CLINICAL HYPERTHERMIA

#. General Considerations

 As mentioned in the biology section, HT is defined as elevation of temperatures to a supraphysiologic range. Typically this is in the range of 40℃ to 45℃ with heating durations of 1 hour. Much higher temperatures, in the range of 50℃ to 100℃ for a few minutes, have been used in single-treatment thermal ablative procedures for a variety of clinical sites, most often for the treatment of metastatic disease. Excellent recent review are available.

 

 HT as defined is almost always used as an adjunctive treatment in conjunction with RT, CT, and more often today with the combination of CT and RT. There have been a number of investigations of the use of HT alone as cancer treatment. For superficial tumors a very transient response may be observed, but no long-term tumor control has been reported. HT alone is widely practiced in certain alternative and complementary medicine clinics, most often in Europe, but occasionally in the Unites States as well. The data offer no support for this practice. HT when used alone should not be confused with thermal ablative therapy, in which heat is used alone but to much higher temperatures and for which there is considerable supporting scientific evidence.

 

#. Radiotherapy Trials

 Historically, HT was developed as an adjunctive treatment of RT because of the biological considerations cited earlier. A large number of reports, mostly phase II trials, involing patients with superficial malignant disease have suggested the efficacy of adjunctive HT. There are, in addition, a moderately large number of phase III trials that attest to the efficacy of adjunctive HT combined with RT. 

 In general, clinical response rates with the addition of HT to RT have approximately doubled from 25% to 35% with RT alone to 5% to 70 % with the combination of RT and HT. Many of the phase III trials demonstrated improvements in disease-free survival, as well as overall survival.

 

#. Chemotherapy Trials

 Local regional HT has also been combined with CT in a variety of clinical situations, including intraperitoneal carcinomatosis from ovarian carcinoma, colorectal carcinoma, appendiceal carcinoma, and primay peritoneal carcinomatosis, limb perfusion primarily for malignant melanoma, the treatment of locally advanced oft tissue sarcomas, the treatment of chest wall recurrences, primarily from breast carcinoma, the treatment of recurrent bladder carcinoma with intravesical CT, the treatment of locally advanced esophageal carcinoma, and finally as a part of trimodality therpay(RT, CT and HT) for locally advanced rectal carcinoma, cervical carcinoma, esophageal carcinoma, and head and neck carcinomas.

 

 Most of the studies reported are phase II trials. The Rottendam group treated 19 patients with locally recurrent cervix carcinoma after RT with a combination of HT and cisplatin. An overall response rate of 53% was observed, with one complete response, and that patient remaining free of disease 4 years later. The use of CT and HT in locally advanced rectal carcinoma has also been explored. Nine patients were treated by Hildebrandt and colleagues with this combination, all patients having failed RT with or without surgery. The CT(oxaliplatin, folinic acid, and 5-FU) in combination with HT was moderately well tolerated and proved quite feasible in this phase I/II trial.

 Another area of very active investigation has been the use of CT and RT for soft tissue sarcomas. Numerous phase II reports have been published, but more significantly, a large multi-institutional phase III trial has just been published and will be described subsequently in the section on phase III trials.

 

#. Intraperitoneal Chemotherapy and Hyperthermia

 Two other areas of active interest involving the use of CT with HT are (a) the use of intraperitoneal CT at the time of cytoreductive surgery in conjunction with HT and (b) the combination of HT and infusion CT for limb perfusion in the management of extremity malignancies(hyperthermia isolated limb perfusion).

