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Between December 1986 and December 1988, the Italian Cooperative Group on AIDS-Related Tumours documented 49 HIV-related tumours other than malignant lymphomas (ML) and Kaposi's sarcomas (KS), predominantly among HIV-infected intravenous drug abusers (IVDA). Of 12 germinal testicular tumours collected, six were seminomas, two of which were pure embryonal and the other four embryonal mixed. Cervical carcinoma was observed in nine IVDAs (intraepithelial in eight and advanced, with rapid progression, in one). Lung cancer associated with HIV infection was reported in eight patients, of whom four had an adenocarcinoma, two a small cell carcinoma, one an epidermoid carcinoma and one a mesothelioma. All patients with non-small-cell-lung cancer (SCLC) were at stage III, while those with SCLC and mesothelioma had limited disease. Five out of eight presented with limited disease at onset. The median age was low; lung cancer occurred predominantly in young adults, of whom all but one were smokers. Three patients could not be treated; four died while on treatment because of progression of the neoplasia and one died of an overdose. Acute lymphoblastic leukaemia (ALL) was diagnosed in five patients. The immunophenotype was always Burkitt-like (L3), and acute myeloblastic leukaemia (M2) was diagnosed in one. Of the central nervous system (CNS) tumours, two cases of glioblastoma and one of medulloblastoma were described. Two cases of young adults with multiple myeloma and two cases of colorectal carcinoma were also reported. One case of chronic lymphocytic leukaemia, one anorectal carcinoma, one oral carcinoma, one pancreatic carcinoma, one thymoma, one kidney carcinoma, one malignant melanoma and thyroid carcinoma were also found.(ABSTRACT TRUNCATED AT 250 WORDS)

The possible synergism of cisplatin (P) and 5 -fluorouracil was studied in 38 consecutive patients with advanced or metastatic colorectal carcinoma. Cisplatin 60 mg/m 2 i.v.q. 4 weeks and fluorouracil 600 mg/m 2 i.v. weekly were administered for at least 2 cycles, on an out-patient basis, to 24 males and 14 females with a median age of 57 years and a medium PS of 80 (Karnofsky). Evaluable lesions were: primary unresectable tumor in 2 patients, local recurrence in 11 , liver, lung, bone and soft tissue metastases in 21, 7, 2 and 3 patients respectively. With a median number of 3 cycles administered to 35 evaluable patients, 6 partial responses, 16 unchanged and 13 progressions were observed. Responses were observed in the liver ( 2 patients), lungs ( 1 ) and soft tissues ( 3 ). Median remission duration was 15 weeks, median duration of ‘unchanged' was 12 weeks. The overall median survival was 24 week ( 30.5 weeks for responders and 22.5 weeks for non-responders). Six patients were pretreated with chemotherapy not containing cisplatin (mainly adjuvant 5 -FU). None of them responded. Toxicity was very tolerable with moderate nausea, vomiting and alopecia in the majority of the patients, bone marrow toxicity was generally mild with no blood transfusions required, no complications of myelosuppression (sepsis or bleeding) and no chemotherapy-related deaths. In this experience the combination of low dose cisplatin with fluorouracil, does not appear to significantly enhance 5 -FU toxicity and the response rate is not superior to that reported with 5 -FU alone. However, better designed schedule combinations with optimal doses, sequences and exposure time of the 2 -drug regimen, seem necessary to obtain the biochemical events that support the potentiation.

One-hundred and ninety-four adult patients with histologically proven stage III and IV non-Hodgkin's lymphomas, treated with CVP (cyclophosphamide, vincristine and prednisone) alternated with ABP (adriamycin, bleomycin and prednisone), were analyzed to test the validity of the clinicoprognostic correlation offered by the working formulation in comparison with the Rappaport and Kiel classifications. Actuarial overall survival at 5 yr showed a significant difference among the three prognostic subgroups of the working formulation (low grade, 53.3%; intermediate grade, 47.5%; high grade, 27.7%). Overall survival of favorable subgroups of the Rappaport and Kiel classifications was superior to that of unfavorable prognostic groups. The percentage of systemic symptoms and bulky disease increased in patients with low-grade compared to those with intermediate-grade and intermediate-to-high-grade malignancy. The achievement of complete remission was not related to any of the prognostic groups of the Working Formulation, and no difference could be detected within the various prognostic groups of the Rappaport and Kiel classifications. Within the diffuse histiocytic lymphomas of the Rappaport classification, two groups with a different prognostic outcome were evidenced by the working formulation (G, with an overall survival of 50%, and H, with an overall survival of 26.7% at 5 yr) and by the Kiel classification. The possibility of reporting results in the three different groups of the working formulation instead of two can be considered a step forward. Within the diffuse histiocytic histology, the working formulation allows separation, as does the Kiel classification, into two main different prognostic subgroups.

The endocrine effects of alternating tamoxifen and medroxyprogesterone acetate have been evaluated in 26 post-menopausal patients with metastatic breast cancer. Endocrine evaluations included the RIA determination of plasma levels of sex-hormone binding globulin, follicle-stimulating hormone, luteinizing hormone, estradiol, prolactin, cortisol, and testosterone. The evaluation of the study parameters at different intervals during therapy indicates that with this schedule an alternate sequential effect on the endocrine system is achievable because each drug exerts its own endocrine activity that is completely reversed when the other drug is administered. We can hypothesize that the same alternate activity as seen on the endocrine system could be obtained also on other tissues and organs including tumors.

