarabine is at least as effective as CAP (cyclophosphamide, doxorubicin and prednisone) or CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone) in previously treated or chemotherapy-naive patients and significantly more effective than chlorambucil in terms of response rate and duration and survival in chemotherapy-naive patients. Promising results have also been reported with fludarabine-based combination therapy in the treatment of patients with CLL. In addition, sequential therapy with fludarabine and cytarabine has demonstrated good efficacy in the treatment of acute leukaemias, as has fludarabine monotherapy and combination therapy in low grade non-Hodgkin's lymphoma. A favourable cytoreductive response has been reported in patients with lymphoplasmacytoid lymphoma and in a smaller number of patients with cutaneous T cell lymphomas, CLL of T cell origin or prolymphocytic leukaemia. Recent data also support the use of fludarabine, either as a component of a nonmyeloablative conditioning regimen or in the attainment of minimal residual disease, in patients undergoing peripheral blood stem cell or bone marrow transplantation. The tolerability profile of fludarabine is similar to that of CAP, with the most common adverse events being granulocytopenia, thrombocytopenia, anaemia and infection. Alopecia and nausea/vomiting appear to be less frequent with fludarabine therapy than with CAP although the development of immune cytopenias is more frequent with fludarabine. Severe neurotoxicity has been reported with fludarabine but this is mostly confined to the use of high doses. Clinical experience therefore indicates that fludarabine is an effective and generally well-tolerated antineoplastic agent for the second-line treatment of advanced CLL. Recent data from comparative studies also support the earlier use of fludarabine in the treatment of chemotherapy-naive patients with CLL. Furthermore, results of available studies are increasingly highlighting an important future role for fludarabine in the treatment of acute leukaemias and low grade NHL and possibly other lymphoproliferative disorders, particularly when used as a component of combination chemotherapy.     

The management of Hodgkin's disease with chemotherapy or combined modality treatment

Systemic polychemotherapy and local radiation are two well-established treatments for Hodgkin's disease. With the use of modern techniques, the great majority of patients with pathologic stage I-II Hodgkin's disease can be cured with irradiation alone. Since the invention of the MOPP and ABVD schemes, polychemotherapy has become indispensable for the treatment of advanced-stage Hodgkin's disease. The role of radiotherapy in combination with chemotherapy is limited to specific indications. ABVD therapy is as effective as MOPP alternating with ABVD, and both are superior to MOPP alone in the treatment of advanced Hodgkin's disease. MOPP/ABVD hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD in 8-year failure-free survival and overall survival. The patients with advanced-stage Hodgkin's disease who did not achieve a complete remission from their initial treatment with combination chemotherapy have a dismal prognosis. Those whose initial remissions had lasted longer than 12 months had a very high probability of obtaining a second complete remission when re-treated with MOPP or ABVD, but those whose remission lasted less than 12 months fared less well with any conventional-dose chemotherapy. High-dose chemotherapy and radiotherapy with autologous hemopoietic stem cell transfusion are superior in the treatment of those whose disease is refractory or resistant to the initial therapy.     

Longitudinal observation and outcome of nonfamilial childhood haemophagocytic syndrome receiving etoposide-containing regimens

The long-term outcome of 22 children treated with etoposide-containing regimens for haemophagocytic syndrome (HS) were longitudinally studied; none of them had a family history of the disease. All patients received etoposide-containing (150 mg/m2/d) regimens, combined, in 16 cases, with intravenous immunoglobulin (IVIG) and prednisolone. Complete remission (CR) was achieved in 12 patients, partial remission in seven, and early mortality occurred in three. Of the 12 CR patients, only four remain alive and disease-free, with a median follow-up of 47.4 months; one CR patient died due to infection and the remaining seven had relapsed diseases. Three patients with a partial response or with relapsed disease progressed to T-cell lymphoma, characterized, in the two cases tested, by clonal chromosomal abnormalities. Epstein-Barr virus (EBV) infection was implicated in disease pathogenesis in 15/22 patients. The overall survival was 45.5%, 40.9% and 40.9% at 1, 3 and 5 years, respectively, and disease-free survival for CR patients at these same times was 45.5%, 36.4% and 36.4%. The etoposide-containing regimen would appear to be an effective initial therapeutic option for childhood HS. However, in view of the frequency of partial remissions and relapsed disease, a more intensive chemotherapy or bone marrow transplantation should be applied. The progression to EBV-containing T-cell lymphoma in three patients is consistent with the previous observation that EBV-associated HS is a potentially malignant disease.     

