Duration Of Response In Responders Research Articles

Documento multidisciplinar de consenso sobre el tratamiento actual del tumor vesical no-músculo invasor que no responde al tratamiento con bacilo Calmette-Guérin

Radical cystectomy is the current treatment of choice for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). However, the high comorbidity of this surgery and its effects on the quality of life of patients require the investigation and implementation of bladder-sparing treatment options. These must be evaluated individually by the uro-oncology committee based on the characteristics of the BCG failure, type of tumor, patient preferences and treatment options available in each center. Based on FDA-required oncologic outcomes (6-month complete response rate for CIS: 50%; duration of response in responders for CIS and papillary: 30% at 12 months and 25% at 18 months), there is not currently a strong preference for one treatment over another, although the intravesical route seems to offer less toxicity. This work summarizes the evidence on the management of BCG-unresponsive NMIBC based on current scientific evidence and provides consensus recommendations on the most appropriate treatment.

Pivotal single-arm, phase 2 trial of tasurgratinib for patients with fibroblast growth factor receptor (FGFR)-2 gene fusion-positive cholangiocarcinoma (CCA).

471 Background: CCA represents ~3% of all gastrointestinal malignancies globally; it is particularly prevalent in Asian countries. Additionally, FGFR2 gene fusions occur in ~13% of intrahepatic CCA cases. Tasurgratinib (E7090) is an orally available selective inhibitor of FGFR 1–3; the recommended dose is 140 mg per day per the dose-escalation part of a first-in-human phase 1 study. In this pivotal phase 2 study, this regimen was evaluated in patients (pts) with FGFR2 fusion-positive CCA. Methods: Japanese and Chinese pts with surgically unresectable advanced or metastatic CCA were treated with tasurgratinib 140 mg PO daily. FGFR2 gene fusion was confirmed by fluorescence in situ hybridization performed in central laboratories; ≥ 1 prior chemotherapy regimen including a gemcitabine-based combination was required; pts treated with FGFR2 inhibitors were excluded. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response [PR]). Secondary endpoints included duration of response (DOR), time to response (TTR), disease control rate (DCR; CR + PR + stable disease [SD]), clinical benefit rate (CBR; CR + PR + SD lasting ≥ 23 weeks), progression-free survival (PFS), overall survival (OS), and safety. The study was considered successful if the lower limit of the ORR 90% CI was > 15% in a planned population. Tumor responses were measured every 8 weeks by RECIST v1.1 per independent imaging review. Adverse event (AE) severity was measured per CTCAE v4.03. Results: 63 Pts (Japanese: n = 28; Chinese: n = 35) were treated (median age: 55 years); 23 pts (37%) had received 1 prior regimen, all others had received ≥ 2. By the data cutoff date (March 15, 2023), 55 pts discontinued treatment (disease progression, n = 48; adverse events, n = 4; pt choice, n = 2; loss of clinical benefit, n = 1). 19 Pts (30%) had a PR; 31 pts (49%) had SD and 13 (21%) had SD for ≥ 23 weeks. The ORR was 30% (2-sided 90% CI 20.7–41.0; 95% CI 19.2–43.0); the DCR was 79% (95% CI 67.3–88.5); the CBR was 51% (95% CI 37.9–63.6). The median [m]TTR / DOR for responders were 1.87 mos (IQR 1.77–2.10; range 1.6–14.7) / 5.6 mos (95% CI 3.7–9.3; range 1.0+–14.8+). The mPFS / OS were 5.4 mos (95% CI 3.7–5.6) / 13.1 mos (95% CI 10.8–17.4). 61 Pts (97%) had ≥ 1 treatment-related AE (TRAE), most commonly hyperphosphatemia (n = 51; 81%); 18 pts (29%) had ≥ 1 grade ≥ 3 TRAE, most commonly lipase increased (n = 4; 6%). 34 Pts (54%) had a dose reduction and 18 (29%) had treatment interruption due to TRAEs. 4 Pts (6%) had a fatal AE, none related to treatment. Conclusions: Tasurgratinib had promising antitumor activity in pts with CCA harboring FGFR2 gene fusion and who received ≥ 1 prior chemotherapy regimen. The primary endpoint (ORR) met the study’s predefined success criteria. Tasurgratinib had a manageable safety profile consistent with previous reports and with the known pharmacological profile of FGFR inhibitors. Clinical trial information: NCT04238715 .

