Myths and facts on adjuvant carboplatin for stage I seminoma.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
Jorge Aparicio
Publications and source records attributed to Jorge Aparicio.
The sword of Damocles and the treatment of stage I seminoma.
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Antineoplastic Agents↗
Treatment of stage I testicular germ-cell tumors.
More than a half of patients with testicular cancer are diagnosed with clinical stage I disease. In this setting, definitive cure is the rule. However, there is no consensus on the optimal treatment choice. A literature review (1990-2005) was performed in order to identify the pros and the cons associated with each therapy, as well as their long-term outcomes. Several treatment alternatives yield similar efficacy results. Thus, therapy-related morbidity, economic costs, quality-of-life issues, and patient preferences should be considered. Refinement in the knowledge of predictive factors for relapse and amounting experience with both surveillance and adjuvant chemotherapy have led to consideration of risk-adapted treatment policies as an alternative to more traditional approaches (i.e., prophylactic irradiation for seminomas and retroperitoneal lymph node dissection for non-seminomas). In conclusion, with cure rates approaching 100%, close surveillance for low-risk patients and adjuvant chemotherapy for those at high risk of relapse seems the preferred option for clinical stage I testicular cancer, in both seminoma and non-seminoma cases.
Chemotherapy, Adjuvant↗
Clinical predictors of severe toxicity in patients treated with combination chemotherapy with irinotecan and/or oxaliplatin for metastatic colorectal cancer: a single center experience.
INTRODUCTION: Little has been published regarding clinical predictors of severe toxicity in patients with metastatic colorectal cancer (CRC) treated with combination chemotherapy (CT) with oxaliplatin and/or irinotecan. MATERIAL AND METHODS: We analyzed retrospectively 142 patients treated between 1996 and 2004 in our center with these regimes with regards to grade 3-4 toxicity and overall survival (OS) rates. Köhne's prognostic classification could be applied in all patients. RESULTS: Köhne classification: good (54.2%), intermediate (26.8%), and poor prognosis (19%). 50.4% received irinotecan-based CT. Median number of cycles 6 with a total response rate of 38.9%. 23.2% stopped first-line CT due to toxicity. 50.7% suffered grade 3-4 toxicity: digestive (28.2%), hematologic (19.7%), and fatigue (25.4%). 7.7% episodes of neutropenic fever with 4.9% toxic deaths. 70.9% of grade 3-4 episodes occurred in the first four cycles. Median follow-up of 33.9 mo; median OS of 15.9 mo. For Köhne classification: good (20 mo), intermediate (15.8 mo), and poor (6.8 mo). Toxicity analysis: female sex and age > 70 yr predicted higher overall grade 3-4 toxicity, with no differences in CT efficacy; age > 70 yr and PS > 1 predicted higher grade 3-4 fatigue. No relationship could be found between baseline laboratory characteristics and higher toxicity, except baseline hemoglobin and grade 3-4 hematologic toxicity. CONCLUSIONS: Female and elderly patients have a higher grade 3-4 toxicity rate when treated with combination CT with oxaliplatin or irinotecan. Prognostic classifications such as Köhne's can help differentiate subgroups of patients who benefit little with the use of combination CT.
Adult↗
Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study.
PURPOSE: To assess the efficacy of a risk-adapted treatment policy for patients with stage I seminoma by using universally accepted risk criteria. PATIENTS AND METHODS: Between 1999 and 2003, 314 patients with clinical stage I seminoma after orchiectomy were prospectively included. One hundred patients (31.8%) presented no risk factors and were managed with surveillance. In contrast, 131 patients (41.7%) had tumors larger than 4 cm, 33 patients (10.5%) had rete testis involvement, and 50 patients (15.9%) had both risk factors. All the latter received two courses of adjuvant carboplatin. RESULTS: Chemotherapy was well tolerated, as only 17 patients (7.9%) presented grade 3 to 4 toxicity. Relapses were observed in six patients (6.0%) on surveillance and in seven patients (3.3%) treated with carboplatin (0.8% of tumors larger than 4 cm, 9.1% of those involving the rete testis, and 6.0% of patients with both risk criteria). All were located at the retroperitoneum, except for one at the spermatic cord. Median tumor size was 25 mm (range, 11 to 70 mm), and median time to relapse was 9 months (range, 4 to 28 months). All patients were rendered disease-free with chemotherapy (etoposide plus cisplatin). Median follow-up was 34 months (range, 12 to 72 months). The actuarial 5-year disease-free survival rate was 93.4% for patients on surveillance and 96.2% for patients treated with adjuvant chemotherapy. Overall 5-year survival was 100%. CONCLUSION: Adjuvant carboplatin is effective in reducing the relapse rate in patients with stage I seminoma and risk factors. A risk-adapted strategy is safe and feasible and should be considered an alternative to systematic approaches, such as irradiation, chemotherapy, or surveillance.