Allogeneic stem cell transplantation for advanced low-grade lymphoproliferative disorders: report of six cases

BACKGROUND: Allogeneic stem cell transplantation is being increasingly used to treat young patients with poor-prognosis low-grade lymphoproliferative disorders. We report our single-center experience. PATIENTS AND METHODS: Six adults (four with advanced chronic lymphocytic leukemia, one follicular center cell lymphoma and one mantle cell lymphoma) underwent allogeneic stem cell transplantation (SCT). Five received bone marrow while one received peripheral blood stem cells. Donors were HLA-identical siblings in five cases and an HLA-haploidentical sibling in one. The conditioning regimen included in five cases cyclophosphamide, TB1 and high-dose chlorambucil, without the latter in the patient with follicular lymphoma. RESULTS: Five patients successfully engrafted, while the patient who received the haploidentical marrow suffered primary graft failure. There were two cases of grade 2 acute GVHD and one limited chronic GVHD. Four patients are alive in complete remission (CR) with a follow-up of 17+ to 118+ months. Additionally, there is no evidence of residual disease by immunologic and molecular techniques in three cases, while one patient has residual disease assessed by molecular methods. CONCLUSIONS: These results suggest that allogeneic SCT can achieve prolonged remissions in advanced chronic lymphoproliferative disorders.     

Intensive therapy with peripheral stem cell transplantation in 16 patients with mantle cell lymphoma

BACKGROUND: Despite improved detection of mantle cell lymphoma (MCL), results of its treatment with conventional therapies remain disappointing and the survival rate poor. The role of high-dose chemotherapy has recently been investigated but no potential benefit has been clearly established. We report here our experience with MCL patients treated with intensive chemotherapy and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Of the 16 MCL patients who received high-dose chemotherapy and ASCT beginning in 1989, six were treated in first-line and 10 in sensitive relapse. Twelve of 16 patients received regimens which included total body irradiation. All patients received peripheral blood stem cells (PBSC) with the exception of one, who underwent bone marrow transplantation. RESULTS: Three patients died of toxic effects of treatment, Three months after transplant, seven achieved complete response, (CR) and two partial responses (PR), two were stable and two had progressed. With a median follow-up after transplant of 22 months, five of the six surviving patients were without progression, and three were in CR. The median times for event-free survival (EFS) and overall survival (OS) were, respectively, 249 and 317 days. The expected three-year EFS and OS were 24%. The median survival after diagnosis was only 29 months. None of the criteria appeared to be significantly associated with a better outcome, but first-line intensification and a short delay after initial diagnosis may be favorable. CONCLUSION: In this study we were not able to confirm the hypothetical benefit of high-dose chemotherapy and PBSC transplantation in mantle cell lymphoma, even though this approach may be promising in a subgroup of patient.     

An EIA method on single donor solubilized HLA antigens for the identification of anti-HLA antibodies

Primary biliary cirrhosis (PBC) is an immunologically mediated disease in which activated T lymphocytes attack and destroy epithelial cells in the small intralobular bile ducts of genetically susceptible patients. This article reviews the results of treatment of PBC with immunomodulatory agents. Results with drugs such as glucocorticoids, azathioprine, and chlorambucil have been disappointing because of either limited efficacy (azathioprine), toxicity (chlorambucil), or both (glucocorticoids). Colchicine improved tests of liver function in three prospective studies and was associated with improved survival for up to 4 years. However, survival benefits were lost at 8 years. Colchicine appears to slow the rate of progression of PBC but not to stop it. Preliminary results suggest that colchicine may have synergistic effects if used together with ursodeoxycholic acid, particularly in patients who are only partially responsive to ursodeoxycholic acid. Results with cyclosporine have been disappointing because of limited efficacy and predictable toxicity. The modest improvement in tests of liver function and survival are counterbalanced by the development of hypertension in some and worsening renal function in most. There is little beneficial effect on symptoms or histology. Results with methotrexate are promising. There are improvements in symptoms and tests of liver function that are equal to those seen with ursodeoxycholic acid and significant improvement in liver histology. Some patients, particularly those with striking inflammation and granulomas in portal triads, appear to have achieved sustained remission while on methotrexate. The effects of methotrexate are additive to those of ursodeoxycholic acid in patients whose blood tests have responded only partially to ursodeoxycholic acid. The most effective treatment of PBC will most likely use a combination of drugs such as ursodeoxycholic acid, colchicine, and methotrexate.     

