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Aims and Background: "Augmented reality" is a technique to create a composite view by augmenting the real intervention field, visualized by the doctor, with additional information coming from a virtual volume generated using computed tomography (CT), magnetic resonance or ultrasound images previously acquired from the same patient. In the present study we verified the accuracy and validated the clinical use of an augmented reality navigation system produced to perform percutaneous CT-guided lung biopsies., Methods: One hundred and eighty consecutive patients with solitary parenchymal lung lesions, enrolled using a nonrandom enrollment system, underwent percutaneous CT-guided aspiration and core biopsy using a traditional technique (group C, 90 patients) and navigation system assistance (group S, 90 patients). For each patient we recorded the largest lesion diameter, procedure time, overall number of CT scans, radiation dose, and complications. The entire experimental project was evaluated and approved by the local institutional review board (ethics committee)., Results: Each procedure was concluded successfully and a pathological diagnosis was reached in 96% of cases in group S and 90% of cases in group C. Procedure time, overall number of CT scans and incident x-ray radiation dose (CTDIvol) were significantly reduced in navigation system-assisted procedures (P <0.001; z = 5.64) compared with traditional CT-guided procedures. The percentage of procedural complications was 14% in group S and 17% in group C., Conclusion: The augmented reality navigation system used in this study was a highly safe, technically reliable and effective support tool in percutaneous CT-guided lung biopsy, allowing to shorten the procedure time and reduce the incident x-ray radiation dose to patients and the rate of insufficient specimens. Furthermore, it has the potential to increase the number of procedures executed in the allocated time without increasing the number of complications.

Aims and Background: Methotrexate (MTX) and leucovorin (LV) can enhance the cytotoxicity of 5-fluorouracil (5FU) by modifying its metabolic pathway inside target cells. Some preclinical studies and clinical trials have suggested that the concurrent or sequential double modulation of 5FU by means of MTX and LV may give a higher activity than single biochemical modulations. The purpose of our phase II study was to assess the activity and toxicity of a biweekly regimen including MTX, levo-LV and 5FU in colorectal cancer patients., Methods: From July 1994 to May 1997, 100 consecutive patients affected by advanced or metastatic colorectal carcinoma were given MTX, 750 mg/m2 iv (2-h infusion) on day 1, and levo-LV, 250 mg/m2 iv (2-h infusion) followed by 5FU, 800 mg/m2 iv bolus on day 2, every two weeks. Patients were treated until complete response or progressive disease was documented, or for a maximum of 16 courses., Results: Among 97 eligible patients, 5 complete and 25 partial responses were obtained, giving an overall response rate of 31% (95% exact confidence limits, 22-41%). Response rate was significantly higher in patients with a good (ECOG scale 0) than with a poor (ECOG scale 1 or 2) performance status (40% versus 17%, P <0.02). Median time to treatment failure was 27 weeks, median survival time was 63 (95% confidence limits, 54-71) weeks, and 2- and 3-year probability of survival were 34% and 12%, respectively. Performance status was the only pretreatment characteristic significantly affecting the outcome of patients. Indeed, median survival time was 94 weeks for patients with a performance status = 0 and 37 weeks for patients with a performance status > or = 1 (P<0.05). Toxicity of the treatment was low and manageable; grade 3 to 4 leukopenia affected 8% of patients, whereas grade 3 diarrhea and mucositis occurred in 5% and 4%, respectively., Conclusions: The double biochemical modulation of 5FU by MTX and levo-LV is at least as effective as, and probably more effective than, the single modulation by MTX or by LV. It may therefore represent a therapeutic option for the palliative treatment of patients with advanced colorectal carcinoma.

Aims and Background: The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy., Methods: From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks., Results: Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity., Conclusions: The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.

