Heating Pelvic Tumors: Hyperthermia a Beneficial Adjunct to XRT
ABSTRACT & COMMENTARY
Synopsis: Primary local control of pelvic tumors remains a major challenge for cancer therapists. This multicenter trial examined the potential role for hyperthermia as an adjunct to external beam radiation for cervical, bladder, and rectal tumors. Although positive effects were seen for each of the tumor types, the data are most encouraging for cervical tumors, for which both primary local control and survival were significantly enhanced.
Source: Van der Zee J, et al. Lancet 2000;355:1119-1125.
Standard therapy to prevent local recurrence of locally advanced tumors of the bladder, cervix, and rectum includes radiotherapy, but results are discouraging. This study was designed to assess the potential for hyperthermia to enhance local control rates for these tumors. This was a prospective, randomized, multicenter trial conducted in the Netherlands from 1990 to 1996 including 358 patients with either bladder cancer (stages T2, T3 or T4, N0, M0), cervical cancer (stages IIB, IIIB, or IV), or rectal cancer (stages M0-1). Enrolled patients were randomly assigned radiotherapy (median dose, 65 Gy [n = 176]) or radiotherapy with hyperthermia (n = 182). The primary outcomes measured were complete response and duration of local control.
Complete response rates were 39% after radiotherapy and 55% after radiotherapy with hyperthermia (P < 0.001) and the duration of local control was significantly longer with radiotherapy plus hyperthermia than with radiation alone (P < 0.04). Treatment effect did not differ significantly between tumor sites. However, the addition of hyperthermia seemed to be most substantial for cervical cancer for which the complete response rate was 83% vs. radiotherapy alone with 57% (P = 0.003). The three-year overall survival was 27% in the radiotherapy alone group and 51% in the radiotherapy/hyperthermia group. For patients with bladder cancer, the initial difference in local control disappeared during follow up.
Van der Zee and colleagues conclude that hyperthermia is likely to be a useful adjunct to radiation therapy for patients with cervical cancer and perhaps other pelvic tumors. They call for additional, more extensive investigation of this approach, but do mention that it has now become standard treatment for stage IIB-IVA cervical cancer at their institutions.
COMMENT BY WILLIAM B. ERSHLER, MD
Local control is a critical determinant of primary treatment success and this is clearly demonstrable with pelvic tumors in which failure of primary control is associated with significant morbidity and mortality. The premise for the current research is that success rates at achieving primary local control remain discouraging despite modern radiation techniques and that hyperthermia has been shown under experimental conditions to enhance radiation induced cytotoxicity. For example, studies have shown that raising the core temperature to 40-45oC is particularly toxic for cells in hypoxic, nutrient deprived, and low pH environments, such as typically observed with advanced primary tumors.1
The study was actually a composite of two Dutch clinical trials run concurrently—one a single institution effort (Academic Medical Center, Amsterdam) and the other a multicenter trial developed at the Daniel den Hoed Cancer Center involving 10 participating centers. The goals and methods were the same, and for the purpose of analysis, the data were merged. From the data presented, it was not possible to determine whether there was any difference in outcomes between the two studies or among any of the participating centers.
Radiation was delivered according to local standards. Hyperthermia was administered once weekly during the period of radiotherapy, 1-4 hours after radiation treatment for a planned total of five treatments. The three institutions providing the hyperthermia treatment each used different systems, but treatment protocol was consistent among the centers. One system (that used in Rotterdam) was a commercially available unit, whereas the two others (in Amsterdam and Utrecht) were custom built.
The local control and survival data demonstrated improvement in these parameters, particularly for cervical cancer (overall survival at 3 years—51% for the hyperthermia/radiation group compared with 27% for the radiation alone group). The hyperthermia treatments were reported to be well tolerated, although 41% of patients refused to receive all five of the planned treatments. Van der Zee et al explain that many of the study participants refused the final treatment because "of their knowledge of the experimental nature of the approach." It is also possible that the hyperthermia-related toxicity, although not major for most, had something to do with this. Reported toxicity included subcutaneous and skin burns and urinary tract infections. In general, however, the numbers of patients with toxicities was small, and there did not appear to be any enhancement of radiation- induced toxicity by hyperthermia.
Despite some of the concerns noted above (merged data from two independent studies, different systems of administering hyperthermia, and relatively high number of incomplete courses of treatment), the data are encouraging, particularly for cervical cancer. It remains to be seen whether the technique will be widely applied, as the equipment is currently not generally available and it is likely to be expensive and labor intensive once it is. Nonetheless, if additional studies including larger numbers of patients, demonstrate significant local control and survival advantages for a spectrum of pelvic tumors (including rectal and bladder), the treatment will likely become widely available. In the meantime, hyperthermia remains an experimental approach, with the exception of stages IIB-IVA cervical cancer for which this study has provided sufficient data to warrant its use under non-experimental circumstances.
Reference
1. Brady LW, et al. Cancer 1990;65:610-624.
Which of the following statements about hyperthermia as an adjunct to radiation therapy for pelvic tumors is true?
a. Hyperthermia enhances both local control and overall survival for patients with locally-advanced cervical cancer.
b. Hyperthermia enhances both local control and overall survival for patients with locally-advanced rectal cancer.
c. Hyperthermia is associated with an increase in death rate (measured 3 years after treatment) in patients with bladder cancer.
d. Hyperthermia provides clear survival advantage for patients with cervical, rectal and bladder cancers.
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