Aug 30, 2004 - 3:01 am
There are few more imprecise and drastic measures than chemotherapy as a treatment for cancer. The process involves poisoning a patient's system with toxic chemicals in an effort to kill malignant cancer cells. As one who has personnally seen a loved one suffer, I can attest to its destructive and debilitating side effects. Patients generally need steroid pre-treatment and many have a severe reduction in white blood cells.
There has been no real progess in the treatment of most common forms of cncer. Recent NCI data showed that U.S. cancer mortality rates have increased and age-adjusted cancer mortality rates in response to treatment have not imporved in several decades, despite the introduction of many new drugs. There is a mind-set of cancer culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievement and publication over all else.
Investigators rely on models that are grossly deficient at predicting success. Hundreds of cancer drugs are pushed into the pipeline and many are approved by the FDA, even though their proven activity has little to do with curing cancer. Hundreds of clinical trials of one-size-fits-all therapy in tens of thousands of patients having results that have trivial hypotheses and produce no progress.
Proof of efficacy of a cancer treatment such as chemotherapy requires a randomized trial in which it has been shown that the group treated with chemotherapy experienced significantly increased survival when compared to that of an untreated group. This has never been done. Most claims for the efficacy of a chemotherapeutic agent comes from trials showing shrinkage of tumors or from comparison of survival rates of unmatched groups over time. Unless tumor shrinkage is accompanied by evidence of increased survival, the treatment cannot be claimed to be effective.
Additionally, in clinical trials, many patients are excluded because they could not complete the rather arduous treatment. So randomized comparisons are of healthier treated patients against all the controls, rendering a lot a trials flawed.
Studies of Assay-Directed Chemotherapy in Ovarian Cancer
Kurbacher and colleagues (Kurbacher, CM, et al. Anticancer Drugs 9:51-57, '98) treated 25 previously treated patients with ovarian cancer with assay-directed chemotherapy and compared outcomes with 30 non-randomized but clinically well-matched controls. In the control group, there was a response rate of 37%, in the assay-directed group, there was a response rate of 64%. Assay-directed therapy also produced a greater benefit with respect to both response rate and progression-free survival in the subgroup of patients with platinum-resistant disease. A current multi-institutional, international trial is currently in progress to further determine whether assay-directed therapy is superior to empiric therapy.
Loizzi and colleagues (Loizzi, V, et al. Am J Obstet Gynecol. 2003 Nov;189(5):1301-7) treated 50 ovarian cancer patients in their first recurrence following platinum-based therapy with assay-directed therapy and compared clinical outcomes with 50 additional non-radnomized but well-matched patients who received chemotherapy without assay information. In the group with initial platinum-sensitive disease, response rates were 65% for assay-directed chemotherapy versus 35% for empiric chemotherapy. However, in the platinum-resistant group, there was no improvement for assay-directed therapy. Response rates were 21% versus 16% (not significant).
Weisenthal and colleagues (Weisenthal, et al.) recently completed an analysis of the overall survival of 549 ovarian cancer patients with tumors submitted to their laboratory for testing between January, 1993 and January, 2001. Kaplan-Meier survival curve analysis showed median survivals of 44 months for first-line chemotherapy of previously untreated patients and 41 months for second-line chemotherapy of patients meeting the clinical definition of initially platinum-sensitive disease.
In addition, recently performed analysis of long-term survival of ovarian cancer patients who had tumor biopsy specimens referred to their laboratory for cell culture drug resistance testing (CCDRT or chemosensitivity testing), with the data analyzed as a function of whether or not the attempted chemosensitivity testing was evaluable or in-evaluable. Approximately 95% of specimens submitted for testing yielded an evaluable result, while approximately 5% were in-evaluable for reasons relating to poor viability of the specimen, insufficient yield of tumor cells in the specimen.
This data represented the survival of patients for whom tumor biopsy specimens were submitted to the laboratory for cell culture drug resistance testing (chemosensitivity testing). There was no information regarding what forms of chemotherapy was actually administered to these patients. The Kurbacher study and Weisenthal series employed assays using cell death endpoints, while the Loizzi study employed a cell proliferation endpoint.
