Improvement Of Antitumor Efficacy Research Articles

What Is the Role of Stem-Cell Transplantation for Follicular Non-Hodgkin Lymphoma in the Rituximab Era?

Defining the best treatment for follicular lymphoma (FL) is still a challenge, partly because the available treatment options are often associated with prolonged overall survival (OS) as a result of the long natural history of this disease. Many clinical studies have used progression-free survival (PFS) as their end point but suffer from insufficient follow-up or lack of statistical power to assess OS, which is the indisputably best end point. Until the introduction of rituximab, standard chemotherapy (varying from low-dose oral chlorambucil to intensive multidrug schedules) was effective in producing responses but did not result in a survival benefit. The introduction of autologous peripheral-blood stem-cell transplantation with its inherent low morbidity and mortality in comparison with autologous bone marrow transplantation resulted in three trials applying high-dose therapy as first-line treatment for FL. All these studies showed an improvement of antitumor efficacy, but none had a significant impact on OS. This is most likely the result of the inability to select patients who might benefit most from this procedure or, again, insufficient follow-up. Patients who experience relapse, especially early relapse, have shown that they have a lymphoma with a clinically less benign behavior. In this patient population, several phase II studies suggested an improved survival, which was confirmed by the only randomized study in relapsed FL that showed a significantly improved OS in patients who underwent transplantation as compared with standard chemotherapy. Several authors have described a relatively high incidence of myelodysplasia, attributed to the high-dose therapy. However, this may also be the result of extensive pretreatment, suggesting that high-dose therapy might be of greater benefit earlier in the treatment course, as opposed to after multiple relapses. After the introduction of rituximab, several groups chose to investigate whether OS was improved with the incorporation of rituximab in standard-dose, first-line treatment of FL. The general conclusion is that PFS was improved in all, but OS was prolonged in only some, of these trials. Likewise, incorporating rituximab into highdose chemotherapy as part of first-line therapy resulted in better PFS but an OS benefit was observed in only one such trial. In the article that accompanies this editorial, Pettengel et al describe the results of the randomized European Group for Blood and Marrow Transplantation (EBMT) LYM-1 study. Rituximab-naive patients with relapsed chemosensitive FL were randomly assigned to analyze the efficacy of in vivo purging and maintenance therapy with rituximab in combination with high-dose therapy and autologous stem-cell transplantation. In 7 years, 280 patients were included. The authors conclude that in vivo purging did not improve outcome; however, maintenance therapy did improve PFS, but not OS at the time of this report. This study was not designed to assess the value of high-dose therapy because all patients received this treatment, which the authors considered standard therapy in relapsed FL. Although an important observation, it is important to realize that the patients in the EBMT LYM-1 study all were rituximab naive, which limits conclusions on current applicability. In addition, from the French Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study, we have learned that the results of high-dose therapy in patients with diffuse large B-cell lymphoma who experience relapse after first-line rituximab-containing therapy are significantly inferior, especially in the situation of an early relapse. Whether this is also the case in FL is an open question, but data from another French study in FL may be reassuring that this is not necessarily the case in FL. We can conclude that high-dose therapy changes the natural behavior of FL in relapsed disease and, probably, also in first-line therapy if PFS is a convincing end point. However, it is not clear that PFS is the best end point in FL. How can we improve the outlook for patients with FL? One approach is to wait for the current studies to mature and report OS data. Alternative options are new and more effective monoclonal antibodies or monoclonals conjugated to either radionuclides or toxins. Currently, there are no randomized data in support of these expensive options. Is allogeneic transplantation the panacea? Although complicated by a high treatment-related mortality (TRM), myeloablative transplants resulted in convincing evidence of cure in patients for whom other intensive therapies had failed. With the introduction of nonmyeloablative transplants, the decreased TRM resulted in better outcomes, even in patients who had previously undergone autograft. The high TRM after allografting in comparison with autografting limits its role in first-line salvage. It remains to be seen whether tandem transplantation combining the efficacy of highdose therapy with the immunological graft versus lymphoma effect will lead to the desired more favorable outcome. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013

Improved Photodynamic Cancer Treatment by Folate‐Conjugated Polymeric Micelles in a KB Xenografted Animal Model

Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT.

Intratumoral Coadministration of Hyaluronidase Enzyme and Oncolytic Adenoviruses Enhances Virus Potency in Metastatic Tumor Models

Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models. The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy. In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P < 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P < 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors. Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.

The anti-tumor efficacy of a GM-CSF-secreting tumor cell vaccine is not inhibited by docetaxel administration.

