Feasibility of total body irradiation in chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas.

Combined total body irradiation (TBI) and Prednimustine were prospectively evaluated in 30 patients affected either with chronic lymphocytic leukemia (CLL) or with low-grade non-Hodgkin's lymphoma (NHL) eleven patients were previously treated. Between January 1984 and May 1987, 20 evaluable patients with CLL, median age 66 years (range 43-82), classified according to Rai (4 in stage I, 10 in stage II, 4 in stage III, 2 in stage IV) and 10 evaluable patients with NHL low-grade malignancy according to the Working Formulation, Stages III and IV, median age 54 years (range 32-71) were treated using a 6 MeV Linear Accelerator, applying two opposite alternating fields including total body, with a fraction of 15 cGy, 2 fractions weekly (3-day interval) for a total dose of 150 cGy given over 5 weeks. Prednimustine (100 mg/m2, orally, for 5 consecutive days, every 3-4 weeks, for 6-9 courses) was administered 2 months after TBI treatment, as consolidation therapy. By May 1989, a total of 85% hematological responses (defined as normalization of the differential white cell count, of the total blood cell count and of bone marrow infiltration) were obtained after combined treatment in CLL patients; moreover 3 CR (according to the WHO criteria), 75% with splenomegaly reduction and 40% with lymphadenopathy reduction were seen. Ninety percent objective responses (5 CR and 4 PR) were observed in the NHL patients, with 50% having splenomegaly reduction and 67% lymphadenopathy reduction. The median response time in the two groups was, respectively, 14 and 23 months. The overall toxicity (WHO grades 1,2,3,4) after combined treatment was 65% and 70% in the two patient groups. WHO grade III toxicity, completely reversible, was verified in only 16.6% of the cases; all cases, except one, were previously treated. Additionally, 1 toxic death (grade IV thrombocytopenia and leukopenia) was observed in a heavily pretreated patient affected with CLL after TBI alone. Prednimustine regimen was generally well tolerated. The high response rate and acceptable toxicity, confirms the feasibility and the usefulness of TBI in the context of a combined treatment for CLL and low-grade NHL patients. However in order to further reduce the severe toxic side effects, observed in one patient, white blood cells and platelet count should be plotted and monitored carefully, particularly in pretreated patients.

Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study.

Between June 1980 and December 1983, 111 patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were entered into a randomized trial comparing radiotherapy alone versus radiotherapy and combination chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), methotrexate, and procarbazine. Thirty-five of 62 (56.4%) patients treated with 4500 rad in 15 fractions in 3 weeks and 19 of 49 (38.8%) patients treated with the same radiation treatment and chemotherapy had an objective response. The difference in response rate was not significant (P = 0.900). Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. The toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant superiority of combined radiotherapy and chemotherapy treatment over radiation therapy alone was evidenced. Whether different chemotherapy regimens may prove more effective in this context should be clarified by further studies.

The uptake of 3H-vincristine by a mouse carcinoma during a course of fractionated radiotherapy.

The variations in uptake of 3H-vincristine sulphate, given as a bolus i.v. injection, by a transplantable murine tumour during a realistic course of fractionated daily gamma-radiation of 25 x 2.0 Gy have been investigated. Maximum levels of 3H in the tumours are found when the tracer is injected 4h after irradiation and the tumours are dissected out 1 h after injection. During the course of daily irradiation the pattern of uptake varies considerably but reproducibly. There are peaks of uptake after 7, 13 and 22 fractions of 2.0 Gy when the amount of 3H in the tumours is as much as three times that found in non-irradiated tumours. After 17-18 fractions, however, the tumour content of 3H is lower than that of non-irradiated tumours. The wave-like pattern of uptake could be due either to capillary occlusion brought about by radiation induced cellular swelling and oedema followed by re-opening of the capillaries during periods of decreased cellularity, or to some mechanism of recovery from radiation damage during the week-end rest period.

Splenic irradiation in chronic lymphocytic leukemia. A 10-year experience at a single institution.

