The management of metastatic spinal cord compression: a radiotherapeutic success ceiling.

PURPOSE: In assessing the effectiveness of the management of metastatic spinal cord or cauda equina compression, we performed a retrospective analysis of 70 patients with this complication whom we treated from 1985 to 1989. METHODS AND MATERIALS: The most frequent primary diagnoses in our series were carcinomas of unknown origin and of the breast, lymphoproliferative disease, lung cancer, and prostatic carcinoma. We used the Findlay classification to group all patients according to their pre-therapeutic functional motor status as Grade I (24 patients or 34%), Grade II (27, or 39%) or Grade III (19 or 27%). Treatment consisted of 30-45 Gy of irradiation (using two different schedules) together with high-dose dexamethasone; in only five cases was there surgical intervention. RESULTS: We found that a powerful predictor of response to radiotherapy was the patient's neurologic status (Findlay grade) at the time of diagnosis: 66% of previously ambulatory patients remained so, whereas 30% of non-ambulatory patients and only 16% of paraplegic patients regained the ability to walk. Another important predictor of response was primary tumor histology, with the most favorable responses to radiation therapy having been observed in lymphoproliferative diseases and in breast cancer, but with some response in other radiosensitive malignancies as well. CONCLUSION: The similarity of our results to those of other centers leads us to conclude that a radiotherapeutic success ceiling of 80% may have been reached for Findlay Grade I patients with metastatic spinal cord compression. In view of this, we suggest that future therapeutic endeavour would be best directed toward early diagnosis of the condition.

Early detection of lymphoma recurrence with gallium-67 scintigraphy.

Early detection of tumor relapse in lymphoma patients is often a difficult diagnostic problem. CT, which detects a mass, often cannot differentiate between fibrosis or relapsed tumor. For this reason, we have studied the value of 67Ga scintigraphy in the diagnosis of tumor recurrence. The sensitivity of 67Ga scintigraphy in the detection of lymphoma recurrence was studied at an average interval of 8.7 mo following treatment in 32 patients who developed recurrent lymphoma. Its specificity was studied in 36 patients with no recurrence who were in continuous clinical remission. At the time of appearance of relapse, the sensitivity of whole-body 67Ga imaging was 95% and the specificity 89%. In 12 events of recurrence in 10 patients, 67Ga scintigraphy was abnormal at sites that later proved to be regions of relapse. In these patients, scintigraphy demonstrated recurrence an average of 6.8 mo before the appearance of clinical symptoms, findings on clinical examination or abnormality on CT or chest x-rays. Gallium-67 scintigraphy, which permits screening of the whole body for recurrence in a single study, was of particular value in evaluating lymphoma recurrence, since 27% of the recurrences were located exclusively in sites different from the original sites of disease. Gallium-67 scintigraphy appears to be a sensitive and specific test for restaging patients with lymphoma recurrence.

Severe giardiasis in two patients undergoing bone marrow transplantation.

Two patients undergoing bone marrow transplantation developed severe gastrointestinal symptoms, one during the peri-transplantation period and the other several months post-transplantation and following documented intestinal graft-versus-host disease. After detection of Giardia lamblia trophozoites in a stool specimen from one patient and a duodenal aspirate from the other, treatment with metronidazole was administered and all symptoms resolved. Giardiasis should be considered in transplant patients with diarrhea. Negative stool examinations do not rule out this possibility, and consideration should be given to examining a sample of small intestinal contents for Giardia trophozoites.

Prolonged daily administration of oral etoposide in lymphoma following prior therapy with adriamycin, an ifosfamide-containing salvage combination, and intravenous etoposide.