Abstract CT202: Xevinapant plus avelumab in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Phase 1b dose-expansion results and exploratory biomarker analyses

Abstract BACKGROUND: Combining anti-PD-1/L1 antibodies and agents that restore cancer cell susceptibility to apoptosis may enhance antitumor activity. We report results from a phase 1b dose-expansion cohort of xevinapant, a first-in-class, oral, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that restores cancer cell sensitivity to apoptosis, and avelumab (anti-PD-L1) in pts with advanced NSCLC. METHODS: The recommended phase 2 dose (RP2D; 28-day cycles of xevinapant 200 mg/day [days 1-10 and 15-24] + avelumab 10 mg/kg [days 1 and 15]) was previously established during the dose-escalation part of this phase 1, open-label study. In this dose-expansion cohort, pts with advanced NSCLC who progressed on first-line (1L) platinum-based chemotherapy (CTx) or anti-PD-1/L1 ± platinum-based CTx received xevinapant (at RP2D) + avelumab for 13 cycles. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics (PK). RESULTS: 38 pts were treated: most had squamous cell carcinoma (45%) or adenocarcinoma (42%) of the lung, 11% had prior anti-PD-L1 therapy, 71% were men, and median age was 62 years (range, 35-75). 1 pt completed 13 cycles, and 37 permanently discontinued treatment; most common reasons were progressive disease (PD; 70%) and adverse events (AEs; 27%). ORR was 10.5% (95% CI 2.9-24.8). Best overall response (BOR): 4 pts had a confirmed partial response (PR), 19 had stable disease, and 15 had PD. Median DoR in responders was 15.9 months (95% CI 3.5-29.7); DCR was 60.5% (95% CI 43.4-76.0). Median PFS was 3.5 months (95% CI 1.9-5.1); median OS was 9.4 months (95% CI 6.7-16.2). Most pts (n=37; 97.4%) had treatment-emergent AEs (TEAEs); 21 (55.3%) had grade ≥3. Most common TEAEs were decreased appetite (n=13; 34.2%) and ALT increase (n=11; 28.9%). Nine pts died due to TEAEs; none were considered treatment-related. Xevinapant and avelumab PK were comparable to monotherapy at the same doses. In exploratory biomarker analyses, plasma IL-10 levels increased during the study treatment period. In blood, activated CD4 T cells and Tregs increased during cycle 1, and activated CD8 T cells increased during the treatment period; however, these did not correlate with antitumor activity. In tumor samples, low Ki67 expression was associated with BOR of PR (n=4), and increases in macrophages, Tregs, Th1 cells, and dendritic cells were associated with disease control. CONCLUSION: Xevinapant + avelumab had tolerable safety in pts with advanced NSCLC who progressed on 1L platinum-based CTx or anti-PD-1/L1 ± platinum-based CTx; however, the study did not meet its primary endpoint as antitumor activity was comparable to historic data for avelumab second-line monotherapy. Citation Format: Quincy Chu, Tudor Ciuleanu, Rodryg Ramlau, Daniel Renouf, Rosalyn Juergens, Ewa Kalinka, Piotr Sawrycki, Jonathan Bramson, Brad Nelson, Rafael Crabbé, Daniela A. Sahlender, Philippa Crompton, Elisabeth Rouits, Dany Spaggiari, Franck Brichory, Luke Piggott, Mike Schenker, Glenwood Goss. Xevinapant plus avelumab in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Phase 1b dose-expansion results and exploratory biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT202.

Results from a phase 1b study of blinatumomab-pembrolizumab combination in adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