A group of 38 patients with a median age of 70 years and chronic lymphocytic leukemia (CLL) were treated using a cobalt 60 U or a 6-MeV linear accelerator. A direct field or two opposite fields covered the palpable spleen area in most patients. 100 cGy were administered weekly for a total dose of 10 Gy, given over 10 weeks. The stage arrangement (according to Rai) for the 32 evaluable patients was as follows: Stage I: 11 patients, Stage II: nine patients, Stage III: three patients, and Stage IV: nine patients. Patients in Stages I and II were treated when symptomatic. Twenty-five patients (78%) achieved hematologic response (HR), defined as normalization of the differential leukocyte count, of the total blood cell count, and of bone marrow infiltration. However, no complete response according to the standard criteria of response has been obtained. The median response time of HR was 7 months (range, 1.5 months to greater than 120 months). The overall median survival time from the start of splenic irradiation (SI) was 40 months. More than 50% splenomegaly reduction was obtained in 63% of patients, whereas no benefit was verified in the lymphadenopathy. The incidence of second tumor was 29%. Fourteen patients benefited from a further 21 SI cycles. SI does not result in a complete remission and therefore cannot modify the course of CLL. This treatment is most advisable for elderly patients with predominant bone marrow lymphocytosis, for patients with previous extensive chemotherapy or radiotherapy, and for patients with poor marrow reserve. Moreover, because of the absence of toxicity subsequent treatment is not compromised.

A phase II study of AMSA in head and neck cancer.

AMSA was given to 22 evaluable patients with advanced head and neck cancer with measurable lesions. The starting dose was 90-120 mg/m2 by i.v. infusion over 45 min every 3 weeks. The dose of AMSA was escalated by 30 mg/m2 in absence of bone marrow toxicity. At least two cycles were given prior to the evaluation of response. Only one patient with oropharyngeal cancer achieved a partial response, lasting for 20 weeks. Toxicity was mild and mainly hematological. We conclude that AMSA given at this dose and schedule has little activity in head and neck cancer.

Non-Hodgkin's lymphoma in the elderly. A retrospective clinicopathologic study of 50 patients.

The pathologic and clinical findings of 50 patients aged 65 or older (median, 71.5 years) with non-Hodgkin's lymphomas (NHL) are reported. These patients formed 27% of all cases of NHL seen in a single institution over a 7-year period. Forty patients presented with nodal and 10 with extranodal NHL. According to the Ann Arbor system, 20 were clinical and/or pathologic Stages I and II, and 30 were Stages III and IV; of the 10 patients presenting with extranodal NHL, 8 were Stages I and II. Histologically, 84% of the cases were of the intermediate and high-grade groups according to the Working Formulation; diffuse histiocytic was the most frequent histotype (34%) according to the Rappaport classification. The pattern was diffuse in 94% of the cases. Five patients received no treatment; treatments were conservative (monochemotherapy and/or local radiotherapy) in 19 patients and aggressive (polychemotherapy and/or extended-field radiotherapy) in 26. Four patients of the latter group died of toxicity; 22 patients died of lymphoma and 13 of other causes; the other 11 (22%) patients are still alive. The overall median survival was 2.2 years. A significantly better survival was observed in patients with Stages I and II (P less than 0.025) and in those with intermediate grade (P less than 0.05) when compared with patients having Stages III and IV and high-grade histology, respectively. Apparently, no significant difference both in response and survival was found between the groups of patients which arbitrarily underwent conservative or aggressive treatments on the basis of their general conditions. Randomized clinical trials should be designed in order to draw more significant conclusions on the correct management of elderly patients with NHL.

Lymphographic findings in prostatic carcinoma with distant metastases.

From January 1976 to December 1981, 25 patients with prostatic carcinoma and distant metastases had lymphangiography (LAG) in their initial workup either to obtain a more precise definition of tumor extension or because at the time of LAG asymptomatic metastases had not yet been detected. In 18 patients extensive bone metastases were present while in seven the only indicator of bone metastases was bone scan (limited bone disease). Positivity rate was 48% (20% in T2 cases, 53% in T3-T4; 29% in limited bone disease, 53% in extensive bone metastases). No correlation was found between LAG positivity and degree of differentiation. Patients with N0 survived longer than patients with N2-N4; however, the difference in survival is not significant and seems to be linked to the extent of bone metastases. Our data substantiate that LAG is of no value in the staging of metastatic prostatic carcinoma.

