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.     

Experimental hepatitis E: pathogenesis in cynomolgus macaques (Macaca fascicularis)

Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6-mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty-eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.     

Safety and efficacy of ECT in patients with head injury: a case series

BACKGROUND: The role of postoperative radiotherapy and adjuvant chemotherapy in the treatment of synovial sarcoma remains to be determined. PROCEDURE: Twenty-five children were treated during a 23-year period with a multimodality approach. All of them had resection of the primary tumor (three amputations), followed by surgical retreatment in eight. Postoperative radiotherapy was delivered to 16 patients and adjuvant chemotherapy was given to 22. RESULTS: At the time of the report, 19 patients were alive and without evidence of disease. Six developed distant metastases (one associated with local recurrence); five of them died of their disease and one was alive in complete remission at 4 years from relapse. With a median follow-up of 9 years (range 2-23), the survival and the event-free survival at 5 years were 80% (SE 8.2) and 74% (SE 9.2), respectively. All relapsing patients had been classified as T2B. CONCLUSIONS: Multimodality treatment yielded satisfying survival results using limb-preserving surgery in most cases. Tumor size > 5 cm and invasiveness, which defined stage T2B, were the most important predictors of poor outcome. Evaluation of the role of adjuvant chemotherapy and radiotherapy awaits prospective studies, even if T2B patients, as well as children having nonradical surgery, seem worth managing by adjuvant treatments.     

Successful treatment of non-Hodgkin's lymphoma of the central nervous system with BMPD chemotherapy followed by radiotherapy

The treatment of patients with primary non-Hodgkin's lymphoma of the central nervous system (PCNSL) is still of limited success, as compared with other extranodal sites. The poor results obtained with radiotherapy alone can be improved by adding chemotherapy reaching a median survival up to over 30 months and 5-years-survival rate up to 35%. The optimal management for patients with CNS relapse of systemic lymphoma remains uncertain and their prognosis is even worse. Here, we describe our preliminary data on the treatment of patients with CNS lymphoma with a new regimen composed of CNS-penetrating drugs, namely: carmustine (BCNU) 80 mg/m2 i.v. dl, methotrexate 1500 mg/m2 over 24h i.v. d2, procarbacine 100 mg/m2 p.o. d1-8, and dexamethasone 3 x 8 mg p.o. d1-14. An average of 3 treatment courses were given under response control seen using CT-scan or NMR. Patients with positive CSF cytology received additionally intrathecal therapy with methotrexate. Until now between March 1994 and September 1997, 7 patients with PCNSL and 4 patients with CNS relapse of systemic lymphoma have been treated. The median age of the patients was 56 (range, 39-74); 5 patients were > or =60 years old. Three patients had multifocal disease. Whole brain radiotherapy with 4000 to 5000 cGy was given in 7 patients (cerebrospinal in 1 patient). Complete response at the end of chemotherapy was achieved in 6 patients, and a partial response in two. Most remarkably, 2 elderly patients (70 and 57 years), 1 patient with multifocal disease and 1 with simultaneous CNS and systemic relapse after chemotherapy had a complete remission lasting for 40 months, and a partial remission lasting for 37 months, respectively.     

The role of cell communication in the pathogenesis of breast cancer]

