Therapeutic implications of mediastinal involvement in advanced Hodgkin's disease

47 patients with advanced Hodgkin's disease (stage IIIB or IV) and mediastinal involvement, treated during the period 1969-78 and followed till death or from 36 to 126 months after initiation of therapy, were analysed. All 47 patients had received combination chemotherapy (MOPP or equivalent regimens). 20 had also received additional radiotherapy to mediastinum (and in some cases to other involved areas as well). The 2 treatment groups did not differ significantly with regard to the more important prognostic factors. Both in the case of stages IV and IIIB patients in the group treated with combination chemotherapy alone, remissions were significantly more often only partial, the frequency of relapse and of treatment failure was significantly higher, and relapse-free survival was significantly poorer than in the group treated with additional radiotherapy. Furthermore, survival from Hodgkin's disease and crude survival including all causes of death were significantly better for patients treated with combination chemotherapy plus mediastinal irradiation. Consequently, for patients with advanced Hodgkin's disease and mediastinal involvement a combined approach including radiotherapy as well as combination chemotherapy would seem advisable.     

Prognostic factors in Hodgkin's disease stage III with special reference to tumour burden

143 patients with Hodgkin's disease stage III (65 PS III, 78 CS III) were treated with radiotherapy alone (33 patients), combination chemotherapy alone (56 patients), or radiotherapy plus combination chemotherapy (54 patients). They were followed till death or from 7 to 191 months. Prognostic factors including treatment, peripheral + intrathoracic tumour burden (assessed by combining tumour size in each involved region with number of involved regions), intraabdominal tumour burden (assessed by combining size of lymphographically involved lymph nodes in each region with number of lymphographically involved regions), histologic subtype, B-symptoms, number of involved regions, mediastinal involvement, pretreatment ESR, sex, age, laparotomy, and substage were examined in multivariate analysis. With regard to disease-free survival, total tumour burden (intraabdominal and peripheral + intrathoracic) emerged as the only pre-treatment factor of independent prognostic significance. With regard to overall survival the only factor of independent significance apart from age turned out to be intraabdominal tumour burden. The results of the present study thus support recently published findings regarding early stage disease to the effect that tumour burden is the single most important prognostic factor in Hodgkin's disease.     

Prognostic factors in Hodgkin's disease stage IV

104 patients with previously untreated Hodgkin's disease stage IV were examined and treated at the Finsen Institute between 1969 and 1983. 99 patients were treated with combination chemotherapy (MOPP or equivalent regiments) with or without additional irradiation of some involved areas. Prognostic factors including age, sex, peripheral plus intrathoracic nodal tumour burden, intraabdominal nodal tumour burden, B-symptoms, histologic subtype, number of involved nodal regions, mediastinal involvement, number of involved extranodal sites, type of extranodal involvement, ESR, and haematologic and other blood values, together with exploratory laparotomy and treatment were examined in multivariate analyses. With regard to disease-free survival, the only factors of independent prognostic significance were sex and lymphocytopenia. With regard to overall survival the factors of independent significance were age, sex, bone marrow involvement, and an elevated serum creatinine. If only deaths of Hodgkin's disease were considered in overall survival, both lymphocytopenia and bone marrow involvement had independent prognostic significance. These two factors thus emerged as the most important prognostic factors in disseminated Hodgkin's disease, and both would appear to be related to the patient's total tumour burden.     

Mantle Field Irradiation for Stages IA and IIA Hodgkin's Disease

Between 1970 and 1975, 73 patients with surgically staged IA and IIA Hodgkin's disease, localized above the diaphragm, were treated with mantle field irradiation only. 24 patients relapsed during the first 5 years after the primary treatment, but 14 of them obtained long-lasting complete remission after retreatment. 23 patients with lymphocyte-depleted histology, more than 3 sites involved or a mediastinal mass of more than 6 cm had a high relapse rate (60%); these patients need treatment additional to the mantle field irradiation. The other 50 patients had an 80% relapse-free survival, 96% complete remission after treatment of the first relapse, and 98 % survival after 8 years. We propose that such patients should receive mantle field irradiation only, as the primary treatment.     

