Prognostic factors for longer disease free survival and overall survival after surgical resection of isolated liver metastasis from breast cancer.

PURPOSE: Isolated liver metastases (LMs) from breast cancer (BC) occur in only 1-3% of the cases. Resection of isolated LMs improves survival. We examined the prognostic factors for time to LM development, disease free survival (DFS) and overall survival (OS) after BCLM resection. METHODS: From 2006 to 2009, 32 patients underwent LM resection. All of them had breast cancer surgery for their primary tumor and developed resectable LMs as the first and only site of disease progression. RESULTS: LMs developed after a median of 25 months. With a median follow up of 37 months (range 7-66) after metastases resection, median DFS and OS (with 95% CI) were 22.5 (12-40) and 37 (≥23) months, respectively. Tumor size ≥3 vs <3 cm and adjuvant chemotherapy vs no adjuvant chemotherapy correlated with shorter time to LM development (p<0.01 for both parameters). These parameters and BC negative estrogen (ER)/ progesterone receptors (PR) (ER?/PR? vs other) were related with shorter DFS. Positive (vs negative) axillary lymph nodes and BC negative ER/ PR (ER?/PR? vs other) status correlated with shorter OS (p<0.01 for both parameters). A period to metastases development ≥ 24 months (vs ≤24) and single (vs multiple) metastases were related with longer DFS and OS (p<0.01 for both conditions). CONCLUSION: Despite the relatively small number of patients in this study, we believe that positive ER/PR status for both BC and LMs, negative axillary lymph nodes, time to liver metastases development >24 months and single liver metastases predict longer DFS and OS after LM resection.

Incidence of brain metastases in early stage HER2 3+ breast cancer patients; is there a role for brain CT in asymptomatic patients?

PURPOSE: Human epidermal growth factor receptor 2 overexpression (HER2 3+) is reported in retrospective studies as a factor that contributes to higher incidence of brain metastases (BM) in patients with metastatic breast carcinoma. Although there are some reports suggesting higher incidence of BM in adjuvant trastuzumab trials, the true incidence, as well as the time of occurrence of BM in early-stage high risk breast carcinoma patients, has not been widely prospectively explored. The main objective of this study was to prospectively explore the incidence of BM during and after adjuvant trastuzumab administration in HER2 3+ early-breast carcinoma patients. METHODS: Two hundred and fifty-eight patients with early, HER2 3+ breast carcinoma have been included in this analysis. Brain computed tomography (CT) scan was scheduled once during adjuvant trastuzumab therapy and thereafter only if central nervous system (CNS) symptoms occurred. RESULTS: Eighty-five patients (33%) underwent brain CT in the absence of CNS symptoms. The median number of trastuzumab cycles at the time of brain CT was 9 (range 4-18). There were no BM detected by brain CT in these 85 asymptomatic patients. However, during a median follow up of 18 months 5/258 patients (1.93%) developed BM, but only 2 (0.77%) while still receiving adjuvant trastuzumab. The median time from breast cancer diagnosis to BM was 24 months (range 14-43). CONCLUSION: BM are a rare event during adjuvant trastuzumab treatment and brain CT screening is not justified in asymptomatic patients with early HER2 3+ breast carcinoma.

Clinical and pathological response to induction chemotherapy used as a prognostic factor in inflammatory breast cancer. Single institution experience.