Aims and Background: The authors report the case of a 23-year-old woman affected by intra-abdominal desmoplastic small round cell tumor (DSRCT) who obtained a complete response to multiagent chemotherapy. DSRCT is a rare, highly aggressive neoplasm generally arising in young people and seldom in females (about 20 cases described in the literature)., Methods: The patient underwent surgical resection of a large 15 x 15 cm mass located in the right lower abdominal quadrant, but after only 2 months later, two liver metastasis were noted. Thus, she was subjected to an aggressive antineoplastic treatment consisting of three groups of alternating non-cross resistant multiagent regimens administered every 21 days (cis-platin-etoposide-adriamycin-bleomicin; gemcitabine-ifosfamide-dacarbazine; methotrexate-5-fluorouracil-folinic acid) for a total of 9 administrations., Results: After one cycle of treatment including the administration of all the three alternated schemes of chemotherapy, a complete disappearance of liver disease was noted. The treatment was relatively well-tolerated and the toxicity was acceptable. At present, after 15 months from diagnosis and 12 months after starting chemotherapy, the patient is disease-free and in good health., Conclusions: Even though this study regards only a single patient, it is noteworthy because of the rarity of this neoplasm and because of the infrequent complete responses reported in the literature. The efficacy and manageability of the treatment, suggests that both the timing and schedule used could constitute an important therapeutical option for this aggressive and poorly chemo-responsive tumor.

Aims and Background: The presence of early metastases to distant sites in breast cancer patients is an infrequent event whose mechanisms are still not clear. The aim of this study was to evaluate the biologic and clinical role of DNA ploidy and cell nuclear grade of primary tumors in the metastatic process of a series of stage IV previously untreated breast cancer patients with only visceral metastases., Methods: DNA flow cytometry analysis on paraffin-embedded material and cell nuclear grading of primary tumors was performed on a series of 50 breast cancer patients with only visceral metastases at the time of initial diagnosis., Results: Aneuploidy was found in 28/46 (61%) of evaluable cases and was independent of site of involvement, clinical response, time of progression and overall survival of patients. Of the 46 cases evaluable for nuclear grade, 5 (11%), 16 (35%) and 25 (54%) were classified as G1 (well-differentiated) G2 and G3, respectively. Nuclear grade also was unrelated to response to therapy and overall survival, whereas time to progression was significantly longer in G1-2 than G3 tumors with the logrank test (P < 0.03) and multivariate analysis., Conclusions: Our results seem to stress the difficulty to individualize different prognostic subsets from a series of breast cancer patients with only visceral metastases at initial diagnosis according to DNA flow cytometry and nuclear grade.

A case of pneumocephalus in a 45-year-old male with undifferentiated rhinopharyngeal carcinoma is described. The patient was initially subjected to radiotherapy and then to transmaxillary resection and a second course of stereotactic radiotherapy for recurrent disease. Lastly, the patient was treated with chemotherapy because of local-regional disease progression. After two cycles of cisplatin, adriablastine and bleomycin, the patient suddenly entered in coma. Cerebral CT scan evidenced the presence of air in the frontal and lateral cornua, in the subarachnoid space of the base cisternae extending to the 7th cervical vertebra. After 8 months of a clinical stationary condition, the patient died. The various treatments used are critically reviewed, and modern therapeutic approaches for the neoplasm and the toxicity involved are discussed. We conclude that in nasopharyngeal carcinoma, for patients who relapse after radiotherapy, successive local-regional therapies (surgery, re-irradiation) should be carefully evaluated to avoid demolishing treatments, which are burdened with severe side effects that might influence the quality of life with only slight improvement of overall survival. Furthermore, the presence of persistant aqueous rhinorrhea in these patients should be carefully evaluated, because it could be an early symptom of a cerebrospinal fluid leak.

Aims and Background: Immunoglobulin heavy chain gene rearrangement serves as a marker of clonality and cell lineage in B-cell lymphoproliferative disorders. In this study we used the polymerase chain reaction (PCR) to detect clonal rearrangements of the immunoglobulin heavy chain gene in a group of patients with B-cell lymphomas., Methods: DNA was extracted from frozen tissue of 40 B-cell non-Hodgkin's lymphomas and subjected to PCR amplification using primers that recognize conserved sequences of the variable and joining regions of the immunoglobulin heavy chain gene., Results: Monoclonal rearrangements were detected in 23 of 40 malignant B-cell lymphomas. No clonal rearrangements were detected in the 10 control cases., Conclusions: We conclude that this PCR-based technique may provide a simplified and rapid approach for the detection of clonal immunoglobulin heavy chain gene rearrangements in B-cell lymphomas without recourse to Southern blotting, which can be reserved for cases in which PCR is negative.