Adolescent↗
First-line treatment with irinotecan and raltitrexed in metastatic colorectal cancer. Mature results of a multicenter phase II study.
OBJECTIVES: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. METHODS: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m(2)) plus raltitrexed (3 mg/m(2)), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. RESULTS: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1-16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18-44%). The incidence of grade 3-4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. CONCLUSIONS: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment.
Adult↗
Neoadjuvant cisplatin and etoposide, with or without tamoxifen, prior to radiotherapy in high-grade gliomas: a single-center experience.
Neoadjuvant chemotherapy (CT), prior to radical radiotherapy (RT), in the treatment of high-grade gliomas may offer several advantages over standard adjuvant CT. The addition of tamoxifen, which can circumvent P-glycoprotein (P-gp)-mediated chemo-resistance, also merits attention. We have evaluated the neoadjuvant regimen of cisplatin and etoposide after surgery of grade III-IV gliomas and prior to radical RT, with regard to response rates (RRs), overall survival (OS) and time to progression (TTP). The synergistic activity between etoposide and tamoxifen was also studied. Forty-four patients were included. CT regime: cisplatin 100 mg/m2 on day +1 and etoposide 100 mg/m2 on days +1 to +3 every 3 weeks for 3 cycles. The initial 24 were also treated with high-dose tamoxifen, 275 mg/m2 on days -3 to +3. An immunohistochemical analysis of P-gp, p53, vascular endothelial growth factor, Ki67 and bcl-2 was also performed. Median follow-up was 11.57 months. In the 16 patients with measurable disease after surgery, a RR of 12.5% was seen, with 37.5% of disease stabilizations and 31.25% of progressions. The median OS and TTP were 11.3 and 5.7 months. Excluding the three deaths possibly related to tamoxifen, grade 3-4 was low, mainly emesis. Favorable prognostic factors were age less than 60 years, extent of surgery, absence of measurable disease, and the absence of radiological necrosis and ring enhancement. Only high p53 expression was associated with better OS. We conclude that neoadjuvant cisplatin and etoposide is a feasible regime, although any real advantage over standard adjuvant CT is dubious. Short-course high-dose tamoxifen should not be used alongside primary CT.
Antineoplastic Combined Chemotherapy Protocols↗
Analysis of prognostic factors and applicability of Kohne's prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy.
BACKGROUND: The objective of this study was to analyze prognostic factors for survival and to assess the applicability of Kohne's classification in patients treated with irinotecan- or oxaliplatin-based first-line chemotherapy. PATIENTS AND METHODS: One hundred forty-two consecutive cases from a single center were retrospectively reviewed. Median patient age was 62 years. Sixty percent were men. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0/1 in 88%. Primary tumor resection (PTR) was performed in 80.6% of patients who initially had stage IV disease. Chemotherapy consisted of fluoropyrimidines or raltitrexed plus irinotecan (50.5%), oxaliplatin (38.5%), or both (11%). Univariate and multivariate analyses for survival were performed using pretreatment patient characteristics. RESULTS: Median follow-up was 33.9 months and median overall survival was 15.9 months. Significantly unfavorable prognostic factors were PTR not being performed, disease involvement of >1 organ, liver metastases, undifferentiated histology, EGOG PS>1, increased serum carcinoembryonic antigen and cancer antigen 19.9 levels, hypoalbuminemia, leucocytosis, and elevated alkaline phosphatase and lactate dehydrogenase (LDH) levels. Only ECOG PS, PTR, increased LDH level, no hypoalbuminemia, and number of organs involved retained prognostic value in the multivariate analysis. The incidence and median survival for Kohne's prognostic groups were as follows: good (54.2%; 20 months), intermediate (26.8%; 15.7 months), and poor (19%; 6.8 months). For patients with stage IV disease at presentation, PTR was associated with a significantly longer survival, mainly in patients with an ECOG PS of 0/1. CONCLUSION: Eastern Cooperative Oncology Group PS, PTR, serum albumin, increased LDH levels, and organ involvement were the main prognostic indicators in our series. Kohne's prognostic groups, developed in the era of 5-fluorouracil treatment, also seem to be applicable to patients treated with combination chemotherapy. Primary tumor resection should always be considered, especially in patients with an ECOG PS of 0/1. However, the benefit of PTR and multiple-agent chemotherapy is questionable in patients with an ECOG PS of >1.
