Objective Partial Remission Research Articles

Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases

Abstract Background The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis. Methods Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated. Results Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P < 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P < 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P < 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P < 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P < 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis. Conclusions Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.

CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results

AbstractCellular immune responses have the potential to elicit dramatic and sustained clinical remissions in lymphoma patients. Recent clinical trial data demonstrate that modification of T cells with chimeric antigen receptors (CARs) is a promising strategy. T cells containing CARs with costimulatory domains exhibit improved activity against tumors. We conducted a pilot clinical trial testing a “third-generation” CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. Four patients were enrolled, and 3 received T-cell infusions after cyclophosphamide lymphodepletion. Treatment was well tolerated, although one patient developed transient infusional symptoms. Two patients without evaluable disease remained progression-free for 12 and 24 months. The third patient had an objective partial remission and relapsed at 12 months after infusions. Modified T cells were detected by quantitative PCR at tumor sites and up to 1 year in peripheral blood, albeit at low levels. No evidence of host immune responses against infused cells was detected. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity. We will pursue alternative gene transfer technologies and culture conditions in future studies to improve CAR expression and cell production efficiency. This study is registered at www.clinicaltrials.gov as NCT00621452.

Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies

Background:Treatment of everolimus-resistant disease remains largely undefined in metastatic renal cell carcinoma (mRCC). We report on 40 patients (pts) who receive systemic treatment after failure of everolimus.Patients and methods:Forty pts received sunitinib (n=19), sorafenib (n=8), dovitinib (n=10) or bevacizumab/interferon (n=3) after failure of everolimus. Median progression-free survival (PFS), overall survival (OS) and best tumour response (according to Response Evaluation Criteria In Solid Tumors) were analysed retrospectively. Kaplan–Meier, log-rank test and Cox regression analyses were used to estimate or predict OS and PFS.Results:Treatment of everolimus-resistant disease was associated with a PFS of 5.5 months. (range 0.4–22.3) and an objective partial remission (PR) in 4 pts (10%) and stable disease (SD) in 22 pts (55%). In univariate analyses, first-line treatment with sorafenib was the only variable to correlate with a prolonged PFS of treatment in everolimus-resistant disease (P=0.036). However, its significance as a predictive marker for subsequent therapy could not be verified in multivariate analyses.Conclusions:Vascular endothelial growth factor targeted therapy shows promising activity in everolimus-resistant metastatic renal cancer and warrants further studies.

Idiotype Vaccination of Untreated Indolent B-Cell Lymphoma: Durable Objective Remissions and Association of Superior Outcome with Cellular Immune Responses

Idiotype vaccination refers to active immunization of B-cell lymphoma (B-NHL) patients with the clonal immunoglobulin (Ig) expressed by the tumor cells. After systemic cytoreductive therapy, idiotype vaccination has been shown to induce specific cellular and humoral immune responses; and humoral responses in particular are associated with prolonged remission and encouraging survival rates. Conventional idiotype vaccines are composed of the entire lymphoma-derived Ig coupled to the immunogenic carrier KLH and are administered subcutaneously with adjuvant. We have developed a idiotype production strategy based on bacterial expression of the lymphoma-derived idiotype as a recombinant Fab fragment (Bertinetti et al., EJH 2006). Intradermal administration of this antigen with lipid-based adjuvant and subcutaneous coadministration of GM-CSF had excellent immunogenicity in a phase I trial of advanced, heavily pretreated B-NHL patients (Bertinetti et al., Cancer Research 2006). In a subsequent phase II trial, 20 patients with untreated indolent B-NHL (14 follicular [FL], 3 nodal marginal zone [nMZL], 3 mantle cell [MCL]) and without immediate need for cytoreduction received at least 6 monthly idiotype vaccinations. No grade IV toxicities were seen, and the sole case of grade III toxicity, generalized erythema, did not preclude completion of the vaccination schedule. Prior to vaccination, 5/19 patients (26%) had decreased CD4+ and 6/19 patients (31%) low CD8+ T cells counts. Furthermore, 10/12 anti-HbS-negative patients (83%) failed to mount a detectable immune response to a conventional hepatitis B vaccine administered concomitantly to idiotype vaccination. Despite this functional immunodeficiency, 12/18 analyzed patients (66%) developed a cellular immune response to idiotype as detected by enumeration of IFNgamma-secreting cells by DC-ELISpot. The ELISpot protocol was validated by blinded interlaboratory testing (www.cimt.de). The frequency of idiotype-responding T cells increased from the 2nd to the 6th vaccination and could be effectively boostered by maintenance immunization in 3-monthly intervals. In vitro stimulation of PBMC from responding patients with idiotype induced specific proliferation of CD4+ T-cells and a shift towards a Th1 response in post-vaccination samples. In addition, 8/18 analyzed patients (44%) developed anti-idiotype IgG or IgM antibodies as assessed by ELISA, and the combined immune response rate was 85%. After a median follow-up of 34 months, 8 patients (40%) are progression-free, and 10 (50%) did not require cytoreductive therapy. Cellular immune responses were associated with superior PFS (p<0.05), and 5 of 6 non-responders eventually required cytoreductive therapy. Humoral immune responses were not related to PFS. Six patients (30%; only FL or nMZL) achieved an objective partial remission, including near-complete disappearance of a large submandibular mass and one subcutaneous lymphoma mass. All objective responders developed specific cellular immunity, but only 4 anti-idiotype antibodies. Five patients are in continuing remission for 12–49 months. Intradermal immunization with the chosen idiotype formulation has excellent immunogenicity despite a severely impaired immune function in untreated B-NHL patients. Furthermore, this is the first active immunotherapy trial showing objective and durable lymphoma responses in first-line therapy at a higher rate than expected for spontaneous remissions. In this setting, and in contrast to conventional idiotype vaccination schedules, cellular anti-idiotype immunity may play a crucial role for a favorable clinical outcome. Since passive humoral anti-lymphoma immunity can be easily transferred by infusions of commercially available monoclonal antibodies, synergistic benefit may be envisioned for an initial vaccination course aimed to prime anti-idiotype T-cells combined with subsequent passive immunotherapy.

