Operational Metrics for the ELAINE 2 Study Combining a Traditional Approach With a Just-in-TIME Model.

PURPOSE: There are numerous barriers to enrollment in oncology biomarker-driven studies. METHODS: The ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data. RESULTS: The study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months. CONCLUSION: The TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors.

PURPOSE: Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers. METHODS: Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion. RESULTS: Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2). Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed. CONCLUSIONS: Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.

A comparison of treatments of squamous cell carcinoma of the base of tongue: surgical resection combined with external radiation therapy, external radiation therapy alone, and external radiation therapy combined with interstitial radiation.

PURPOSE: The outcomes of patients treated at a single institution over a specific time frame using three different therapeutic approaches for cancer of the base of tongue were reviewed. METHODS AND MATERIALS: Between 1992 and 1998, 53 patients were treated with curative intent for base of tongue cancer. Seventeen patients underwent surgical resection with postoperative radiation therapy, 16 patients received definitive external radiation therapy only, and 20 patients were treated with external and interstitial radiation, with neck dissection in 16 of those patients. Local control, survival, and functional status were assessed with each approach. RESULTS: The 5-year actuarial local control and survival for the surgically treated patients were 74% and 44%, respectively. The patients treated with external radiation therapy alone had local control of 28% and 5-year survival of 24%. The patients treated with external and interstitial radiation with neck dissection as indicated had 5-year actuarial local control of 87% and survival of 33%. Survival was not statistically different between the three treatment approaches (p=0.0995) but local control was worse in the definitive external radiation group (p < 0.0001). Speech and swallowing function among the long-term survivors was superior in the definitively irradiated patients compared with the operated patients. CONCLUSION: In this retrospective analysis, survival and local control was lowest in the patients treated with external radiation alone, however, patient selection likely played an important role. Local control was far better with surgical treatment and with external combined with interstitial radiation but survival remains less than 50% with each approach. Surgical treatment was superior for patients with T4 disease. Functional status was higher in the long-term survivors treated nonsurgically.

Major histocompatibility gene therapy: the importance of haplotype and beta 2-microglobulin.

OBJECTIVES/HYPOTHESIS: Alloantigen gene therapy with the genes for the Class I major histocompatibility complex (MHC) HLA-B7 and beta 2-microglobulin in HLA-B7-negative patients has potential efficacy in the treatment of head and neck cancer, although the mechanism of response is unclear. Whether tumor regression is due to a response to HLA-B7 in HLA-B7-negative patients (i.e., due to "foreign" antigen) or simply to MHC overexpression is unknown. Therefore, a mouse model was used to compare tumor growth following syngeneic MHC transfection to alloantigenic MHC transfection. The importance of the beta 2-microglobulin gene was also evaluated. STUDY DESIGN: Prospective animal study. METHODS: The head and neck cancer cell line SCC-VII that grows in immunocompetent C3H mice, which are MHC haplotype H2-K, was used. Stable transfections were made with H2-K, H2-K, and beta 2-microglobulin in the SCC-VII cells. To test the importance of MHC "foreignness," mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, and SCC-VII plus H2-K plus beta 2-microglobulin transfected cells. To evaluate beta 2-microglobulin, mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, SCC-VII plusH2-K transfected cells, and SCC-VII plus beta 2-microglobulin transfected cells. Tumor growth in all groups was compared statistically. RESULTS: Major histocompatibility complex foreignness was a part of the antitumor response. Foreign MHC routinely abrogated tumor growth, whereas syngeneic MHC only slowed tumor growth. beta 2-microglobulin aided the MHC tumor inhibition but did not inhibit tumor without the MHC. CONCLUSION: The antitumor response was greater when the MHC gene used was foreign. beta 2-microglobulin increased the efficacy of MHC gene therapy. Both of these findings are important when designing clinical trials of immunologically based gene therapies for head and neck cancer.

Recurrent advanced (T3 or T4) head and neck squamous cell carcinoma: is salvage possible?