 Hyperthermic intraperitoneal chemotherapy was introduced approximately 20 years ago for tthe treatment of peritoneal carcinomatosis, primarily by the group at Washington Hospital Center. This procedure is and aggressive attempt to treat a situation generally considered incurable, that is, widespread peritoneal carcinomatosis. It is a complex, technically demanding procedure involving extensive cytoreductive surgery and a variety of chemotherapeutic agents subsequently installed into the peritoneal cavity with the perfusate heated to a temperature of 40℃ to 43℃. Typically, the CT is infused over an approximately 5-day period. In highly selected patients this procedure has been associated with a significant cohort of long-term survivors but also significant morbidity and mortality. Survival rates ranging between 27% and 50% have now been reported from a number of studies, with the mortality of the treatment being reducedd to less than 10% and the morbidity in the range of 30%. One randomized trial has been performed suggesting that this treatment is superior to palliative surgery and systemic CT, but almost all other reports are phaseI/II trial. The primary lesions most often treated have been colorectal cancer and ovarian cancer. Success and patient selection are very much dependent on the ability to achieve surgical resection of visible abdominal disease, leaving only microscopic intraperitoneal disease to be treated by the hyperthermia CT perfusate.

 

 Results of these pahse II trials have been reviewed extensively. Although the phase II data and the one phase III trial look quite promising in comparison with standard CT and palliative surgery, it is unclear which components of the treatment are essential to its success. For example, would cytoreductive surgery combined with intraperitoneal CT without the HT component achieve results as good as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy? Definitive phase III trials are necessary to answer this question.

 

#. Limb Perfusion Chemotherapy and Hyperthermia

 Another application of HT has been in conjunction with limb perfusion with CT, primarily for the treatment of in-transit malignant melanoma and locally advanced soft tissue sarcomas that might otherwise require amputation. This procedure is commonly referred to as hyperthermic isolated limb perfusion(HILP). It was initiated almost 50 years ago. The rationale was that much higher doses of chemotherapeutic agents could be used by isolating the extremity circulation. The initial agent employed was melphalan; this has remained the standard of care. HT was added in an attenpt to achieve chemosensitization. The current procedure calls for the use of a membrane oxygenator to maintain acid-base balance, as well as oxygenation of the isolated limbb in the physiologic range. HT is achieved by heating the perfusate, as well as using external warming blankets. Temperatrues are generally in the range of 38℃ to 40℃. Isolation from the systemic circulation is achieved by the placing of a touriquet proximal to the cannulated blood vessels.

 

 The data have been reviewd by several authors. For melanoma, complete response rates in the range of 50% to 70% are achieved, with overall 5-year survival in the range of 30% for this generally poor prognostic clinical scenario. For extremity sarcomas, complete response rates have ranged from 10% to 50% and partial response rates from 17% to 64%, with most reports toward the higher end of the range. Limb salvage has generally been achieved in about 60% to 85% of patients. The use of HILP for extermity sarcoma is a more recent procedure than that for melanoma. It was introduced in Europe with experience gained at many European centers but has not been approved by the U.S. FDA for use in the Unites States.

 

 Few randomized trials are availabe comparing HILP with systemic CT, nor has the use of HT as a component of the procedure been compared with the use of infused CT alone. Phase II data, however, suggests a very poor response for systemic CT alone in the circumstances in which isolated limb perfusion is employed. The extensive experience with external applicator HT combined with CT for the treatment of locally advanced soft tissue sarcomas suggests that HT is an important component of the limb perfusion therapeutic package.

 

#. Trimodality Therapy Trials

 The combination of CT, RT, and HT was explored in an international collaborative study for locally advanced cervix carcinoma. Sixty-eight patients were treated in Europe and the United States with this program. Whole-pelvic RT to a dose of 45 to 50 Gy was delivered, followed by a brachytherapy boos, with the total dose to point A being approximately 86 Gy. All patients received weekly concurrent cisplatin. External microwave HT was delivered once weekly with different equipment, depending on the institution. The 2-year survival was 78% and the disease-free survival was 71%-encouraging data compared with historic controls, but needing to be confirmed in a phase III trial.