A phase I-II study of 9-cis retinoic acid and interferon-α2b in patients with advanced renal-cell carcinoma: An NCIC Clinical Trials Group study

Although advanced renal-cell carcinoma (RCC) responds poorly to standard therapies, phase I-II trials have shown activity for combinations of interferon-alpha2b (IFN) with a retinoid. Alitretinoin (9-cis RA) is an endogenous retinoid with high binding affinity for both RAR and RXR receptor families. This phase I-II study enrolled 38 patients with RCC in a dose-escalation study of tolerability, pharmacokinetics (PK), and efficacy of twice daily oral 9-cis RA with subcutaneous IFN. In contrast to studies with similar doses of daily 9-cis RA, PK studies found a consistent reduction in 9-cis RA concentrations of about 50% after multiple b.i.d. doses of 30 or 50 mg/m2, independent of cotreatment with IFN. In the phase I portion, toxicities included systemic symptoms typical of IFN and biochemical abnormalities previously associated with retinoids. Two patients experienced dose-limiting toxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus the recommended phase II dose was 30 mg/m2 b.i.d. One of twenty-six evaluable patients achieved a durable objective partial remission, and repeated dosing with this regimen was poorly tolerated. This combination of retinoid and interferon is not recommended for further study in RCC.

Phase II Clinical Trial of Lobaplatin (D-19466) in Pretreated Patients with Small-Cell Lung Cancer

Background: Laboplatin, D-19466, 1,2-diaminomethylcyclobutaneplatinum(II) lactate, is a novel, water-soluble platinum complex which showed a better therapeutic index than Cisplatin or Carboplatin in murine and human tumor models. In a preceding Phase I study myelosuppression with predominant thrombocytopenia was the dose-limiting toxicity. Besides nausea and vomiting no further side effects were observed. Patients and Methods: The phase II study group of the AIO performed a phase II study in pretreated patients with advanced small-cell lung cancer (SCLC). 19 patients received Lobaplatin without hydration from which 18 were evaluable for toxicity and 17 for antitumor activity. The dose of 40 mg/m² was given by intravenous bolus injection repeated every 4 weeks. Results: No objective complete or partial remissions were observed. 2 Patients showed a short-lasting no change. Thrombocytopenia was the dose-limiting toxicity: 11/18 (61%) patients presented WHO grades 1-4 and 5 WHO grades 3-4 (28%). The nadir occurred after 2 weeks with recovery within a week. Anemia WHO grades 1-3 were seen in 11 patients (61%), leukopenia grades 1-3 in 10 patients (56%). The nadir of leukopenia occurred after 3 weeks. Nausea and vomiting occurred in two thirds of the patients; however, were well controlled by antiemetics. No renal, CNS or ototoxi-city was observed. Conclusions: In patients heavily pretreated with chemotherapy, Lobaplatin did not show therapeutic activity at the dose of 40 mg/m2, although 33% of the patients experienced a grade 3 or 4 thrombocytopenia as the dose-limiting toxicity. Secondary resistance to chemotherapy and compromised bone marrow reserve due to intensive prior treatment may have contributed to this study outcome since Lobaplatin was clearly active in SCLC patients with no or one prior chemotherapy only, allowing administration of Lobaplatin at a dose of 50 mg/m² and a repeat interval of 3 weeks.