Initial chemotherapy for clinically localized lymphomas of unfavorable histology

Forty-five patients with localized non-Hodgkin's lymphoma of unfavorable histologic type (41 patients had diffuse histiocytic, 2 had nodular mixed, and 2 had minimally nodular histiocytic lymphoma) were treated with initial chemotherapy (28 patients), including cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP), or with initial CHOP followed by involved field radiotherapy (17 patients). Patients were clinically staged and found to have stage I (7 patients), stage IE (8), stage II (12), and stage IIE (18). Despite the presence of potentially adverse prognostic factors, including age older than 65 yr (11 patients), bulky disease (17), gastrointestinal involvement (9), and "B" symptoms (4), 44 of 45 patients (98%) achieved a complete response. Forty-two patients (93%) are alive with a median follow-up time of 41 mo (range 3-128 mo). Thirty-eight patients (84%) remain continuously free of disease. Neither the pretreatment clinical features nor the type of treatment significantly influenced the outcome for patients treated with initial chemotherapy. Patients who failed treatment relapsed at distant sites or in initially involved sites whether or not they received radiotherapy. Initial treatment for localized lymphomas of unfavorable histology with chemotherapy regimens of proven curative potential in advanced disease is a successful treatment strategy and obviates the need for extensive staging. The role of involved field radiotherapy following initial chemotherapy needs to be defined.     

Combination chemotherapy followed by radiation therapy in patients with regional stage III unresectable non-small cell lung cancer

A chemotherapy combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was administered to 30 patients with stage III M0 or M1 (supraclavicular nodes) unresectable non-small cell lung cancer before and after radiotherapy. All patients had mediastinal metastases and most had T2 or T3 primary lesions. The response rate (complete plus partial) after two cycles of CAP was 47%, which increased to 66% (24% complete response rate) following radiotherapy. The overall median survival from initiation of chemotherapy was 9 months. CNS relapse occurred in five (26%) of 19 responding patients who did not receive prophylactic cranial irradiation in the early part of the study.     

Sternberg's Lymphoma: Effect of Treatment Regimen upon Prognosis in 38 Cases

Thirty-eight cases of diffuse poorly differentiated lymphoma with an anterior mediastinal mass were reviewed. Nine patients had stage I disease, 11 stage 11, one stage 111 and 17 stage IV. Survival was prolonged in those stage III and IV cases whose treatment had commenced with chemotherapy rather than with radiotherapy. Survival and relapse-free interval were prolonged in all cases when chemotherapy had begun within a week of diagnosis and had continued with intervals of not more than 21 d between courses.
Although patients whose chemotherapy had been delayed while radiotherapy was given fared worse overall, the incidence of mediastinal relapse was significantly increased when Mediastinal irradiation had been omitted altogether or had been given in fractions of less than 100 rads. Prophylactic cranial irradiation and intrathecal Chemotherapy reduced the incidence of CNS involvement in all stages of the disease. Testicular involvement occurred in three patients, two of them detected only at post-mortem, and occult ovarian involvement was also found in two post-mortems.
Therapeutic principles are proposed including immediate systemic chemotherapy followed by mediastinal irradiation and CNS prophylaxis as soon as practicable after chemotherapy is begun and, later, testicular biopsy, or CT scan or ultrasound assessment of pelvic organs.     