Combined modality therapy in previously untreated patients with advanced Hodgkin's disease: A 24-year follow-up study

PURPOSE: To describe the long-term results of treatment with chemotherapy plus adjuvant low-dose, involved-field radiation therapy (CMT) in patients with advanced Hodgkin's disease. Data on disease-free and failure-free survival, second malignancies, and the results of salvage therapy are presented. PATIENTS AND METHODS: From 1969 to 1989, CMT was administered to 186 patients with previously untreated stage IIB, III, and IV Hodgkin's disease. Chemotherapy included MVVPP (47%), MOPP (25%), MOPP/ABVD (26%) and ABVD (2%). After 6 months of chemotherapy, patients received radiation to all involved sites with the exception of the bone marrow. RESULTS: The failure-free survival for all patients was 63% at 5 years, 56% at 10 years, and 40% at 23.5 years, respectively. Significantly worse results were observed in patients older than 40 years and those with stage IV disease. The overall survival of 45 patients after recurrence was 39% at 10 years, but was only 21% if the initial complete remission lasted less than 1 year. Thus far, 21 of 165 patients (12.7%) who achieved complete remission have developed a second malignancy, and 16 have died. CONCLUSIONS: In comparison with comparable chemotherapy programs, chemotherapy plus radiation therapy may improve disease-free survival; however, the results of treatment in patients older than age 40 or with stage IV disease are still poor. Although patients with initial remissions lasting longer than 1 year can have durable second remissions, the long-term disease-free survival is poor and in the current series the majority of failures were due to recurrent Hodgkin's disease.     

Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation

PURPOSE: To review the treatment of cirrhotic patients with hepatocellular carcinoma in the era of liver transplantation and to determine the most appropriate approach to the treatment of patients at different stages of disease. DATA SOURCES: A MEDLINE search of English-language articles published between 1981 and 1997 and the clinical experience of the Mount Sinai Liver Transplant Program. STUDY SELECTION: Selected studies were 1) original articles reporting results of resection and transplantation in the treatment of hepatocellular carcinoma in cirrhotic patients and 2) initial reports from major transplantation centers of multimethod therapies combining chemotherapy with transplantation. DATA EXTRACTION: Study designs were assessed with careful attention to methods and aims. Relevant data on patient population, tumor stage distribution, treatment, survival, and rate of recurrent disease were extracted and analyzed. DATA SYNTHESIS: Options for the treatment of hepatocellular carcinoma in cirrhotic patients vary according to tumor stage and severity of underlying liver disease. Resection remains an important method primarily in eastern countries, where the screening of high-risk populations has been associated with early detection of small asymptomatic lesions. Long-term survival after resection, however, is low. In western countries, liver transplantation is becoming the treatment of choice in patients with advanced cirrhosis and small, unresectable lesions; resection is reserved for cirrhotic patients with small, peripheral lesions and preserved hepatic function. Minimally invasive procedures (such as percutaneous ethanol injection and transarterial chemoembolization) have been developed to treat unresectable tumors. Transarterial chemoembolization may also be effective in patients with advanced cirrhosis and unresectable lesions who are awaiting transplantation. CONCLUSIONS: The efficacy of liver transplantation for hepatocellular carcinoma has been proven mainly in patients with advanced cirrhosis and small lesions. Future studies may clarify the role of approaches combining neoadjuvant chemotherapy with transplantation for large (stage III) tumors.     

Transplantation of hematopoietic stem cells. II: Indications for transplantation of hematopoietic stem cells after myeloablative therapy

The destruction of hematopoiesis and lymphopoiesis by total body irradiation or high dose chemotherapy for the treatment of malignancy can be reversed by the transplantation of allogeneic or autologous hematopoietic stem cells. In primary disorders of bone marrow or immune system, allogeneic stem cells replace deficient cells. Acute leukemias can be cured, with in 50 to 80% disease free survival after 5 to 8 years. The allogeneic graft versus leukemia effect by immunoreactive cells reduces the relapse rate in myeloid and lymphoid malignancies. 40 to 70% of patients with chronic myeloid leukemia remain disease free after more than 5 years. Patients with malignant lymphoma have a 40 to 70% chance of cure with autologous transplantation, which is not increased by allogeneic cells, because of a higher incidence of severe complications. An increasing number of patients without option for cure is treated with the aim of prolonging remission or retarding disease progression, such as in chronic myeloid leukemia, multiple myeloma and certain solid tumors. New studies suggest in breast cancer with axillary lymph node metastases, that adjuvant high dose chemotherapy with autologous stem cell support will significantly improve disease free survival from 30 to over 60% after 3 to 5 years. In congenital metabolic and storage diseases deficient enzymes are substituted by the allogeneic cells. Clinical trials explore the use of stem cell transplantation after myeloablative therapy in autoimmune disorders as well as in gene therapy with transfected hematopoietic stem cells.     