Docetaxel has demonstrated therapeutic efficacy against breast, prostate, and ovarian cancer and other solid tumors. The tumoricidal activity of docetaxel is mainly attributed to its ability to block microtubule depolymerization, thus inducing G(2)-M arrest and apoptosis. Mounting evidence indicates that docetaxel also possesses immunomodulatory activity such as augmenting macrophage and lymphokine activated killer activity and inducing pro-inflammatory cytokines, suggesting that docetaxel may be a good chemotherapeutic agent to combine with cancer immunotherapies, assuming that it does not inhibit the vaccine-induced immune response. The anti-tumor activity of the combination of docetaxel and a GM-CSF-secreting B16F10 tumor cell vaccine (B16.GM) was evaluated in the murine B16 melanoma model. Dose levels of docetaxel and the B16.GM vaccine known to be ineffective when used as single agents were selected. Three iv treatments of 6 mg/kg docetaxel per injection given on days 5, 9, and 13 after tumor challenge or a single vaccination with 2-3 x 10(6) B16.GM cells on day 3 were ineffective at inhibiting tumor growth when used as single agents [median survival time (MST)=24 days in both treatment groups and in control animals]. However, combination of docetaxel and B16.GM vaccine significantly delayed tumor growth, increasing MST to 45 days. A similar improvement in anti-tumor efficacy was observed using multiple treatment cycles of the B16.GM vaccine/docetaxel combination. Administration of docetaxel every 4 days between bi-weekly B16.GM vaccinations increased the median survival of tumor-bearing mice from 31 to 52 days compared to multiple B16.GM vaccinations alone. In summary, these data demonstrate that rather than inhibiting the anti-tumor effects of a GM-CSF-secreting tumor cell vaccine, docetaxel combined with a whole cell vaccine significantly inhibits tumor growth, increases survival time and does not impede T-cell activation in the murine B16F10 melanoma tumor model. GM-secreting tumor cell vaccines in combination with docetaxel may represent a new strategy for combining chemo and immunotherapy for cancer.

Definitive radiotherapy ± erythropoietin for squamous cell carcinma of the head and neck: Preliminary report of RTOG 99–03

Anemia has been associated with poor local-regional control and survival for squamous cell carcinoma of the head and neck (SCCHN). Recombinant human erythropoietin (Epo) elevates hemoglobin levels in anemic patients receiving radiotherapy. We thus designed a prospective randomized trial to determine if concurrent Epo administration with radiotherapy (±concurrent chemotherapy) could improve local-regional control in non-operative SCCHN. Eligible patients had non-metastatic, non-resected SCCHN, and a pre-treatment hemoglobin level between 9.0 g/dl and 13.5 g/dl (between 9.0 and 12.5 g/dl for women). Stratification was performed for stage, planned use of chemotherapy, pre-treatment hemoglobin level and gender. Randomization consisted of radiotherapy (XRT) alone (66–72 Gy) or XRT + Epo 40,000 units, subcutaneously injected, starting 7–10 days before the start of XRT. In the original protocol design, concurrent chemotherapy was not allowed; the study was later modified to allow (but not mandate) the use of concurrent high-dose intermittent cisplatin or weekly moderate dose platin/paclitaxel for Stage III/IV patients. Epo was continued throughout radiotherapy unless/until hemoglobin level reached 16 g/dl (14 g/dl for women); these “target” levels are above the package-insert labeling for erythropoietin. Epo was discontinued if hemoglobin exceeded these target levels and was restarted if hemoglobin fell below 13.5 g/dl (12 g/dl for women). The study commenced June 2000. Upon recommendation of the RTOG Data Monitoring Committee, the study was permanently closed to accrual after 148 patients were enrolled; interim analysis revealed that it would be extremely unlikely that Epo would benefit local-regional control (LRC) or survival. There are 135 patients evaluable for this report and the median followup is 12 months. In the Epo arm, hemoglobin level increased by a mean of 1.59 g/dl, while in the control arm, hemoglobin level decreased by a mean of 0.19 g/dl (p = 0.0001 by t-test). However, as shown in the table below, there was no improvement in anti-tumor efficacy. There was no significant difference in the overall rate of Grade 3 + toxicity between the two arms. There was one fatal cardiovascular event attributed to Epo (suspected pulmonary embolism). Despite significantly improving patients’ hemoglobin levels, the addition of concurrent Epo to definitive radiotherapy does not improve local-regional control or survival for mildly/moderately anemic patients with SCCHN.

Combination of IDN5390, an orally active taxane, with paclitaxel in a human tumor xenograft: improvement in antitumor efficacy without increase of toxicity

Combination of IDN5390, an orally active taxane, with paclitaxel in a human tumor xenograft: improvement in antitumor efficacy without increase of toxicity