A 15-year experience with chemotherapy of patients with paraganglioma

Paraganglioma is a rare tumor thought to arise from the neuroectodermally derived paraganglionic cells that are dispersed widely along the autonomic ganglia. They can metastasize to bones, lymph nodes, and lungs and occasionally present with spinal cord compression. Up to 60% of retroperitoneal paragangliomas can be functional, with symptoms and signs of norepinephrine overproduction. A 15-year experience with chemotherapy of patients with paraganglioma was reviewed. The patient population was identified through a search of the data-base maintained by the Departments of Melanoma-Sarcoma Medical Oncology and Pathology at the University of Texas M.D. Anderson Cancer Center (Houston, TX). Thirteen of 84 patients with histologically confirmed diagnosis of paraganglioma were treated with chemotherapy. The median age was 42 years (range, 25-67 years); there were eight males and five females. Primary sites included retroperitoneum (seven patients), head and neck (two patients), pelvis, bladder, mediastinum, and paravertebral (one patient each). Twelve patients received chemotherapy for metastatic disease, and 1 had an unresectable mediastinal primary tumor. Eleven patients received cyclophosphamide, doxorubicin, and DTIC/dacarbazine (CyADIC)/cyclophosphamide, vincristine, doxorubicin and DTIC/dacarbazine (CyVADIC), and 2 received doxorubicin and dacarbazine (ADIC) at standard doses for a median of 4 cycles (range, 2-12 cycles). Six of 13 patients achieved an objective partial remission (response rate = 46%, 95% confidence interval = 19-73%); 6 other patients had stable disease, and one developed progressive disease. At the time of last follow-up, eight patients were alive with disease, four died, and one patient was alive with no evidence of disease. The median follow-up from diagnosis was 45 months (range, 12-300 months). Cyclophosphamide, doxorubicin, dacarbazine chemotherapy is active in the treatment of patients with paraganglioma.

Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer

Advanced adenocarcinoma of the prostate after hormonal manipulation has been noted to be a relatively chemotherapeutic nonresponsive tumor. Earlier reviews have reported objective responses, that is, complete and partial remissions in 6.5% of 3184 patients, and the current review examines the efficacy of new agents. The current review consists of 26 new drug trials culled from papers and abstracts published between 1987-1991. Results of these 26 drug trials found a similar trend, 8.7% (95% confidence interval, 6.4-9.0%), indicating that hormone-resistant adenocarcinoma of the prostate still fails to respond to most cytotoxic agents. The most interesting of the new therapeutic agents is the combination of vinblastine plus estramustine. Only six agents had an objective response rate greater than 10%, such as vinblastine by continuous infusion, trimetrexate, mitoguazone, and estramustine. The recent introduction of radioactive-labeled monoclonal antibodies is intriguing and these will undoubtably be used as carriers for radiotherapeutic and cytotoxic compounds. Although multidrug resistance may explain the marginal efficacy of cytotoxic drugs, methods to overcome such resistance and, more importantly, new classes of agents must be developed. In addition, reliable disease markers must be found for osseous and visceral metastases to avoid the prevailing confusion in evaluating more precisely the destruction of prostate cancer cells.

Experience of the Belgian Society of Medical Oncology with single-administration 5 g/m2 ifosfamide with mesna as second- or third-line therapy in advanced breast cancer

In an ongoing phase II trial conducted in advanced breast cancer, we tested a therapy schedule consisting of continuous, 24-h infusion of 5 g/m2 ifosfamide (IFO) in 3 1 dextrose saline with mesna (MSN), repeated every 3 weeks until disease progression. Since September 1988, 16 heavily pretreated patients with advanced disease (11 with visceral lesions) considered refractory to standard chemotherapy (regimens always including cyclophosphamide) have been included. Objective partial remissions were observed in two cases (one in liver and one in soft-tissue and pleural lesions), and disease stabilization for at least 3 months occurred in four cases. No treatment-related death was recorded and tolerance was judged to be excellent (six cases) or acceptable in all instances. The haematological toxicity consisted mainly of transient leucopenia (nadirs evaluated by WHO scale as grade 3 in 43% and grade 4 in 29%), sometimes associated with thrombocytopenia (grade 3 in 7% and grade 4 in 7%). Other side effects included nausea and/or vomiting (grade 3-4 in 33%); worsening of preexisting alopecia (five cases); haemorrhagic cystitis (one case); mild, transient somnolence (two cases); and moderate fluid retention (two cases). We concluded that infusion of 5 g/m2 IFO over 24 h with MSN rescue might represent an acceptable second- or third-line salvage regimen. Close monitoring of haematological and renal function parameters is recommended. A larger number of patients will be treated in a continuation of this study to evaluate the true response rate within narrower confidence limits.