Effect of prior radiotherapy on tolerance and response to chemotherapy in non-hodgkin's lymphoma

Twenty-five patients who had received radiotherapy as their primary treatment for non-Hodgkin's lymphoma subsequently relapsed; they were then treated with combination chemotherapy and their tolerance and response evaluated. Radiotherapy delivered as total body irradiation and other forms of radiotherapy delivered to > 15% of the bone marrow caused significantly lower platelet nadirs during subsequent chemotherapy when compared to patients receiving radiotherapy to ≤ 15% of their bone marrow. In spite of this thrombocytopenic effect, the eventual total doses of chemotherapy delivered were not significantly compromised. A response to chemotherapy was more likely in patients with a prolonged (> 6 months) response to radiotherapy. However, a chemotherapy response was equally likely in patients receiving involved field (IF), extended field (EF), or total nodal irradiation (TNI) as compared to those receiving total body irradiation (TBI). Chemotherapy responses (complete and partial) occurred in 75% of both radiotherapy groups with complete responses more likely in the IF, EF, or TNI group. The median durations of response were slightly longer in the IF, EF, or TNI radiotherapy group (6 months vs 5 months; p = 0.07) but were shorter than those in previously reported patients not receiving prior radiotherapy. Similarly the duration of a chemotherapy response was not affected by the histology of the tumor. However, although the survival of patients following chemotherapy was not significantly affected by the histology of the tumor there was a tendency towards a longer survival for lymphocytic histology as compared to histiocytic.     

Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a report from the United Kingdom's Children's Cancer and Leukaemia Study Group

There is a paucity of data on the treatment outcome in children with relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). This retrospective report evaluates the treatment outcome in a national cohort of children with relapsed or poorly responsive nLPHL. A total of 37 patients, 22 with relapsed and 15 with poorly responding disease, are the subjects of this report. Of the 22 patients with relapsed nLPHL, 11 had relapsed after primary excision biopsy, 10 after chemotherapy and 1 after chemotherapy and involved field radiotherapy. The majority had localized disease at relapse. The median time to relapse was 8 months after chemotherapy and 11 months after excision biopsy. Seven of the 15 patients with poorly responding nLPHL had variant histology. Three patients with initial poor response did not receive any further treatment and have had no disease progression. Transformation to diffuse large B cell lymphoma, in addition to evolution from typical to variant nLPHL occurred in one patient each. Thirty‐four patients have been successfully re‐treated with second chemotherapy or radiotherapy. Multiple relapses were uncommon but treatable. Relapse or poorly responsive nLPHL is fully salvageable with either additional chemotherapy and or radiotherapy.     

Critical value of laparotomy with splenectomy in stage III Hodgkin's disease as restaging procedure after chemotherapy

38 patients with stage III Hodgkin's disease underwent laparotomy with splenectomy as restaging procedure after first line chemotherapy which included MOPP, ABVD, or both. 28 patients were judged to be in clinical complete remission (CR) and 10 were resistant or had relapsed. Among patients in CR, 27 (96%) were confirmed to be in pathological CR; among patients resistant or relapsed, 9 (90%) were confirmed to have disease in the abdomen or retroperitoneum. The therapy for patients in clinical remission before laparotomy consisted of TNI or sTNI in 19 patients, mediastinal radiation in 6 patients and no further therapy in the remaining 3 patients. No significant differences were seen in survival and relapse-free survival between those patients treated by extensive and those treated by local radiotherapy or no further therapy. Instead, among those patients who received extensive radiotherapy 3 developed acute non-lymphoid leukemia (ANLL). The therapy for this group of patients consisted of further chemotherapy in 7 who had concomitant liver involvement and TNI in the remaining 3 who had the disease confined to the spleen and/or lymph nodes. Among these patients, only 3 obtained CR; 2 with radiation and 1 who was resistant to MOPP, with ABVD. This study leads us to re-consider the role of laparotomy in stage III HD which should be used as non-routine procedure only in selected patients without poor prognostic factors who may be cured by radiotherapy alone. In patients resistant to chemotherapy, an early evaluation of disease in the abdomen may be useful for a better salvage treatment.     

Isolated primary oesophageal involvement by lymphoma: a rare cause of dysphagia: two case histories and a review of other published data.