In order to improve the prognosis of patients with localized non-Hodgkin's lymphomas (NHL) who are treated with radiotherapy (RT), a prospective controlled study utilizing a combined modality approach was carried out in patients with pathologic Stage 1[-II NHL. After treatment with regional RT, patients in complete remission were randomized to receive either no further therapy or 6 cycles of cyclophosphamide, vincristine and prednisolone (CVP). At 5 years from completion of irradiation, the relapse-free survival was 46.3% after RT and 72.1% after RT plus CVP ( P = 0.005). The corresponding findings for the overall survival calculated from the beginning of irradiation were 55.8 and 82.8% respectively ( P = 0.03). The favorable effects of adjuvant chemotherapy on relapse-free survival were statistically significant only in the subgroup with diffuse histology. In patients who relapsed after RT alone, the salvage therapy failed to induce a high incidence of second durable remission. Adjuvant chemotherapy is indicated to improve the cure rate in pathologic stage I-II NHL with diffuse histology when regional RT is utilized.

In a previous report on patients with resected stage II nonseminomatous germinal cell testis tumors the findings of retroperitoneal metastases larger than 5 cm., macroscopic extranodal spread and tumor invasion into retroperitoneal veins (pathologic stage IIC) almost invariably were associated with relapse and poor survival in the absence of adjuvant chemotherapy, while postoperative cisplatin, vinblastine and bleomycin therapy was effective in preventing relapses in all cases. From February 1980 to January 1982, 40 consecutive patients underwent retroperitoneal lymphadenectomy for stage II disease. Only patients with pathologically assessed stage IIC cancer received 4 cycles of adjuvant cisplatin, vinblastine and bleomycin, while those with pathologic stages IIA and IIB disease, with or without microscopic extracapsular extension of the tumor, received no further therapy and were followed carefully at monthly intervals. After a median followup of 26 months or more relapses were noted in none of the 14 treated patients compared to 9 of 26 untreated patients (35 per cent). Of the latter 9 patients 8 (89 per cent) had continuous complete remission after salvage therapy and 39 of 40 patients (97.5 per cent) currently are free of disease. No difference was observed in the relapse rate and survival between patients with stages IIA and IIB disease. We conclude that patients with pathologic stages IIA and IIB disease can be treated safely only at the time of relapse, while the usefulness of adjuvant chemotherapy has been confirmed in those with stage IIC cancer.

Methotrexate (MTX) was given by weekly rapid intravenous injections to 27 patients with inoperable oropharyngeal carcinoma. 9 cases were untreated while 18 had received radiotherapy or chemotherapy before administration of MTX. In 20 cases the dose was 40 mg/m2/week (patients over 50 years) and in 7 cases 60 mg/m2/week (table 1). In responsive patients, maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. 23 cases were adequately evaluable, i.e. they received treatment for a minimum of 3 weeks. Response to treatment was evaluated according to Karnofsky's scale. Considering only category 1 regressions, 11/16 (75%) patients adequately treated with 40 mg/m2 showed objective improvement and respectively 4/7 (57%) given 60 mg/m*. 8 out of 15 cases (41%) with category 1 response showed a regression greater than 50%. The mean duration of response for category 1 patients was 3.5 months, while the longest regression lasted 9 months (table 2). 18 patients had one or more side effects: 9 had oral lesions or gastroenteritis, 12 bone marrow depression, 3 hepatic and 1 renal toxicity. One patient died from hepatic and renal toxicity; in the remaining cases the side effects were quickly reversible (table 3). The percent regression rate for category 1 response and its average duration obtained with intravenous MTX seems comparable to intraarterial infusion (table 4). Systemic toxicity seems also comparable (table 5). Furthermore, intravenous administration obviates the typical local complications occurring with intra-arterial treatment and therapy can be given also at outpatients. For this reason, intravenous administration of MTX is preferred to intra-arterial infusion in the control of primary inoperable oropharyngeal carcinomas, provided no severe depression of liver, kidney and bone marrow is present.

The therapeutic results obtained in 59 patients with advanced Hodgkin's disease treated from 1964 to 1969 with sequential chemotherapy employing a single agent are reported. The main sequence was alkylating agent first, vinblastine second and procarbazine third. Complete plus partial remission (> 50 %) ranged from a minimum of 37 % for patients treated with procarbazine to a maximum of 42 % for those given vinblastine. The median duration of response ranged from 4 to 5 months. Overall median survival from institution of chemotherapy was 24 months. Patients (26 cases) responding to 2 or more drugs showed a median survival of 40 months, which was statistically greater than that observed in an equal number of cases responding only to one drug (13 months) and than that of 7 patients unresponsive to all drugs (9 months). It is concluded from this retrospective study that survival in advanced Hodgkin's disease is longer in patients responding to at least two drugs that in patients responding less or not at all.