Background: The relationship between solitary plasmacytoma and multiple myeloma is still unclear, but they can be distinguished by their different clinical course. Indicators of disease activity and extension, and of a possible evolution to multiple myeloma, have not been identified as yet., Methods: Two cases of solitary plasmacytoma are described: one of the mandible and one extramedullary plasmacytoma (EMP) of the rhinopharynx. Pathologic data included immunohistochemical staining for heavy and light Ig chains, and for the proliferating cell nuclear antigen (PCNA). Analysis of the peripheral immunological status and serum parameters (beta 2 microglobulin, thymidine kinase, IL-2, IL-6 and soluble IL-2 receptor) was performed and correlation was made with the clinical status. Flow cytometry analysis of nuclear DNA content and S-phase cell fraction were also studied in both neoplasms., Results: Solitary plasmacytoma of bone (SPB) showed important basal immunologic alterations and a marked increase in all serum parameters considered with respect to EMP. Ploidy analysis demonstrated an almost complete aneuploidy cell population for the SPB patient (80%), whereas in the EMP patient only 2% of the cells were aneuploid. The S-phase cells were 16% and 4%, respectively. PCNA index was 60% in SPB and 10% in EMP., Conclusions: Solitary plasmacytoma of the bone appeared to be a more aggressive form of plasmacellular neoplasia, distinct from EMP and similar to multiple myeloma. The study of serum parameters, together with analysis of PCNA, ploidy and S-phase fraction, can aid in better understanding disease activity, and in the choice of more adequate treatment. Moreover, serial analysis of some serum factors might be useful markers for monitoring the disease.

Aims: A comparative analysis was performed to verify a possible correlation between mammographic features and morphobiologic characteristics of the tumor in a series of 176 invasive primary breast cancer patients., Methods: Breast cancers were grouped according to mammographic features as follows: tumor mass with spiculated borders; tumor mass with well-circumscribed borders; tumor with density alteration of parenchyma with no clear borders; a cluster of microcalcifications as the only sign of tumor presence; tumor without mammographic abnormality. The tumor tissue biologic characteristics investigated were: hormone receptor content, tumor proliferative activity, DNA content and cytohistologic tumor-grade differentiation., Results: Spiculated tumors showed a significantly higher percentage of estrogen-receptor-positive cases with respect to circumscribed tumors, independently of the patient's menopausal status. Tumors with only microcalcifications were all from premenopausal patients and showed a significantly higher percentage of progesterone-receptor-positive cases (83%). Tumor proliferative activity did not significantly differ in the 5 mammographic breast cancer groups; aneuploidy was less frequent in tumors with spiculated borders than in mammographic types (39% vs 57%; p = 0.05); percentages of G1-G2-G3 tumors did not differ significantly among the mammographic groups considered., Conclusions: Certain relationships between mammographic features and biologic characteristics could be of potential clinical interest and stimulate more detailed studies on this issue.