BACKGROUND: Salvage surgery is often the only curative option for recurrent cancer. In patients whose initial tumor is stage T3 or T4, the primary therapy often makes salvage even more difficult. We therefore analyzed the outcome in patients who were originally treated for T3 or T4 squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx and who then had a recurrence and chose to undergo further therapy for cure. PATIENTS AND METHODS: From 1980 to 2000, a total of 940 patients were treated for stage T3 or T4 cancer. Forty-eight patients underwent salvage therapy for recurrence: 24 for primary site recurrence, 20 for regional recurrence, and 4 for locoregional recurrence. RESULTS: The mean time to recurrence was 14.0 months, and the mean survival time was 26.2 months. Among the 28 patients treated for primary site recurrence, the mean time to rerecurrence was 12.6 months, and the mean survival time was 27.3 months. Only 5 of the 28 patients had prolonged survival. The stage of the recurrent disease did not influence outcome. Among the 20 patients treated for neck recurrence, the mean time to recurrence was 14.0 months, and the mean survival time was 25.0 months. Six of the 20 patients had prolonged survival, but none had a recurrence in a previously dissected and irradiated neck. CONCLUSIONS: These results show the limited potential for survival in patients who have a recurrence after treatment for advanced primary site head and neck cancer. Patients who have not undergone all modalities of therapy have the potential for salvage, but even then the chances are limited. Given the morbidity of salvage therapy, and the limited chance for cure, physicians must cautiously counsel patients who are contemplating treatment of recurrent cancer after therapy for advanced disease.

Microsatellite instability as a predictor of survival in head and neck cancer -- is there a link with colon cancer?

OBJECTIVE: A reliable genetic marker to predict outcome for head and neck cancer is needed. In colon cancer, microsatellite instability (MSI) predicts response to therapy and improved prognosis. Colon cancer patients with MSI have a 60% improvement in survival as compared to patients without MSI. To assess whether MSI is a predictor of improved prognosis in head and neck cancer we used our tumor registry to find 8 patients treated between 1995 and 1998 with head and neck squamous cell carcinoma and either a history of colon cancer or a parent who had colon cancer. As a control, 15 T(2) or T(3) oral cavity cancers were used. METHODS: The tumor specimens were obtained and laser capture microdissected for analysis using the following microsatellite markers: BAT25, BAT26, BAT40, D1S2883, D2S123, D3S1611, D5S346, D7S501 and D8S25. RESULTS: All 8 patients with head and neck cancer and a colon cancer history exhibited MSI or loss of heterozygosity (LOH) at 1 or more of the markers tested. Three patients had 2 abnormal markers, 1 patient had 3 abnormal markers and 1 had 7 abnormal markers. Only 1 of the patients with a colon cancer history, all of whom had MSI, developed recurrent head and neck cancer. Of the 15 control patients, 5 had MSI or LOH and 1 had MSI or LOH at 2 markers. Three of the 5 patients with MSI or LOH had a recurrence; hence MSI and LOH at these markers were uncommon, and there was no relation between MSI and outcome in patients without a history of colon cancer. CONCLUSIONS: These results support a possible alternative mode of carcinogenesis in patients with head and neck cancer and a history of colon cancer and, most significantly, that these cancers are a subgroup of head and neck cancer that may have a better prognosis.

Dietary antioxidant intake in patients at risk for second primary cancer.

OBJECTIVES: To analyze dietary antioxidant intake for head and neck cancer patients at risk for development of second primary cancers. STUDY DESIGN: Prospective observational study. METHODS: Twenty-four patients underwent three random, unscheduled, 24-hour dietary recalls over a 15-day period within 6 to 60 months after successful treatment for stage I or II oral cavity squamous cell carcinoma. RESULTS: The study sample had a lower mean daily dietary intake of fruits and vegetables and antioxidant nutrients, including vitamins A, C, E, and total carotenes than age- and sex-matched historic control subjects (all P <.05 except vitamin A). A positive linear correlation was noted between daily servings of F&V and dietary intake of vitamins A, C, E, and total carotenoids (all P <.05 except vitamin A). Compared to current recommendations, the study sample had lower mean daily dietary intake of vitamins A, C, and E (P =.81,.06, and <.01) and servings of fruits and vegetables (P <.01). When vitamin supplements were included in the analysis, mean daily intake exceeded recommended dietary allowance (RDA) for vitamins A, C, and E (all P <.05). CONCLUSION: This study suggests that patients treated for early-stage oral cavity carcinoma, at risk for second primary cancers, have a statistically significant deficiency in dietary (food) sources of antioxidant nutrients when compared with both historic control subjects and current recommendations. Vitamin supplementation significantly exceeded current RDAs. Because increased fruit and vegetable intake, but not vitamin supplementation exceeding RDA, is associated with reduced cancer risk, physicians may consider recommending at least five daily servings of fruits and vegetables as an alternative to vitamin supplementation.

Alloantigen gene therapy for head and neck cancer: evaluation of animal models.