OBJECTIVE: The aim of the study is to analyse long-term results of patients with small cell lung cancer (SCLC) treated at the same institution according to a prospective study including surgery, chemotherapy, and radiotherapy. METHODS: From 1981 to 1995, 104 patients with a proven histology of SCLC underwent surgery, chemotherapy, and radiotherapy. Fifty-one patients with operable stage I or II lesion received surgical resection followed by adjuvant chemotherapy and radiotherapy. Fifty-three patients with proved SCLC and clinical stage III received induction chemotherapy followed by surgery and radiotherapy. All patients received from four to six courses of chemotherapy and 36 had prophylactic cranial irradiation (PCI). All patients had follow-up for at least 1 year, and survival time was calculated from the date of the diagnosis until death or most recent follow-up. RESULTS: Ninety-six patients were male and eight female. We performed 29 pneumonectomies, eight bilobectomies, 66 lobectomies and one no resection. Regarding the clinical stage, 35 patients (33.6%) had stage I, 16 patients (15.4%) had stage II and 53 (51%) had stage III. Post-operative pathologic staging revealed stage I in 37 patients (35.6%), stage II in nine patients (8.6%), stage III in 45 patients (43.3%), and in 13 patients (12.5%) there was no more tumor. The 30-day mortality was 2% (two patients). Fourteen patients (13.4%) had post-operative complications. Fifty-one patients (49%) had a relapse. The median follow-up was 55 months. Twenty-six patients remain alive and 78 patients have died. The overall 5-year survival rate was 32%, with an estimate median survival time of 28 months; according to the pathologic stage, the survival data were 52.2%, 30% and 15.3% for stage I, II and III, respectively (P < 0.001). The 5-year survival was 41% in patients without SCLC after chemotherapy. CONCLUSION: As with non-small cell lung cancer, survival following surgery and chemotherapy clearly correlates with the stage. At present, it is not clear whether surgery is truly effective for patients with SCLC. In our experience, the complete elimination of small cell lung cancer is associated with an improvement in survival (41% at 5 years).     

Treatment of localized non-Hodgkin's lymphomas of the head and neck

BACKGROUND: Localized non-Hodgkin's lymphomas of the head and neck are generally treated with radiotherapy with or without chemotherapy, although the results of treatment of localized non-Hodgkin's lymphomas with of treatment of localized non-Hodgkin's lymphomas with chemotherapy alone appear to be favorable. It is unclear if and when combined modality therapy should be used. METHODS: The authors reviewed the records of 53 patients with Stage I or II non-Hodgkin's lymphoma of the head and neck, who were treated with radiotherapy alone (13 patients), chemotherapy according to the cyclophosphamide, doxorubicin, vincristine, prednisone- (CHOP) regimen (27 patients), or a combination of both treatments (13 patients). RESULTS: A complete remission was achieved in 43 (81%) patients. The 5-year survival for all patients was 78%. A significant difference (P = 0.03) in 5-year relapse-free survival was observed between Stages I and II disease, of 92 and 60%, respectively. Extensive tumor was a significantly poor prognostic factor (P = 0.04) with a 5-year relapse-free survival of 52 versus 84% for patients with nonextensive lymphoma. Eight relapses occurred; in five patients, a local relapse was the first presentation. Although salvage radiotherapy was successful in these five patients, a distant relapse developed in three. No relapses were observed in previously irradiated areas. CONCLUSIONS: Our results suggest that radiotherapy alone is the appropriate treatment for nonextensive Stage I intermediate grade non-Hodgkin's lymphoma of the head and neck. For extensive Stage I or II non-Hodgkin's lymphomas, chemotherapy is preferable. The value of combined modality therapy remains unclear.     

Radiotherapy in the treatment of solitary plasmacytoma

Solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) are rare. High local control rates are reported with radiotherapy, although the optimal dose and extent of radiotherapy portals remains controversial. Between 1983 and 1993, 30 patients with solitary plasmacytoma were seen at the Regional Cancer Centre, Trivandrum, India. 23 patients had SPB and seven EMP. The mean age was 52 years and the male to female ratio 3.2:1. Diagnosis of SPB was confirmed by biopsy in 16 patients and tumour excision in seven. 20 patients received megavoltage radiotherapy to the bone lesion with limited margins, and one received chemotherapy. Two patients who underwent complete tumour excision received no further treatment. All seven patients with EMP received megavoltage radiotherapy, four following biopsy and three after tumour excision. Local control was achieved in all patients with SPB. Nine progressed to multiple myeloma and one developed a solitary plasmacytoma in another bone. Six patients with EMP achieved local control. Three later progressed to multiple myeloma and one had local relapse. Median time to relapse was 28 months in SPB and 30 months in EMP. 5-year overall survival rates were 82% and 57% for patients with SPB and EMP, respectively. The corresponding progression free survival rates were 55% and 50%, respectively. Age, sex, site of tumour, serum M protein and haemoglobin levels did not significantly influence progression free survival. The extent of surgery, radiotherapy dose or time to relapse were not significant prognostic factors. Radiotherapy appears to be an effective modality of treatment of solitary plasmacytoma. No dose-response relationship is observed, and high local control rates are achieved with limited portals. Progression to multiple myeloma is the commonest pattern of failure, although no prognostic factors for progression are identified. The role of chemotherapy in preventing disease progression needs further evaluation.     