Primary oesophageal involvement by lymphoma in two patients, one with Hodgkin's disease and one with non-Hodgkin's lymphoma is reported. In both, there were no manifestations of the disease outside the oesophagus, which is exceptionally rare. In the patient with non-Hodgkin's lymphoma, the oesophageal tumour was the first manifestation of lymphoma. Shortly after admission he developed a tracheo-oesophageal fistula from which he died before treatment could be started. In the patient with Hodgkin's disease, isolated oesophageal lymphoma was the first relapse after a 13 year interval free of disease. As he had previously received mediastinal irradiation he was treated with combination chemotherapy that resulted in long term survival (> five years). Several other long term survivors have been described but only after radiotherapy or surgery. These findings suggest that systemic chemotherapy may be equally successful in treating isolated primary oesophageal lymphoma, thus offering an alternative for those patients in whom local treatment is contraindicated.     

A novel treatment of childhood lymphoblastic non-Hodgkin's lymphoma: early and intermittent use of teniposide plus cytarabine

We treated 24 children and adolescents with stage III or IV lymphoblastic non-Hodgkin's lymphoma, using a protocol designed for patients with poor-prognosis acute lymphoblastic leukemia (ALL). Early therapy consisted of teniposide plus cytarabine administered before and immediately after prednisone, vincristine, and asparaginase. The two- drug combination was also given intermittently with continuous 6- mercaptopurine and methotrexate during the first year of continuation chemotherapy. Periodic intrathecal methotrexate and delayed cranial irradiation were used to prevent central nervous system involvement. Anthracycline compounds, alkylating agents, high-dose methotrexate, and involved-field irradiation were not used in any phase of treatment. Twenty-two (96%) of the 23 evaluable patients achieved complete remission. With a median follow-up of 2 1/2 years, only four patients have relapsed; the remainder have been disease-free for eight months to more than five years. The projected four-year continuous complete remission rate is 73% for all patients and 79% for the 19 with mediastinal involvement at diagnosis. These results demonstrate that use of teniposide plus cytarabine with an otherwise conventional plan of ALL therapy is an effective approach to the treatment of childhood lymphoblastic lymphoma.     

Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients.

To evaluate the efficacy of a combined modality treatment (MACOP-B plus mediastinal radiotherapy) and the advantages of Gallium-67-citrate single-photon emission ((67)GaSPECT) over computed tomography (CT) for restaging in patients with primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis. Between 1989 and 1998, 50 previously untreated patients with PMLBCL with sclerosis (70% with bulky mass) were treated with MACOP-B regimen plus mediastinal radiotherapy. The radiologic clinical stage with evaluation of tumor size included CT and (67)GaSPECT at diagnosis, after chemotherapy, and after radiotherapy. Forty-three patients (86%) achieved a complete response and 7 were nonresponders to treatment. For the imaging evaluation, only 47 patients were evaluable because 3 had disease progression during chemotherapy. After treatment, 3/5 (60%) patients with positive (67)GaSPECT and negative CT scan relapsed, as against 0/21 (0%) with negative (67)GaSPECT and CT scan. Twenty-one patients had a positive CT scan: of these, the 4 with positive (67)GaSPECT all progressed, whereas there were no relapses among the 17 with negative (67)GaSPECT. After radiotherapy, there was a decrease of positive CT (from 33 to 21 cases) and of positive (67)GaSPECT (from 31 to 9 cases). Relapse-free survival rate was 93% at 96 months (median 39 months). In patients with PMLBCL with sclerosis, MACOP-B plus radiation therapy is a very useful first-line treatment and radiation therapy may play an important role. As regards restaging, (67)GaSPECT should be considered the imaging technique of choice at least in patients who show CT positivity.     