Daunomycin was administered to 16 patients with chronic lymphoproliferative disorders (10 with Stage IV lymphoreticular sarcomas and 6 with chronic lymphocytic leukemia). The age of subjects was ranging between 36 and 64 years (average 54 years). 8 out of 16 patients had been previously treated with radiotherapy and/or chemotherapy. The drug was injected intravenously at the initial dose of 0.6 mg/kg (7 cases), 0.8 mg/kg (8 cases) and 1 mg/kg (1 case) for 3–4 consecutive days. After 1 day interval, treatment was continued in most cases on alternate days schedule until signs of toxicity appeared. In some patients after the initial course the dose/kg was increased or decreased according to the peripheral blood picture. The total dose ranged between 2.2 to 13.3 mg/kg. In 7 patients prednisone (50 mg daily by mouth) was given in association to daunomycin (tables 1 and 2). Objective responses were seen in 5 out of 6 patients with chronic lymphocytic leukemia. While a consistent shrinkage of the nodes and especially of the spleen was observed in all responsive cases, the fall in the leukocyte level was mild and transient. In lymphoreticular sarcomas 5 out of 10 patients responded; the most significant regression was obtained in patients with splenomegaly, but also lymphonodes, hepatomegaly, pulmonary and cutaneous lesions responded. Two patients had also the bone marrow infiltrated with extrinsic cells: no significant changes were seen after treatment with 6 and 6.2 mg/kg. Regression usually occurred after few doses; nevertheless in all but one responsive patients they were incomplete. Maintenance treatment was then started with alkylating agents. The patients treated with daunomycin and prednisone did not show any better response than those treated with daunomycin alone. In 5 cases a sudden dyspnea, tachycardia and hypotension developed after different doses of daunomycin ranging from 2.2 to 8 mg/kg. Four patients died within 24 hours and one after 5 days from the beginning of symptoms. EKG abnormalities (tachicardia, flattening of ST and T waves) were recorded in all patients died with cardiac failure. In two cases the EKG changes appeared only after daunomycin administration while in three cases mild electric abnormalities present before the treatment got worse after few doses of daunomycin. Necroscopy was performed only in one case where besides superficial necrosis of the intestinal mucosa no specific alterations of the heart and vessels were seen. The conclusion is that daunomycin can produce rapid objective responses in chronic lymphoproliferative disorders, although the quality of these regressions in the majority of patients is insufficient to influence the natural course of the disease. Prolongued administration of the drug especially in patients previously treated with chemotherapy is not recommended because of the severe marrow depression. The so-called cardiac toxicity seems from this study to be dose-indipendent in patients with cardiovascular disease and EKG abnormalities before drug administration. Daunomycin therefore should not be given even in small dosage to patients with EKG abnormalities.

A total of 225 consecutive untreated patients with lymphoreticular sarcomas with primary involvement of Waldeyer's ring was evaluated (151 without lymphography and 74 with lymphography). On admission, the anatomical distribution of the primary growth within Waldeyer's ring was as follows: tonsil, 40%; nasopharynx, 27.5%; base of tongue, 2.7%; soft palate, 2.7%; oropharynx, 0.9%; other sites, 26.2%. In the group studied without lymphography, the disease was confined to Waldeyer's ring in 22.5% of cases and had spread to the cervical nodes in 62.3% and to distant nodes in 15.2%. In the group studied more recently with lymphography, these figures were 13.5%, 41.9%, and 44.6%, respectively. At the time of initial evaluation, the lymphoma involved extranodal sites in only 24 of 225. In the 74 cases evaluated with lymphography, the mode of spread was studied by observing the first site of recurrence after radiotherapy. New manifestations occurred in most patients within 2 years from the end of treatment and preferentially in extranodal sites. The involvement of the gastointestinal tract, either at the time of admission or early in the follow-up, was 20% in the group studied with lymphography. The possibility that a certain number of lymphoreticular sarcomas could arise concomitantly in Waldeyer's ring and in the gastrointestinal tract is discussed.

A phase II study of iproplatin was conducted in advanced squamous cell carcinoma of the head and neck both in patients previously treated with chemotherapy or not. Iproplatin was given intravenously every 4 weeks at the dose of 240–300 mg/m 2 without hydration. A total of 101 4-week courses was given to 50 eligible patients. No antitumor activity was detected. Drug-induced toxicity consisted in moderate myelosuppression, frequent but mild nausea and vomiting, and occasionally diarrhea and stomatitis. This study demonstrates that iproplatin given in this dose and schedule is devoid of activity in advanced squamous cell carcinoma of the head and neck.

We investigated for rearrangements of the immunoglobulin (Ig) heavy and light chain genes and of the T cell receptor gamma (TCR gamma) and beta (TCR beta) genes 45 biopsy samples from a variety of lymphoproliferative disorders. They were diagnosed histopathologically and immunophenotypically as non-Hodgkin's lymphomas (NHLs) of the B cell type (19 cases), NHLs of the T cell type (3 cases), NHLs of "undetermined" cell type (3 cases), atypical lymphoid proliferation (1 case) and AIDS-related lymphadenopathies with florid polyclonal follicular hyperplasia (19 cases). A monoclonal proliferation of B cells was shown by DNA analysis in all 19 B cell NHLs. In two immunohistologically determined T cell NHLs (both diagnosed as mycosis fungoides) the cells had rearrangements of TCR beta gene, whereas in the third case (lymphoblastic NHL) the cells had rearrangements of Ig heavy chain and TCR gamma and TCR beta genes. None of the B cell NHLs exhibited TCR gamma and TCR beta gene rearrangement bands. All the "undetermined" cell NHLs demonstrated rearrangements of Ig heavy chain gene associated with the germ line TCR gamma and TCR beta genes; in two cases light chain gene rearrangements were also found. The atypical lymphoid proliferation, in which the differential diagnosis was between a reactive or malignant process, and two out of 19 cases of florid polyclonal follicular hyperplasia showed a clonal B cell population by DNA analysis. This study indicates that there was a strong correlation between the rearrangements of specific genes and the immunophenotype of the NHL; moreover, DNA analysis of tissue biopsy specimens from phenotypically "undetermined" cell NHLs and from equivocal lymphoid proliferation using Ig and TCR gene probes yielded an answer in the cases analyzed. The significance of clonal B cell expansions found in two AIDS-related lymphadenopathies should be interpreted with caution.

