When it comes to adding hyperthermia treatment to radiation therapy for advanced cervical cancer patients, hotter and longer treatment is better. That's the conclusion of a Dutch study that found that more intense hyperthermia treatments can extend overall survival.
Hyperthermia is the artificial generation of a higher temperature at a tumor-involved region of the body. It has shown success as a complement to radiation therapy in treating a number of different types of cancer.
The technique is a standard treatment in the Netherlands for patients with advanced cervical cancer, or patients with less advanced cervical cancer who cannot clinically tolerate chemotherapy. It is recommended and used as an alternative to the international gold standard of combined radiation therapy and cisplatin-based chemotherapy.
To help guide hyperthermia treatments, researchers from the Erasmus Medical Center in Rotterdam announced that they have identified the prognostic factors that can achieve better patient outcomes for these patients. They published the results of their study in the July issue of the European Journal of Cancer (2009, Vol. 45:11, pp. 1969-1978).
The timing could not be more appropriate. Last month, the Dutch healthcare system added payment of deep hyperthermia treatments to its hospital reimbursement schedule, thus enabling all cancer centers in the Netherlands to offer this treatment. Because hyperthermia treatments have been funded by clinical trial grants in the Netherlands, treatment had been available only in two cancer centers, Erasmus Medical Center in Rotterdam and Maastricht Radiation Therapy and Oncology Clinic (MAASTRO) in Maastricht, to which all advanced cervical cancer patients commuted.
Many cancer centers in the world are not familiar with the protocols for treating certain cancers with deep hyperthermia, because the medical device equipment needed either has not been approved for commercial clinical use, or, as is the case in the U.S., is in the final stages of awaiting the U.S. Food and Drug Administration (FDA) approval.
The protocols developed through former and current clinical trials in Europe will provide proven guidelines and facilitate adoption when commercial products become available.
The Dutch Deep Hyperthermia Trial
To put the discovery by the Erasmus Medical Center researchers in perspective, the results of the two clinical trials from which their current study was derived need to be understood.
The Dutch Deep Hyperthermia Trial, conducted between 1990 and 1996 and published in the Lancet in 2000, was a prospective, randomized trial that compared the outcomes of 358 patients with advanced bladder, cervical, and rectal tumors. Half of the patients received only radiation therapy and the other half received both radiation therapy and hyperthermia. Three-year outcomes revealed that hyperthermia improved both pelvic control and overall survival rates, but seemed to be most effective for patients with advanced cervical cancer.
At 36 months, of an original cohort of 114 patients with advanced cervical cancer, the 58 patients receiving both treatments showed a complete response rate of 83%, compared with 57% for the 56 patients who only received radiation therapy. The survival rate was 51% for the combined treatment group, compared with 27% for the radiation therapy-only group.
Furthermore, hyperthermia treatments did not enhance radiation toxicity and were reported to be cost-effective, according to the trial's principal investigator, Dr. Jacoba van de Zee, Ph.D., a radiation oncologist at the University Hospital of Daniel den Hoed Cancer Center in Rotterdam.
The Dutch Deep Hyperthermia Trial was the first randomized trial that showed a survival advantage for patients receiving radiation therapy and hyperthermia treatments in women with locoregionally advanced cervical cancer. Its three-year outcomes were similar to the results of radiation therapy and cisplatin-based chemotherapy for comparable patients that were published in 1999 and 2000.
However, long-term outcomes had yet to be determined.
12-year follow-up
That question was addressed by a follow-up study published in 2008 in the International Journal of Radiation Oncology, Biology, Physics (March 15, 2008, Vol. 70:4, pp. 1176-1182) that tracked outcomes for both groups 12 years following treatment. The patients who received the combined treatment continued to have significantly better outcomes.
The outcomes for the combined therapy group remained consistent. At the end of the study period, 37% of this group was still alive, compared with 20% who received radiation only.
Of the combined therapy group, 56% retained pelvic tumor control, compared with 37% for the radiation therapy group. Pelvic recurrence developed in 25% of the combined therapy group and 31% of the radiation therapy group. Approximately one-third of both cohorts developed distant metastasis. Both groups experienced the same number of grades 3-5 radiation-induced toxicities.
Dr. Martine Franckena, a radiation oncologist in Erasmus Medical Center Rotterdam's hyperthermia unit, and colleagues suggested that the more positive outcome of patients receiving both treatments was the fact that hyperthermia acts both as a cytotoxic agent, directly killing cells at temperatures of 40-44° C, and also increases the cytotoxic effect of radiation therapy. By increasing blood flow, hyperthermia may improve tissue oxygenation and make cells more sensitive to radiation therapy, they speculated.
Continuing the research: 1996 to 2005
After the Dutch Deep Hyperthermia Trial was closed in 1996, both Erasmus Medical Center and the MAASTRO Clinic offered radiation therapy and hyperthermia as a standard treatment, as well as chemotherapy and radiation therapy. The treatment produced less toxicity to the seriously ill women, according to Franckena.
