José Manuel Aramendía

Front-Line Paclitaxel/Cisplatin-Based Chemotherapy in Brain Metastases from Non-Small-Cell Lung Cancer

Objective: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. Methods: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0–2 were treated with paclitaxel (135 mg/m2) on day 1, cisplatin (120 mg/m2) on day 1, and either vinorelbine (30 mg/m2) on days 1 and 15 or gemcitabine (800 mg/m2) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. Results: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22–59%). WHO grade 3–4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. Conclusions: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.

Combined treatment in superior sulcus tumors

January 1988 to August 1992, 18 patients (pts) with the established diagnosis of non-small cell lung cancer of the superior sulcus have been treated with a multidisciplinary approach, which includes 1–3 cycles of neoadjuvant chemotherapy (MVP or MCP regimens) followed by simultaneous preoperative chemotherapy and external beam irradiation. Radical surgery plus intraoperativc radiotherapy (IORT) was planned 4–5 weeks after the end of the preoperative protocol. Tumor stages were IIIA (9 pts) and IIIB (9 pts). Tumor characteristics included rib and vertebral involvement in 15 and 4 pts, respectively. Fatal toxicity was present in 3 pts (16.6%). Resectability rate was 76.4%. Pathologic findings disclosed complete response (pT0) in 70.5% of the surgical specimens and viable tumor (pT+) in 29.5%. With a median follow-up of 24+ months (2–52+), 4-year actuarial local control, and overall survival rates are 91% and 56.2%, respectively. Four-year actuarial overall survival according to pathologic response was 87.5% for pT0 patients and 20% for pT + patients. We conclude that this regimen promotes a high rate of pT0 as well as better than expected local control and survival rates. The presence of a pT0 specimen seems to correlate with the patient outcome.

Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcoma of the extremities

PURPOSE To analyze the patterns of failure and the toxicity profile of intraoperative electron beam radiotherapy (IOERT) after resection of soft tissue sarcomas of the extremities (STS). PATIENTS AND METHODS Forty-five patients with extremity STS were treated with IOERT and moderate-dose postoperative radiotherapy (45-50 Gy). Twenty-six patients were treated for primary disease (PD) and 19 patients for an isolated recurrence (ILR). Tumor size was >5 cm (maximum diameter) in 36 patients (80%), and high-grade histology in PD patients was present in 14 patients (54%). In nine patients, IOERT was used alone, due to previous irradiation or patient refusal. Chemotherapy (neoadjuvant and/or adjuvant) was mainly given to high-grade tumors. RESULTS Nine patients relapsed in the extremity (20%), and 12 patients in distant sites (28%). Actuarial local control at 5 years was 88% for patients with negative/close margins and 57% for patients presenting positive margins (P=0.04). Five patients (11%) developed neuropathy associated with the treatment. Extremity preservation was achieved in 40 patients (88%). With a median follow-up of 93 months (range: 27-143 months) for the patients at risk, 25 patients remain alive (a 7-year actuarial survival rate of 75% for PD and 47% for ILR; P=0.01). CONCLUSIONS IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity STS. Peripheral nerves in the IOERT field are dose-limiting structures requiring a dose compromise in the IOERT component to avoid severe neurological damage.

Diagnostic accuracy of FDG PET in the follow-up of platinum-sensitive epithelial ovarian carcinoma