This paper reports the preliminary results of a controlled study randomizing MOPP vs. a new four-drug combination (ABVD) in advanced Hodgkin's disease. ABVD consists of 6 cycles of adriamycin, bleomycin, vinblastine, and imidazole carboxamide. The purpose for designing this new combination was two-fold: to compare the efficacy of ABVD with MOPP, and to demonstrate absence of cross-resistance between the two regimens. Of 60 patients entered into the study, 45 (MOPP25, ABVD20) are presently evaluable for the analysis of remission induction. No patient was previously treated with chemotherapy; 20% had relapsed after primary radiotherapy. Whenever possible, complete remission was defined also through rebiopsy of known organ involvement. Complete remission occurred in 76% of patients treated with MOPP and in 75% of those given ABVD, with no difference between the two regimens as far as stage (IIIB-IIIS and IV), histologic type, and prior irradiation were concerned. Crossover carried out for progressive disease or for relapse after initial remission showed absence of cross-resistance between MOPP and ABVD. Toxic manifestations after ABVD were in general well tolerated and reversible. The percent of optimal dose for each drug was as follows: adriamycin 87%, vinblastine 87%, bleomycin 96%, and imidazole carboxamide 96%. These preliminary results indicate that in terms of complete remission, ABVD could represent a successful alternative to MOPP to be used either in MOPP failures or in sequential combination with MOPP. However, the lack of long-term followup limits at the present time an adequate comparison between the two treatments.

The results of treatment in 210 patients with testicular carcinomas other than pure seminoma are analysed. Patients with negative retroperitoneal nodes had a very good prognosis following lymph node dissection alone. Patients with positive nodes did much better after adjunctive chemotherapy than after post-operative irradiation. Patients with advanced disease showed significant improvement with intensive chemotherapy combined with surgery. Presently retroperitoneal lymphadenectomy combined with intensive chemotherapy seems to be the treatment of choice for metastatic testicular carcinomas.

Medical oncology is now accepted in Europe as a branch both of internal medicine and of clinical oncology. In this article the present situation of this discipline is analysed with reference to the plateau in the results achieved in chemosensitive tumours and to the small effect of chemotherapy in tumours considered to be "big killers". Although new avenues in tumour biology do not necessarily mean therapeutic success in the near future, at present basic discoveries are being developed for clinical therapy faster than before. Besides biological response modifiers, the development of new drugs should receive constant attention from medical oncologists. This attitude has persisted despite an awareness that the political community has had little interest in the allocation of funds for the development of new anticancer agents. Clinical trials have recently been subjected to some criticism. But unless large multicentre trials are continued with better quality control and organization it will not be possible to provide adequate resources for the many and various new drugs and biological response modifiers expected to enter the field in the next few years. The active involvement of medical oncologists in controlled clinical trials should then continue. Finally, the task and achievements of the scientific society, which allows close contacts among European medical oncologists, are briefly underlined.

Twenty-seven evaluable patients with small cell lung cancer (SCLC) resistant to, or relapsed after induction combination chemotherapy (CT) were treated with etoposide (VPJ6) plus cisplatin (DDP). Previous treatment was: alternating CT with cyclophosphamide (C), adriamycin (A), methotrexate (M), procarbazine (P) (CAMP)/VP16, BCNU (B), hexamethylmelamine (H) (VP16BH) in 16 patients; C, A, vincristine (CAV) in 6 patients; C, A, and VP16 (CAVP16) in 5 patients. We observed 2 (7%) complete responses (CR) and 9 (33%) partial responses (PR). Duration of CRs was 8 and 14 weeks, respectively. PRs lasted a median of 22 weeks (range 16-44). Seven of 21 (33%) patients previously treated with VP16 responded to DDP plus VP16 (D-V). These results confirm D-V regimen as active in SCLC patients even when heavily pretreated. Our 33 % response in patients who had VP16 in their induction treatment regimen provides further evidence of an important potentiating effect of DDP, as reported in animal system.

In an attempt to define the activity and toxicity of low-dose aminoglutethimide plus steroid replacement in advanced breast cancer, we treated 40 patients with aminoglutethimide 500 mg/day + hydrocortisone 50 mg/day. Previous treatment consisted of additive hormones in 29 patients, oophorectomy in 8, and chemotherapy in 32. Among the 37 patients evaluablefor response and toxicity, 5 objective responses (16.2%) and 20 stable diseases (54%) were noted. Toxicity, absent in 23 patients (62.I %) and mild in 14, consisted mainly of Grade I (WHO) nausea, drowsiness, cutaneous rash, and dizziness. Responders and patients with stable disease experienced a similar survival (median not reached at 22 months). Aminoglutethimide at low doses appears to be beneficial in patients refractory to conventional therapies even if the objective response rate is low.