Prolonged daily administration of oral etoposide has been reported to be active in refractory lymphoma. The purpose of this phase II trial was to confirm the activity of this schedule of etoposide in a selected group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 26 patients (20 with NHL and 6 with HD) were entered in the trial; all had previously been treated with an Adriamycin-based chemotherapy, an ifosfamide-containing salvage combination, and i.v. etoposide. Etoposide was given in a fixed oral daily dose of 100 mg over 3 weeks; the weekly dose (500-700 mg) was selected such that the average daily dose was approximately 50 mg/m2. Cycles were repeated on day 29. An objective response was seen in 16 patients (62%; 95% confidence interval, 42%-80%), with a complete response (CR) being observed in 3 cases (12%) and a partial response (PR), in 13 (50%). The median duration of PRs was 3 months. CRs lasted for 15 months in one patient and continue at 12+ and 20+ months in the remaining two patients. The overall actuarial survival for the entire group was 40% at 2 years; the median survival time was 12 months. The main toxicity was myelosuppression; WHO grade 3 or 4 leukopenia and thrombocytopenia developed in 31% and 12% of the patients, respectively. There was no drug-related death. We conclude that oral etoposide is an effective and tolerable palliative treatment for heavily pretreated lymphoma patients.

Salvage therapy for non-Hodgkin's lymphoma with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin.

A total of 30 consecutive patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) were treated with a combination of dexamethasone, etoposide (VP-16), ifosfamide, and cisplatin (DVIP). In all, 9 subjects (30%) showed a partial response and 10 (33%) achieved a complete response (CR) lasting from 2.5 to 24+ months. Aggressive histology, no prior therapy with VP-16, a CR to previous chemotherapy, and a treatment-free interval of greater than 6 months prior to the present study were associated with the high CR rate. DVIP caused pronounced myelosuppression (median granulocyte nadir and median platelet nadir, 380/mm3 and 73.000/mm3, respectively), but no drug-related death occurred. We conclude that DVIP is an effective salvage combination, especially in aggressive NHL, that produces acceptable toxicity.

Intermediate and high-grade gastric non-Hodgkin's lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy.

The role of surgery as initial treatment in gastric lymphoma remains controversial. We have prospectively evaluated a stomach conservation strategy in histologically aggressive gastric lymphoma, using primary adriamycin-containing chemotherapy, followed by involved-field radiotherapy in patients with limited disease. Twenty-six patients (median age 69 years) were entered in this study; 15 had stage I disease, 7 had stage II disease and 4 had stage IV disease. The chemotherapy combinations were CHOP (18 patients) and ProMACE/MOPP (8 patients). Radiotherapy was given to 11 patients. Of the 24 patients evaluated for response, 18 (75%) achieved endoscopically-confirmed complete response and 4 (17%) partial response. During follow-up (median 22 months), none of the complete responders developed recurrent lymphoma. Gastric resection was performed in 1/26 patients who did not respond to primary chemotherapy. There were no cases of perforation, but three patients (12%) developed acute gastro-intestinal bleeding a few days after the onset of chemotherapy, one of whom required a surgical devascularization procedure. There was no treatment-related mortality. These data further support the non-surgical approach in histologically aggressive gastric lymphoma, using primary chemotherapy with or without radiation therapy.

Haptoglobin-related protein as a serum marker in malignant lymphoma.

A novel serum 21 kDa haptoglobin-related protein (Hpr) was investigated in patients with malignant lymphoma, to evaluate its correlation with clinical and histologic features at presentation and its possible role as a tumor marker for patient outcome. One hundred fifty eight serum samples were taken from 88 patients with non-Hodgkin's lymphoma (n=58) and Hodgkin's disease (n=30) at presentation and in the course of follow-up. Sera from 61 healthy volunteers served as normal controls. Serum Hpr levels in the lymphoma patients (median 430x10 u/ml, range 0-4000x10 ) were significantly higher than in the control group (median 68x10 u/ml, range 0-180x10 )(p=0.0001). Higher median Hpr values were detected in patients with advanced disease (p=0.013), "B" symptoms (p=0.029) and in males (p=0.053). There was also a significant correlation between Hpr and erythrocyte sedimentation rate (p=0.028). Serial determinations showed a significant decrease of the initial Hpr values obtained after treatment in 41 patients, 38 of whom achieved complete remission. In the follow-up period additional Hpr measurements were taken from 17 patients. Three of them eventually relapsed, and showed increased Hpr levels at the time of relapse. Hpr levels remained low in 11 of 14 patients who maintained complete remission, and increased in three. In conclusion, serum Hpr is a new serum tumor marker of potential use in the clinical setting of lymphoma.