Radiotherapy alone versus neo-adjuvant chemotherapy and irradiation in the treatment of carcinoma of the cavum

Radiation therapy is the usual treatment for nasopharyngeal carcinoma. However, in recent years the use of neoadyuvant chemotherapy in the treatment of local and regionally advanced carcinoma has been investigated. We report the results of a retrospective study of two treatments used in our center. The study included 68 patients: 34 (group A) who received radiotherapy alone and 34 (group B) who received neoadyuvant chemotherapy before radiotherapy. In group A, 70.6% achieved a complete clinical response: 23.5% relapsed: 5 patients presented distant metastases. Survival rates at 5 and 10 years were 53% and 27% respectively; the disease-free survival was 71.4% at 5 years and 54% at 10 years. In group B, the complete clinical response rate to neoadyuvant chemotherapy was 35.3%, which increased to 73.5% when the treatment was complemented with radiotherapy. The relapse rate was 14.7%; the survival rates at 5 and 10 years were 49.5% and 49%, respectively; and the disease-free survival was 77.2% at 5 and 10 years.     

A study of intermittent alternating drug program reinduction therapy on the frequency and duration of response in adult acute leukemia

Of 41 adults with a diagnosis of acute leukemia that were randomized for induction therapy in combination with methotrexate, 6-MP, vincristine and prednisone (POMP) versus a combination of cytosine arabinoside, cytoxan, vincristine and prednisone (COAP), 23 (56%) patients achieved a complete remission. During remission, patients received consolidation therapy with the three courses of remission induction regimen that they had not received initially. They then received daunomycin (three courses) and L-asparaginase and were then maintained for two years with their induction therapy. The median duration of survival for all patients was 40 weeks; the median duration of survival of those patients that responded to chemotherapy was 80 weeks. There was no significant difference between the two induction regimens with regard to complete remission more than four and one half years from diagnosis and two and one half years from discontinuation of all therapy.     

Thymoma: prognostic factors and treatment outcomes

BACKGROUND: The objective of this study was to establish prognostic factors for thymoma and determine the impact of surgery with or without postoperative radiotherapy. METHODS: Seventy patients treated at the University Hospital Düsseldorf during the period 1954-1991 were retrospectively studied. All thymoma patients underwent surgery, 22 received postoperative radiotherapy, and 3 also received chemotherapy. According to thymoma staging as described previously by Masaoka et al., 21% were Stage I, 26% Stage II, 43% Stage III, 7% Stage IVA, and 3% Stage IVB. Lymphocytic type disease was found in 36% of patients, lymphoepithelial type in 33%, epithelial type in 23%, and spindle cell type in 9%. The relevance of Karnofsky performance status (KPS), gender, age, myasthenia gravis, histology, tumor size, and stage to survival was determined by univariate analysis, and their independent significance was tested by multivariate analysis. Survival rates were calculated using the Kaplan-Meier method and the log rank test. RESULTS: In univariate analysis, KPS (P < 0.001), histologic type (P=0.0093), and stage (P=0.0001) proved to be significant predictors of overall survival. Spindle cell type was associated with the best and epithelial type the worst prognosis; patients with the latter type had a 5-year survival rate of 30%. Multivariate analysis revealed that stage, histology, and KPS were predictive of overall survival. In Stages III and IV, relapses were reduced by postoperative radiotherapy from 50% to 20%. The site of relapse was outside the irradiated area in 80% of patients. Disease free survival (P=0.36) and median survival (P=0.72) of patients with completely resected advanced thymomas did not differ from that for patients with incompletely resected tumors who received radiotherapy. CONCLUSIONS: Postoperative radiotherapy can improve local control in patients with advanced thymoma. Survival after incomplete resection is not compromised when postoperative radiotherapy is employed. KPS should be considered an important prognostic factor in future studies.     

