Full Title:Individual versus standard quality of life assessment in a phase II clinical trial in mesothelioma patients: Feasibility and responsiveness to clinical changes

With cancer research so often dominated by talk of scientific programs and technological advances, it is often easy to forget that this research exists for one reason only: to save people’s lives. While improvements in the science behind cancer treatments have been the primary reason for the great advances made in cancer therapies during the last ten years, we must always remember that an individual person is at the center of this process and so we must remain dedicated to listening and responding to his or her needs as he or she undergoes treatment. To accomplish this, doctors have developed a number of scales and questionnaires that attempt to track patient progress, but these assessments have rarely received the same level of study that the actual treatment experiments have received, so questions regarding which of the assessments is most effective in diagnosing quality-of-life issues remain unanswered.

These kinds of questions are important for the treatment of all forms of cancer, but they are especially important to track how patients with mesothelioma respond to their treatments because of the aggressive nature of the protocols themselves. Even though truly curative treatments for pleural mesothelioma and peritoneal mesothelioma have not been developed, recent research has indicated that trimodal therapy—consisting of surgery, chemotherapy and radiation—is the most effective way to manage the disease in some patients. However, trimodal therapy often leaves the patient quite weakened and a full recovery can take months, so the development of effective quality-of-life (QoL) scales for these patients is an important aspect to their overall recovery. To asses the efficacy of some of these competing QoL scales, researchers from Switzerland conducted a study on patients undergoing a Phase II clinical trial for the treatment of pleural mesothelioma and they have recently released their results. The study compared the effectiveness of a standardized quality-of-life assessment scale with a personalized one based on patient interviews.

Overview of the Study

The authors enrolled 61 patients undergoing treatment for pleural mesothelioma into their study. These patients were participating in a Phase II clinical trial involving trimodality therapy. The treatment protocol stipulated 3 cycles of neoadjuvant chemotherapy, followed by extrapleural pneumonectomy and then adjuvant radiotherapy. The quality-of-life assessment was tracked according to two different systems and the comparison of these systems was the endpoint of the study under discussion.

The first QoL system the patients responded to was the Rotterdam Symptom Checklist (RSCL), a standardized assessment that tracks a patient’s response to clinical treatment along a number of defined axes. The authors describe RSCL as “a cancer-specific self-report questionnaire consisting of subscales for physical symptom distress, psychological distress, activity impairment and an overall evaluation of QoL.” The main thrust of RSCL tracks responses to 23 physical symptoms and 7 psychological symptoms.

The second system was known as the Schedule for the Evaluation of Individual Quality of Life (SEIQoL). This system is a personalized system that begins from the premise “quality of life is what the individual determines it to be,” and proceeds through an individual interview to determine one’s own personal meaning regarding “quality of life.” Here, a trained research nurse interviews the patient in three stages. During the first stage, the patient identifies the most important areas of his or her life at the time; during the second stage, he or she then rates his or her overall level of functioning for each of these activities, while in the third stage the patient has to determine the relative weight his or her previous answers are given to determining an overall quality-of-life.

The answers to each of these two scales were then converted to a numerical system and a single overall score was then developed.

Patients underwent the QoL assessments five times during treatment: at registration, at the start of the third chemotherapy cycle, at four weeks after surgery, and then again at 3 months after surgery and 6 months after surgery.

Results

Of the 61 patients, 58 completed three cycles of neoadjuvant chemotherapy, 45 then went on to receive an extrapleural pneumonectomy, while 36 of these patients then completed the radiotherapy section of the protocol. Of these patients, more completed the RSCL assessment (95%), than did the SEIQoL assessment (82%).

When analyzing the results, the authors determined that the two systems did not correlate over the same domain and concluded that this was because they were measuring different things: the RSCL assessment was focused on tracking particular aspects of treatment response and because of this, was more effective at diagnosing a patient’s individual reactions to the therapy than was SEIQoL, while the SEIQoL assessment was more effective at determining individual patient needs and revealing more about the patient’s psychological state than was the RSCL assessment.

While the RSCL only took on average 8 minutes to complete, the SQEIQoL averaged 24 minutes to completion because of its personalized nature. The authors felt this was generally acceptable because it did reveal important information regarding the patient’s needs.