Dexamethasone, cytarabine, ifosfamide, and cisplatin as salvage therapy in non-Hodgkin lymphoma.

The authors conducted a phase II study to evaluate a new combination of chemotherapeutic drugs that includes dexamethasone, cytarabine, ifosfamide, and cisplatin as salvage therapy in non-Hodgkin lymphoma after prior exposure to both adriamycin and etoposide. All drugs were administered intravenously over 4 consecutive days. The daily dose of dexamethasone was 20 mg twice daily. The maximal daily doses of cytarabine, ifosfamide, and cisplatin were 75 mg/m2, 1,200 mg/m2, and 20 mg/m2, respectively. Cycles were repeated every 3 weeks. A total of 31 patients were entered in the trial. Thirty patients were evaluable for response. A complete response was seen in 11 patients (37%), and a partial response was noted in six patients (20%). A significantly higher complete response rate was seen in patients with relapsing non-Hodgkin lymphoma compared with those who failed to achieve a complete response with the last chemotherapy (10/14 vs. 1/16; p < 0.013). A complete response continues in two patients who received consolidation with high-dose chemotherapy for more than 49 months and more than 60 months for each patient. Median time to treatment failure and median survival were 3.3 months and 7.5 months, respectively, for the entire group and 11 months and 30 months, respectively, for complete responders. Myelosuppression was pronounced but was usually of short duration. Neutropenic fever developed in 13 patients (42%) and in 15 of 96 cycles (16%). Platelet transfusions were required in seven patients (23%). There was one drug-related death associated with myelotoxicity. Nonhematologic toxicity was not dose limiting. The authors conclude that dexamethasone, cytarabine, ifosfamide, and cisplatin is active and a relatively tolerable regime for patients with non-Hodgkin lymphoma previously treated with adriamycin and etoposide.

Malignant thymoma associated with progressive systemic sclerosis.

A 65-year-old man manifested certain features of scleroderma several years before discovery of malignant thymoma. Following tumor resection, the signs and symptoms of scleroderma did not improve, and the patient experienced the abrupt onset of renal failure with malignant hypertension 7 months after the operation. The scleroderma renal crisis caused terminal renal failure, which was treated by chronic hemodialysis. This is the second reported case of thymoma associated with progressive systemic sclerosis (PSS). The authors suggest that thymoma and various immunologic disorders have a common etiologic factor which has not yet been found. This case emphasizes that thymectomy frequently has little effect on the course of the immunologic disease. The implications of the association of thymoma and PSS are discussed.

[Treatment of large cell lymphoma].

During 1977-1985, 50 patients with Stages III and IV large cell lymphoma (diffuse histiocytic [DH] and diffuse mixed [DM] types, Rappaport classification) were treated with the CHOP regimen (cyclophosphamide, adriamycin, Oncovin and prednisone). The male:female ratio was 1:1, the mean age at treatment 57 years, and mean follow-up 37 months. 80% had the DH type and 20% the DM type. 46% were in Stage III and 54% in Stage IV. The average relative dose intensity of CHOP was 0.68, which was well tolerated. In 68% a complete response was achieved after a mean of 4 treatment cycles. The average number of cycles for all patients was 7.2. The 5-year survival for those in Stage III was 50% and in Stage IV, 34%. Females survived better than males (60% vs 23%, respectively; p less than 0.02). The 5-year survival of the complete responders was 60% and their relapse-free survival 44%. In our experience, CHOP is a useful combination in the treatment of DH and DM lymphoma; it has yet to be proved in a randomized fashion that the current third generation of combinations is superior to it.

[Primary malignant lymphoma of the testis].