Etoposide, Adriamycin, and Cisplatinum (EAP) Combination Chemotherapy for Advanced Gastric Cancer

In a multicenter trial, 49 patients with histologically proven advanced gastric cancer were treated with a combination chemotherapy consisting of etoposide 120 mg/m2 d 4, 5, 6 adriamycin 20 mg/m2 d 1, 7 and cisplatinum 40 mg/m2 d 2, 8. Therapy was repeated every 4 weeks, 45 patients were evaluable for response after 8 weeks of treatment. Eight patients achieved a partial remission (PR: 18%), 17 patients had no change (NC: 38%), and 20 patients showed tumor progression (P: 44%). Four patients with primarily inoperable tumor and without distant metastases who achieved a partial remission, underwent second look operation with curative intention. All 4 patients died within 12 months after second look operation due to tumor recurrence. Median survival time of all patients was 9 months. Toxicity was considerable. WHO grade 3/4 toxicity appeared in 20-30% of patients (nausea, vomiting, loss of appetite, leucopenia). After 3 cycles complete alopecia was present in 70% of patients. Severe infection, requiring treatment, occurred in 10 patients. Five patients discontinued therapy because of intolerable subjective toxicity. The observed response rate of 18% objective partial remissions is disappointing and does not give support to the communications reporting response rates over 50% with EAP and other regimens including cisplatinum. In conclusion, and considering the high subjective and objective toxicity of this regimen, it can not be recommended for standard use in patients with advanced gastric cancer.

A Study of Aminoglutethemide and Hydrocortisone in Patients with Advanced and Refractory Prostate Carcinoma

We have studied aminoglutethemide (AG) combined with hydrocortisone in 28 patients with advanced and refractory prostate carcinoma. All the patients had failed at least one endocrine therapy. Six patients received only one prior hormonal treatment. Five patients were off study within 3 weeks due to early death and toxicity, 14 had progressive disease, and 9 had stable disease. No objective partial remission was observed, but the nine stable patients had therapeutic benefit, with improvement in bone pain and performance status for a median duration of 153 days. Three patients withdrew because of postural hypotension, dizziness, weakness, and lethargy. The median survival of the entire group was 186 days (range 41-606 days). Our results suggest that aminoglutethemide and hydrocortisone can be an alternative treatment for patients with advanced and refractory prostate carcinoma.

Isotopic immunoglobulin: a new systemic therapy for advanced Hodgkin's disease.

Thirty-eight patients with advanced, progressive Hodgkin's disease who had relapsed from or who had not responded to treatment with at least two potentially curative combination chemotherapy regimens were entered into this phase 2 study. All patients received 131I antiferritin antibody administered intravenously (IV) at a dose of 30 mCi on day 0 and 20 mCi on day 5. Antibody was derived from rabbit, pig, and monkey species. Objective partial remission of measurable disease was recorded in 40% of patients. Symptomatic response was recorded in 77% of patients. Toxicity was restricted to bone marrow depression with thrombocytopenia greater than leukopenia. These responses are comparable to other reported phase 2 drugs in this patient population and subsequent trials of antibody free of radioactivity and antibody using a beta emitting isotope are being carried out to expand upon these results.

Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas.

High-dose recombinant leukocyte A interferon (50 X 10(6) U/m2 body surface area, intramuscularly, three times weekly) was tested in a clinical trial involving patients with advanced cutaneous T-cell lymphomas to determine its effectiveness and toxicity. All 20 patients had advanced stages of disease refractory to two or more standard therapies. Objective partial remissions lasting 3 months to more than 25 months (median, 5 months) were documented in 9 patients. The major dose-limiting toxicity was a severe influenza-like syndrome with malaise, anorexia, depression, weight loss, and decreased performance status; this effect was reversible after dose reductions in all patients and did not recur with re-escalation of doses in 10 patients. This interferon preparation is highly effective in the treatment of advanced refractory cutaneous T-cell lymphomas, and new schedules to reduce toxicity and achieve complete responses, combined treatment with chemotherapy or serotherapy, and its use in earlier stages of disease should be investigated.