Chemotherapy of advanced malignant lymphomas comparative evaluation of results with single agent and combination therapy

86 patients with advanced malignant lymphomas (stage III and IV) were treated either with Vinblastine given as a single agent (49 cases) or with combination chemotherapy MOPP or COP (37 cases). In both, Hodgkin's disease and non-Hodgkin's lymphomas, induction of remission, relaps-free survival and prognostic significance of initial clinical stage were evaluated, in relation to the therapeutic modality. In patients with Hodgkin's disease, combination chemotherapy was found to produce significantly more durable remissions, when compared with single agent therapy. However, difference in the response rate, which was found to be more effective following the combination chemotherapy, was not statistically significant. In patients with non-Hodgkin's lymphomas overall lower response was recorded, regardless of the therapy applied. In all patients, better response rate and longer lasting remissions correlated with initial stage III.     

Preoperative portal embolization: an effective means for inducing hypertrophy of the healthy liver and increasing indications for hepatic resection]

BACKGROUND: This study was carried out to investigate the efficacy and safety of high-dose chemotherapy (HDC) for the treatment of patients with advanced testicular cancer. METHODS: Seven patients were treated with high-dose carboplatin, etoposide, and ifosfamide followed by autologous blood stem cell transplantation. One patient received 1 cycle, 4 patients received 2 cycles, and 2 patients received 3 cycles of HDC. We performed a total of 15 autologous blood stem cell transplantations: 8 with autologous bone marrow; 6 with peripheral blood stem cells; and 1 with peripheral blood stem cells in addition to autologous bone marrow. RESULTS: Four of the 7 patients achieved a pathologic complete response via early use of HDC and additional salvage surgery. All 4 patients are still alive without evidence of disease at 12, 30, 33, and 54 months, respectively. One patient is alive with active disease at 35 months. Two patients refractory to conventional chemotherapy died of progressive disease at 5 and 27 months, respectively. The hematologic recovery after HDC was rapid, and peripheral blood stem cells tended to have shorter hematologic recovery compared with those from autologous bone marrow, although the difference was not significant. Nonhematologic toxicity was usually mild and manageable. CONCLUSION: High-dose chemotherapy, followed by autologous blood stem cell transplantation, may be safe and effective for patients with advanced testicular cancer, particularly when early use of HDC is conducted for chemotherapy-sensitive patients. A further large, long-term, follow-up study will be needed to define the role of HDC.     

Prognosis of hematological patients with relapse following high-dose chemotherapy and autologous stem cell transplantation

A retrospective analysis of the outcome for 283 haematological patients who relapsed after high dose chemotherapy and autologous stem cell transplantation during a five year period from 1989 to 1994 is presented. The patients were treated in accordance with local regimes at 20 Nordic transplantation centers and included patients with acute leukemia (157 patients), multiple myeloma (16 patients) and lymphoma (110 patients). Two hundred and twenty-nine patients with relapse or progressive disease were given chemo- and/or radiotherapy and the response was evaluated after 90 days. Fifty-four patients (24%) obtained a complete remission and 44 patients (19%) partial remission. The overall median survival after relapse was five months. In the group who received salvage treatment the median survival was seven months, and for the 54 patients in complete remission the median survival was 15 months. We found that survival after relapse depends upon primary disease, the time from transplantation to relapse and whether salvage therapy was initiated.     