PurposeThis study was designed to retrospectively evaluate the diagnostic yield of FDG PET for the diagnosis of recurrent ovarian cancer.MethodsEighty FDG PET scans were performed on 55 patients owing to suspicion of relapse, and 45 FDG PET scans were performed on 31 patients who were clinically disease free. PET results were compared with the results of conventional radiological imaging (CIM) and serum CA 125 levels, and related to pathological findings in 54 cases or clinical follow-up in 71 cases.ResultsCIM correctly identified 49 cases with recurrence [sensitivity (SE) 53.3%] ,and there were 27 true negatives [specificity (SP) 81.8%] However, 43 cases were false negative and six were false positive. The positive predictive value (PPV), negative predictive value (NPV) and accuracy (ACC) of CIM were 89%, 38.6% and 60.8%, respectively. FDG PET correctly detected recurrent disease in 80/92 cases (SE 86.9%, p < 0.05) and ruled out relapse in 26/33 cases (SP = 78.8%). The PPV, NPV and ACC of PET were 91.9%, 68.4% and 84.8%, respectively. Standardised uptake values did not provide additional diagnostic accuracy compared with visual analysis. The CA 125 results showed an SE of 57.6%, an SP of 93.9% and an ACC of 67.2%. In 23 patients with positive serum CA 125 levels, but negative CIM, FDG PET was positive and relapse was confirmed. Furthermore, FDG PET was positive and relapse was confirmed in 11 patients with negative serum CA 125 levels and CIM.ConclusionFDG PET may detect recurrent ovarian cancer earlier than CIM, with higher sensitivity and even higher diagnostic accuracy.

Combined irinotecan, oxaliplatin and 5-fluorouracil in patients with advanced colorectal cancer. a feasibility pilot study.

Objectives: To evaluate the feasibility and a possible activity range of combination irinotecan (CPT-11), oxaliplatin, and 5-FU in advanced colorectal cancer (ACC). Patients and Methods: A total of 53 patients (51% chemoresistant) were treated. Twenty-eight received monthly intravenous oxaliplatin (120 mg/m2) and CPT-11 (250 mg/m2) on day 1 and a course of 5-FU; these constituted the IRI250 group. Twenty-five received monthly intravenous oxaliplatin (120 mg/m2), CPT-11 (300 mg/m2) on day 1, and a course of 5-FU (IRI300 group). 5-FU administration was carried out as follows. Those with predominant hepatic disease (n = 32) received an intra-arterial infusion of 5-FU (2,500 mg/day on days 1–4); these were the IA-FU group. The remaining 21 patients received intravenous 5-FU (2,600 mg/m2 plus leucovorin 500 mg/m2 on days 1 and 15); these constituted the IV-FUFOL group. Results: Intention-to-treat response rate was 54.7% (4 CR, 7.5%). Twelve patients (22.5%) had stable disease; only 4 (7.5%) progressed. Median progression-free and overall survivals were 10 and 18 months, respectively. One-year progression-free and overall survival rates were 44.3 and 67.4%, respectively. Grade 3–4 toxicities included diarrhea (45.3% of patients), neutropenia (52.8%), mucositis (13.2%), and emesis (11.3%). There were 3 treatment-related deaths (5.7%), all in the IA-FU/IRI300 subgroup. Severe adverse effects requiring chemotherapy dose adjustment were observed in 67.9% of the patients, with odds ratios 9.04-fold higher in the IA-FU/IRI300 group (95% CI: 1.07–76.20) and 0.23-fold lower in the IV-FUFOL/IRI250 group (95% CI: 0.05–0.97). Conclusion: This combination seems to have substantial activity in ACC. Overall toxicity was unacceptable in the IA-FU and IRI300 groups, with diarrhea and cytopenia constituting the dose-limiting side effects. Tolerance and efficacy profiles achieved with IV oxaliplatin (120 mg/m2 day 1), IV CPT-11 (250 mg/m2 day 1) and IV 5-FU 2.6 g/m2 with IV leucovorin (500 mg/m2 days 1 and 15) was favorable and deserves further investigation.

Induction platinum-based chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy in the treatment of locally advanced non-small-cell carcinoma of the lung.