Aims and Background: Urothelial cancer is a chemosensitive disease. However, cisplatin or anthracycline-containing regimens still provoke severe toxicity mainly due to reduced renal function and poor performance status (PS) of patients. The aim of this study was to verify the possibility of substituting carboplatin for cisplatin and epirubicin for doxorubicin in the M-VAC regimen in order to reduce toxicity and improve patient tolerance., Methods: Twenty patients with advanced urothelial tract tumors were treated with a chemotherapeutic regimen composed of methotrexate (30 mg/mq iv on days 1, 15, 22), vinblastine (3 mg/m2 iv on days 2, 15, 22), epidoxorubicin (35 mg/m2 iv on day 2) and carboplatin (250 mg/m2 iv on day 2) every four weeks (M-VECA). All patients had bidimensionally measurable disease., Results: Of the 18 evaluable patients, 3 (17%) obtained complete response and 7 (33%) obtained partial response (50% overall response). The median duration of response was 50 weeks (range, 28-88+). Grade III-IV toxicity (leukothrombocytopenia and mucositis) was observed in 20% of cases. Nevertheless, recovery was prompt in all but 2 patients with poor PS who died of nadir sepsis., Conclusions: M-VECA was an effective regimen for the treatment of patients with metastatic urothelial tumors and was safely employed in patients with a good PS. However, the possibility of substituting carboplatin for cisplatin as neoadjuvant therapy for less advanced stages needs further investigation in randomized studies.

To evaluate different methodologic approaches for HER-2/neu analysis, we performed Southern, Northern, Western blot and histochemical assay on 112 samples from 86 primary tumors and 26 synchronous axillary metastatic lymph nodes of patients affected by operable breast cancer. Simultaneous statistical analysis of data obtained with the four methods (31 samples) showed that Western blot detected a higher percentage of alterations than the other assays (Cochran and Victor tests, 0.01 less than p less than 0.05). The same result was emphasized by pair analysis (McNemar, p less than 0.05), which evaluated the assay data two by two. Immunohistochemical evaluations were more in accord with immunoprecipitation data when performed on frozen or Bouin-fixed, paraffin-embedded tissues than on formalin-fixed, paraffin-embedded tissues.

From January 1985 to September 1988, 60 women with advanced breast cancer were randomized in two arms to receive: A) tamoxifen (TAM) (20 mg/die) until progression or B) TAM (20 mg/die for 14 days) then medroxyprogesterone acetate (MPA) (1500 mg/die p.o. for 14 days) followed by 7 days of wash-out before repeating the TAM/MPA treatment. All patients were post-menopausal, previously untreated with hormone therapy, and with tumor receptor status determined immediately before randomization; all had objectively evaluable lesions. In order to verify hormone receptor variations due to the antiestrogen, when possible a second biopsy was performed after the initial 14 day cycle of TAM. Thirty-one and 29 patients were included respectively in arms A and B. Objective regression (CR + PR) was observed in 58% of group A and 75% of group B, with CR in 11% and 23%, respectively. Differences were not statistically significant. Median time to progression was 12 months for group A and 9 for group B. Overall survival has not yet been reached in group A while it was 34 months for patients of group B. Metrorrhagia was observed in two cases of group A and in 6 of group B, and thrombophlebitis in 1 and 3 cases, respectively. The second biopsy confirmed a clear increase of PgR content in 8/11 cases (75%). Plasma level variations of TAM, N-desmethyl TAM and MPA were checked at various intervals on 3 patients of group B, and confirmed that our schedule is able to produce a drug wash-out period for tumor cells. In conclusion, our study demonstrated that while the manipulation of hormone receptors seems possible, results indicating better overall survival and time to progression were not obtained with alternate sequential TAM-MPA therapy.

Sixty-nine postmenopausal women with disseminated breast cancer previously treated with endocrine and cytotoxic therapy were treated with tamoxifen (20 mg/day). Complete plus partial response (CR+PR) was observed in 29 % (CR 16 %) and stable disease in 28 %. The objective response was higher in soft tissue sites (52 %) compared to osseous (12 %) and visceral (13 %) disease. No regression or disease stabilization was observed in the presence of liver involvement. Free-interval, length and type of menopause, and estrogen receptor status (carried out only 26 patients) did not statistically influence the percent of objective response. Only 1 of 16 patients (6 %) who did not respond to previous endocrine therapy responded to tamoxifen, while 3 of 9 previous hormonal responders (33 %) achieved objective regression with antiestrogen therapy. On the contrary, the response to previous chemotherapy failed to influence the subsequent response to tamoxifen. The median duration of the response was more than 12 months and the median survival more than 18 months. Treatment was generally very well tolerated and in only one patient was temporarily discontinued because of thrombocytopenia.