PURPOSE: To evaluate clinical and pathological characteristics of patients with inflammatory breast carcinoma (IBC). Also, to evaluate the importance of achieved clinical and pathological responses to induction chemotherapy (iCT) and their role in the prognosis of IBC. METHODS: The medical records of 81 female patients with stage IIIB IBC, diagnosed between January 2008 and December 2010 at the Institute for Oncology and Radiology of Serbia (IORS) were evaluated. Almost all of the patients received anthracycline-based iCT. After 3-4 cycles of iCT, the clinical response (defined as complete response/CR, partial response/PR, stable disease/SD and disease progression/ PD) was assessed. Also, pathological response to iCT (defined as pathological complete response/pCR, near complete response/pNCR, partial response/pPR and no change/ pNC) was estimated in patients who had undergone surgery. All first metastatic sites were recorded. RESULTS: Clinical CR/PR was observed in 61.8% of the patients, while the pathological response (pCR, pNCR/near complete response, and pPR) rate in patients who had undergone surgery was 70%. During follow-up 22 (27.2%) patients developed PD (8 responders and 14 non-responders). Most common metastatic sites were the skeleton in non-responders and the liver in responders. Central nervous system (CNS) metastases developed in 24% of non-responders while no responder developed such metastases. Non-responders had shorter OS compared to responders, but without statistical significance. CONCLUSION: Although the number of the patients analysed in this study is relatively small, we believe that response to iCT could be used as a prognostic marker, since patients who initially failed to respond to iCT showed a higher risk for PD with development of distant metastases, primarily in bones and CNS, and shorter survival.

Do we know how many cancer patients have a family history of cancer?

PURPOSE: It has been estimated that approximately 5-10% of the general population have a family history that is indicative of hereditary cancer, predominately breast and colorectal. However, it is not precisely known how many patients have positive family history of cancer. The purpose of this study was to determine how many cancer patients have positive family history of cancer. METHODS: Patients were interviewed during the first visit to Daily Chemotherapy Hospital (DCH) of the Institute for Oncology and Radiology of Serbia, Belgrade. Data about patient cancer type and cancer types among family members were recorded in the hospital chart and analyzed. RESULTS: During an 8-month period, 677 newly diagnosed cancer patients with 9 cancer types were referred to DCH for chemotherapy. Positive family history (at least one first degree relative) for any cancer type was recorded in 163 (24.1%) patients and in 47 (6.9%) patients for the same cancer type. The highest percentage of the positive family history for the same type of cancer showed patients with breast cancer (9.9%), followed by colorectal (7.2%) and brain tumors (6.25%). CONCLUSION: The overall incidence of positive family cancer history was 31.0% and was higher than expected. Cancer can be more disturbing for persons who already had experience with this disease in a close family member. Those patients need special attention with more intensive and carefully preplanned psychological support.

Brain metastases as late breast cancer relapse. Single institution experience and review of the literature.

PURPOSE: Approximately 40% of HER2-positive breast cancer patients will develop brain metastases, usually during the first 2-3 years following initial diagnosis and up to 2 years after overt metastatic spread. However, there are no data about brain metastases development as a late disease relapse. In addition, there are no data whether the high incidence of brain metastases is maintained in patients with HER2 overexpression even in late brain metastases. The aim of this paper was to determine the incidence of brain metastases and the HER2 status in patients who developed late relapse, at least 5 years after the initial diagnosis. PATIENTS AND METHODS: Among 384 consecutive breast cancer patients with late relapse, only 8 developed brain metastases. Archival pathological specimens of the primary tumors of those 8 patients were tested by immunohistochemistry (IHC) for HER2 status. RESULTS: The incidence of late brain metastases was 2% (8/384). None of these patients had HER2 3+ primary breast cancer. CONCLUSION: This study shows that the risk for brain metastases in HER2 3+ breast cancer patients is very low or might be even absent as a late relapse. Absence of late brain metastases in HER2 3+ breast cancer might be attributed to specific biological characteristics of HER2 3+ carcinomas to develop brain metastases mostly in the early course of metastatic disease.

Incomplete operative removal of colorectal liver metastases followed by chemotherapy decreases survival in comparison to chemotherapy alone.