e19584 Background: This open-label, multicenter, phase 1b study evaluated the safety and efficacy of blinatumomab and pembrolizumab combination therapy in patients (pts) with R/R DLBCL (NCT03340766). Methods: Key inclusion criteria included adults with ECOG performance status ≤2 and life expectancy ≥12 weeks. In cycle 1, pts received a continuous intravenous (cIV) infusion of blinatumomab followed by step dosing to the target dose (TD; Table). After a 28-day treatment-free interval, cIV infusion of blinatumomab was administered for 28 days in cycle 2 with the same dose escalations as in cycle 1. Pembrolizumab 200 mg IV was administered once every 21 days starting on day 15 in cohort 1a, and on day 19 in cohorts 2a and 3a. Pts were premedicated with dexamethasone. Dose-limiting toxicities (DLT) were the primary endpoint. The maximum tolerated dose (MTD) was the highest dose level at which ≤1 of 6 or ≤2 of 10 pts experienced a DLT. Results: As of June 10, 2021, 31 pts were enrolled in cohorts 1a, 2a, and 3a (Table). DLTs occurred in 1 (10%) pt in cohort 1a (neutropenia) and 2 (40%) pts in cohort 3a (cognitive impairment, and elevated AST, ALP, and GGT levels). Treatment-emergent (TE) adverse events (AEs) were observed in 31 (100%) pts; grade ≥3 AEs occurred in 29 (94%) pts. The most frequent grade ≥3 TEAE attributed to blinatumomab was nervous system disorders (11 [35%]) and that attributed to pembrolizumab was blood and lymphatic system disorders (5 [16%]). Serious blinatumomab-related and pembrolizumab-related AEs were observed in 15 (48%) and 2 (6%) pts, respectively. Fourteen (45%) deaths occurred; none were treatment-related. Cohort 2a dose was determined as the MTD (Table). In cohort 2a, the objective response rate within 12 weeks of blinatumomab treatment was 30%; the median duration of response in responders (n = 8) was 176.5 (range: 28–680) days. Exposures of blinatumomab and pembrolizumab in this combination study were consistent with historical data for the individual agents. Conclusions: The cohort 2a dosing schedule with TD of 56 μg/day of blinatumomab was established as the MTD. The study was terminated after dose finding because the MTD of blinatumomab in combination with pembrolizumab was lower than the MTD of blinatumomab monotherapy, with no apparent efficacy gain. Clinical trial information: NCT03340766. [Table: see text]

A Phase I/Ib Trial of PD 0332991 (Palbociclib) and T-DM1 in HER2-Positive Advanced Breast Cancer After Trastuzumab and Taxane Therapy

BackgroundPreclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. Patients and MethodsA phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. ResultsFrom May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1–22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%–59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5–11.6). ConclusionsThe combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.

Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: An updated integrated analysis.

3605 Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]

Phase II study of AZD4547 in FGFR amplified tumours: Gastroesophageal cancer (GC) cohort pharmacodynamic and biomarker results.

154 Background: FGFR amplified tumors demonstrate oncogene addiction in vitro and in vivo. We examined the efficacy of AZD4547, an orally available inhibitor of FGFR 1, 2 & 3, in FGFR1/2 amplified cancers, and herein present results from a gastroesophageal cancer (GC) cohort. Methods: Phase II Simon 2 stage design (3 independent cohorts) for previously treated patients (pts) with advanced FGFR1 (HER2 negative breast/NSCLC) or FGFR2 amplified tumors. FGFR1/2 amplification was centrally assessed using FISH. Pts received AZD4547 80mg twice daily. Primary endpoint is centrally confirmed response rate (RR), with the study concluding efficacy if ≥ 3/17 patients in a cohort had a confirmed response. PET-CT was performed at baseline, D14 and 8 wks, biopsy at baseline and D14 and optionally on progression. Biomarkers included FGFR copy number variation in tumor and plasma, NanoString gene expression, MIRAX digital FISH imaging and phospho-immunohistochemistry. Results: Of 288 pts with screening results, 9% (12/138) gastroesophageal (GC) pts had FGFR2 amplification with 5% (7/138) highly amplified (FGFR2 ratio > 5.0). Confirmed RR was 33% (3/9) in FGFR2 amplified GC. Mean duration of response in responders was 5.7 months. All GC responders had a PET response on D14 PET. Common toxicities (all pts n = 18) included fatigue (72%), constipation (50%) mucositis, skin and eye changes (44% each). Phospho-immunohistochemistry on pre-treatment and D14 biopsies demonstrated an increase in S6 and decrease in p-ERK following treatment. Using digital droplet PCR (ddPCR) elevated FGFR2 copy number was detected in free plasma DNA of all responding GC pts, and no non-responding pt. NanoString and MIRAX imaging analysis revealed the presence of truncated C3 FGFR2 isoform and high level homogenous FGFR2 amplification in all GC responders respectively. Conclusions: AZD4547 demonstrated promising activity in FGFR2 amplified GC. On treatment biopsies demonstrate evidence of target inhibition. Clonal, high level amplification appears to be required for response to AZD4547. As all responding patients had FGFR2 copy number gain detected in plasma using ddPCR this technique will be developed as a screening tool. Clinical trial information: NCT01795768.