The medical records of 407 consecutive patients with malignant lymphoma (Hodgkin's disease 184, non-Hodgkin's lymphomas 223) admitted to the Istituto Nazionale Tumori of Milan from August 1970 to April 1973 were analyzed for the occurrence of varicella-zoster (V-Z). Two hundred and thirty-two patients underwent laparotomy with splenectomy as part of their diagnostic work up. This procedure was not carried out in 175 either because of extralymphatic involvement before surgery or because they were high risk patients. V-Z occurred in a total of 17% of patients with Hodgkin's disease and in 9% of those with non-Hodgkin's lymphomas, respectively. In Hodgkin's disease the infection was more often encountered in the lymphocytic depletion type (26%), while no statistical difference was observed among lymphocytic, histiocytic and mixed type lymphomas. The incidence of infection during the first 12 months from staging was 58% for Hodgkin's disease and 71% for non-Hodgkin's lymphomas. The incidence of V-Z was higher (16%) in splenectomized compared to non-splenectomized (9%) patients. The difference was statistically significant (P

The use of antitumoral drugs is increasing constantly. The economic cost pro capite of the commonest oncotherapeutic treatments has been analysed. The calculation is carried out on the basis of out-patient as well as in-patient treatment. The costs were identical in the hospital where the study was carried out due to the application of the recent regional health legislation. A number of considerations are made regarding the implications of unqualified use of the medical treatment of cancer.

Twenty-two patients with advanced testicular cancer received iproplatin at a dose of 180–240 mg/m 2 every 4 weeks. All the patients progressed or recurred after chemotherapy including cisplatin. The most severe toxicity was thrombocytopenia with two toxic deaths after a first cycle of 240 and 180 mg/m 2 respectively. Nausea and vomiting were almost universal but mild in intensity. One renal failure occurred 6 weeks after the first cycle while the tumor was progressing. No antitumor activity was observed in this heavily pretreated population of patients.

A sequential combination of tamoxifen and medroxyprogesterone acetate has been evaluated in 42 postmenopausal untreated patients with metastatic breast cancer. Patients received tamoxifen 10 mg b.i.d., days 1-14, followed by medroxyprogesterone acetate 500 mg b.i.d., days 15-28, orally in an alternating sequence until progression. Twenty-two out of 40 evaluable patients showed an objective response to treatment (55%, 95% confidence limits 38-75%). A significantly higher response rate was observed in patients with age greater than or equal to 70 years, with soft tissue dominant lesions and with only one metastatic site. Median time to progression was 41 weeks and the median survival time 88 weeks. In 4 cases treatment was discontinued because of severe toxicity while in the remaining patients no toxicity (20 patients) or mild side effects (17 patients) have been observed. After 2 months of therapy, this combination showed a progestogenic effect on the endocrine parameters inducing a significant decrease of SHBG, gonadotropins, testosterone and cortisol. These preliminary clinical results and the moderate toxicity of the sequential combination support the need to further investigate this approach.

RUDOLF A. JOSS,* SILVIO MONFARDINI,t MOGENS HANSEN,; PER DOMBERNOWSKY,§ JOSETTE RENARDfl and HERBERT M. PINED07 for the EORTC Early Clinical Trials Group** *Institute for Medical Onzology, lJniversi@ of Bern, Inselspital, Bern, Switzerland, TCentro di Rifcrimtnto Oncologico, Aviano, Itab, $Bispebjerg Hospital, Copenhagen, Denmark, § lJniversi& Hospital, Herlev, Denmark, [(EORTC Data Center, Brussels, Belgium and TDepartment of Oncolo~, Free University Hospital, Amsterdam, The Netherlands

Thirty-one patients with advanced, biopsy-proven squamous cell carcinoma (SCC) of the head and neck were treated with intraarterial chemotherapy (IAC) and subsequent radical surgery. Cisplatin at 25 mg/d (4 hours of infusion) and bleomycin at 15 mg/d (20 hours of infusion) were administered for 10 consecutive days. Radical surgery was performed after clinical evaluation 2 weeks later. Clinical tumor regression (total disappearance or shrinkage of the tumor mass by more than 50%) was recorded in 28 of 31 (90.3%) patients. Tumor regression was then assessed pathologically using a procedure based on examination of large serial histologic sections of the whole surgical specimen. Tumor residue was classified pathologically according to the TNM categories: RO, no residual tumor (five cases [16.1%]); R1, microscopic residual tumor (tumor residue detectable only at the microscopic level; 12 cases [38.7%]); and R2, macroscopic residual tumor (tumor mass detectable also on the fresh or fixed specimen and/or by the naked eye on the stained tissue sections; 14 cases [45.2%]). Moreover, tumor cell and/or stromal changes possibly associated with tumor regression were found in 77.4% of the cases. Metastatic lymph nodes were found in 12 cases (38.7%), and regression changes were observed in most lymph node metastases. Only standardized, prospective pathologic protocols for the analysis of whole specimens by serial sections permit the assessment of existing tumor residue. The TNM classification of pathologic tumor residue and definitions that we used appear feasible and reliable enough in evaluating postchemotherapeutic tumor regression.