Pelvic recurrence of cervical cancer: the prognostic relationship to the retreatment modalities

OBJECTIVE: To investigate the prognostic factors in relation to retreatment modalities in patients with recurrent cervical carcinoma. METHODS: According to initial therapy, 194 patients with recurrence were grouped as: (1) surgery, 22 cases; (2) surgery and radiotherapy, 24 cases, and (3) radiotherapy alone, 148 cases. Factors such as clinical stage, sites of recurrence, time of diagnosis of recurrence after initial therapy and modalities of retreatment were analyzed. RESULTS: There were 19 cases alloted to stage I, 51 cases to stage II (IIa 23 and IIb 28) and 124 cases to stage III (IIIa 21 and IIIb 103); histopathologically confirmed squamous cell carcinoma in 181 cases and adenocarcinoma 13 cases. Central recurrences were found in 91 cases and lateral or pelvic recurrences in 103 cases. Time of diagnosis of recurrence within 2 years from initial treatments was shown in 118 patients and above 2 years in 76 patients. In 147 of the 194 patients retreated, those of the group 1 obtained a median survival rate of 24 months, which was significantly longer than that of group 2, and group 3. The sites of recurrence did not significantly affect the survival. CONCLUSION: Radiotherapy remains the treatment of choice for patients with pelvic recurrence after surgery. Previously irradiated patients retreated for recurrence by radiotherapy and (or) chemotherapy had lower response rates. The optimal therapy for these patients should be comprehensive managements including surgery, radiotherapy and chemotherapy.     

Effect of prostaglandin A1 on proliferation and telomerase activity of human melanoma cells in vitro

BACKGROUND AND OBJECTIVE: Idarubicin, an anthracycline analogue, is active in non-Hodgkin's lymphoma. This study evaluates the efficacy and toxicity of a combination of idarubicin, etoposide and intermediate-dose cytarabine (IVA) in unfavorable lymphoma in relapse or resistant to prior doxorubicin- or novantrone-based regimens. DESIGN AND METHODS: Thirty patients with relapsing or resistant unfavorable lymphoma received a combination of idarubicin 12 mg/m2 i.v. on day 1, etoposide 60 mg/m2 i.v. every 12 hours for 3 days, and Ara-C 1 g/m2 i.v. every 12 hours for 3 days (3-hour infusion). Median age was 39 years (range: 22-60). All patients had been given prior doxorubicin or novantrone; 54% of them had received 2 or more chemotherapy regimens; 67% of total were in clinical relapse (30% in their second relapse), and 23% had resistant disease. RESULTS: The overall response rate to IVA was 60% (18 of 30 patients). Complete remission rate was 20% (6 of 30) in the whole group, 45% (5 of 11) among patients in their first relapse. Remission median duration was 9 months (range: 1-18), with a 3-year relapse-free and overall survival of 20% and 15%, respectively. Severe neutropenia occurred in 13 patients (43%) and severe thrombocytopenia in 11 patients (37%), with a median duration of 9 and 13 days, respectively. No cardiac toxicity developed; sepsis during neutropenia was documented in four instances and two patients (7%) died of therapy-related events (septic shock). INTERPRETATION AND CONCLUSIONS: Idarubicin combined with etoposide and intermediate-dose cytarabine proved to be an active salvage therapy in unfavorable lymphoma given prior doxorubicin or novantrone; the best results were obtained among patients in their first relapse, with low tumor burden.     

Initial relapses in previously treated Hodgkin's disease. I. Results of second treatment

Two hundred forty-three consecutive patients with Hodgkin's disease who relapsed after an initial course of treatment at the Stanford University Division of Radiation Therapy underwent subsequent systematic evaluation and retreatment. An analysis of the influence of numerous parameters, including sex, histopathology, original stage, relapse site, and original and second therapy, on actuarial survival and on relapse-free survival was undertaken. Most relapses (87%) occurred within 3 years of the initial treatment course. The 5-year relapse-free survival measured from the time of second treatment increased from 14% before to 39% after the introduction of multiple agent chemotherapy (MOPP) for relapsing disease. Patients treated with MOPP chemotherapy for nodal relapses showed increased subsequent relapse-free survival (61%) when compared with patients treated only with radiotherapy for nodal relapses. Based on the combined findings of this analysis, recommendations are made regarding the management of patients with Hodgkin's disease who have suffered a relapse.     