Staging and treatment with cyclophosphamide, vincristine and prednisone (CVP) in advanced cutaneous T-cell lymphomas.

Twenty-three consecutive patients with cutaneous T-cell lymphomas were submitted to staging procedures including lymphangiography, bone marrow biopsy and aspiration, peripheral blood morphological examination, peritoneoscopy with liver and spleen biopsy, and in selected patients lymph node biopsies. Extracutaneous disease (lymph nodes, bone marrow, liver and spleen) was detected in 12 patients. Bone marrow was involved in 25 per cent of the patients at presentation (all patients had lymph node involvement) and in two of nine patients with advanced disease during the follow-up. Peripheral blood was involved in 65 per cent of the patients at presentation (ten patients with advanced disease) and in six of nine patients with advanced disease during the follow-up. In 16 patients with advanced disease (T3-T4 and/or extracutaneous disease), CVP was given with a 50 per cent objective response rate and four complete remissions of 47+, 12+, 19 and 19 months duration. Median survival of patients with advanced disease was 4 years.

Randomized crossover antiemetic study in cisplatin-treated patients. Comparison between high-dose i.v. metoclopramide and high-dose i.v. dexamethasone.

This prospective, randomized, nonblind study comparing the antiemetic effectiveness of high-dose IV metoclopramide and high-dose IV dexamethasone was performed in 78 advanced cancer patients. Chemotherapeutic treatment consisted in cisplatin at a high-dose (120 mg/m2) (HD-CDDP) and at a low-dose (LD-CDDP), either alone (60 mg/m2) or in combination with other chemotherapeutic agents (50 mg/m2). The evaluation of the effectiveness of antiemetic therapy was based on three parameters: prevention of vomiting ("major protection"), number of emetic episodes, and subjective preference. Out of 78 study patients, 67 were evaluable. Overall, metoclopramide proved to be statistically superior to dexamethasone in preventing vomiting (P less than 0.005), in reducing the median/mean number of emetic episodes (P less than 0.001/0.001), and in subjective preference (P less than 0.01). The results divided between HD-CDDP and LD-CDDP groups were also in favor of metoclopramide for reduction of the median/mean number of emetic episodes (P less than 0.001/0.001 for the HD-CDDP group and P less than 0.001/0.005 for the LD-CDDP group) and in subjective preference (P less than 0.001 and P less than 0.001 for the HD- and LD-CDDP groups, respectively). No statistical differences were noted when LD-CDDP was used in monochemotherapy, whereas when LD-CDDP was used in combination chemotherapy, statistical differences in favor of metoclopramide were noted again for the median/mean number of emetic episodes (P less than 0.01/0.05) and for subjective preference (P less than 0.01), even though the effectiveness of both antiemetic agents was greatly reduced. The evaluation of previously untreated patients reflected the overall results: for the HD-CDDP group all three parameters demonstrated statistical significance in favor of metoclopramide; for the LD-CDDP group, of all three parameters, prevention of vomiting (major protection) was the only one for which there was no significant difference. Mild sedation was the only side effect of metoclopramide. No extrapyramidal reactions were noted during this trial, but concomitant orphenadrine treatment was given. Dexamethasone was always well tolerated. In conclusion, high-dose IV metoclopramide demonstrated its superiority over high-dose IV dexamethasone in all subsets of our population except the LD-CDDP monochemotherapy group, in which the two antiemetics were found to be equivalent in effect.

Teniposide is not effective in chronic lymphocytic leukemia.

Teniposide has been evaluated in a phase II clinical trial in chronic lymphocytic leukemia (CLL). Among 16 consecutive patients with CLL entered in the study and treated with Teniposide, 100 mg/m2 weekly, no objective response was observed. Toxicity was generally mild and mainly hematologic. Teniposide at this dosage and schedule is an inactive drug in CLL.

Lymph node immunohistology in intravenous drug abusers with persistent generalized lymphadenopathy.