Persistent mediastinal mass is not indicative of recurrence after chemotherapy only in paediatric Hodgkin's disease

Most patients with Hodgkin's disease are treated with chemotherapy in conjunction with radiotherapy, but at the end of treatment a residual mass is often present. After combined therapy, it has been assumed that no additional treatment is needed. However, for children treated without radiotherapy, no data exist on the relevance of a residual mediastinal mass to risk of relapse. We report on the findings of follow-up thorax radiographs of a group of 27 children with initial mediastinal involvement, who were treated with chemotherapy only. We conclude that the regression rate of the mediastinal mass was not related to a later recurrence. Regression after chemotherapy without radiotherapy is probably slower than after combined therapy. We consider chest radiograph examinations to be appropriate for the follow-up of tumour regression. When the data were compared with a group of children with Hodgkin's disease without mediastinal involvement, we found that survival was not related to initial mediastinal involvement.     

Surgery of microcellular bronchial cancer: retrospective multicenter study apropos of 110 cases

The results of a multicentric retrospective study of 110 cases of small cell bronchial cancer are reported. In 57 of these patients the histological diagnosis was unknown before surgery. Among the remaining 53 patients, 22 were operated upon immediately and 31 after chemo-and/or radiotherapy (12 full responders, 10 partial responders, 5 no change and 4 in relapse). Operative data were as follows: 100 excisions and 10 exploratory thoracotomies; 19 perioperative complications, including 12 deaths; excision considered complete in 78 cases; pericardial involvement in 14 cases; invasion of the hilar lymph nodes in 57 cases, of the mediastinal lymph nodes in 39 cases; positive bronchial section in 16 cases. Overall median survival was 13.8 months for all patients and 18.3 months (perioperative deaths excluded) for patients whose tumour had been excised. At the moment, 46 patients have relapsed with recurrence at the initial site of malignancy alone in 6 cases (13%) and both at this site and at one or several metastatic sites in 10 cases (21.7%). Nineteen patients have survived for more than 2 years. An analysis of the subgroups in this population showed that the longest survivals were obtained in patients who had undergone preoperative chemotherapy.     

Complete remissions in metastatic breast cancer treated with combination drug therapy

One hundred sixteen patients with metastatic breast cancer who achieved complete remission with combination chemotherapy were analyzed to ascertain the factors that affect the duration of complete remission and the patterns of relapse. The median duration of complete remission was 17 months. Disease recurred in 81 patients (70%) at periods ranging from 3 to 44 months after achievement of complete remission. The duration of complete remission was inversely related to the bulk of metastatic tumor. Twenty-three patients treated with combined oophorectomy and chemotherapy experienced the longest remissions (median duration of 33 months); only eight (35%) of them have relapsed. Seventy-six percent of the relapses occurred in previously known sites of tumor involvement; most of the remainder involved the brain. The short duration of complete remissions and tendency to relapse in sites of initial involvement suggest that patients with metastatic breast cancer who achieved complete remission with combination chemotherapy still had substantial residual tumor. Consolidation treatments, using hormonal therapy and non-cross-resistant chemotherapy along with irradiation to initial sites of metastases, whould be investigated to ascertain their usefulness in prolonging the remissions.     

Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma

Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well-established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here 15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post-ASCT and 1/16 post-alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD-chemotherapy and local radiotherapy followed by a mini-allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12-20 months post-plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub-clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.     

Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal irradiation and stem cell transplantation for adult patients with lymphoblastic lymphoma

The therapeutic role of mediastinal radiotherapy and stem cell transplantation (SCT) in lymphoblastic lymphoma (LL) remains controversial. In a risk-oriented design, we adopted a flexible treatment program in which (1) patients with persistent mediastinal abnormality, evaluated by post-induction computed chest tomography, received mediastinal irradiation; and (2) those with persistence of minimal residual disease (MRD), evaluated by MRD analysis of the bone marrow, underwent SCT. Twenty-eight out of 30 patients (T-lineage, n?=?24; B-lineage, n?=?6) achieved a complete response. Of 21 patients with mediastinal mass, 13 (62%) achieved a complete response after chemotherapy alone, while 6 (28.5%) required additional irradiation. Eleven patients were evaluated for MRD: 6 were negative and 5 positive. On the basis of MRD findings and clinical risk characteristics, 14 patients underwent SCT, 13 received maintenance chemotherapy, and 1 had local radiotherapy. Five patients relapsed. Among the 14 non-irradiated patients with T-LL, the mediastinal recurrence rate was only 7%. After a median follow-up of 3.9?years, 21 patients who responded were alive without recurrence (75%). The projected 5-year survival, disease-free survival, and relapse rate were 72%, 77%, and 18%, respectively. This program induced high remission and survival rates, indicating the feasibility and the benefits potentially associated with a selective, response-oriented policy of mediastinal irradiation and a concurrent MRD-based strategy to assign adult LL patients to SCT.     