Metastatic colorectal carcinoma (CRC) has an inevitable fatal outcome except in a small percentage of selected patients, approximately 10-20%, with good prognosis after successful complete operative removal of the liver metastases. In patients not eligible for surgical resection of the liver metastases, chemotherapy is currently the only widely available treatment option. Controversy still exists about the criteria for operability of CRC liver metastases, and some patients, still undergo ineffective, i.e. unnecessary surgery. The aim of this paper is to analyse and compare the overall survival (OS) and time to progression (TTP) in patients who underwent incomplete removal of liver CRC metastases followed by chemotherapy, and patients treated with chemotherapy alone. Seventy-three patients with CRC liver metastases underwent incomplete operative removal of the metastases followed by FOLFIRI (Cohort A - 27 patients) or with FOLFIRI alone (Cohort B - 46 patients). Patients received FOLFIRI until progression. FOLFOX4 was used as second line chemotherapy. The median OS in Cohort A was 8 months, the median TTP was 5 months, and the response rate was 44%; the median OS in Cohort B was 19 months, the median TTP was 8m, and the response rate was 39%. There was a significant difference in OS and in TTP (p < 0.01) in favour of the chemotherapy alone group (B). Patients undergoing incomplete removal of the liver metastases had shorter survival and TTP in comparison with patients treated with chemotherapy alone.

Fluoropyrimidine therapy: hyperbilirubinemia as a consequence of hemolysis.

BACKGROUND: Hemolytic anemia has been noted during treatment with a variety of chemotherapeutic agents. We observed mild compensated hemolytic anemia in a patient receiving capecitabine during a randomized, controlled trial of adjuvant therapy. In order to investigate the hypothesis that hemolysis is the underlying cause of the hyperbilirubinemia sometimes observed during capecitabine treatment, we evaluated factors associated with hemolysis in ten patients. Factors were also analyzed in ten patients receiving 5-fluorourocil/leucovorin (5-FU/LV). METHODS: Twenty chemotherapy-naïve patients undergoing surgery for Dukes' C colon cancer were included in the phase III, 'X-ACT' trial, and randomized to receive 24-week adjuvant treatment with either oral capecitabine (eight cycles of 1,250 mg/m2 twice daily for 14 days, followed by a 7-day rest period) (n=10) or 5-FU/LV administered according to the Mayo Clinic regimen (six cycles of LV 20 mg/m2 followed by 5-FU 425 mg/m2, administered as an i.v. bolus on days 1-5 every 28 days) (n=10). Ten patients randomized in each treatment arm were evaluated. Hemolytic parameters evaluated included bilirubin, lactate dehydrogenase, haptoglobin, and reticulocytes. RESULTS: Seven patients receiving capecitabine and three patients receiving 5-FU/LV experienced grade 1/2 elevations of bilirubin during the 24-week treatment period. In most cases, hyperbilirubinemia was associated with concomitant alterations in other hemolytic parameters. Five episodes of grade 1 compensated hemolytic anemia were reported in four capecitabine-treated patients, all of which were associated with hyperbilirubinemia. CONCLUSION: Adjuvant treatment with capecitabine or 5-FU/LV in a small sample of patients with Dukes' C colon cancer was associated with alterations in hemolytic parameters. These alterations, in particular hyperbilirubinemia, were associated in some patients with low-grade compensated hemolytic anemia. All changes were clinically insignificant, fully reversible, and may represent a fluoropyrimidine class effect. Further studies are indicated to evaluate the incidence and implications of this effect.

Therapy of aggressive fibromatosis is still an open question: a series of patients treated at a single institution.

PURPOSE: This study was an attempt to evaluate the possible role of chemo-hormonotherapy as a possible approach in managing inoperable, deep extra-abdominal aggressive fibromatosis. PATIENTS AND METHODS: A series of patients with inoperable, deep extra-abdominal aggressive fibromatosis, were treated with combination chemo-hormotherapy. Therapy consisted of 6 cycles standard CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2), given bolus intravenously (i.v.) on day 1, plus prednisone 40 mg/m(2)/day, days 1-5, every 3 weeks) and tamoxifen 20 mg daily. RESULTS: From 1995 to 2004, 9 patients, concomitantly, without selection, were included in this investigation. Their median age was 24 years (range 18-47), with predominantly male sex (6/9). Extremities were the most frequent localization (5/9), followed by chest wall in 3 and abdominal wall in one patient. Tumor size in most patients was 5-10 cm, and 3 patients had bulky disease (over 10 cm). Five patients had undergone previous surgery (3 wide excisions and 2 palliative interventions). Complete remission (CR) was observed in one patient, partial remission (PR) in 4 and stabilization of disease (SD) in 4 patients. In responders, the median duration to the onset of response was 10 months (range 4-14); median response duration was 32+ months (range 14-82). No relapse of disease was observed up until now. CONCLUSION: Systemic treatment should be considered in patients with aggressive fibromatosis for whom local treatment approaches are not possible or have failed. All patients should be included in clinical trials.

