Takuhito Tada

Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer.

PURPOSE To determine the response rate, survival, and toxicity of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, in refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS Twenty-five patients with refractory or relapsed SCLC were entered onto the trial. All 25 patients had been pretreated with some form of cisplatin-based combination chemotherapy and had also received previous etoposide- or anthracyclinecontaining chemotherapy. The median time off chemotherapy was 6.7 months (range, 0.9 to 23.5). Patients were treated at 4-week intervals using CPT-11 (a starting dose of 70 mg/m2 intravenously on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3), with a subsequent dose based on toxicity. In addition, recombinant human granulocyte colony-stimulating factor (rhG-CSF; 2 microg/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. RESULTS All patients were assessable for toxicity and survival. Twenty-four patients were assessable for response. There were 14 partial responses (PRs) and three complete responses (CRs), for an overall response rate of 71% (95% confidence interval, 53% to 89%). The median response duration was 4.6 months. Median survival was 271 days. Major toxicities were myelosuppression (predominantly leukopenia) and diarrhea. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 56% and 20% of patients, respectively. Grade 3 to 4 diarrhea was observed in 4%. There was one treatment-related death due to severe myelosuppression. CONCLUSION A combination of CPT-11 and etoposide with rhG-CSF support is an active therapy against refractory or relapsed SCLC and deserves to be studied more extensively in a phase III trial.

Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated with radiation therapy.

BackgroundWe evaluated the efficacy and toxicity of reirradiation for patients with loco-regional relapse of non-small-cell lung cancer after radiation therapy.MethodsBetween 1992 and 2002, 19 patients with loco-regional relapse underwent reirradiation. The median interval between the initial irradiation and reirradiation was 16 months, with a range of 5 to 60 months. The prescribed dose of reirradiation was 50 Gy in 25 fractions over 5 weeks for 18 patients and 60 Gy in 30 fractions over 6 weeks for 1 patient.ResultsFive patients could not receive the prescribed dose of reirradiation. The response rate was 43% among the 14 patients who received the prescribed dose of reirradiation. The overall 1-year and 2-year Kaplan-Meier survival rates were 26% and 11%, respectively, and the median survival time was 7.1 months. The median survival times associated with intervals between the initial irradiation and reirradiation of less than 12 months, 12–18 months, and more than 18 months were 2.1, 7.1, and 11.5 months, respectively. There were significant differences in survival between patients with an interval of less than 12 months and those with an interval of 12–18 months, and between those with an interval of less than 12 months and those with an interval of more than 18 months (generalized Wilcoxon method; P < 0.05 for both). Grade 3 radiation pneumonitis and grade 2 radiation esophagitis occurred in 1 and 3 patients, respectively.ConclusionReirradiation is considered to contribute to salvage in selected patients with relapsed non-small-cell lung cancer. Patients with a long interval after the initial irradiation are good candidates for reirradiation. On the other hand, patients with Eastern Cooperative Oncology Group (ECOG) performance status 3 were not goodcandidates.

Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer

SummaryA study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m–2 and dose escalation was done in 15 mg m–2 increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m–2). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m–2. Three of the five patients given 60 mg m–2 developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m–2 in the phase II study. The objective response rate was 76.9% (95% CI, 53.0–88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m–2 wk–1, respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity.

Phase II Study of Etoposide and Cisplatin With Concurrent Twice-Daily Thoracic Radiotherapy Followed by Irinotecan and Cisplatin in Patients With Limited-Disease Small-Cell Lung Cancer: West Japan Thoracic Oncology Group 9902

PURPOSE We initially conducted a randomized phase II study to compare irinotecan and cisplatin (IP) versus irinotecan, cisplatin, and etoposide (IPE) after etoposide and cisplatin (EP) with concurrent twice-daily thoracic radiotherapy (TRT) in limited-disease small-cell lung cancer (LD-SCLC). We amended the protocol to evaluate IP after EP with concurrent twice-daily TRT in a single-arm phase II study because of an unacceptable toxicity in IPE. PATIENTS AND METHODS Previously untreated patients with LD-SCLC were treated intravenously with etoposide 100 mg/m2 on days 1 through 3 and cisplatin 80 mg/m2 on day 1 with concurrent twice-daily TRT (1.5 Gy per fraction, a total dose of 45 Gy) beginning on day 2 followed by three cycles of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 of a 4-week cycle. RESULTS Of the 51 patients enrolled, 49 patients were assessable for response and toxicity. The overall response rate and complete response rate were 88% and 41%, respectively. The median survival time for all patients was 23 months. The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months. The major toxicities observed were neutropenia (grade 4, 84%), febrile neutropenia (grade 3, 31%), infection (grade 3 to 4, 33%), electrolytes imbalance (grade 3 to 4, 20%), and diarrhea (grade 3 to 4, 14%). CONCLUSION EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be an active regimen which deserves further phase III testing in patients with LD-SCLC.

