New approach may enhance the effectiveness of hyperthermic chemotherapy for peritoneal metastatic cancer

Image: PD

Key Study Points:

1. Oxidative stress and hyperthermic conditions work synergistically with traditional chemotherapy to curb tumor cell growth in in vitro and in vivo models of peritoneal carcinomatosis.
2. The addition of diethyldithiocarbamate (DCC) to a traditional hyperthermic intraperitoneal chemotherapy (HIPEC) regimen shows a synergistic affect that can be harnessed in the treatment of peritoneal carcinomatosis in humans.
3. DCC can be used to inhibit superoxide dismutase (SOD) and increase endogenous levels of reactive oxygen species (ROS) in mice with few adverse effects.

Primer: One of the major challenges facing treatment for colorectal cancer is the occurrence of residual disease after surgical resection. One in seven patients develop peritoneal carcinomatosis, a disseminated metastatic spread of tumor cells to various intraperitoneal surfaces. Hyperthermic intraperitoneal chemotherapy (HIPEC), a procedure whereby high doses of heated chemotherapeutic solutions are pumped into the abdominal cavity, is used in attempts to eradicate microscopic tumor foci left after bulk resection. Resistance to standard chemotherapeutics, however, renders HIPEC an ineffective treatment in many cases. The authors of this study hoped to show that by adding oxidative stress (in the form of superoxide dismutase inhibition) to a traditional HIPEC protocol, the synergistic effects of targeted chemotherapy, hyperthermic stress, and oxidative stress can induce a greater anti-tumor response than any of the three alone.

Background Reading:

1. Peritoneal minimal residual disease in colorectal cancer: mechanisms, prevention, and treatment [Lancet]
2. Thermal sensitization using induced oxidative stress decreases tumor growth in an in vivo model of hyperthermic intraperitoneal perfusion [Ann Surg Oncol]

This [in vitro/in vivo, randomized controlled] study:  SW403 and HT29 human colorectal carcinoma cells as well as MC38 cells from mice were utilized as in vitro and in vivo models (respectively) for peritoneal carcinomatosis. The in vitro study compared (1) tumor cells treated with HIPEC (incubation at hyperthermic temperatures (42C) + chemotherapy with mitomycin C/doxorubicin or oxaliplatin) versus those that received only chemotherapy and (2) tumor cells treated with hydrogen peroxide and hyperthermic temperatures versus those treated with only hyperthermia. The murine in vivo model involved injection of MC38 cells into the mice to induce low volume of peritoneal carcinomatosis. The HIPEC procedure was then carried 24 hours after injection. Mice were perfused during the operation for 60 minutes at either normal (37C) or hyperthermic (40C) temperatures and treated with DCC (an inhibitor of SOD) + chemotherapy or chemotherapy alone.

The in vitro cell cultures showed that HT29 cells were highly sensitive to mitomycin C/doxyrubin, with less than 10% of cells viable at one week, but mildly resistant to oxaliplatin (only at 37 degrees). SW403 cells on the other hand were fairly resistant to both regimens of HIPEC with 15-40% of cells viable at one week. However, addition of hydrogen peroxide treatment to HIPEC led to increased ROS as well as activation of cell signaling pathways that result in cell death. Supporting the in vitro findings, in vivo models showed that mice with MC38 cancer cells that were treated with 10mM DCC at hyperthermic temperatures had significantly lower (P < 0.001) residual tumor than did mice treated with DCC at normal temperatures. In addition, it was shown that DCC combine with both hyperthermia and mitomycin C/doxyrubicin treatment had significantly (P = 0.011) decreased tumor cell survival at 40 days.

In sum: This study showed that oxidative stress as induced by DCC combined with hyperthermia and chemotherapeutics (mitomycin C, etc.) has a beneficial effect over that of traditional HIPEC alone in models of peritoneal carcinomatosis. These findings indicate that an effective approach to cancer treatment may be found by attacking broad aspects of cell stress in addition to current selective chemotherapeutics. However, while this article finds strength in its combination in vivo-in vitro approach, the application of its findings is limited as these results may not be applicable in a real life clinical setting. Moreover, there remains the inherent concern with production of large amounts of ROS in the body and the long-term effects this may have on human morbidity and mortality. Further studies are needed to translate these laboratory findings to clinical practice.

Click to read study in [Annals of Surgery]

By [DM] and [MK]

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