Salvage therapy of aggressive non-Hodgkin's lymphoma with a combination of vinblastine, bleomycin, and cisplatin.

Thirteen patients with aggressive histologic types of non-Hodgkin's lymphoma had failed to respond or relapsed after intensive polychemotherapy of curative intent. They were treated with a combination of vinblastine, bleomycin, and cisplatin. All were Stage III or IV, and eight had systemic symptoms. There were five objective partial remissions, and no complete remissions. The Kaplan-Meier 50% survival estimate is 5 months from initiation of the salvage chemotherapy. Seven of 13 patients had grade II nausea and vomiting, and 7 had nadir platelet counts less than 70,000/mm3. All had significant anemia. There were two episodes of sepsis, and two patients had pulmonary and nephrotoxicity. The program is not effective in this situation, and is quite toxic.

Failure of effective initial chemotherapy to modify the course of stage IV (MO) squamous cancer of the head and neck.

Twenty-four patients with advanced squamous cancer of the head and neck without distant metastases were given combination chemotherapy including methotrexate, bleomycin and diamminedichloroplatinum before planned local treatment with irradiation or surgery. Of 22 evaluable patients, 17 had objective partial or complete remission to initial chemotherapy. However, only ten patients ever had complete clearing at any time of all tumor on clinical evaluation. Median survival was ten months, and only two patients remained alive 14 and 29 months, respectively, from entry. Toxicity was minimal with the three-drug treatment, but the addition of mitomycin-C at the start of chemotherapy substantially increased toxicity without improving efficacy. Subsequent surgery and radiotherapy were accomplished without unusual difficulty.

N-(Phosphonacetyl)- l-aspartate (PALA) in advanced breast cancer: a phase II trial of the EORTC breast cancer cooperative group

Twenty-nine evaluable patients with extensively pretreated breast cancer received PALA, a new pyrimidine antimetabolite. The drug was given by intravenous infusion over 60 min, at a daily dose of 2.5 g/m 2 for 2 consecutive days. Courses were repeated at 2-week intervals and doses were escalated to toxicity. Two objective partial remissions were observed, lasting for 3 and 4.5 months respectively. Toxic effects were dose-related and consisted mainly of mucocutaneous manifestations, i.e., skin rashes, stomatitis, diarrhea, conjunctivitis and corneal ulcerations. Evidence of antitumor potential in far-advanced disease and lack of myelosuppression point to the need for additional trials of PALA in a more favorable selection of patients with breast cancer.

The value of serial carcinoembryonic antigen (CEA) in predicting response rate and survival of patients with gastrointestinal cancer treated with chemotherapy.

Elevated serum levels of carcinoembryonic antigen (CEA) were found in 70% of 141 patients with advanced gastrointestinal (GI) cancers. Serial CEA measurements were performed on 70 patients before and during chemotherapy. The majority were treated with 5-FU and Methyl-CCNU (33 patients), 5-FU (19 patients), or 5-FU and mitomycin-C (8 patients). In 49 patients with colorectal carcinoma who had elevated serum CEA prior to chemotherapy, 18 had objective partial tumor remission, 16/18 (89%) showed definite decrease in CEA level, one had no change, and one had an increase CEA titer. Thirty-one patients had either stable disease (10 patients) or increasing disease (21 patients) while on chemotherapy. Of these patients four showed decrease in CEA, eight had no change, and 19 had increase in CEA levels as compared to pretreatment value. The survival of patients with a decrease in CEA during chemotherapy was statistically significant (p = .03) as compared to survival of those with no change or increasing CEA levels. In 21 patients with other GI cancers, the correlation between the clinical response and change in CEA level observed was not as definite as in patients with colorectal carcinoma.

Medical Adrenalectomy With Aminoglutethimide

To the Editor.— The recent article by Santen et al (230:1661, 1974) is certainly an excellent and useful contribution in regard to the pharmacology of aminoglutethimide and dexamethasone interaction. There are, however, points that deserve comment. The authors state that large doses of glucocorticoids are established in the treatment of breast cancer. A review of 12 of the cited references fails to establish either the efficacy or the dose response relationship of glucocorticoids (Table). 1-12 In addition, the cited studies did not utilize the now accepted criteria of objective partial remission, ie, greater than or equal to 50% reduction in the product of the two greatest diameters of palpable or measurable lesions. In regard to the response data cited for aminoglutethimide, the earlier series did achieve objective partial remissions in three of nine cases. 13 However, of the 22 patients reported by the authors of the current study, there were