BACKGROUND: Human trials of alloantigen gene therapy, using the class I major histocompatibility complex (MHC) HLA-B7, have demonstrated the potential efficacy of this treatment for head and neck cancer. Its mechanism remains unclear. An immune-competent mouse model of MHC gene therapy to test factors potentially important to the tumor response is needed. METHODS: Two cell lines were used, B4B8 cells that grow in Balb/c mice and SCC-VII cells that grow in C3H mice. The mouse MHC H2-K(b) was used as the therapeutic gene, because it is an alloantigen to both mice strains. Plasmids that encode the H2-K(b) cDNA were prepared, and the cell lines were transfected. Mice were injected subcutaneously with naive cells to determine the tumor kinetics and serve as controls. Mice were injected with H2-K(b) transfected cells and tumor growth was compared with controls. Mice that did not grow tumor were rechallenged with naive cells to assess for tumor immunity. Mice were injected with transfected and naive cells admixed to determine whether the concentration of the alloantigen is important. RESULTS: B4B8 tumors grew slowly, whereas SCC-VII tumors grew rapidly. Transfection with H2-K(b) plasmid prevented or inhibited tumor growth of both the B4B8 and SCC-VII tumors. This growth inhibition was independent of the number of cells injected. In the mice that did not grow tumor, tumor immunity was demonstrated after challenge with naive cells in both models. There was no relationship between induction of immunity and the timing of the challenge or initial cell quantity. The mice injected with a mixture of naive and transfected cells grew tumor, although growth was delayed in the B4B8 model. CONCLUSIONS: The results demonstrate that the two mouse models can serve as a rapid and slow growing tumor model of alloantigen gene therapy. In addition, it was noted that initial tumor cell number is not a significant factor for predicting tumor response and demonstrated that in both of these models alloantigen gene therapy results in significant antitumor immunity.

Antitumor effect of secreted Flt3-ligand can act at distant tumor sites in a murine model of head and neck cancer.

The Flt3 ligand (Flt3-L) manifests antitumor activity, presumably due to its capacity to recruit dendritic cells and cause their proliferation. To assess whether local production of Flt3-L can mediate a "distant bystander" effect, murine B4B8 squamous cell carcinoma cells were transfected with a plasmid encoding a secretory form of Flt3-L to produce B4B8FL cells. Similarly, B4B8FL and B4B8 cells were transfected with herpes simplex virus thymidine kinase (HSVTK) to produce B4B8TK and B4B8FL/TK cells, which should be sensitive to ganciclovir (GCV), to know whether the effects of Flt3-L and HSVTK/GCV would be synergistic. To test for a distant bystander effect in vivo, B4B8FL, B4B8TK, and B4B8FL/TK cells were injected subcutaneously into the left flank of syngeneic Balb/c mice, and naïve B4B8 cells were injected into the right flank. The formation of tumors derived from B4B8FL and B4B8FL/TK cells was significantly delayed in both flanks compared with naïve B4B8 and B4B8TK cells. Growth of B4B8TK tumors in the ipsilateral flank was retarded following GCV treatment, but in contrast to B4B8FL and B4B8FL/TK cells, no distant bystander effect in the contralateral flank was observed. Immunohistochemistry showed lymphocytic infiltrates in both flanks of the B4B8FL and B4B8FL/TK groups. The data indicate that in these cells, local secretion of Flt3-L is sufficient to evoke a distant bystander effect but that expression of HSVTK, even after GCV administration, is not. Furthermore, the combination of local Flt3-L and HSVTK production, together with GCV administration, does not enhance the distant bystander effect produced by Flt3-L alone.

Therapeutic decision making in stages III and IV head and neck squamous cell carcinoma.