 

 Rau and colleagues from Berlin also explored the use of preoperative trimdality therapy for locally advanced, untreated rectal carcinoma(RT, HT, and 5-FU/leucovorin). RT was given to 45 Gy. External microwave HT was administered once weekly with the BSD 2000. Thirty-six patients were treated with this program, which was generally well tolerated. Thirty-two of 36 patients subsequently were surgically resectable. In 5 patients patholotic complete response(CR) was observed, with a partial response in ad additional 17 patients. After surgery, overall survival was 86% at 38 months with no local recurrences. Again, these were quite encouraging results compared with historic controls, but phase III validation remains necessary. 

 

 Kang et al. from Korea reported on the treatment of 235 patients with locally advanced rectal cancer with concurrent preoperative radiochemotherapy with or without heat, although the patients were not randomized. The CT consisted of 5-FU, leucovorin, and mitomycin C in most patients. HT was delivered twice weekly with a readiofrequency capacitive heating device. Intrarectal temperature was recorded, with the highest temperatures in the range of 40℃. One hundred thirty-seven patients were treated without HT and 108 with HT. Fifty-eight percent of the patients treated with trimodality therapy were downstaged, compared with 38% in the group receiving CT and RT without heat. The radiation dose was 40 to 45 Gy. Survival also seemed somewhat increased in the group of patients receiving HT. Again, confirmatory phase III data are necessary.

 

The use of trimodality therapy has also been reported for locally recurrent breast cancer. Twenty-seven patients were treated, 23 of whom had been previously irradiated and 22 of whom had received prior CT. Patients were treated with superficial HT and RT to a dose of 45 Gy and capecitabine CT in 21 patients, vinorelbine in 2 patients, and paclitaxel in 4. Eighty percent of patients achieved a CR, with 76% locally controlled at 1 year. The treatment was quite well tolerated.

 

 Investigators at Duke University also treated a novel approach of liposomal CT combined with HT for locally advanced breast cancer. This approach is based on preclinical studies demonstrating that HT augments liposomal CT delivery to tumors and consequently will deposit a higher dose of CT at the heated tumor compared with surrounding normal tissue. A phase I/II trial enrolled 43 patients with stage IIB-III locally advanced breast cancer. Fourteen of these 43 patients had inflammatory cancer. The overall clinical response rate was 72%, with a 10% pathologic CR rate. The 4-year disease-free survival in these patients was 63%, and overall survival was 75%, again results that are quite promising but in need of confirmation.

 

 A number of studies, principally from Japan, reported on the use of trimodality therapy for patients with esophageal carcinoma. Kuwano et al. reported on 136 patients receiving preoperative trimodality therapy, with the CT consisting of cisplatin and bleomycin and 30 Gy of RT combined with heat from an endocavitary radiofrequency heating device. Approximately two-thirds of patients with locally advanced esophageal carcinoma achieved pathologic CR. The program was well tolerated. Five-year survival rates of 22% were obtained, compared with 13% in a matched group of patients recceiving only preoperative CT and RT without HT. Phase III confirmatory trials are lacking.

 

#. Normal-Tissue Damage from Hyperthermia

 With the use of HT-either superficial or deep heating-the most commonly encountered toxicities are superficial tissue burns. They are generally first or second degree in nature, occurring in approximately 5% to 10% of patients in the Duke experience and characteristically being relatively small in volume, generally less than 4 cm in maximum diameter. Careful monitoring of surface temperature is necessary to keep this problem at a low incidence, but hot spots do occur. Third-degree burns are fortunately very unusual-<1% of patients in our experience.

 With deep regional heating, subcutaneous fat necrosis may be encountered with a frequency of about 10%. Usually thsis presents as firm small(1 to 2 cm) subcutaneous nedules. They rare rarely painful and gradually resolve with time. They may be confused with local recurrence of cancer. Monitoring of intratumoral temperature is frequently done in our institution, and catheter comlications may occur if they are left in place throughout the course of HT(e.g., for several weeks). The most frequently reported complication in this instance is infection at the catheter site. If intratumoral temperature measurement catheters are removed and replaced with each treatment, catheter complications then become infrequent-less than 5%.