The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m2. The drug disappeared from plasma biexponentially with a mean elimination half-life of 38 +/- 3 h; the mean apparent volume of distribution and the plasma clearance were 805 +/- 91 1/m2 and 14 +/- 2 1/h per m2. Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%-15% and 0.1%-6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.

In stage IV non-Hodgkin's lymphomas, CVP (cyclophosphamide, vincristine, and prednisone) was randomly compared to ABP (adriamycin, bleomycin, and prednisone). Of 62 patients entered into the study, 57 (CVP 27, ABP 30) were considered evaluable for comparison. In patients with liver and/or marrow involvement a second biopsy was performed to define complete remission (CR). CR occurred in 48% of patients treated with CVP and in 50% of those given ABP. The median duration of CR was 10.5 and 20.5 months, respectively. The difference is not statistically significant. Also the survival of complete responders was not significantly different between the two treatment groups. After cross-over, secondary treatment with CVP produced an overall response rate of 40% (six of 15), compared to 50% (six of 12) obtained with ABP. In the ABP group, four patients developed a reversible interstitial penumonia. In two other patients, cardiomyopathy (fatal in one) was observed. In conclusion, although complete remission was similar in both groups, cumulative toxicity occurred in few patients given ABP. However, this combination could represent in effective alternative treatment to be used either in CVP failures or in sequence with CVP.

Sixty consecutive patients with Stage III or bulky Stage II nonseminomatous germinal testis tumors were treated with cisplatin, vinblastine, bleomycin combination chemotherapy (PVB). One patient died of acute toxicity after the first course of therapy, 16 entered complete remission (CR) after two or three inductions, and 36 underwent surgery for removal of residual masses after the third cycle. No residual tumor was found in 16 cases, 10 had mature teratoma, and residual malignant tumor was completely resected in 8 of 10 patients. On the whole, 52 of 59 cases (88%) who completed the therapy entered CR, 34 (58%) with PVB and 18 (30%) with PVB and resection of the residual disease. The major beneficiaries of surgery were patients with bulky metastases (17 of 45, 38%) and those with primary teratocarcinoma (13 of 24, 54%). All of the patients who entered CR received two additional inductions and no maintenance. After a median follow-up period of greater than 3 years, 40 patients (68%) remain continuously disease-free, 1 died in CR, and 3 of the 11 who had relapse were salvaged. All of the 32 patients with lung deposits less than 5 cm and/or lymph node metastases less than 10 cm entered CR after the combined treatment modality, and 29 (91%) are alive disease-free. Also, 20 of 27 patients (74%) with far-advanced disease (lung and lymph node metastases larger than 5 and 10 cm, respectively, extrapulmonary disease) entered CR after PVB and surgery, but only 11 (41%) are continuously disease-free. Early resection of the residual tumor during PVB combination chemotherapy greatly increased the CR rate, but relapses were very frequent in patients with far-advanced disease.

Eighteen cases of malignant lymphoma associated with pregnancy observed at the National Cancer Institute of Milan from 1953 to 1968, are reported. Four patients without retroperitoneal adenopathies were treated prophilactically with endolymphatic radiotherapy (Lipiodol Fluide 181I) and became pregnant afterwards. Their pregnancy had a normal outcome. Two patients treated respectively during the first 4 months and from the 6th to the 7th month of pregnancy with antiproliferative agents (chlorambucil, vinblastine) delivered a normal infant while a third patient treated during the third month of pregnancy had a miscarriage. Two patients were treated with radiotherapy on adenopathies above the diaphragm and had normal pregnancy and delivery, with normal foetuses. The importance of diagnostic lymphography during pregnancy to define the stage of the disease and to plan the appropriate treatment is stressed. A therapeutic abortion is indicated only in presence of adenopathies below the diaphragm or in case of visceral involvement, discovered during the first three months of pregnancy. It was performed in one case after a lymphographic diagnosis of pelvic involvement.

The natural history of 292 consecutive cases of reticulum cell sarcoma and lymphosarcoma of Waldeyer's ring and the survival rate after radiotherapy are reported. In our institute since 1928 from 30 to 35% of pharyngeal neoplasms have been lymphomas, and of these 55% have been reticulum cell sarcomas, 21% lymphosarcomas, and 1% Hodgkin's disease. This high incidence may probably be ascribed to the fact that in all malignant lymphomas, irrespective of the clinical presentation, a systematic biopsy of the whole Waldeyer's ring was carried out. Pharyngeal lymphomas were confined to Waldeyer's ring in 19.6% of cases, with initial spread to contiguous cervical nodes in 43.8%, to distant nodes in 24.2%, and to extranodal tissues in 12.4%. Lymphography showed abnormal retroperitoneal lymph nodes in 38.3% of cases. There was gastrointestinal involvement either initially or later in 17.6% of cases. High-energy radiation therapy to both sides of the neck was the treatment of choice for local and regional disease. It achieved a five-year survival rate of 41.9% in the group of 97 patients treated during the past decade. The incidence of relapse (recurrence and new manifestations) was highest in the first year after treatment.