Cis-diamminedichloroplatinum (CDDP) was administered i.v., at the dosage of 20 mg/m2 for 5 consecutive days and recycled every 3 weeks, to 11 patients with bidimensionally measurable metastatic lesions from bladder cancer previously untreated with antineoplastic drugs. Eight patients (6 men and 2 women) were evaluated for clinical response and 9 for toxicity. No complete regression was observed, and partial regression was obtained only in 3 patients (37.5%). Severe leukopenia and thrombocytopenia occurred only occasionally; moderate nausea and vomiting were observed in 5 cases. Nephrotoxicity was noted in 4 of the 9 patients evaluable for toxicity, and 2 of them, with ureteral obstruction, died of renal failure.

Mitomycin C was administered to 22 patients with metastatic breast cancer, refractory to hormonal therapy and conventional chemotherapy. Treatment was given by intravenous bolus injection at 20 mg/m2 of the drug and repeated at 6-week intervals. The overall response rate was 23%. Two complete remissions were seen in soft tissue lesions. Leukopenia occurred in 68% of the patients, thrombocytopenia in 36%, and anemia in 14%. One case of cardiotoxicity after previous treatment with adriamycin was observed. We conclude that mitomycin C is an active agent in disseminated breast cancer resistant to hormone therapy and chemotherapy. Combination of mitomycin C with other chemotherapeutic drugs will be tested.

Sixty-two women with advanced breast cancer were admitted to a pilot study in which a modified CMF regimen was administered. Cyclophosphamide was administered i.v. at a dosage of 600 mg/m2 on the same day as fluorouracil (600 mg/m2/i.v.) and methotrexate (40 mg/m2/i.v.). The therapy was recycled on the 21st day and in the presence of myelosuppression, the administration of the drugs was delayed for 1-2 weeks recovery of the hematologic values. CR + PR were obtained in 42% of patients and no change in 32% (U.I.C.C. criteria). Metastases to soft tissues showed CR + PR in 55% of the cases, bone in 33% and viscera in 35%. The menopausal status, the disease-free interval and the number of involved sites did not influence statistically the percentage of responses; however, the response rate was influenced statistically by previous treatment. The median duration of response was 7.5 months; the median overall survival of the 60 evaluable patients was 18 months. Due to myelosuppression, CMF i.v. administration was delayed 90/620 times (14%). Toxicity was acceptable and had a lower incidence than that reported in the literature in different series of CMF administered p.o. Nausea and vomiting, in particular, were limited to 24-48 h after administration of the drugs, and alopecia was seldom observed.

Twenty-five patients with advanced breast cancer were treated with 4-demethoxydaunorubicin (4-DMDR), a new antitumor analogue of daunorubicin, at the dose of 15-20 mg/m2/day x 3 days by oral route every 3-4 weeks. All patients were previously treated with chemotherapy and/or hormone therapy but none with anthracyclines. Of 23 evaluable patients, 1 complete and 5 partial remissions (26%) were observed for a median duration of 4+ months. Leukopenia and nausea occurred in 61% of the patients, vomiting in 30%, diarrhea in 17% and alopecia in 43%. There were 2 cases with minimal and transient EKG variations. 4-DMDR, administered orally in advanced breast cancer, was found to be generally well tolerated. Nevertheless, randomized trials with adriamycin or epirubicin are necessary to compare and to define the therapeutic activity and the toxicity of 4-DMDR.