Lymph node biopsy specimens from 16 intravenous drug abusers with persistent generalized lymphadenopathy were evaluated by immunohistochemical methods using a panel of antisera to detect different cell populations. The 11 cases that we tested on cryostat sections showed an increased number of Leu-2a-positive cells (cytotoxic-suppressor phenotype) in the follicular centers and a significantly reduced helper-to-suppressor T-cell mean ratio when compared with control tissues. In these 11 patients the peripheral helper-suppressor ratio was at the lower normal limit or inverted. Ten cases tested for anti-human T-cell lymphotropic virus type III antibodies were positive. In all 16 cases, immunohistology of paraffin-embedded sections demonstrated a polyclonal B population; 12 of 15 patients tested had polyclonal hypergammaglobulinemia, mostly IgG. The mixed-cell population of the lymph node sinuses was composed mostly of Leu-M1-positive and lysozyme-positive cells and, to a lesser extent, by alpha 1-antichymotrypsin-positive and S100 protein-positive cells. It seems that many of the immunologic dysfunctions found in these patients appear to be reflected in a fairly repetitive immunohistologic pattern.

Phase II trial of oral VP 16-213 (etoposide) in patients with advanced head and neck cancer.

We tested VP 16-213 in 16 patients with advanced head and neck cancer after conventional treatments. VP 16-213 was administered orally at the dosage of 100 mg/mq for 5 consecutive days every 3 weeks. No patient achieved an objective response. Toxicity was mild. VP 16-213 given at this dose and schedule revealed no activity in pretreated patients with head and neck cancer.

Phase II study of teniposide (VM-26) in multiple myeloma.

From September 1979 to December 1983, a phase II trial with teniposide (VM-26) in multiple myeloma (MM) was conducted at our institution. Of the 30 patients entered, 25 were evaluable for response, 12 previously treated with M-2 protocol and 13 previously untreated elderly (greater than or equal to 70 years) patients. A median of nine cycles (range 1-21) of VM-26 was administered. Seven responses (28%) according to Myeloma Task Force criteria were observed with a median duration of 4 months (range 2-12+). Four responses (33%) were observed in the 12 previously treated patients. Overall toxicity was mild. VM-26 seems an active drug in MM, without significant toxicity even in elderly patients.

High-dose versus low-dose cisplatin in advanced head and neck squamous carcinoma: a randomized study.

From November 1981 to February 1983, 64 patients with advanced head and neck squamous carcinoma were randomly treated with either high-dose (120 mg/m2) or low-dose (60 mg/m2) cisplatin. Of the 62 eligible patients, 59 were evaluable: the response rate observed in patients receiving high-dose and low-dose cisplatin was 16.1% and 17.8%, respectively. Survival was superimposable in the two treatment arms. No evidence of dose dependency of cisplatin activity in advanced head and neck squamous carcinoma was noted in this randomized trial.

Reproductive and hormonal factors and breast cancer in a Northern Italian population.

Between January 1980 and March 1983, data were collected to evaluate risk factors for breast cancer in a case-control study based on 368 women with breast cancer admitted to the General Hospital of Pordenone (a district in North Eastern Italy with a particularly high breast cancer mortality rate), and 373 age-matched controls. Nulliparity or low parity, late age at first birth and later menopause were associated with an increased risk of breast cancer. The elevated risk associated with nulliparity could be almost completely explained by marital status, thus pointing to a specific protection given by parity, rather than some putative influence of infertility or subfertility in breast cancer cases. Likewise, risk did not vary materially according to history of abortions when marital status was controlled for. Increased risk associated with later age at first birth, on the other hand, was not accounted for by marital status or parity. The population studied, though frequently multiparous, showed late average at first birth: this might, at least partly, explain its high mortality rate from breast cancer. The risk estimate was higher if menarche occurred below age 15; however, there was no evidence of a trend for the relative risk to rise with lower age at menarche. The use of oral contraceptives or other female hormones (such as oestrogen replacement therapy) did not appear to be related to the risk of breast cancer. The role of the major menstrual and reproductive variables considered (age at menarche, parity, age at first birth) was apparently stronger in pre-menopausal women, thus suggesting an influence of these factors (and possibly, their hormonal correlates) on one of the latter stages of the process of carcinogenesis.

Phase II study of VM 26 in extensively pretreated breast cancer.

A significant activity of VM 26 in solid tumors has been established in brain tumors, bladder cancer, and neuroblastoma. Preliminary favorable results in breast cancer stimulated a phase II study at our institution to define the activity of VM 26 in patients with advanced, homogeneously pretreated breast cancer.