Negative CEA values in metastatic colorectal carcinoma and the likelihood of complete chemotherapy response.

INTRODUCTION: Experimental results reported in the literature have suggested that CEA might inhibit host defense mechanisms and that immunotolerance to CEA could play an important role in the development of metastases in colorectal carcinoma. It might therefore be assumed that negative CEA values during metastatic disease represent a favorable prognostic factor. Surprisingly, there are very few data available about negative CEA. The aim of this study was to determine the significance of negative initial CEA values in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Initial CEA values were determined in 114 patients with metastatic colorectal carcinoma. The patients were divided into three groups according to these values: I (n=22) <5 ng/mL; II (n=33) 5-100 ng/mL; III (n=59) >100 ng/mL. RESULTS: Seven/114 complete responses (CR), 22/114 partial responses (PR), 45/114 instances of stable disease (SD) and 38/114 of progressive disease (PD) were registered, while two patients were not evaluable. There were six long-lasting CRs (median 24 months, range 10-37 months) in the CEA-negative patient subset, while in the CEA-positive subset there was only one CR, in a patient with an initial CEA level of 18 ng/mL. The mean initial CEA values in the different response categories were: CR: 4.0 ng/mL; PR: 436 ng/mL; SD: 1442 ng/mL; PD: 6071 ng/mL. The likelihood of response, in particular CR, was highly dependent upon CEA levels (Fisher's exact test, 0.00001). The median survival decreased significantly with increased values of CEA (p=0.006). CONCLUSION: Negative CEA in metastatic disease was the main characteristic of the patient subset capable of attaining CR. When relapsing, all patients but one became CEA positive.

The changes of serum immunoglobulins in patients treated by a combination of anti-CD20 monoclonal antibody rituximab plus chlorambucil for low-grade non- Hodgkin's lymphoma.

PURPOSE: To assess whether the therapeutic application of monoclonal anti-CD20 antibody (rituximab) may affect normal B lymphocyte function, since CD20 is involved in their activation, proliferation and differentiation. PATIENTS AND METHODS: Serum immunoglobulins (Igs) concentrations and their possible relation to pretreatment levels of Igs and B-cells ratio as well as the T/B cell ratio were investigated in 9 patients with low-grade non Hodgkin's lymphoma (NHL) during the administration of rituximab (Mabthera(R)) and chlorambucil combination therapy. Serum Igs concentrations were determined by the radial immunodiffusion (RID) method and the number of B and T lymphocytes by flow cytometry analysis. RESULTS: The altered values of Igs concentration and B cell number were registered in each patient before therapy. Generally, the therapy did not normalize the pretreatment alterations of these parameters, though it depleted malignant clones from peripheral blood. Nevertheless, IgM and IgA concentrations have been considerably changed from baseline level (35-74%) in 5 patients. The concentration of IgA and IgM raised in 4, while the IgM declined from baseline values in 1 patient, irrespective of their therapeutic response. Four of these patients had a normal concentration of these Igs classes, and a profound B cell number alteration before therapy. CONCLUSION: The changes of IgM and IgA concentrations in relation to pretreatment B cell number, although found in a small number of patients, might deserve further investigation with an aim to study any interference of the anti-CD20-based therapy with lymphocytes function.

Amsacrine and cisplatin in poor prognosis patients with metastatic transitional cell carcinoma of the urothelium: a phase-II study.