Aged↗
FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer.
BACKGROUND: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin are the most active drugs in advanced colorectal cancer (CRC), and survival is improved with patient exposure to all of them. The efficacy and safety of an alternating schedule of continuous-infusion 5-FU with leucovorin (LV) plus oxaliplatin (ie, FOLFOX regimen) or irinotecan (ie, FOLFIRI regimen) was assessed in the first-line setting. PATIENTS AND METHODS: Seventy-nine patients with previously untreated, unresectable CRC were included. Treatment consisted of 5-FU/LV (de Gramont schedule) plus oxaliplatin (85 mg/m2) alternated biweekly with the same 5-FU/LV regimen plus irinotecan (180 mg/m2). Treatment was maintained until tumor progression or unacceptable toxicity was noted. RESULTS: Median age was 62 years. Performance status was 0/1 in 91% of patients, 63% had 1 organ involved, and 80% had liver metastases. A median of 6 courses per patient (range, 1-9) and a total of 952 infusions were given. The most frequent grade 3/4 toxic events were neutropenia (32%), diarrhea (26%), and asthenia (7%). Grade 1/2 neurotoxicity was seen in 59% of cases, but no grade 3/4 neurotoxicity was observed. There were no toxic deaths. An objective response rate of 54% (4 complete responses plus 39 partial responses) was attained. Median time to progression and overall survival were 13 months and 18 months, respectively. CONCLUSION: This alternating schedule is active, with efficacy results similar to those seen with sequential protocols, the advantages of less toxicity, and 100% patient exposure to irinotecan and oxaliplatin.
Adenocarcinoma↗
Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years' follow-Up.
PURPOSE: To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. PATIENTS AND METHODS: Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. RESULTS: All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. CONCLUSION: UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.
Adenocarcinoma↗
A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer.
PURPOSE: In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m2 i.v. on day 1, alternating with LV 20 mg/m2 i.v. and 5-FU 425 mg/m2 i.v. daily for five consecutive days, on days 22-26 (Mayo Clinic regimen). One cycle consisted of 6 weeks. RESULTS: A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16-44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients). CONCLUSIONS: The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.
Adolescent↗
Primary hepatic gastrinoma.
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Adolescent↗
Analysis of clinical prognostic factors for survival and time to progression in patients with metastatic colorectal cancer treated with 5-fluorouracil-based chemotherapy.
Colorectal cancer (CRC) is one of the most common malignant tumors in adults. Twenty-five percent of patients are not amenable to surgical resection because they have locally advanced or metastatic disease. For these patients, median survival time is between 4 and 13 months, and chemotherapy is used mainly with palliative intent. We conducted this study to evaluate potential prognostic factors for time to progression and survival. A retrospective review of 91 patients with metastatic CRC treated with bolus 5-fluorouracil-based chemotherapy (Mayo Clinic schedule) was performed. Univariate and multivariate analyses of clinical prognostic factors were carried out. Median follow-up time was 53 months (range, 17-107 months). Median time to disease progression was 9.6 months, and median survival time was 15.4 months. Actuarial 5-year survival was 17%. In the univariate analyses, factors predictive of time to progression were visceral metastases, elevated alkaline phosphatase (AP) levels, performance status (PS), and elevated carcinoembryonic antigen (CEA) and CA 19-9 levels. Multivariate analyses confirmed the independent prognostic value of PS and AP levels. In the univariate analyses for survival, significant prognostic factors were visceral metastases, hypoalbuminemia, elevated lactate dehydrogenase levels, elevated AP levels, PS, and elevated CEA and CA 19-9 levels. In the multivariate analyses, only PS, elevated CEA and CA 19-9 levels, and liver involvement retained prognostic significance. This study confirms the prognostic value of PS for both time to progression and survival. AP levels are significantly related to time to progression. Additional factors influencing survival time are elevated tumor marker levels and the existence of liver metastases.
Adult↗
Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer.
Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250-350 mg/m(2) as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3-4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m(2)) and raltitrexed (3 mg/m(2)) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.
Aged↗