It is important to note what has been known for more than 40 years, that ovarian and other forms of cancer represent heterogenous diseases where the tumors of different patients have different responses to chemotherapy, and where important treatment advances will require individualizing treatment based on testing the individual properties of each patient's cancer. This is far superior to empiric analaysis which which results in a one-size-fits-all treatment paradigm. Cell culture drug resistance testing improves patient survival in chemotherapy for ovarian cancer.
Cell Culture Drug Resistance Testing Predicts for Patient Survival in Ovarian Cancer
Konecny, et al. (Gynecol Oncology 77:258-73,'00) tested the tumors of 38 previously untreated FIGO stage III patients who received treatment (independent of assay results) with one of serveral platinum-based regimens. Drugs were tested as combinations: cicplatin + cyclophosphamide, cisplatin + Taxol, etc. Twenty nine assay-sensitive patients had a significantly longer progression-free survival (median 28.5 vs 12.6 months, P=0.033) and overall survival (median 46 vs 18 months, P=0.03), compared with nine patients classified as assay-resistant. The ATP endpoint was used in this study.
Taylor, et al. (Eur J Gynaecol Oncol 22:278-82,'01) tested the tumors of 93 previously untreated FIGO stage III and IV patients who received treatment (independent of assay results) with either a platinum-based regimen (71 patients) or with a single agent alkylator (22 patients). Drugs were tested as single agents, with the tumor classified as sensitive, if at least one drug used in subsequent treatment was active in cell culture drug resistance testing and as resistant, if all drugs were inactive in cell culture drug resistance testing. Fifty-one assay-sensitive patients had a median survival of 23 months, while fourty-two assay-resistant patients had a median survival of 19 months. The three year survival of the sensitive group was 36% compared to 16% in the resistant group, while five year survivals for the sensitive group were 24% versus 12% for the resistant group (P=0.033). The MTT endpoint was used in this study.
Holloway, et al. (Gynecol Oncology 87:8-16,'02) tested the tumors of 79 previously untreated patients with optimally debulked stage III/IIc disease (63 cases) and suboptimally debulked stage III or stage IV disease (16 cases). Patients were treated with platinum/taxol if cell culture drug resistance testing did not show resistance to Taxol or else cyclophosphamide/platinum, cyclophosphamide/doxorubicin/platinum or platinum alone if cell culture drug resistance testing showed resistance to Taxol. Median progression-free survival was 6 months in 17 cases with platinum resistance in the assay, compared to 24 months for 62 cases exhibiting sensitivity to platinum. Median overall survial for the resistant group was 24 months, but was not reached in the sensitive group. Estimated 5 year survival was 19% in the resistant group, compared to 68% in the sensitive group. The tritiated thymidine endpoint was used in this study.
Nagourney, et al. (Gynecol Oncology 88:35-39,'02) tested the tumors of 17 previously treated ovarian cancer patients with the combination of gemcitabine + cisplatin. Assay results were cut at the median IC50 value for the drug combination. Patients with sensitive tumors had an 85% progression-free survival probability at 6 months, compared to approximately 28% for assay-resistant tumors, and Kaplan-Meier progression-free survival curves were superior in the assay-sensitive group (P2=0.012). Overall survival was also superior in the assay-sensitive group (P2=0.05). The DISC assay endpoint (delayed loss of cell membrane integrity) was used in this study.
Weisenthal, et al correlated the results of cell culture drug resistance testing to both cisplatin and carboplatin with long-term, overall patient survival in ovarian cancer. Specimens from previously treated patients were significantly more resistant to platinums than were specimens from untreated patients, and this difference was most pronounced in the case of poorly-differentiated tumors. Well-differentiated tumors had significantly greater platinum resistance than poorly-differentiated tumors. In untreated patients, resistance to cisplatin and (separately) to carboplatin correlated significantly with long-term survival, as reported prospectively. This relationship was strongest in the case of poorly-differentiated tumors. There was also a significant relationship between platinum resistance and patient survival in previously treated patients who relapsed greater than 6 months following the most recent chemotherapy with the primary, platinum-based regimen.