OBJECTIVES: Amsacrine, as a single agent, was reported to be effective in patients with metastatic transitional cell carcinoma of the urinary bladder. Amsacrine is also associated with a lower toxicity than cyclophosphamide, doxorubicin and cisplatin therapy and has similar activity. But amsacrine has been forgotten in clinical studies of transitional cell carcinoma of the urinary bladder. The aim of present study was to investigate the toxicity and efficacy of amsacrine and cisplatin in chemotherapy-naive patients with metastatic transitional cell carcinoma of the urinary bladder. METHODS: We have treated 54 patients (41 males/13 females) with a median age of 62 (38-72) years. Performance status was 0/2, I/27 II/17 and III/8. The treatment included: amsacrine 85 mg/ m(2), days 1-2, and cisplatin 30 mg/m(2), days 2-5. Cycles were repeated every 4 weeks. We applied 169 cycles (median 3/patient). Of 54 patients, 39 had previous surgery and 12 had previous radiotherapy. Histological tumor grade was I/7, II/27 and III/20. RESULTS: 51 patients were evaluable for response (3 patients refused further treatment during the first cycle): 2 complete remission (4%); 15 partial remission (29%); 23 stable disease (45%), and 11 progressive disease (22%). The response rate was 33% (95% CI 21-46). On an intent-to-treat basis the response was 32% (95% CI 19-44). Durations of complete and partial responses were 14 (range 12-16) and 6.5 (range 3-11) months, respectively. Median survival was 9 (range 3-21) months. All patients were evaluable for toxicity. Grades III-IV toxicity was as follows: anemia 11%; neutropenia 37%, and thrombocytopenia 20%. None of the patients was excluded from the study because of toxicity. CONCLUSION: The combination of amsacrine and cisplatin is a regimen with mild and manageable toxicity. The present regimen seems to be active. Randomized study of the present regimen versus another low-toxicity regimens are necessary, especially for poor prognosis patients including those with a low performance status.

Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study.

This communication represents the definitive report of a randomized phase III study comparing cisplatin and carboplatin, in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma. A total of 221 patients entered the study and were randomized into two arms. Of these, 114 patients (109 evaluable for activity) were randomized to arm A, receiving cisplatin 120 mg/m(2), mitomycin C 8 mg/m(2) and vindesine 3 mg/m(2) per cycle; 107 patients (101 evaluable for activity) were randomized to arm B receiving carboplatin 500 mg/m(2) with the same doses of mitomycin C and vindesine per cycle. Patients with progressive disease (PD) were excluded from the study after the 2nd cycle, and those with stable disease (SD), partial response (PR) and complete response (CR) received six cycles of chemotherapy (or less in case of early progression). Patients were stratified according to the clinical stage (IIIB vs. IV), performance status (0+1 vs. 2+3) and tumor histological grade (I+II vs. III). In the cisplatin arm two patients (1.9%) achieved a CR, 38 (34.9%) a PR, 45 (41.2%) a SD and 24 (22.0%) had PD; the overall response rate was 40/109 (36.8%). In the carboplatin arm five patients (5.0%) achieved a CR, 31 (30.7%) a PR, 40 (39.6%) a SD, and 25 (24.7%) had PD; the overall response rate was 36/101 (35.7%). No statistically significant difference in response rate was present between the two arms, and the response rate was not influenced by performance status, histological grade or clinical stage. The Kaplan-Meyers curves displayed a significant advantage both for time to progression (P=0.005) and overall survival (P=0.008) for patients in the carboplatin arm. The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV, and occurred irrespectively of tumor histological grade; response duration and survival of responders was identical in the two arms. Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm (P=0.012). Thus, substitution of cisplatin by carboplatin in the combination chemotherapy regimen, although more hematologically toxic (but less emetogenic) resulted in a similar response rate, but a significantly longer time to progression and overall survival.

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.

Circulating immune complexes in advanced Hodgkin's disease: qualitative analysis and prognostic significance.