Conclusion

The author’s feel that using both systems would be an effective method of determining patient quality of life because their combination returns a wider domain of patient response than using either method in exclusion of the other does: RSCL is effective for individual response assessment, while SEIQoL is effective for determining patient needs. The incorporation of these assessments into treatment protocols are important steps in the determination of a patient’s treatment needs—both physical and emotional. This is especially so for mesothelioma patients, both because mesothleioma is very difficult to manage medically and because the treatments themselves are physically demanding. RSCL and SEIQoL can both play an important role in the treatment of the disease.

Improvements in the traditional therapeutic options available to mesothelioma patients have led to longer median survival times for a subset of these individuals, but the overall effectiveness of these treatments is still quite disappointing—especially when compared to the great advances that have been made in the treatment of other forms of cancer. Because of this, a number of researchers are actively investigating the development of alternative treatment strategies in the hope that more effective therapeutic management of the disease will one day be available to people diagnosed with pleural mesothelioma and peritoneal mesothelioma. One of these alternative strategies involves the use of gene therapy to combat tumor genesis.

Gene therapy is a disease-fighting technique where genes are inserted into a patient’s cells to replace defective or mutated alleles with functional ones. Although a relatively recent invention, it has already shown great promise in the treatment of a variety of disorders. It is an active area of research for mesothelioma treatments and this research is being conducted in a number of institutions around the world. One of the latest articles in the field, which describes a study on the efficacy of “suicide gene therapy” on individual mesothelioma cell lines, was recently published in the journal Onkologie.

Overview of the Study

The article describes a study by German researchers who conducted a number of interesting investigations of three mesothelioma cell lines. Histologically, two of the lines presented with a biphasic subtype, while the histological type of the third line was not known. To analyze the individual lines’ genetic makeup and particular chromosomal structure, the authors utilized multiplex fluorescence in situ hybridization (M-FISH) analysis. They also studied the tumorgenicity of each line by injecting mice with the one of the cell lines and then tracking the course of its health after injection. The cell lines were then studied for their susceptibility to genetic changes introduced by a rAAV2-based vector (recombinant adeno-associated virus 2-based vector). In molecular biology, a vector refers to a piece of foreign DNA that is used to transfer gene sequences from one organism to another, so the authors were interested in the extent to which the mesothelioma cell lines were reactive to the gene sequences that were inserted into the lines. The final phase of the study was to investigate the feasibility of using in vivo therapy to precisely target and attack these rAAV2-transduced mesothelioma cell lines.

Results

M-FISH analysis of the cell lines revealed a number of aberrations in each of the individual cell lines’ chromosomal structures, as well as clear differences in the underlying structures between the cell lines themselves. One of the cell lines, H-Meso-1, exhibited more aberrations than did the other two lines, but all lines exhibited non-standard genetic structures. After H-Meso-1, the cell line MSTO-211H exhibited the most aberrations, while the cell line NCI-H28 exhibited the least. When the authors compared the particular aberrations within each of the lines, they sometimes found that two of the lines shared the same recurrent aberrations, but the exact aberrations were not found among all three lines.

When the authors investigated the tumorgenicity of each of the lines, they discovered that H-Meso-1 was also the most tumorgenic of them. The NCI-H28 line did not cause any tumors at all. All of the cell lines were found to be rAAV2 susceptible, with H-Meso-1, again, exhibiting the highest gene transfer and expression rate. To study the feasibility of the in vivo gene therapy, the authors injected mice with the H-Meso-1 cell line and then separated them into groups treated with GVC and NaCl. The GVC group was the study group in this setting, because it should activate the rAAV2-vector. This is just what the authors found. Their analysis showed that GVC-treated mice demonstrated a near doubling of median survival time as compared to the NaCl group. This is a statistically significant finding, with the authors noting that future optimizations of the protocol could likely give even better survival figures.

Conclusion

The authors conclude their article by calling for additional research into the development of rAAV2-based treatments for patients with pleural mesothelioma. The results as presented in their paper were designed as a proof-of-feasibility test, not as an official clinical modality. Much more work is necessary before more comprehensive studies could even be considered, but the encouraging results as presented here certainly warrant this further research. The question of whether these therapies will be effective for humans is still years from being answered, but this study, as well as the numerous other studies that are investigating the creation of novel treatments, is another sign that improving the efficacy of mesothelioma treatments remains a top priority for researchers the world over.