The clinical records and histologic material of 18 consecutive patients with malignant histiocytosis were reviewed. The age of the patients ranged from 20 months to 72 years (median 35 years). There were 14 males and 4 females (3.5:1). Lymph node and liver enlargement, fever, and skin nodules were the most common physical findings; and leukocytosis was frequently the most abnormal laboratory test. Seven of 18 patients died, and their survival ranged from 1 to 15 months (median 8 months) after histopathologic diagnosis. The histologic findings on lymph nodes, spleen, liver, bone marrow, and skin were investigated with special reference to both the cellular composition and the pattern of lymph node involvement. Vascular invasion of small perinodal vessels was observed in 4 fatal cases. The absence of capsular invasion and the lack of cohesiveness among atypical proliferating histiocytes of malignant histiocytosis appeared to be inconstant. Sequential lymph node biopsies revealed in later stages the extension of the histiocytic proliferation from the sinuses into the cords and the complete obliteration of the nodal structures. The radiologic investigations yielded numerous pathologic findings that were consistent with the dissemination of the disease. Complete response to initial treatment was achieved in patients that were treated with radiotherapy and/or chemotherapy. Complete response with chemotherapy was achieved only when the treatment included adriamycin. The histologic and clinical features of the present series provide future evidence for the recognition of malignant histiocytosis as a distinct clinical and pathologic entity.

The possibility to administer chemo-hormone- and immunotherapy on an out-patient basis has greatly increased because of the progress reached in the management of the out-patient departments. The improved knowledges on tossicological, pharmacodynamic and therapeutic data as well as the advent of the cyclic schedules determined the feasibility of medical treatments even when they are combined with surgical and/or radiotherapeutic modalities. To the patient, the possibility to be carefully and effectively treated on out-patient clinic, renders more acceptable, both from a psychologic and economic point of view, even a prolonged combined treatment. On the same time, also the Institutions have some advantages both on their organization (a shorter median stay in hospital and consequently a reduced waiting list) and for their scientific program (increased number of patients who can be treated according to a therapeutic program, possibilities to obtain statistically valuable information on the treatment program of a given disease and on the knowledge of its natural history). The last five year increasing activity of the Out-Patient Clinic for Medical Oncology Treatment of the Istituto Nazionale Tumori of Milan is illustrated in Text-figure 1, while Text-figure 2 represents its actual organization; this is obviously of a multidisciplinary type, both on its diagnostic and therapeutic phase. Table 1 shows the activity carried out in 1975; it is noteworthy that 2,570 patients have been followed, thus accounting for a total of 20,164 medical examinations and/or intravenous drug administrations. Table 2 presents the incidence of the different types of neoplasia followed in the out-patient department: the large majority was represented by breast cancer (40%); followed by malignant lymphomas (31.5%) and pediatric tumors (7.5%). During 1975, 22 therapeutic protocols have been applied, 10 of which (table 4) required an initial hospitalization and 12 (table 5) could be entirely carried out in the out-patient department. As shown in Table 6 chest x-rays accounted for 52% and skeletal survey for 18% of the 11.906 radiological examinations. Table 7 shows the number of off-hand required radiological reports carried out for patients not geographically accessible who, in one signle day, could have their radiological, and medical examinations as well as their hemogram and treatment performed. A total 467 scintiscans have been required, 86% of which of the liver (table 8). The hemato-pathology unit counted out about 16,000 hemograms with platelets (table 9). The hemograms were always performed within 1-2 hours with immediate communication of the counts to the out-patient department. In order to modify clinical situations which were deteriorated because either of the disease or of the treatment 358 blood units were transfused.

Thirty-six patients with stage III-IV ovarian cancer, bulky disease, were treated with adriamycin and cyclophosphamide administered in two different dosages. Three or four cycles of chemotherapy were administered before the first surgery to facilitate the surgical debulking. After surgery, 6 additional cycles of chemotherapy were administered, and a second look was performed. Clinical CR + PR was observed in 19/30 (63%) evaluable patients after the first part of chemotherapy, but pathologic CR + PR was confirmed in only 13 (43%) patients. After the second part of chemotherapy and the second surgery, 5/30 (17%) patients had pathologic CR and 3/30 (10%) showed residual disease. The two regimens demonstrated similar activity (67% vs 56% clinical CR + PR) but a very different toxicity. In fact, 50% of patients treated with higher doses showed severe leukopenia and 25% severe thrombocytopenia, and 2/13 died of sepsis. The significant activity of adriamycin plus cyclophosphamide in ovarian cancer was confirmed, and increasing the dosage of the two drugs did not increase their activity but only their toxicity.