Among 715 patients with non-Hodgkin's lymphoma referred to this oncology center between 1973-1989, there were 7 (0.9%) with primary lymphoma of the testis. The mean age was 55 (range 23-78). The presenting symptom in all the 7 was testicular mass or swelling. 6 of them underwent inguinal orchiectomy and 1 had a testicular biopsy. The pathological subtype of the lymphoma in all 7 was the diffuse large cell type. The disease stage was IE in 3, IIE in 3 and IVE in 1. Only 1 had bilateral testicular involvement. 6 were treated primarily with various combinations of chemotherapy and 1 by radiotherapy. 3 developed recurrent disease (2 treated primarily with chemotherapy and 1 by radiotherapy) and died 14, 19 and 27 months, respectively, after diagnosis. 3 are alive with no evidence of recurrent lymphoma. Follow-up in an additional patient has been too short for evaluation. Primary testicular lymphoma is a relatively rare form of extranodal lymphoma. It has a tendency to early systemic progression and is potentially curable by aggressive combination chemotherapy.

[Malignant mesothelioma in families of asbestos workers].

Malignant mesothelioma is primarily an occupational disease of asbestos workers. While there is usually a latent period of 20-40 years between exposure and appearance of the tumor, the duration of exposure may be as short as a single month. Rarely, it may appear in family members and others living with asbestos workers who might be exposed to asbestos from work clothes during laundering, or from fibers on the skin or hair of the asbestos worker. Attention should therefore be paid to those with nonoccupational contact with asbestos. We report 2 cases of pleural mesothelioma in families of asbestos workers. In both cases the laundering of work clothes was done at home. The first was a 33-year-old man; during his childhood his father worked with asbestos boards for 5 years. The second was a 76-year-old woman whose husband worked in an asbestos factory for 32 years, up to 18 years before diagnosis.

[The chemotherapeutic treatment of advanced Hodgkin's disease].

Between 1972 and 1994, 121 adult patients with advanced Hodgkin's disease received MOPP (M) combination chemotherapy, MOPP alternating with ABVD (M-A) or MOPP and ABV hybrid (M/A). Radiation therapy was given to 1/3 of them. The median age was 35 years, 58% had stage III and 42% had stage IV disease. Failure-free survival at 10 years was 43.9%. It was 66.7%, 48.4% and 29.9% for patients treated by M/A, M-A and M, respectively. Overall survival at 10 years was 40.8%, and 78.2%, 48% and 27.7% for patients treated by M/A, M-A and M, respectively. Multivariate analysis found age (above or below 65 years) and combination chemotherapy (with or without adriamycin) to be significant prognostic factors. M/A combination was more myelotoxic, while M combination caused more second primaries. Today, 80% of patients with advanced Hodgkin's disease may be cured, with low rate of long-term toxicity.

Treatment of diffuse histiocytic and diffuse mixed non-Hodgkin lymphomas with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

During 1977 to 1985 90 patients with large-cell non-Hodgkin lymphoma (diffuse histiocytic or diffuse mixed according to Rapport classification) were treated by the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with a mean follow-up of 41 months. Thirty-four patients were treated with radiation therapy as well. The mean number of CHOP cycles to achieve complete response was 4.0 and the mean total number of cycles was 6.6. For 78 patients it was possible to calculate relative dose intensity (RDI) for each drug and the average RDI. Sixty-four patients (71%) achieved CR. The actuarial 5-year survival rate of all patients was 52%. The median RDI for cyclophosphamide was 0.72, for doxorubicin 0.70, for vincristine 0.69 and the median average RDI was 0.69. The following favorable prognostic factors were found to be of statistical significance: female sex and stages I-III as compared to stage IV. The 5-year survival rate for stage I & II patients treated by CHOP plus radiotherapy was 70% as compared to 55% for those treated by CHOP only; this difference was not statistically significant.

Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma.

Dose intensity may play an important role in the success of cancer chemotherapy. We have investigated the relationship between RDI of the combination of cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) and the results of therapy in a group of 78 newly diagnosed patients with diffuse histiocytic and diffuse mixed non-Hodgkin's lymphoma. The achievement of CR was associated with high DI. In the initial cycles needed to achieve a maximal response, a significantly greater proportion of complete responders received average RDI, RDI of CTX and RDI of adriamycin greater than 0.8, as compared with noncomplete responders: 52 vs. 23%, 62 vs. 34% and 61 vs. 29%, respectively (P less than 0.05). Sixty-one patients achieved CR. Among these, RDI of CTX was best and significantly correlated with survival: 81 and 54% 5-year actuarial survival of patients receiving greater than 0.7 and less than 0.7 RDI, respectively (P less than 0.05). Our data indicate that there is a clear dose-rate effect of CHOP, particularly of CTX, on the therapeutic outcome. High DI may improve results of treatment in patients with diffuse, large cell lymphoma.

