Dose-dense chemotherapy (DDC) is a concept of chemotherapy administration that is being used more and more. Understanding DDC requires an understanding of tumor cell replication and growth, sometimes referred to as the Gompertzian growth curve. This theory represents the fact that tumor growth follows a mathematically predictable growth curve, with rapid growth initially, then leveling off to slower growth. For example, while a tumor is small and often undetectable by available tests, its cells grow very rapidly. Eventually, the tumor reaches a size where it outgrows the available nutrients and blood supply, and tumor growth slows down.
Cells are most sensitive to chemotherapy when they are rapidly dividing, therefore the early stage, smaller tumors are often more sensitive to chemotherapy. This is also why surgery may be used to remove as much of the tumor as possible, leaving a small number of cells to then be treated by chemotherapy. Standard chemotherapy regimens call for a standard dose of chemotherapy given every 3 or 4 weeks, depending on the regimen, allowing for healthy cells to recover between doses (such as blood counts, oral mucosa, and GI lining). However, we now understand that this 3-week break may also allow the now smaller, more rapidly dividing tumor cells to start growing rapidly again.
Dose-Dense Chemotherapy (DDC) aims to achieve maximum tumor kill by increasing the rate of chemotherapy delivery, not by increasing dosage (which is the theory behind many stem cell transplant protocols). By administering the same doses of chemotherapy previously given every 3 weeks on an every 2 week schedule instead, the chemotherapy interrupts the rapid growth phase of the tumor cells. Thus, the therapeutic drugs interfere with the Gompertzian curve, hitting the tumor cells at the time when they are just beginning to grow rapidly again. In other words, "hit them while they are down." This model was called the Norton-Simon model, after the researchers who first described it.
You may ask, why we haven't tried this before? The concern has always been that giving chemotherapy more frequently would lead to low white blood counts and infection, a potentially deadly combination in a patient receiving chemotherapy. Through the use of growth factors (Neupogen, Neulasta, Leukine), we are able to have faster recovery of white blood cells, decreasing the chance of infection. Several DDC studies have shown a higher incidence of anemia (low red blood cell count) and bone pain (likely related to the use of a growth factor) with these regimens, but the DDC regimens also mean a decrease in the length of therapy by 4-6 weeks, which may be appealing to some.
While the theory seems logical, in practice the results have not been so convincing. The first study was done in women with node-positive breast cancer who were receiving chemotherapy with cytoxan, Adriamycin, and taxol. The women who received DDC every two weeks had an overall survival of 92% three years after treatment, versus 90% for the every 3 week regimen. The same result in favor of DDC was found whether Adriamycin and cytoxan were given at the same time or sequentially (one after the other). As for recurrence of their cancer, 82% of women receiving DDC remained cancer-free, compared to 75% of the women on the every three week regimen. Longer follow-up will give additional information in the coming years.
Two additional studies in women with node-positive breast cancer, using different chemotherapy medications, did not find a statistically significant difference in survival or recurrence rates. (Statistical significance is the method researchers use to determine if the rate is greater than what might happen by chance) However, both studies showed a trend toward improved survival and fewer recurrences. This may mean that certain subgroups of women would benefit from DDC. Based on study results, researchers theorize that the benefit may be greatest for women under 50, those with ER negative and/or Her2 positive tumors.
A trial for women with metastatic breast cancer looked at giving paclitaxel weekly, compared with the standard every three weeks, and saw a benefit in response and survival for the DDC group.
Several studies utilizing DDC prior to breast surgery (called neoadjuvant chemotherapy) have shown improved response rates in operable breast cancer, resulting in higher rates of breast conserving surgery as opposed to mastectomy.
Studies are ongoing looking at various drug regimens in dose-dense format and in combination with newer biologic therapies, such as Herceptin. It appears that certain high-risk women (such as those with positive lymph nodes and/or negative estrogen/progesterone receptors) or those for whom neoadjuvant chemotherapy is an option would benefit most from DDC.
Attempts have been made to improve first-line therapy of diffuse large B-cell lymphoma by delivering CHOP chemotherapy on a two-week rather than three-week schedule, with growth-factor support to prevent neutropenia. Two multi-institution phase II studies (one from Italy 1 and one from the Southwest Oncology Group 2 ) have shown reasonable response rates, short-term progression-free survival, and overall survival utilizing CHOP-14 (every 14 days) or R-CHOP-14 (including Rituxan) with Neulasta (growth factor) support. There were no significant unexpected side-effects, with the exception of a high rate of interstitial pneumonitis seen in the Italian study (14%) associated with pneumocystis carinii in 6% (a type of pneumonia).
A large, randomized, phase III study completed by the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) 3 in young patients with good-prognosis, aggressive non-Hodgkin lymphoma, directly compared CHOP-21 (every 21 days) with CHOP-14 (every 14 days). Chemotherapy dose delivery was not compromised by the dose-dense schedule (meaning doses did not need to be changed or delayed due to severe side effects), and patients were able to complete treatment on the average at 76 days on CHOP-14 and 106 days on CHOP-21. Toxicity and secondary malignancies (cancers caused by the chemotherapy) were not significantly different between the two groups. The study observed statistically significantly higher complete response rates for CHOP-14 vs. CHOP-21 (76.1% vs. 60.1% respectively), as well as better 5-year event-free survival (survival with no relapses) and overall survival (survival despite relapses) rates (43.8% vs. 32.5%, and 53.3% vs. 40.6% respectively).
Even though the results of this study are significant, they were derived in the pre-rituximab era and may not hold for the combination of rituximab with CHOP. A randomized phase III study is underway by the GELA to directly compare R-CHOP-21 (every 3 weeks with Rituxan) with R-CHOP-14 (every 2 weeks with Rituxan) and address the issue of pulmonary toxicity seen in the prior phase II study. Early results (at median 14 months) have demonstrated similar rates of side effects and equal complete response rates in both arms of 47%, but longer follow up is needed to determine the benefit of the DD regimen.
In advanced ovarian cancer, paclitaxel and carboplatin given every 3 weeks has been compared to dose-dense weekly administration of paclitaxel. In this Japanese study, women were given weekly paclitaxel in addition to the every three week carboplatin. Median** progression free survival was longer in the DDC group (28 months vs. 17.2 months) and overall survival at 3 years was higher in the dose dense regimen group (72%) than in the conventional treatment group (65%). Neutropenia and anemia were more common in the DDC group.
It is clear that there is a benefit to DDC for certain patients. Determining who will benefit is the focus of current studies in these and other types of cancer. In addition, longer follow-up of previously reported studies will give more information on the use of DDC and long-term benefits or complications.
**To learn more about understanding study results, see: Interpreting a Cancer Research Study.
Some terms used in this article:
Median: The median is the "middle of the pack." In this example of years since treatment, the median is the time when half of the patients have had more years since treatment and half have less. For instance, if the patients were 2, 4, 6, 10.8, 12, 12 and 14 years since treatment, 10.8 is the mid- point, or the median. This is different from the mean, which would be the average time since treatment.
Progression free survival: Also called PFS, this refers to the number, percent, or time of survival (in days, months, or years) before the patient's disease progresses/ recurs.
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