Radiotherapy in Ewing's sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92

PURPOSE: Treatment results and the pattern of relapse were evaluated in the multimodal treatment of Ewing's sarcomas of the chest wall. METHODS AND MATERIALS: In a retrospective analysis, 114 patients with non-metastatic Ewing's sarcoma of the chest wall were evaluated. They were treated in the CESS 81, CESS 86, or EICESS 92 studies between January 1981 and December 1993. The treatment consisted of polychemotherapy (VACA, VAIA, or EVAIA) and local therapy, either surgery alone (14 patients), radiotherapy alone (28 patients) or a combination of both (71 patients). The median follow-up was 46.6 months (range 5-170). A relapse analysis for all patients with local or combined relapses was performed. RESULTS: Overall survival was 60% after 5 years, event-free survival was 50%. Thirty-seven patients had a systemic relapse (32.4%), 11 patients had a local relapse alone (9.6%), and 3 patients had a combined local and systemic relapse (2.6%). The risk to relapse locally after 5 years was 0% after surgery alone, 19% after radiation alone, and 19% after postoperative irradiation. None of the 8 patients with preoperative irradiation have failed locally so far. With the introduction of central radiotherapy planning in CESS 86, local control of irradiated patients improved. Ten of 14 patients with local failure could be evaluated in the relapse analysis: 3 patients had an in-field relapse, 4 patients had a marginal relapse, 2 patients had a relapse outside the radiation fields, and 1 patient failed with pleural dissemination. Six treatment deviations were observed. CONCLUSION: Local control was best after surgery alone in a positively selected group of patients. Local control after radiation or combined radiation and surgery was good. With diligent performance of radiotherapy, it will be possible to further improve the results in the radiotherapy group.     

Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma

BACKGROUND: Controversy exists as to the treatment regimen necessary to best provide optimal local control for inflammatory breast carcinoma (IBC). This study was conducted to determine if mastectomy combined with radiotherapy offered any advantages over radiotherapy alone in patients with IBC who had been treated with doxorubicin-based combination chemotherapy. METHODS: A retrospective review of 178 women treated for IBC on doxorubicin-based multimodality therapy protocols between January 1974 and September 1993 was performed. Clinical and histologic response to treatment, time to local recurrence, survival, and ultimate control of local disease were analyzed. Kaplan-Meier analysis was used to examine survival and relapse times, and Fisher's exact test was used to test differences in treatment outcomes. Significance was determined at p < or = 0.05. RESULTS: Median follow-up was 89 months (range 22 to 223 months). Locoregional disease persisted in seven patients and recurred in 44 patients who had been rendered disease free at a median time of 10 months. The mortality rate after a local recurrence (LR) was 98%, and all patients but one with LR developed systemic metastases. Response to induction chemotherapy influenced the incidence of LR, and the amount of residual disease found on histologic examination of mastectomy specimens was highly prognostic for local failure. Patients who underwent mastectomy in addition to radiotherapy had a lower incidence of LR than did patients who received radiotherapy alone (16.3% vs. 35.7%, p = 0.015). CONCLUSIONS: The addition of mastectomy to combination chemotherapy plus radiotherapy improved local control in patients with IBC. The addition of mastectomy to chemotherapy plus radiotherapy improved distant disease-free and overall survival in patients with a clinical complete or partial response to induction chemotherapy. Patients who had no significant response to induction chemotherapy received no survival or local disease-control benefit from the addition of mastectomy to their treatment regimen. These patients should be considered for entry into clinical trials of new treatment regimens.     

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma

BACKGROUND: Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery. METHODS: Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. RESULTS: Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases, as compared with 45 of the 55 patients (82 percent) who underwent surgery alone (P<0.001). Thirteen of the 52 patients (25 percent) who underwent surgery after multimodal therapy had complete responses as determined pathologically. The median survival of patients assigned to multimodal therapy was 16 months, as compared with 11 months for those assigned to surgery alone (P=0.01). At one, two, and three years, 52, 37, and 32 percent, respectively, of patients assigned to multimodal therapy were alive, as compared with 44, 26, and 6 percent of those assigned to surgery, with the survival advantage favoring multimodal therapy reaching significance at three years (P=0.01). CONCLUSIONS: Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus.     