Non-Hodgkin's lymphoma presenting with spinal epidural involvement.

Cord compression was noted at presentation in 10 of 453 (2.2%) previously untreated non-Hodgkin's lymphoma patients seen at the Northern Israel Oncology Center between 1968 and 1983. A prodromal phase of local back pain occurred in eight patients, persisting up to 1 year, followed by a second phase of rapidly progressive signs of cord compression. Five of the ten patients presented with primary spinal epidural involvement (Stage IE), whereas the others had Stage IIE and IIIE (one patient each) and Stage IV, with bone and bone marrow involvement (three patients). All patients had unfavorable histologic diagnoses, mostly of the intermediate grade malignancy types according to the Working Formulation. The patients were treated by radiotherapy (two patients), chemotherapy (three patients), or both modalities (five patients). Seven of the ten patients achieved complete remission, but four of them have subsequently had relapses (two patients in bone, one in central nervous system, and one in mediastinum). The 5-year actuarial survival and 3-year relapse-free survival were 66% and 32%, respectively. Median survival has not been reached after a mean follow-up of 34 months. Non-Hodgkin's lymphoma with spinal epidural involvement at presentation is an aggressive disease. An intensive treatment combining irradiation with chemotherapy, and surgery as needed, is suggested in order to achieve good local response and long-term survival.

Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy.

To examine whether the concomitant administration of a gonadotrophin-releasing hormone agonist (GnRHa) during combination chemotherapy to young women with lymphoma may facilitate preservation of gonadal function, a prospective clinical protocol was undertaken in 18 cycling women with lymphoma, aged 15-40 years. Thirteen patients suffered from Hodgkin disease (HD) and 5 from non-Hodgkin lymphoma. After informed consent a monthly injection of depot D-TRP6-GnRHa was administered for a maximum of 6 months starting prior to chemotherapy. Most of these patients (15/18) were treated with the MOPP/ABV(D) combination chemotherapy followed by mantle field irradiation in 10 patients. Hormonal profile [luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol, testosterone, progesterone, insulin-like growth factor (IGF)-1, prolactin] was taken before the GnRHa/chemotherapy co-treatment, and monthly thereafter until resuming spontaneous ovulation and menses. This group of prospectively treated lymphoma patients was compared to a matched control group of 18 women (aged 17-40 years) who have been treated with chemotherapy, mostly MOPP/ABV (14/18), with (11) or without (7) mantle field radiotherapy. Fourteen had Hodgkin's and four non-Hodgkin's lymphoma. Gonadal function was determined clinically, hormonally (LH, FSH, oestradiol, progesterone), and sonographically. Two of the patients in each group died from refractory disease. Of the remaining 16 patients, 15 (93.7%) resumed spontaneous ovulation and menses within 3-8 months of termination of the combined chemotherapy/GnRHa co-treatment. In contrast, only seven (39%) of the 18 similarly treated patients in the control group (chemotherapy without GnRHa) resumed ovarian cyclic activity (regular menses). The other 11 experienced premature ovarian failure (POF) (61%). Out preliminary data suggest a possible significant protective effect of GnRHa co-treatment with chemotherapy from irreversible ovarian damage (POF).