Adriamycin is a new antitumor antibiotic of the anthracycline group. Its chemical structure is very close to that of daunorubicin. Pharmacological studies demonstrated that adriamycin has a higher therapeutic index (1.21) than daunorubicin (0.67). Adriamycin was given intravenously to 53 patients with different types of leukemia and cancer (13 children and 40 adults). Three doses were used: 0.4 mg/kg (pretreated patients), 0.65 mg/kg (untreated adults), 0.8 mg/kg (children). Three different schedules were also employed regardless of the single dose/kg (table 1): A) Loading-dose schedule: treatment for 4 consecutive days followed by a 3 day interval: the drug was then restarted 1–2 times a week; B) Alternate day-dose schedule: treatment every other day for 4–6 doses followed by a 3 day interval; the drug was then restarted 1–2 times a week; C) Intermittent-dose schedule: two treatments for 3 consecutive days separated by two intervals of 4 days; the drug was then restarted 1–2 times a week. The chief evidence of toxicity was a triad of symptoms: stomatitis, bone marrow depression and alopecia (table 2). The oral ulcerations where the first sign of toxicity in more than 50 % of cases. The first sign of toxicity usually precedes the other side effects by 1–3 days. Fever, gastroenteritis and phlebitis at the site of injection were toxic signs of minor importance. However, to avoid phlebitis the drug should be injected through a tube of a free-running intravenous infusion. Adriamycin seems from the present series to be devoid of significant cardiac toxicity. As expected, children tolerated higher doses than adults and all pretreated patients became rapidly intoxicated with small doses. The less toxic schedule appears to be the intermittent one (C). Prompt and consistent responses were observed in many cases (table 4), but they were usually short lived. The drug appears therefore to be a potent growth-inhibiting compound more useful for inducing the first remission than for mantaining it. Acute lymphoblastic and chronic myelogenous leukemias as well as malignant lymphomas, neuroblastomas and soft tissue sarcomas were the diseases most sensitive to adriamycin.

A retrospective study was conducted on the survival of 178 patients with chronic myelogenous leukemia from January 1948 through December 1967. Through analysis of survival time, comparison has been made between a group of 50 patients treated with chemotherapy alone vs. a group of 84 patients treated with radiation therapy to the spleen and chemotherapy. No difference could be found in these two major therapeutic groups (median survival 31 months for both). Further analysis has been made to determine whether survival could be correlated to the initial extent of disease. Initial hemoglobin value, WBC, platelet counts, absolute blast count, spleen size, and selected combination of these factors showed no significant correlation with survival. Acute blastic transformation occurred in 60% of 117 patients. Infection as a cause of death was less frequent in patients with progressive disease without acute blastic transformation, while renal failure due to hyperuricemia and thromboembolic phenomena occurred more often in this group as compared with patients dying in acute blastic phase.

Encephalopathy is a serious adverse reaction occurring in 15-30% of patients treated with the alkylating agent ifosfamide. Patients with this adverse effect may experience seizures, drowsiness, confusion and hallucinations of different grades of severity. In this article, we describe five cases of acute CNS toxicity in patients aged > or =65 years of age treated with ifosfamide and we review data on the management and outcome of this serious complication in elderly patients. All five patients experienced symptoms of encephalopathy soon after receiving combination chemotherapy including ifosfamide for different tumours. All of the patients had been assessed by means of a Comprehensive Geriatric Assessment for the presence of associated diseases, disability, cognitive status and depression, and scores were satisfactory in all patients, although case 5 was deemed frail because of cancer-related limitation in movement. In four patients, the antidote methylene blue (methylthioninium chloride) was administered intravenously, with successful recovery in three patients and a fatal outcome in the fourth patient. The fifth patient rapidly recovered after discontinuation of ifosfamide and did not receive methylene blue. The roles of older age, peak ifosfamide concentration, low albumin levels, increased serum creatinine and bulky abdominal disease as predisposing factors for ifosfamide-related encephalopathy in retrospective series are controversial.Although methylene blue has been frequently administered in patients with ifosfamide-related encephalopathy, its efficacy in this context has not been assessed objectively. Thus, careful baseline evaluation of elderly patients and constant clinical observation during infusion, especially during the first course of therapy, are recommended to reduce the risk of severe CNS toxicity from ifosfamide.

We report the case of a woman with HER2-positive metastatic breast cancer who achieved prolonged complete remission of multiple liver metastases after treatment with weekly trastuzumab plus paclitaxel but relapsed in the brain soon after stopping trastuzumab maintenance therapy which had been prosecuted for almost three years. In the absence of randomized trials, the optimal duration of trastuzumab administration after achieving complete remission of metastatic breast cancer remains questionable.

6593 Background: Recently, a Multidimensional Prognostic Index (MPI) based on a Comprehensive Geriatric Assessment (CGA) was developed and validated in independent cohorts of older patients (pts) demonstrating good accuracy in predicting 1-year mortality. Aim of the study was to validate a cancer-specific modified MPI (Onco-MPI) for mortality prediction in older cancer pts. Methods: 658 consecutive new cancer pts aged ≥70 years (mean age 77,1 years, 433 females, 65.8%) referred to the Geriatric Oncology Program from Sep 2004 to June 2011 were included. MPI was calculated according to a previously validated algorithm (derived from multivariate Cox regressions) as a weighted linear combination of the CGA domains: age, sex, basal and instrumental activities of daily living (ADL, IADL), Performance Status, Mini Mental State Examination, Body Mass Index, comorbidity by Cumulative Illness Rating Scale, number of drugs and presence of caregiver. To develop the Onco-MPI, cancer sites (breast 46.5%, colorectal 21.3%, lung 6.4%, prostate 5.5%, urinary tract 5.0%, other 15.3%) and cancer stages (I 37%, II 22%, III 19%, IV 22%) were also included in the model. Pts were followed for a median of 2,5 years and mortality was recorded. Three grades of severity of the onco-MPI (low 0.0-0.46, medium 0.47-0.63, high-risk 0.64-1.0 score) were calculated on the basis of estimated recursive partition and amalgamation method (RECPAM) cut-offs. Discriminatory power and calibration were further assessed. Results: Overall 1-year mortality incidence rate (events/person-years) was 17.4%. A significant difference in mortality rates was observed for Onco-MPI low-risk compared to medium- and high- risk pts (2.1% vs 17.7% vs 80.8%, p