A phase II study of capecitabine and cisplatin (XP) as first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma

The combination of 5-fluorouracil (5-FU) and cisplatin (FP) remains the mostly used regimen for metastatic esophageal squamous carcinoma. This phase II study assessed the efficacy and safety of capecitabine/cisplatin (XP) as a first-line chemotherapy in a homogenous cohort of patients with metastatic or recurrent esophageal squamous cell carcinoma. Patients received 60 mg/m(2) of cisplatin intravenously (IV) on day 1 and capecitabine 1,250 mg/m(2)/dose orally twice a day on days 1-14. Treatment cycles were repeated every 3 weeks until the documented disease progression, unacceptable toxicity, or patient's refusal. Immunohistochemical studies against thymidylate synthase (TS) and thymidine phosphorylase (TP) were performed to seek predictive markers for treatment response. Between December 2003 and March 2006, 45 patients entered the study. All patients had histologically proven squamous cell carcinoma of the esophagus. The overall response rate (ORR) was 57.8% (95% CI, 43.3-72.2) with 0 CR and 26 PRs. The median duration of response in responders was 4.6 months (1.0-15.6 months). With a median follow-up duration of 25.7 months (10.8-42.6 months), the median time to progression was 4.7 months (95% CI, 2.5-7.0) and the median survival time was 11.2 months (95% CI, 8.5-13.9). Common grade 3 or 4 non-hematological adverse events were anorexia (18/191, 9.4%), fatigue (9/191, 4.7%), constipation (6/191, 3.1%), hand-foot syndrome (6/191, 3.1%) and diarrhea (4/191, 2.1%). The most common grade 3 or 4 hematological adverse events were neutropenia (33/191, 17.3%), followed by leucopenia (11/191, 5.8%), anemia (2/191, 1.0%) and thrombocytopenia (1/191, 0.5%). There was no treatment-related death. Neither TS nor TP showed predictive value for treatment response. The XP regimen demonstrated a promising antitumor activity in metastatic esophageal squamous cell carcinoma, which may potentially replace the FP regimen.

Subcutaneous interleukin-4 (IL-4) for relapsed and resistant non-Hodgkin lymphoma: A phase II trial in the North Central Cancer Treatment Group, NCCTG 91-78-51

Interleukin-4 (IL-4), a pleiotropic cytokine, has in vitro activity against non-Hodgkin lymphoma (NHL). This phase II study was conducted to learn the efficacy and toxicity of IL-4 in patients with NHL. Patients with relapsed or refractory indolent or aggressive NHL were eligible to receive 2.5 or 5.0 mcg/kg of subcutaneous IL-4 for 28 days of a 42-day cycle. Patients with response and acceptable toxicity after two cycles were eligible to continue treatment for six cycles. The target overall response rate (ORR) was 20%. Forty-one patients were enrolled and assessable for toxicity; two were ineligible after histology review. The ORR was 13% (5/39) with one complete and four partial responses. All responders were treated with 5.0 mcg/kg; the median time to progression was 84 days, the median duration of response for responders was 8.3 months. The most common toxicities of any grade in all patients were edema (66%), malaise (56%), and elevated liver function tests (56%). Grade 3 and 4 toxicities were more common at 5.0 mcg/kg, leading to a reduction in the starting dose. Although the study observed anti-tumor activity with IL-4, the ORR goal of the study was not achieved. Agents that target the IL-4 receptor can potentially benefit patients with NHL; however, alternative schedules using IL-4 in shorter duration and in combination with other agents would be required to overcome toxicities observed in this study.

Long-term follow-up of a phase I/II trial of radioimmunotherapy (RIT) with yttrium 90 (90Y) ibritumomab tiuxetan for CD20+ B-cell non-Hodgkin's lymphoma (NHL)