Evaluation of primary standard cisplatin-based chemotherapy for clinical stage II non-seminomatous germ cell tumours of the testis

OBJECTIVE: To evaluate the use of primary cisplatin-based chemotherapy before retroperitoneal lymph node dissection (RPLND) in patients with clinical stage II non-seminomatous germ cell tumours of the testis. PATIENTS AND METHODS: Between 1984 and 1992, 55 patients with clinical stage II testicular cancer (12 with stage IIA. 33 stage IIB and 10 stage IIC disease) were treated at Institut Gustave Roussy with primary chemotherapy using three conventional regimens including cisplatin. Patients were assessed 4 weeks after the end of chemotherapy and depending on the response, underwent RPLND; the overall survival and disease progression were monitored. RESULTS: Sixteen (29%) patients achieved a sustained complete remission after chemotherapy only, while 30 (55%) patients required subsequent RPLND for persistent residual tumour masses: nine other patients obtained a clinical partial remission. Six patients who initially had achieved either a clinical complete response (three) or a surgical complete response (one) or a clinical partial response (two) subsequently relapsed. Overall, 52 of 55 (95%) patients remained free of disease 33 to 111 months after the end of treatment. CONCLUSION: These results show that primary cisplatin-based chemotherapy can effect a cure of the tumour in all subgroups of patients with stage II disease.     

An early phase II trial combining cisplatin and carboplatin in advanced non-small cell lung cancer

We conducted an early phase II trial in advanced non-small cell lung cancer (NSCLC) to evaluate response efficacy of a combination of Cisplatin (CDDP) and Carboplatin (CBDCA). The twenty-six patients in the study had had no previous treatment. They received a sequential administration of 300 mg/m2 CBDCA and 80 mg/m2 CDDP with approximately 3,500 ml of hydration on day 1 every 4 weeks. All patients were evaluable for response and toxicity. Ten (38.5%) of all assessable patients achieved a partial response (95% confidence interval, 19.8-57.2%). Response rates for patients with stage III A, III B and IV- disease were 40.0 (2/5), 70.0 (7/10) and 9.1% (1/11), respectively. Response rates for patients with squamous cell carcinoma, adenocarcinoma and large cell carcinoma were 35.7 (5/14), 45.5 (5/11) and 0.0% (0/1), respectively. The median survival time (MST) of all patients was 11 months. The MST for patients with stage III disease was 14 months; for those with stage IV disease it was 7 months. The MST for responding patients was 15 months and for not responding patients 5 months. Major toxicities were hematologic and gastrointestinal, and the dose-limiting factor was thrombocytopenia. This combination chemotherapy was effective against NSCLC with tolerable toxicities. Further trials are warranted to determine the efficacy of the combination chemotherapy.     

Indications and relative indications for stem cell transplantation in non-Hodgkin's lymphoma

High dose chemotherapy with or without total body irradiation and autologous stem cell rescue has proven to be effective treatment to cure patients with relapsed intermediate grade and high grade non-Hodgkin's lymphoma. Important factors for selection of candidates most likely to do well with these approaches include patients whose disease is responsive to conventional therapy and those who have minimal disease volume at the time of transplant. The treatment-related mortality of autologous stem cell transplantation has diminished from 20% to less than 5% with improved supportive care and selection of patients with less advanced disease. Although the treatment-related mortality of allogeneic stem cell transplantation may be as high as 20-40%, a graft versus lymphoma effect may decrease relapse with the result that overall survival is not substantially different between autologous and allogeneic transplantation. The definitive indications for stem cell transplantation include patients who have relapsed with intermediate or high grade NHL. Relative indications include intermediate/high grade non-Hodgkin's lymphoma patients, "high risk" first complete remission (CR), resistant relapse; low grade non-Hodgkin's lymphoma in sensitive or resistant relapse, advanced disease (sensitive or resistant relapse, transformation), first CR (younger patients). Relative contraindications include specific patient profiles such as bulky high grade lymphoma which progresses on appropriate conventional therapy, poor performance status, active serious infection, serious cardiac, renal, pulmonary or liver dysfunction, active, central nervous system (CNS) disease unresponsive to cranial irradiation/intrathecal therapy. For patients with previous marrow involvement or active marrow involvement at the time of harvest or transplant, "purged" autografts, peripheral blood stem cell transplantation and allografts have been used successfully.     

Confirmation of quantitative trait loci for ethanol sensitivity in long-sleep and short-sleep mice