The level of circulating immune complexes (CIC) may be a reflection of the underlying malignancy and appears to be related to the stage of disease, tumor burden and prognosis. Prognostic factors at diagnosis, clinical response, survival and CIC were analyzed in 89 patients with Hodgkin's disease. All patients were newly diagnosed, in advanced stage and treated with MOPP regimen. The median follow-up was 41 months. CIC were estimated by the polyethylene glycol precipitation test. The median age was 40 years and 52% were under the age of 45. Nodular sclerosis and mixed cellularity were the most common histologies, 36 and 35% respectively. "B" symptoms were present in 65%, bulky disease in 29% and bone marrow involvement in 4% of the total. The erythrocyte sedimentation rate (ESR) was over 30 in 72% of patients and 27% had one or two extranodal localizations. Complete remission (CR) was obtained in 69 patients (77%). The only factor influencing the CR rate was the number of extranodal localizations (p<0.05). The ten-year relapse-free survival (RFS) and overall survival (OS) were 63 and 83%, respectively. RFS was adversely influenced by lymphocyte depletion histology (p=0.009) and by performance status over 1 (p=0.003). Elevated CIC levels were detected in 58% of the total. Patients with ESR over 30 had significantly higher values of CIC (p<0.05). Qualitative analysis of the CIC showed high levels of positivity to immunoglobulin G and M. C-reactive protein (CRP) was identified in 42% of all samples. CRP is an acute phase protein which shows conformational similarity to the immunoglobulin molecule. There were no significant correlations between levels of CIC and the other prognostic factors. Survival was not influenced by the CIC level.

Colorectal cancer: dilemmas regarding patient selection and toxicity prediction.

Irinotecan (Campto, Rhône-Poulenc Rorer) is probably the most studied drug used as second-line treatment for colorectal cancer. Its main disadvantages are toxicity and cost. Delayed diarrhea and neutropenia are the most common toxic side effects, both of which can usually be predicted, by knowing the criteria for patients who are at increased risk for those side effects. These criteria include poor performance status (>2), bulky disease, previous abdominal-pelvic irradiation, hyperleukocytosis and increased bilirubin >1.5 x normal upper range. There are some other less common toxic effects of irinotecan, such as pneumonitis, cardiac arrhythmia, paralytic ileus, liver dysfunction, tumor lysis syndrome. While these side effects are very rare, physicians should be able to recognize them, because the number of patients being treated with irinotecan is increasing. The authors report four cases of probable irinotecan-related toxicity with fatal outcome in all 4 patients. Two of these 4 patients were not in the known risk categories for irinotecan toxicity. One patient died with signs of hepato-renal syndrome, the other with signs of rapid tumor lysis-like syndrome. Two other patients with bulky disease and performance status 2, had increased urea, creatinine and bilirubin serum levels after irinotecan administration, that could not be explained as manifestation of disease progression only. Data on all uncommon irinotecan toxic effects should be gathered and analyzed so that toxic effects, other than diarrhea and neutropenia, are better defined and predicted.

Eight-hour infusion versus bolus injection of doxorubicin in the EAP regimen in patients with advanced gastric cancer: a prospective randomised trial.

BACKGROUND: Doxorubicin (40 mg/m2/cycle), etoposide (360 mg/m2/cycle) and cisplatin (80 mg/m2/cycle) comprise an efficient regimen in patients with advanced gastric cancer (AGC). However, its excessive hematological toxicity led doctors to avoid using the combination. Doxorubicin is the main cause of myelotoxicity in the EAP regimen. The aim of this study was to compare an eight-hour infusion of doxorubicin (arm A) with intravenous injection of doxorubicin (arm B) in the EAP regimen with respect to toxicity, objective responses, time to progression (TTP) and survival in patients with AGC. PATIENTS AND METHODS: One-hundred twenty chemotherapy-naïve patients with measurable AGC were randomised between September 1994 and August 1998. Sixty patients in arm A and sixty patients in arm B were considered as fully evaluable. The arms were well balanced for age, sex distribution, previous therapy, histological grade and performance status. One-hundred eighty cycles were applied in arm A (median 2) and 201 in arm B (median 4). RESULTS: No difference was detected (P = 0.28) in the response rate of arm A 20% (CR 3; PR 9; 95% CI: 10-30) and B 28% (CR 3; PR 14; 95% CI: 17-40). But there was a significant difference in PD (P = 0.005) between arm A (51%) and arm B (36%). TTP (P = 0.01) and survival (P = 0.02) analyses detected an advantage for arm B vs. arm A. Grades 3-4 toxicity were as follows (arms A%/B%): anemia 8/10, leukopenia 24/26, thrombocytopenia 6/16 (significance, P = 0.05), nausea/vomiting 5/8, diarrhea 6/2, mucositis 8/5. Apart from the trombocytopenia, there was no significant difference in toxicity grades 3-4 between the two arms. Four treatment-related deaths occurred, two in each arm. CONCLUSIONS: Bolus injection of doxorubicin is superior to eight-hour doxorubicin infusion in the EAP regimen in terms of survival, TTP and PD without being significantly more toxic.