Non-small cell lung cancer: radiation therapy for locoregional recurrence after complete resection

BackgroundWe investigated patterns of failure after radical radiation therapy in relation to the radiation field in patients with postsurgical locoregional recurrence of non-small cell lung cancer.MethodsBetween 1992 and 2002, 31 patients with locoregional recurrence were treated with radiation therapy. At the time of radiation therapy, the sites of recurrence were the bronchial stump, the regional lymph nodes, the chest wall, and both the regional lymph nodes and the chest wall in 7, 20, 3, and 1 patient, respectively. The prescribed dose was 60 Gy in 30 fractions over 6 weeks in all patients.ResultsThe response rate was 87%. The overall 1-year, 2-year, and 4-year Kaplan-Meier survival rates were 61%, 30%, and 15%, respectively, and the median survival time was 14 months. Locoregional relapse with or without distant metastasis occurred in 15 patients (in-field, 7; marginal, 7; out-field, 1), and distant metastasis alone occurred in 7 patients. The sites of marginal relapse were the upper margin in two patients, the ipsilateral margin in one patient, the contralateral margin in one patient, and the lower margin in three patients, respectively (in one patient, the data for marginal relapse overlapped). In all patients with relapse on the lower margin, the mediastinal lymph nodes were dissected at the initial surgery.ConclusionPostoperative recurrent non-small cell lung cancer showed distinctive features: the response rate was high, and the incidence of marginal relapse was also high, as in small cell lung cancer. The incidence of lower marginal relapse was high, in contrast to that in surgery-naive patients.

Single institutional experience of the treatment of angiosarcoma of the face and scalp

OBJECTIVE Angiosarcoma is a rare malignant neoplasm with a poor prognosis. A retrospective study was performed to accumulate radiotherapy (RT) data. METHODS Data from 17 patients with angiosarcoma of the face and scalp (AFS) who were treated with definitive RT between January 1999 and July 2011 were retrospectively analysed. The total radiation dose was 70 Gy, and the fractional doses were 2.0-2.5 Gy. Combined with RT, chemotherapy using docetaxel alone, recombinant interleukin-2 immunotherapy alone and both of these was performed in 10, 4 and 2 patients, respectively. Three patients underwent limited surgery before RT. RESULTS The response rate was 82%, and the median overall survival (OS) rate was 26 months. Locoregional relapse alone, distant metastasis alone and both of these were confirmed in 4, 5 and 4 patients, respectively. Patients treated with docetaxel showed a better prognosis (p=0.0477), a distant metastasis-free rate (p=0.0063) and a better in-field control rate, although the last was not statistically significant (p=0.1645). CONCLUSION Definitive RT combined with docetaxel chemotherapy provided an effective approach for treating AFS. ADVANCES IN KNOWLEDGE Since patients treated with chemoradiotherpy using docetaxel showed better OS and distant metastasis-free rates than those who did not receive docetaxel, it was warranted to continue use of docetaxel. In chemoradiotherapy at a dose of 70 Gy using docetaxel, 2-year in-field control rate was 67%.

Radiosensitizing, toxicological, and pharmacokinetic properties of hydroxamate analogues of nitroimidazoles as bifunctional radiosensitizers/chemical modifiers

We examined the pharmacokinetics of KIH-802, potassium 2-nitroimidazole-1-acetohydroxamate, using its radioisotope-labelled compound and the acute toxicity in mice. We discovered that the concentration of KIH-802 was very low in the brain and its LD50 was nearly half the value of that of MISO. We also present here new 2-nitroimidazole radiosensitizers/chemical modifiers (KIN-804, 811, 831, 841, 844, 821, 823 and 824) designed to enhance their sensitizing ability intensely by substituting various biologically active groups, such as hydroxamic acids and oximes, with moderate lipophilicity to the aromatic ring, if necessary, through some spacers. The sensitizing effects of all compounds were estimated to be almost equal to or better than that of MISO. The results of their toxicities shows that new hydroxamates KIN-804 and 831 are less toxic than KIH-802 and MISO. Their in vitro enhancement ratios are 2.00 and 1.75, respectively, compared with those of KIH-802, MISO and SR-2508, 1.77, 1.72 and 1.72, respectively, at each dose of 1 mM for EMT6/KU single cell. We concluded that they may be superior radiosensitizers of hydroxamic acid analogues to KIH-802.