The essential role of the caregiver in the management of elderly cancer patients is still poorly documented. This case report concerns a woman with metastatic lung carcinoma who was sincerely informed and successfully treated with chemotherapy and gefitinib only after gaining the trust of her overprotective daughter. Devoting time to the relatives represents a key element to create a communicative and efficient relationship with older cancer patients.

After review of the pertinent literature on pathologic findings associated with Interleukin-2 (IL-2) therapy for metastatic malignancies (melanomas, renal cell carcinomas), two autoptic cases are described with particular emphasis on the cardiovascular and pulmonary changes. The authors report on the occurrence of massive transmural acute myocardial infarct in a patient with metastatic cutaneous melanoma, treated with recombinant IL-2, who did not show atherosclerotic lesions of the coronary arteries. Conversely, myocardial lesions were not found in the other patient with metastatic renal cell carcinoma, treated with recombinant IL-2; he had severe generalized atherosclerosis and died of pulmonary causes. It is suggested that myocardial direct toxic effects of IL-2 associated with capillary leak syndrome may determine a myocardial infarct. It is concluded that IL-2 therapy is not contra-indicated in oncologic patients with atherosclerosis of the coronaries if they are carefully monitored.

A case of extensive bone marrow infiltration due to gastric cancer is reported. A 65-year old man with an acute episode of anemia (Hb 4.1 mg/dl) and dyspnea was admitted to the Medical Department of a general hospital. Bone marrow biopsy showed extensive paratrabecular infiltration of a poorly differentiated adenocarcinoma of gastric origin. The primary tumor in the stomach was confirmed, and the patient was referred to our Institute and treated with combination chemotherapy (FAMTX) for 6 cycles. Due to the disappearance of bone marrow infiltration, the patient was considered for curative resection of the primary gastric cancer. After 27 months the patient is alive and in clinical complete remission.

A Phase II study of teniposide (VM26) in cutaneous T-cell lymphoma (CTCL) was performed in 15 patients affected by stage III, IV according to TNM (mycosis fungoides or Sezary syndrome). All patients were pretreated, and VM26 was administered at a dose of 100 mg/m2 weekly for at least 3 weeks. Objective responses were observed in 40% of the patients, with two complete responses lasting 26 and 46 months. The drug was well tolerated in elderly patients and deserves further evaluation either for inclusion in first-line combination regimens or for palliative treatment in heavily pretreated or elderly patients.

The clinicopathologic features of 45 human immunodeficiency virus (HIV)-infected patients (mainly intravenous drug users [IVDU]) with lymphoid neoplasias seen from September 1984 through July 1990 at an Italian cancer center are reviewed. Thirty-five had systemic non-Hodgkin's lymphoma (NHL), and ten had Hodgkin's disease (HD). Histologically, 27 NHL cases were intermediate grade (five cases) or high grade (22 cases, 14 of the small noncleaved cell type), according to the Working Formulation. Eight NHL cases, including four anaplastic large cell (ALC) BerH2 (CD30)-positive lymphomas, were in the miscellaneous group. Immunohistologic and/or gene rearrangement analysis showed the B-cell origin of 20 of the 24 NHL cases studied. At presentation, 71% of NHL patients had advanced stages (Stage III or IV), and 85% had extranodal disease (predominantly gastrointestinal tract and marrow). Of the 23 patients evaluable for treatment, only seven had a complete clinical response after lymphoma therapy; the median survival of 34 evaluable patients was 22 months after the diagnosis of NHL. Fifteen patients died; most deaths were attributable to progressive lymphoma and opportunistic infections. As with NHL, advanced disease, extranodal involvement, aggressive histologic findings, and poor response to therapy were also observed in patients with HD. This study shows that lymphoid neoplasias occurring in Italian IVDU with HIV infection and those previously reported in North American homosexual men with HIV infection share similar clinicopathologic features. However, some features such as the absence of history of Kaposi's sarcoma at diagnosis, the lack of detection of primary brain and rectal NHL, and the occurrence of B-cell ALC BerH2 (CD30)-positive NHL were observed uniquely in this series of patients.

Aims and background Patients included in clinical trials are “selected”, and they usually differ from those commonly treated. Methods: From 1999 to 2004, in the Medical Oncology Department of Padua (Italy), 70 metastatic colorectal cancers were treated with FOLFOX4. Results Our results, compared with those of the registration trial (response rate, duration of response and progression-free survival) appeared lower; overall survival was improved. Conclusions The number of therapeutic regimens more than their type influenced the results.