Between 1996 and 2005, 378 patients received this treatment, with 49% of the women having International Federation of Gynecology and Obstetrics (FIGO) stage IIIB/IVA cervical cancer. CT scans verified that 93% had tumors larger than 6 cm, and 30% had positive lymph nodes. The patients were referred from a total of 14 cancer centers where they received radiation therapy.
Franckena and colleagues conducted a study to determine if the outcomes of the rates of complete response, local control, and survival were comparable to the patients in the Dutch Deep Hyperthermia Trial who received the combined therapy. The findings were published earlier this year (Int J Radiat Oncol Biol Phys, January 2009, Vol. 73:1, pp. 242-250).
As with patients in the original landmark trial, all patients received external-beam radiation therapy in 23 to 28 daily fractions of 2.0-1.8 Gy five days a week, for a total dose of 46.0-50.4 Gy. Patients with residual tumor in the parametrium received an additional pelvic sidewall boost, and 22 patients with positive lymph nodes or bulky tumor load had chemotherapy treatment prior to radiotherapy. All patients also had brachytherapy for a total dose of 17 Gy applied in two fractions, 18-21 Gy applied in three fractions, or 30 Gy in 60 hours.
Patients received deep hyperthermia treatment (BSD 2000, BSD Medical, Salt Lake City) once each week during the five weeks of radiotherapy treatment. Thermometry Bowman probes were placed in the bladder, rectum, and vagina. Each treatment lasted 90 minutes, during which time temperatures were increased as high and homogenous as patient tolerance and normal tissue temperatures permitted.
Normal tissue temperatures did not exceed 43° C during the first 60 minutes, and 44° C for the final 30 minutes. Temperatures were reduced if a patient felt pain or intolerable discomfort.
Not all patients completed one or both courses of treatment --13% did not complete radiation therapy and 25% did not complete all five treatments of hyperthermia (15% at four; 10% at three or fewer).
The outcomes were different and statistically significant, because the patients treated from 1996 to 2005 were sicker and had more advanced symptoms, according to Franckena. Overall, 77% of the patients achieved a complete recovery, and 40% of the patients were alive. The pelvic tumor control rate at five years was 53%, and disease-free survival was 47%.
The major discovery made by the researchers was that the number of hyperthermia treatments proved to be a predictive factor. The researchers hypothesized that an increasing number of hyperthermia treatments corresponded to an increasing thermal dose administered to the patient. They decided to conduct a more detailed analysis.
The current study
Using the combined database of patients evaluated in both clinical trials, a total of 420 of 436 patients, the research team conducted a retrospective analysis to identify the relationship between thermal dose parameters and complete response rate, pelvic tumor control, disease-specific survival, and acute and late toxicities.
Treatment parameters were calculated using the Rotterdam Hyperthermia Thermal Modulator. In this study, the thermal dose parameter expressed the temperature as dose, but with the actual treatment time normalized to the overall treatment time of 450 minutes. TRISE -- a custom-made thermal dose parameter based on the temperature exceeded by 50% of the monitored sites in the bladder, vaginal, and rectal lumen together and averaged over all treatments -- produced a measurement incorporating temperature and duration of treatment.
Thermal dose analyses were performed only when temperature measurements were available for at least 50% of the treatments of a patient to ensure that the temperature measures accurately depicted a patient's treatment. If these were not available, the average temperature dose of all treatments with thermometry was used, and this was done for 10.5% of the total treatments.
The researchers found a significant relationship between thermal parameters that included both height of temperature and duration of heating and all disease control end points. This discovery of a thermal dose-effect relationship for dose parameters derived from intraluminal measurements suggests that outcomes may be improved by increasing the thermal dose of the hyperthermia treatment.
By adding one treatment to the current schedule, the probability of a complete response for a patient who receives the average hyperthermia dose increases by 4%, according to Franckena. Increasing the temperature during treatment is not feasible because it is already at maximum patient tolerance. Treatment protocols are being modified to include a sixth treatment.
Current status
In June 2009, the Nederlandse Zorgautoriteit, the Dutch Health Authority, authorized the reimbursement of both deep and superficial hyperthermia treatments, adding these into its radiotherapy general code structure for use in treating recurrent breast cancer, cervical cancer, head and neck cancer, and melanoma. This reimbursement policy puts the Netherlands in line with Austria, Italy, and Switzerland, according to Rick White, international vice president at BSD Medical.
Cancer centers in Germany are strong proponents of hyperthermia treatment for cervical cancer and receive annual clinical grants. At least 15 major cancer centers in China also offer this treatment.
Clinical trials are ongoing. A Dutch multicenter phase III trial (RADCHOC) is enrolling patients to compare the outcomes of patients randomized to receive either radiation therapy and hyperthermia treatments or radiation therapy and cisplatin chemotherapy. An international multicenter phase III trial is evaluating whether the effect of radiotherapy plus cisplatin can be further improved by the addition of hyperthermia.
By Cynthia E. Keen
AuntMinnie.com staff writer
July 15, 2009
Related Reading
Easier cisplatin regime for advanced cervical cancer appears less effective, February 2, 2007
Triple modality approach effective against cervical cancer, August 31, 2005
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