Usefulness of FDG-microPET for early evaluation of therapeutic effects on VX2 rabbit carcinoma

PurposeThe aim of this study was to determine the potential use of high-resolution FDG-microPET for predicting the primary effects of radiotherapy and/or hyperthermia on tumor-bearing rabbits.MethodsTwenty-eight VX2 xenografts in the thighs of rabbits were divided into the following 5 treatment groups: radiotherapy at a single dose of 10, 20 or 30 Gy, hyperthermia (43 degrees Celsius, 1 hour), and the combination of radiotherapy and hyperthermia ( 10 Gy + 43 degrees Celsius, 1 hour). FDG-microPET images were obtained by using a microPET P4 system at pretreatment and at 24 hours and 7 days after treatment. For the evaluation by FDG-microPET, tumor/muscle (T/M) ratios, retention index [RI = (T/M ratio at 120 min - T/M ratio at 60 min) / T/M ratio at 60 min], and time activity curve (TAC) were acquired.ResultsWe divided the xenografts into a responder group (partial response + stable disease, n = 14) and a non-responder group (progressive disease, n = 14). The T/M ratio at 24 hours after the treatment in the responder group was decreased remarkably with that at pre-treatment (p < 0.05), while in the non-responder group it showed no significant change between the time points. The RI and TAC patterns were comparable to T/M ratios in each treatment group. T/M ratios, RI, and TAC indicated marked changes at the time point of 24 hours in the responder group, although the tumors did not show any significant change in volume at that time. Photomicrographs of sections showed that the number of viable tumor cells in the responder group decreased at 24 hours after treatment and that inflammatory cell infiltration was marked and almost all viable tumor cells had disappeared by day 7 after treatment.ConclusionThese results suggest that early evaluation by FDG-microPET, especially 24 hours after treatment, is useful to predict the primary effects of the treatment. Histological analysis showed that inflammatory cell infiltration at 7 days after treatment was considered to be a cause of accumulation of FDG in the tumors that showed a significant decrease in tumor cell number. This false-positive should be noted when predicting tumor response by FDG accumulation.

Comparison of dosimetric parameters and acute toxicity after whole-pelvic vs prostate-only volumetric-modulated arc therapy with daily image guidance for prostate cancer.

OBJECTIVE To compare dosimetric parameters and acute toxicity rates between whole-pelvic (WP) and prostate-only (PO) volumetric-modulated arc therapy (VMAT) in patients with localized prostate cancer. METHODS A total of 224 consecutive patients treated with definitive VMAT to 78 Gy in 39 fractions were enrolled. Of these, 119 patients received initial WP VMAT at 46.8 Gy in 26 fractions using a simultaneous integrated boost technique, and 105 patients received PO VMAT. Image-guided radiotherapy was practised with daily cone beam CT. RESULTS The mean rectal dose, the rectal volume receiving ≥30 Gy (V30Gy), rectal V50Gy, the mean bladder dose, bladder V30Gy and bladder V50Gy were significantly increased in the WP group (p < 0.05 each); however, the rectal V70Gy did not differ between groups (p = 0.101), and the bladder V70Gy was significantly lower in the WP group (p = 0.029). The WP group experienced a significantly increased frequency of acute grade 2 diarrhoea relative to the PO group (5.9% vs 0%; p = 0.015). No differences were seen between the WP and PO groups in terms of acute grade 2 proctitis (10.1% vs 6.7%; p = 0.360) and genitourinary (GU) toxicity (12.6% vs 10.5%; p = 0.620). CONCLUSION Despite larger rectum and bladder volumes at low- and medium-dose levels, WP VMAT resulted in no significant increase in acute proctitis or GU toxicity when compared with PO VMAT. ADVANCES IN KNOWLEDGE This study demonstrates that whole-pelvic radiotherapy has comparable acute toxicity to those observed with prostate-only radiotherapy when VMAT with daily image guidance is used.

Whole-pelvic volumetric-modulated arc therapy for high-risk prostate cancer: treatment planning and acute toxicity

The objectives of this study were to evaluate dosimetric quality and acute toxicity of volumetric-modulated arc therapy (VMAT) and daily image guidance in high-risk prostate cancer patients. A total of 100 consecutive high-risk prostate cancer patients treated with definitive VMAT with prophylactic whole-pelvic radiotherapy (WPRT) were enrolled. All patients were treated with a double-arc VMAT plan delivering 52 Gy to the prostate planning target volume (PTV), while simultaneously delivering 46.8 Gy to the pelvic nodal PTV in 26 fractions, followed by a single-arc VMAT plan delivering 26 Gy to the prostate PTV in 13 fractions. Image-guided RT was performed with daily cone-beam computed tomography. Dose–volume parameters for the PTV and the organs at risk (OARs), total number of monitor units (MUs) and treatment time were evaluated. Acute toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. All dosimetric parameters met the present plan acceptance criteria. Mean MU and treatment time were 471 and 146 s for double-arc VMAT, respectively, and were 520 and 76 s for single-arc VMAT, respectively. No Grade 3 or higher acute toxicity was reported. Acute Grade 2 proctitis, diarrhea, and genitourinary toxicity occurred in 12 patients (12%), 6 patients (6%) and 13 patients (13%), respectively. The present study demonstrated that VMAT for WPRT in prostate cancer results in favorable PTV coverage and OAR sparing with short treatment time and an acceptable rate of acute toxicity. These findings support the use of VMAT for delivering WPRT to high-risk prostate cancer patients.