6574 Background: Updated time to disease progression (TTP) and duration of response (DR) are reported for responders from a multicenter phase I/II dose-escalation trial of 90Y ibritumomab tiuxetan (Zevalin®) in 51 patients (pts) with relapsed or refractory CD20+ B-cell NHL. Methods: 5 pts were treated at a dose of 0.2 mCi/kg, 15 at 0.3 mCi/kg, and 30 at 0.4 mCi/kg; 1 pt was not treated. Maximum tolerated dose (MTD) was 0.4 mCi/kg for pts with baseline platelets (plts) ≥ 150,000/μL (0.3 mCi/kg for plts 100,000–149,000/μL). Maximum dose for all pts was 32 mCi. Median age was 60 years (yrs) (range, 24–82). Median time from diagnosis to treatment was 3.8 yrs (range, 0.7–33.1). Median number of prior chemotherapy regimens was 2 (range, 1–7); 47 pts (92%) had received an anthracycline. 10 pts (20%) were resistant to prior chemotherapy. At study entry, 59% of pts had ≥ 1 tumor mass ≥ 5 cm; 43% had bone marrow involvement. Results: TTP and DR in responders were updated, response rates (RR) reported at all dose levels by International Workshop Response Criteria. Complete response (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%, 22%, and 22%, respectively, for an overall RR (ORR) of 73% (51% CR/CRu). ORR in pts with follicular lymphoma (FL) was 85% (58% CR/CRu, 27% PR). TTP and DR in all responders were 12.6 months (mos) and 11.7 mos, respectively. At MTD, TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 mos, respectively. 9 pts (24% of responders) had TTP >3 yrs; 5 had FL and 4 had diffuse large cell lymphoma (DLCL). 5 pts (FL, 3; DLCL, 2) are still in CR (range, 60+-74+ mos). Conclusions: 90Y ibritumomab tiuxetan produces high RRs and durable responses in pts with relapsed or refractory B-cell NHL. Durable responses >5 years have been seen in FL and DLCL. Because most relapses in DLCL occur early, the 2 DLCL pts with durable remissions might be cured. This observation provides the basis for further studies to define the efficacy of 90Y ibritumomab tiuxetan in relapsed DLCL. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen/IDEC Biogen/IDEC Biogen/IDEC Biogen/IDEC

Long-term follow-up of a phase I/II trial of radioimmunotherapy (RIT) with yttrium 90 (90Y) ibritumomab tiuxetan for CD20+ B-cell non-Hodgkin's lymphoma (NHL)

6574 Background: Updated time to disease progression (TTP) and duration of response (DR) are reported for responders from a multicenter phase I/II dose-escalation trial of 90Y ibritumomab tiuxetan (Zevalin®) in 51 patients (pts) with relapsed or refractory CD20+ B-cell NHL. Methods: 5 pts were treated at a dose of 0.2 mCi/kg, 15 at 0.3 mCi/kg, and 30 at 0.4 mCi/kg; 1 pt was not treated. Maximum tolerated dose (MTD) was 0.4 mCi/kg for pts with baseline platelets (plts) ≥ 150,000/μL (0.3 mCi/kg for plts 100,000–149,000/μL). Maximum dose for all pts was 32 mCi. Median age was 60 years (yrs) (range, 24–82). Median time from diagnosis to treatment was 3.8 yrs (range, 0.7–33.1). Median number of prior chemotherapy regimens was 2 (range, 1–7); 47 pts (92%) had received an anthracycline. 10 pts (20%) were resistant to prior chemotherapy. At study entry, 59% of pts had ≥ 1 tumor mass ≥ 5 cm; 43% had bone marrow involvement. Results: TTP and DR in responders were updated, response rates (RR) reported at all dose le...

Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion.

The aim of this study was to report the long-term results of percutaneous isolated liver chemoperfusion with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) in patients with multiple advanced hepatocellular carcinoma (HCC). The results of conventional chemotherapy including regional and systemic chemotherapy in patients with HCC remain dismal, and long-term survivors after treatment are rare among patients with multiple advanced HCC. In an effort to improve this situation, we previously developed a novel system of percutaneous isolated liver chemoperfusion with HVI-CHP. Doxorubicin (60 to 150 mg/m2) was administered via the hepatic artery, under conditions of extracorporeal drug elimination by HVI-CHP in 28 consecutive patients with advanced HCC (39 total treatments). Hepatic venous isolation and charcoal hemoperfusion was accomplished mainly by the single catheter technique using a newly developed 4-lumen-balloon catheter, which was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. Complete remission was achieved in five patients, of which four received repeated treatments (two or three times). Although 1 of 5 patients with complete remission died of pulmonary metastases at 8 months, the other 4 remain healthy and free of disease at 20, 24, 27, and 42 months after the first treatment. Partial responses were observed in 12 patients. Duration of response in responders (complete and partial) with repeated treatments was significantly longer than that with a single treatment (p = 0.01). The overall survival rate by the Kaplan-Meier method was 39.7% at 5 years. The treatments were well-tolerated, and the primary side effects were mild to moderate chemical hepatitis and reversible myelosuppression. The results suggest that percutaneous isolated liver chemoperfusion with HVI-CHP is an effective palliative treatment in the majority of patients and yields long-term complete remission in some patients with multiple advanced HCC.