Hemodynamic response to oxygen administration in chronic heart failure: role of chemoreflexes

OBJECTIVE: To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. RESULTS: Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. CONCLUSION: Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.     

Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases. The FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer

PURPOSE: Thymoma is a rare disease. The treatment of patients with invasive thymoma remains controversial. The prognosis of such patients is poor, even with the use of postoperative radiation therapy and chemotherapy. We retrospectively reviewed the outcome and prognostic factors in a series of 90 patients presenting with an invasive thymoma treated by partial resection or biopsy and radiation therapy. METHODS AND MATERIALS: From 1979-1990, 163 patients with the diagnosis of lymphoepithelial thymoma were treated in 10 French cancer centers. Patients were staged using the postoperative "GETT" classification derived from that of Masaoka. Ninety patients who presented with an invasive thymoma, 58 Stage III (21 IIIA: partial resection and 37 IIIB: biopsy) and 32 Stage IVA (intrathoracic thymoma spread), are the subject of this report. Treatment combined surgery and radiation therapy (+/- chemotherapy), with curative intent. Surgery consisted of partial resection in 31 patients (21 Stage III), and biopsy in 55 patients (37 Stage III). The median radiation dose to the tumor was 50 Gy (30-70 Gy). Supraclavicular radiation was performed in 59 patients (median dose 40 Gy). Chemotherapy, combined with radiation in 59 patients, consisted of multidrug regimens, mainly platinum based. RESULTS: The median follow-up is 105 months (20-165 months). The 5- and 10-year overall survival rates are 51 and 39%, respectively. There is a great impact of the extent of surgery on survival: the 5- and 10-year survival rates were 64% and 43%, respectively, after partial resection, compared to 39% and 31% after biopsy (p < 0.02). Local control at 8.5 years was obtained in 59 of 90 patients (66%): 40 Stage III, 19 Stage IVA. There is a significant relationship between the extent of surgery and the local control (16% of relapse after partial resection vs. 45% after biopsy, p < 0.05). Seven patients developed significant (grades 3-4 WHO grading system) treatment-induced side effects. Stage, histologic type, and chemotherapy were not prognostic factors. CONCLUSION: In this large multicentric retrospective study of invasive thymomas (Stage III-IVA) treated by surgery and radiation, results show the importance of loco-regional treatments, such as surgery and radiation therapy. There is also a great impact of radiation on local control. However, the rate of local recurrence (34%) justifies recommending a higher dose of radiation (> 50 Gy) than doses used in this study, for incompletely resected patients. The role of chemotherapy needs to be further assessed.     

Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the     

Pre-operative chemotherapy and radiotherapy in breast cancer

Primary systemic treatment of breast cancer with cytotoxics yields a high response rate and allows conservative surgical procedures in bulky tumours. In order to maximise local control of disease, two innovations were introduced in a pilot study. The first was to identify the good responders after three cycles of chemotherapy and to treat them with three additional cycles. The second was to also give this group of patients a full dose of radiotherapy before surgery with the aim of verifying the rate of pathological complete remissions in view of a possible treatment of breast primary with chemoradiotherapy only. Patients were treated with doxorubicin 60 mg/m2 and cyclophosphamide, 600 mg/m2 both intravenously on day 1, every 21 days for three courses. Partial or complete responders received three more courses followed by radiotherapy (50 Gy plus a 10 Gy boost). The others underwent immediate surgery. A total of 32 patients (median age, 50 years; range 28-69 years); performance status, 0-1; T2 22, T3 8, T4 2) were enrolled and were evaluable for response and side-effects. 9 patients had only three cycles of chemotherapy due to absence of response and 23 patients had six cycles of chemotherapy. Overall, 7 patients had a complete remission, 16 a partial remission and 9 had stable disease, for an overall response rate of 72% (95% confidence interval 53-86%). In the group of patients that completed the programme, two complete pathological remissions were observed and 5 patients had only microfoci of tumour. No toxic death or grade III-IV toxicities were observed. Mild or moderate side-effects included mucositis, nausea/vomiting and leucopenia. In conclusion, our results indicate that the addition of radiotherapy to pre-operative chemotherapy did not significantly enhance the incidence of pathological complete remissions. New primary treatment approaches should be explored in this subset of patients in order to improve outcome.