BACKGROUND: The best treatment for advanced head and neck cancer remains unclear. Proponents of various therapeutic regimens continue to debate this issue with inconclusive and frequently biased data and with carefully selected patients in controlled trials to support their approach. To assess the outcome of patients in a real-world situation, we reviewed a prospectively maintained database of patients with head and neck cancer. METHODS: We reviewed data from 591 consecutive patients with stage III or IV squamous cell carcinoma treated at a university medical center from January 1, 1992, through December 31, 2000, and analyzed survival using the Kaplan-Meier method. RESULTS: Overall survival was 48%, 40%, and 33% at 2, 3, and 5 years, respectively. We found a significant death rate due to comorbid conditions. The primary tumor was treated surgically (with or without postoperative radiation) in 363 patients, with survival of 55%, 46%, and 38% at 2, 3, and 5 years, respectively. The tumor was treated primarily with radiation therapy (with or without neck dissection) in 193 patients, with survival of 40%, 33%, and 27% at 2, 3, and 5 years, respectively. Overall survival in the surgical group was better than in the radiation group (P =.005, log-rank chi 2 test). The radiation group was subcategorized into those who underwent radiation because the tumor was so advanced as to be unresectable (n = 86), because they were too unhealthy to undergo radical surgery (n = 23), and because they elected radiation therapy (n = 84). Survival in each of the radiation subgroups at 2, 3, and 5 years was 28%, 20%, and 14%, respectively, in the unresectable group; 34%, 22%, and 11%, respectively, in the unhealthy group; and 57%, 53%, and 46%, respectively, in the elective group. Thus, survival in the elective radiation subgroup exceeded that of the surgical group, although not statistically. We analyzed data regarding T and N stages, age, race, surgical margin status, postoperative radiation therapy, chemotherapy, radiation dose, and tumor site. Multivariate analysis of the surgical group and elective radiation subgroup showed that N stage and age were the strongest predictors of survival and that the method of therapy was not significant. For oropharyngeal cancer, the patients in the elective radiation subgroup did as well as the surgical group. Many patients were noncompliant with portions of therapy, with a resulting reduction in survival. CONCLUSIONS: The data demonstrate the value of analyzing a consecutive series of patients with advanced head and neck cancer. By including patients with comorbidities and those who are noncompliant, we determined a realistic expectation of patient outcomes. By including all patients, the data dramatically show the impact of age, comorbidity, and advanced stage on survival. The survival of patients who underwent elective radiation therapy in combination with neck dissection was similar to that of patients treated with primary tumor surgery. This was particularly true for oropharyngeal tumors. The site and stage-specific data are useful in counseling patients with advanced head and neck cancer regarding treatment choices.

Molecular genetics of head and neck cancer.

BACKGROUND: Head and neck cancers have multiple genetic abnormalities that influence tumor behavior and may be useful in developing new treatments. METHODS: Genetic alterations implicated in head and neck cancer oncogenesis and behavior are reviewed, and molecular techniques for detection and treatment are evaluated. RESULTS: The large number of genetic changes present in head and neck cancer cells precludes meaningful use of simple molecular tests and treatments. Detection of abnormalities in multiple genes provides better prognostic information than the detection and assessment of single mutations. Screening tests that rely on amplification of genetic material present in bodily fluids are hindered by the genomic complexity of head and neck cancer. Introduction of genetic material into head and neck cancer cells for gene therapy has shown some efficacy. CONCLUSIONS: Head and neck cancers comprise a complex genetic disease. Although much has been learned about the molecular genetics of head and neck cancers, continued study of multiple genes is critical for further progress. Gene therapy, although promising, must also overcome this complexity.

Organ preservation with interstitial radiation for base of tongue cancer.

Management options for squamous cell carcinoma of the base of tongue include surgical resection (often with adjuvant radiation), definitive external radiation and external combined with interstitial radiation. The reported series is a single institution experience with interstitial radiation for base of tongue cancer. Twenty patients were treated definitively with interstitial radiation as a boost to external radiation, and four patients were treated palliatively with interstitial radiation alone for recurrent base of tongue cancers or disease arising in a previously irradiated base of tongue. Patient, tumor, and treatment details were analyzed relative to disease control and posttreatment patient function. The 5-year actuarial local control, locoregional control, distant metastasis-free survival, overall disease-free survival, and actuarial overall survival of the definitively treated patients were 86%, 84%, 57%, 41%, and 30%, respectively. The 5-year actuarial rate of tolerating a normal diet was 86%, and all long-term survivors had normal speech function. Of the four patients treated palliatively with interstitial implant alone for recurrent disease (three patients), or a second primary cancer in a previously irradiated site (one patient), local control was obtained in three and long-term disease-free survival was obtained in one. Interstitial implantation combined with external radiation is associated with a high rate of disease eradication with preservation of speech and swallow function. Interstitial radiation alone can achieve effective palliation.

A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma.

BACKGROUND: The anti-cancer gene, E1A, can be complexed to a lipid carrier, DC-Cholesterol:DOPE, to form tgDCC-E1A, which can be injected directly into tumors. METHODS: Twenty-four patients with recurrent, unresectable, head and neck cancer were treated with intratumoral injections of tgDCC-E1A over 8 weeks. Tumor response was assessed using CT scans. Time to progression and overall survival were calculated. RESULTS: Intratumoral tgDCC-E1A was well tolerated in all patients. No significant toxicities related to tgDCC-E1A were reported. One patient (4.2%) had a complete response, two patients (8.3%) had minor response, and seven patients (29.2%) had stable disease by two-dimensional cross-products on blinded CT scans. The median time to progression was 8.6 weeks (range, 3.3-43.7 weeks), and median survival was 4.6 months (range, 1.3-15.6 months). CONCLUSIONS: Intratumoral injections of tgDCC-E1A were safe and well tolerated. Modest tumor response was observed. Further development of tgDCC-E1A is warranted in combination with other treatment modalities.