This study evaluated tolerance, local control, and short-term survival in patients with locally advanced non-small-cell lung carcinoma treated with induction chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy. Thirty-one patients with stage IIIa (N2) or IIIb tumors were treated with cis-platinum-based induction chemotherapy for 1 to 4 courses followed by radical hyperfractionated radiotherapy (69.6 Gy) with concurrent chemotherapy given at the beginning and end of radiotherapy. Induction chemotherapy produced no complete responses and 18 (58%) partial responses. After completion of radiotherapy, 4 patients had complete response (13%) and 23 patients (74%) partial response. The patterns of failure were as follows: intrathoracic, 6 patients (22%); intrathoracic + distant metastasis, 6 patients (22%); distant metastasis without thoracic failure, 5 patients (19%). Six patients of the 12 with intrathoracic failure experienced in-field radiotherapy pure local failure. At the time of this analysis, 10 patients were alive and well (4 complete and 6 partial responders). Actuarial survival projected at 39 months is 35%. No benefit was observed for those patients responding to induction chemotherapy. Toxicity was as follows: grade III neutropenic fever in 4 patients (13%), grade IV neutropenia in 13 patients (42%), pneumonia in 6 patients (19%), grade III esophagitis in 4 patients (13%) and severe clinical pneumonitis in 1 patient (3%). Induction chemotherapy followed by chemoradiotherapy is feasible, and the preliminary results are encouraging. Complete response after radiotherapy appeared to be related to short-term disease-free survival, and decisions based on the response to chemotherapy may be equivocal.

Second-line chemotherapy with irinotecan and vinorelbine in stage IIIB and IV non-small-cell lung cancer: a phase II study.

The purpose of this study was to evaluate the efficacy and tolerance of combined irinotecan and vinorelbine in previously treated patients with stage IIIB and IV non–small-cell lung cancer (NSCLC). Thirty-three patients with NSCLC (7 stage IIIB and 26 stage IV) were enrolled. All had been previously treated with cisplatin, paclitaxel, and gemcitabine as first-line chemotherapy. In addition, 24 patients had received radiotherapy. Irinotecan (300 mg/m2) was administered on day 1 and vinorelbine (30 mg/m2) on days 1 and 14, every 4 weeks. Partial response was achieved in 3 patients (9%; 95% CI: 2–24%), stable disease (SD) in 13 (39%; 95% CI: 23–58%), whereas 17 patients progressed (51%; 95% CI: 33–69%). Median event-free survival was 10 weeks and median overall survival was 25 weeks. Three patients were event free at the end of the study with a follow-up of 40, 73, and 75 weeks. Toxicity was mild, with leukopenia grade III–IV in 8.6% of cycles. No episodes of diarrhea III-IV were observed. Three patients died early after administration of this combination, one of them in the context of severe leukopenia and thrombocytopenia. Approximately 50% of patients treated with CPT-11 and vinorelbine in combination show partial response or stable disease with minimal toxicity.

Early breast cancer treated with conservative surgery, adjuvant chemotherapy, and delayed accelerated partial breast irradiation with high-dose-rate brachytherapy

PURPOSE To evaluate the feasibility and intermediate-term results of conservative surgery, adjuvant chemotherapy, and delayed accelerated partial breast irradiation (APBI) with high-dose-rate brachytherapy. METHODS AND MATERIALS Between 2000 and 2007, a total of 26 patients with a median age of 54 years were treated with conservative surgery followed by adjuvant chemotherapy and exclusive high-dose-rate brachytherapy. Inclusion criteria followed the Radiation Therapy Oncology Group 95-17 trial guidelines. The tumor bed was marked at the time of surgery (n = 2) or before brachytherapy (n = 24). The brachytherapy procedure was performed at a median of 22 weeks after surgery. A median of 14 brachytherapy catheters were placed in three to four parallel planes. A dose of 34.0 Gy in 10 b.i.d. fractions given over 5 consecutive days was prescribed to the clinical target volume (CTV90). RESULTS After a median followup of 53 months (range, 6.8-81), Radiation Therapy Oncology Group Grade 1-2 events and Grade 3 events were observed in 10 (38.4%) patients and 3 (11.5%) patients, respectively. No Grade 4-5 events were observed. Patients rated their cosmetic result as excellent (37.5%), good (50.0%), fair (8%), or poor (4%) based on the Wazers Criteria. The 6-year actuarial local, elsewhere in the breast, and distant control rates were 100%, 96.2%, and 96.2%, respectively. Six-year disease-free survival and overall survival were 92.3% and 96.2%, respectively. CONCLUSIONS Patients undergoing surgery and adjuvant chemotherapy can still be candidates for APBI. Optimal visualization of the internal lumpectomy scar before implantation is mandatory. Cosmetic results may be slightly worse due to the interaction between chemotherapy and APBI, and technical refinements may be needed in this group of patients.