Dexamethasone, etoposide, ifosfamide, and cisplatin as second-line therapy in patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND: This study analyzed the long term results of a combination of dexamethasone, etoposide, ifosfamide, and cisplatin (DVIP) used at the study center as standard second-line combination therapy in patients with aggressive non-Hodgkin's lymphoma (NHL) after prior exposure to doxorubicin. METHODS: All drugs were given intravenously for 4 consecutive days. The maximum daily doses of etoposide, ifosfamide, and cisplatin were 75 mg/m2, 1200 mg/m2, and 20 mg/m2, respectively. The dexamethasone dose was 20 mg twice daily. Cycles were repeated every 3 weeks. RESULTS: Fifty-six patients were included in the study. Partial response was noted in 18 patients (32%) and complete response (CR) in 18 patients (32%). Pretreatment factors that predicted CR were CR with prior therapy (CR in 17 of 34 in patients with a recurrence vs. 1 of 21 in patients with primary refractory NHL) and age (CR in 12 of 25 patients age < or = 65 years vs. 6 of 31 patients age > 65 years). Median time to treatment failure (TTF) and median survival were 11.5 months and 30 months, respectively, for patients with a CR and 3.5 months and 8 months, respectively, for all patients. Five patients (9%) remained disease free for > 24 months. By multivariate analysis, age was the only independent prognostic factor for TTF, whereas age, serum lactate dehydrogenase, and number of extranodal sites were independent predictors for survival. Myelosuppression (median granulocyte nadir and median platelet nadir of 350/mm3 and 77,000/mm3, respectively) was the major toxicity. There was one possible drug-related death associated with myelosuppression. CONCLUSIONS: DVIP is a relatively safe salvage combination therapy in patients with aggressive NHL. Response to first-line therapy and age are the most important predictors for prognosis after the administration of DVIP. This regimen is highly active in patients with recurrent NHL, but relatively ineffective in patients with primary refractory NHL.

Inhibin A concentrations in the sera of young women during and after chemotherapy for lymphoma: correlation with ovarian toxicity.

PROBLEM: Inhibin A concentrations in serum may reflect the ovarian granulosa cell compartment. To characterize the correlation between ovarian function after gonadotoxic chemotherapy for Hodgkin's or non-Hodgkin's lymphoma in young women, the immunoreactive inhibin A concentrations in the sera of these patients was measured before, during, and after the gonadotoxic chemotherapy. METHOD OF STUDY: A prospective clinical protocol was undertaken in 20 cycling women with lymphoma, aged 15-40 years. A monthly injection of depot D-TRP6-GnRH-a (Decapeptyl CR, Ferring) was administered from before starting the chemotherapy until its conclusion, up to a maximum of six monthly injections. Most of the patients were treated with the mustargen-oncovin-procarbazine-prednisone (MOPP)/actinomycin D-bleomycin-vincristine (ABV) chemotherapy combination; 13 with and 7 without radiotherapy. A hormonal profile [follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-beta-estradiol (E2), testosterone (T), progesterone (P4), insulin-like growth factor (IGF)-1, IGF-BP3, and prolactin (PRL)] was taken before starting the gonadotropin-releasing hormone agonist (GnRH-a)/chemotherapy co-treatment and monthly thereafter until resuming spontaneous ovulation and menstrual cyclicity. This group of prospectively treated lymphoma patients was compared with a control group of 22 regularly cycling women who had been treated with chemotherapy (mostly MOPP/ABV) with or without radiotherapy for Hodgkin's or non-Hodgkin's lymphoma. Inhibin A immunoactivity developed by Nigel Groome was measured by an enzyme-linked immunoadsorbent assay (ELISA) commercial kit (Serotec). RESULTS: Whereas all but one (40 years of age) of the surviving patients in the GnRH-a/chemotherapy co-treatment group resumed spontaneous ovulation and menses within 6 months, only one half of the patients in the "control" group (chemotherapy without GnRH-a co-treatment) resumed ovarian function and regular cyclic activity (P < 0.05). The remaining 50% experienced premature ovarian failure (POF). Temporarily increased FSH concentrations were experienced by approximately one third of the patients resuming cyclic ovarian function, suggesting a reversible ovarian damage in a larger proportion of women than those experiencing POF. The inhibin A immunoactive concentrations decreased during the GnRH-a/chemotherapy co-treatment but increased to normal levels in patients who resumed regular ovarian cyclicity, and/or spontaneously conceived, as compared to low levels in menopausal women and those who had developed POF. CONCLUSIONS: If these preliminary data are consistent in a larger group of patients, inhibin A concentration may serve as a prognostic factor for predicting the resumption of ovarian function, in addition to the levels of FSH, LH, and E2.