3种不同化疗方案治疗套细胞淋巴瘤的疗效分析

目的:探讨3种不同化疗方案治疗套细胞淋巴瘤(MCL)的临床效果.方法:19例确诊MCL患者,分别用3种不同的方案治疗.CHOP方案:初治患者13例,复发患者9例;单用福达拉宾4例,均为初治患者;美罗华加福达拉宾加环磷酰胺加米托蒽醌(R-FCM)方案治疗4例,均为复发患者.结果:CHOP方案:初治患者中政11例(84.6%)例有效,复发患者中1/9(11.1%)例有效;单用福达拉宾:4例均为初治患者,3例CR 1例PR(75.0%)有效;R-FCM方案:4例均为复发的患者4/4(100%)例.结论:以CHOP为基础方案和单用福达拉宾对于初治的MCL均有较好的疗效,但是生存时间短,复发的患者单纯化疗效果不理想,加用美罗华可以明显提高治疗效果.     

Impact of tumor control and presence of visible necrosis in head and neck cancer patients treated with radiotherapy or radiochemotherapy

Purpose: Tumor volume after the lymph node involvement is one of the most important single prognostic factor in patients of head and neck cancers treated with radiotherapy. We have recently demonstrated that the hypoxic subvolume is more important than the total tumor volume. We therefore propose the hypothesis that the presence of visible necrosis might be an important factor for cure by radiotherapy in squamous cell cancers of the head and neck. Methods: A total of 51 patients with locally advanced inoperable (T3-4 or N2-3) squamous cell cancers of the head and neck (mean age 57 years, range 41–75 years) were prospectively investigated with regard to a possible impact of tumor volume. All patients received CT examination of the head and neck according to a standardized protocol (spiral CT, contrast enhancement after automatic injection), and the total tumor volume was calculated as the sum of volumes of all visible macroscopic tumor sites. Poorly perfused and necrotic areas (no contrast enhancement) within macroscopic tumor sites were also calculated. Patients were then treated with accelerated-hyperfractionated radiotherapy in about 6 weeks. Seventeen patients were treated with only radiation. Patients without contraindications to cisplatin chemotherapy received cisplatin chemotherapy or a combination of cisplatin and paclitaxel (N=34). The allocation of patients to certain treatment regimens was based on individual decisions in each case and not randomized. Results: In patients treated with radiation alone, 12/17 (71%) got recurrence whereas in patients treated with radiation plus cisplatin, only 14/34 (41%) recurred (P=0.05). The 2-year overall survival was for radiation alone versus radiation plus cisplatin 0% vs. 62% (P<0.0008). Tumors with smaller amount of necrosis (necrosis volume<4 cm³) had a good prognosis irrespective of type of treatment (radiation alone or radiation plus cisplatin). However, patients with tumors with a larger amount of necrosis (necrosis volume≥4 cm³) had a significantly better outcome if they were treated with radiation plus cisplatin as compared to patients treated with radiation alone. In a multi-variate analysis using a Cox-regression model the type of treatment (radiotherapy plus versus without cisplatin) was the only independent prognostic factor for event-free survival (P<0.03) in the whole group. Conclusions: In this non-randomized retrospective investigation with limited sample size, radiation plus cisplatin was superior to radiation alone. This resulted mainly from a higher efficacy of the radiochemotherapy regimen in patients with large and especially necrotic tumors. The prognostic and predictive impact of visible necrosis should be further evaluated.