Cisplatin, mitomycin, and vindesine followed by intraoperative and postoperative radiotherapy for stage III non-small cell lung cancer: final results of a phase II study.

Sixty-two patients with stage III non-small cell lung cancer (NSCLC) were treated with neoadjuvant chemotherapy consisting of cisplatin 120 mg/m2 day 1, mitomycin 8 mg/m2 day 1, and vindesine 3 mg/m2 days 1 and 14. Each cycle was repeated every 4 weeks for a total of 1 to 6 cycles (median, 3 cycles). Resection was attempted 4 to 5 weeks after the last course of chemotherapy. Intraoperative radiation therapy (IORT) (10-15 Gy) was delivered during surgery and postoperative external beam radiotherapy (EBRT) (46 Gy) was begun 4 weeks after surgery. Fifty-five patients (25 IIIA, 30 IIIB) were evaluable. Only partial responses occurred (64%), and 29 patients (53%) underwent resection. Complete resection rates were 85% (12/14) and 40% (6/15) in stage IIIA and IIIB, respectively (p = 0.01). In 3 of 29 patients (10%), no tumor was found in the resected specimen. There was one chemotherapy-related death and three postoperative-related deaths. The median survival time was 10 months, and the 5-year survival rate was 29 and 7% for stage IIIA and stage IIIB, respectively (p = 0.3). High complete resection rates and modest increase in 5-year survival have been observed in stage IIIA NSCLC. Although a number of stage IIIB patients can be made technically resectable, the low complete resectability rate reflects the lack of survival benefit in these patients.

A phase II trial of less than 7 weeks of concomitant cisplatin-paclitaxel chemoradiation in locally advanced cervical cancer.

Objectives: This study was undertaken to determine the tolerability of a 7-week schedule of external beam radiation therapy, high-dose-rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix. Methods: Twenty-nine patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m2 per week of intravenous (i.v.) cisplatin and 50 mg/m2 per week of i.v. paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 30 Gy of high-dose-rate brachytherapy. Results: Eleven patients (37.9%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5 (range, 2-7). Thirty-five (20.1%) of 174 cycles of chemotherapy were not given because of toxicity. The median dose intensity of cisplatin was 31 mg/m2 per week (95% confidence interval [CI], 25.2-36.8); that of paclitaxel was 44 mg/m2 per week (95% CI, 39.9-48.3). Twenty-two patients (78.6%) were able to complete the planned radiation course in less than 7 weeks. Median radiation treatment length was 45 days (95% CI, 43.4-46.6). After a median follow-up of 48 months, 7 patients (24.1%) experienced severe (Radiation Therapy Oncology Group grade 3 or higher) late toxicity. No fatal events were observed. Seven patients have failed, 1 locally and 6 at distant sites. The 8-year local/pelvic control rate was 95.7%, and the 8-year freedom from systemic failure rate was 76.1%. Eight-year actuarial disease-free survival and overall survival were 63.1% and 75.9%, respectively. Conclusions: This study demonstrated unacceptable toxicity of combining the stated doses of concurrent cisplatin and paclitaxel chemotherapy with definitive radiotherapy for patients with advanced cervical cancer. Additional phase I/II trials are recommended to clearly establish the recommended phase II dose for these drugs.