PURPOSE: To determine the efficacy of the combination of cisplatin, fluorouracil, and high-dose l-leucovorin (PFL) as organ-preserving induction therapy followed by radiotherapy in untreated patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: This was a phase II study of PFL in 47 patients with resectable stage III (n = 20) and IV (n = 27) M0 squamous cell carcinoma of the head and neck, including larynx (n = 20), hypopharynx (n = 14), and oropharynx (n = 13). The PFL regimen consisted of cisplatin 25 mg/m2 on days 1 through 5, fluorouracil 800 mg/m2 CI on days 2 through 6, and l-leucovorin 250 mg/m2 on days 1 through 6, all by continuous intravenous infusion every 21 to 28 days for three courses. The primary study endpoint was initial response to and local disease control rate with PFL as induction chemotherapy, with an aim to confirm the previously reported complete response rate of 60% to 70%. RESULTS: Of 47 patients enrolled, 46 were evaluable for response to PFL, 14 (30%) achieved a complete response, and 25 (54%) achieved a partial response, for an overall response rate of 84%. Of 39 patients evaluable for response after radiation therapy, 27 (69%) achieved a complete response and 11 (28%) a partial response. Local disease control was achieved in 37 of 46 (80%). Grade 3 or 4 toxic effects occurred frequently, with neutropenia in 27 (59%) of 46 evaluable patients, thrombocytopenia in 30%, mucositis in 41%, diarrhea in 13%, and nausea/ vomiting in 13%, but there were no treatment-related deaths. With a median follow-up of 35 months there have been nine recurrences (four local/regional and five distant) and 17 deaths (12 in patients with disease progression and five not directly related to the primary tumor). Second primary tumors have developed in six patients. At 3 years 62% of the patients remain alive with no disease progression, and the 3-year survival estimate with preserved organ function is 66%. CONCLUSION: PFL induction chemotherapy produced only a modest complete response rate, possibly due to suboptimal dose intensity, and was associated with substantial, although not life-threatening, toxicity. Newer regimens and treatment modalities are still needed in the management of advanced squamous cell carcinoma of the head and neck.     

Therapy of anthracycline-resistant metastatic breast carcinoma

Treatment of anthracycline-resistant metastatic breast cancer with new antineoplastic agents remains a challenge for the next future. The 5-year survival for this disease is only 15%, and hormonal and chemotherapeutic options remain essentially palliative. New treatment drugs or drug combinations are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Taxanes are promising new drugs and have shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both with a poor prognosis. Paclitaxel (taxol) is applied with a dose of 175 mg/m2 in a 3 hour infusion and docetaxel (taxotere) with a dose of 100 mg/m2 q 3 weeks. Remission rates are expected between 6-30% for taxol and between 29-48% for docetaxel. Highly active in patients with anthracycline-resistant disease appears to be the vinca-alkaloid vinorelbine too. In patients treated with adriamycin objective remissions between 15-33% can be obtained. The long time known 5-fluorouracil comes to the third place of the effective drugs. Continuous infusion or addition of folic acid increases the intracellular efficacy and results in 5-53% objective remissions. In second-line chemotherapy platin-analogues together with etoposide, vincristine and 5-FU achieve partial or complete remissions between 19-37% for cisplatin containing and 5-12 for carboplatin containing combinations. This may eventually play a role especially if three drug combinations containing paclitaxel, epirubicin and vinorelbine will be used, which are reported to result in 20-33% complete response rates and 66% objective response. The indication for other new drugs like tomudex, topoisomerase-I-inhibitor and gemcitabine for anthracycline-resistant breast cancer remains to be established in multicenter studies.     

Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study

Disseminated neuroblastoma after infancy has a prognosis of approximately 10-20% with conventional therapy. We investigated the role of high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) rescue in combination with 131I-metaiodobenzylguanidine ([131I-m]IBG). 11 children with neuroblastoma stage 4 were pretreated within the German Neuroblastoma Trial NB90 and included in a high-dose concept for consolidation. Remission was documented by ultrasound, CT, NMR, or [123I-m]IBG scanning. HDCT was a combination of melphalan (180 mg/m2), carboplatin (1,500 mg/m2) and etoposide (40 mg/kg). All children were treated by [131I-m]IBG (0.58 GBq/kg) prior to high-dose treatment. All 11 children were additionally treated with antiGD2 murine- or chimeric-antibody (ch14.18). 4 children had no change to their remission status but three achieved a complete response (from a partial response to first line) and one a partial response (from no response to first line). The other 3 children progressed, 2 dying of their disease. Using Kaplan-Meier analysis, the probability of progression-free survival was 0.70 +/- 0.15 with a median observation time of 19 months. 9/11 children are alive, 8 without progression or relapse, whilst 2 have died of their disease. The combination of mIBG plus high-dose chemotherapy with PBSC support supplemented by immunotherapy with antiGD2 antibody appears to be a feasible and effective treatment regimen for disseminated neuroblastoma in this limited series. Larger numbers of patients should be treated to confirm these results.