High-dose anthracyclines in the treatment of advanced primitive neuroectodermal tumors in adults--a single institution experience.

Primitive neuroectodermal tumors (PNET) are rare malignancies of presumed neural crest origin, most often presenting as bone or soft tissue masses in the trunk or axial skeleton, in children and young adults. Treatment of advanced PNET in adults is not clearly defined in the literature. Data concerning dose-intensive chemotherapy regimens for poor-risk patients with those tumors are sparse, due to rarity of PNET in adults, their diverse presentation, the variable treatment procedures applied and the absence of direct comparisons. On the other hand, the role of anthracyclines in the treatment of advanced soft tissue sarcomas is well known and substantial. Six advanced PNET patients were treated at the Institute for Oncology and Radiology of Serbia, during last five years, with high-doses of doxorubicin or epidoxorubicin combined with cisplatin. The paper reviews each of our patients, discussing how does chemotherapy influence the outcome in these patients, in context of the feasibility of high-doses of anthracyclines in advanced settings. High dose anthracyclines (epidoxorubicin 150 mg/m2) in combination with cisplatin 120 mg/m2 induced a complete response lasting for 63+ months in a patient with desmoplastic medulloblastoma of the cerebellum metastatic to bones and bone marrow. The same treatment but with the epidoxorubicin dose of 180 mg/m2 induced a complete response in a patient with olfactory neuroblastoma. Administration of high dose Doxorubicin (75 mg/m2) seems feasible in association with irradiation treatment in patients with extraosseal Ewing sarcoma/PNET but the place of high dose chemotherapy within this setting remains to be determined.

The role of stable disease in objective response assessment and its impact on survival in advanced colorectal cancer: is "stable disease" a homogenous response category?

Stable disease is a category which is not included in the evaluation of the overall treatment response rate. In many studies with a response rate below 20%, chemotherapy almost doubles the survival of patients. In the most chemotherapy trials with advanced colorectal cancer patients, about 30-50% had stable disease. Despite belonging to the same category of therapy response, some patients with stable disease have achieved symptom improvement, but some have not. The aim of the study was to investigate whether the stabilization of the disease with clinical benefit is associated with benefit in survival. A total of 99 patients with advanced colorectal cancer were treated with carboplatin (80 mg/m2, day 1-7), 5-FU (750 mg/m2, day 1-5), leucovorin (100 mg/m2, day 1-5) every 4 weeks. After 4 courses, in the case of stable disease (SD), the patients were stratified according to clinical benefit achievement in: Group A--patients with clinical benefit who continued with chemotherapy until 8 cycles or until disease progression; group B--patients without clinical benefit in whom chemotherapy was stopped after 4 cycles. Clinical benefit was a composite of assessment of pain, ECOG performance status, weight and temperature. Clinical benefit required a sustained improvement in at least one parameter without worsening in any other. Of 97 evaluable patients 48 achieved stable disease. Of 22 pts. with SD clinical benefit performance status improvement was recorded in 17, pain relief in 14, improvement in body weight in 14 and temperature disappearance in 8 pts. Of 26 pts. with SD without clinical benefit, 7 were asymptomatic from beginning of the chemotherapy. No difference was detected in the survival between responders and SD clinical benefit pts. (p = 0.24), but there was significant difference between responders and SD pts. without clinical benefit (p = 0.0004). SD clinical benefit pts. had significant difference in survival in comparison to pts. with progressive disease (p = 5.1 x 10(-6)). The results of our study indicate that under category "stable disease" there are two different subpopulations of patients with quite different symptom response to chemotherapy, different time to progression and possible different survival.