 

 There are potential medical contradindications to deep regional HT related to the potential physiologic stress of the procedure. Both the Raditation Therapy Oncology Group and the European Society of Hyperthermic Oncology hae guidelines for the use of regional HT.

 

#. Thermal Dosimetry and Clinical Outcome

 The description, prescription, and delivery of a thermal dose is a complex problem. Although many advances have been made, the issue is far from solved and remains a work in progress. Thermal dose delivery is very different from conventional RT, where a dose may be precisely prescribed and delivered. Biologic tissue effects from heat are related in temperature depends not only on the energy deposited, but also on how much is carried away by thermal conduction and tissue blood perfusion. Theses factors almost always result in nonuniformity of tumor/tissue heating. Time-temperature relationships vary from patient to patient and may vary from treatment to treatment within the same patient.

 Accordingly, a method is necessary to normalize time-temperature measurements and convert them into a standard dosimetry unit so that different heat treatments may be compared. This is the basis for the concept of the cumulative equivalent minutes at 43℃ described earlier(CEM 43℃). Typically during a heat treatment, temperature measurements are made at multiple points throughout the tumor, and minimal, average, and maximum temperatures are recorded. It has been found useful to describe temperature distribution in terms of percentile ranking. The T90 for example, indicates that 90% o

f measured points exceed that temperature value. The T50 wouldl indicate that 50% of measured points exceed the value in question. Taking into account the time of heating leads to the calculation of parameters such as the CEM 43℃ T90, which converts the temperature-time profile of any given heating session into the equivalent number of minutes for which 90% of the tumor exceeds 43℃.

 

 Retrospective evaluation of many phase II and III trial results has often(but not always) shown a position relationship between the thermal dose delivered and the treatment outcome, with higher doses producing a better outcome. Retrospective studies by our group suggested that a minimum thermal dose of 10 CEM 43℃ T90 is necessary for clinical effectiveness.

 

 We then attempted to confirm this in prospective trials with soft tissue sarcomas, as well as in a randomized trial involving superficial chest-wall recurrences of breast carcinoma. The sarcoma trial was unsuccessful, in that despite delivery of appropriate thermal doses, the obtained pathologic response rate was not as predicted. The phase III trial with superficial chest-wall recurrences, however, with the thermal dose prescribed prospectively showed a clear relationship of thermal dose administered to outcome. A third trial in pet dogs with soft tissue sarcomas also demonstrated a clear correlation between thermal dose and clinical outcome. It thus appears that prospective control of thermal dose will lead to improved clinical outcomes, but the issue is by no means settled. Work continues on delineating the appropriate descriptors of thermal dose and how to integrate and normalize different patient and institutional data.

 

#. Phase III Clinical Trials

 A surprising number of phase III trials have been conduccted involving the use of HT and RT, HT and CT, or trimodality therapy. These trials have involved both superficial and the deep malignancies in various sites throughout the body and in patients in whom the treatment attempt was either curative or palliative. For the most part, the reported trials have shown benefit to the addition of HT.

 

#. Breast Cancer Hyperthermia Trials

 Locally recurrent breast cancer on the chest wall is probably the primary clinical situation in which the use of HT has been investigated because of the frequency of this clinical scenario, as well as its superficial nature, which facilitates heating.

 Many pahse II trials have bee published, generally showing positive effect for the addition of HT to RT.

 Five separate phase III trials were combined for analysis in an international collaborative study by Vernon. Patients were randomized to either RT alone or RT combined with HT. Heating techniques differed somewhat among institutions. Nonetheless, significant improvement in the complete response rate of patients receiving HT + RT was demonstrated, with 59% complete response in the combined treatment group and 41% of those receiving RT alone. No survival difference were apparent, which is no unexpected, given that most patients had widespread disease. The difference were most pronounced in those patients who had been previously irradiated and were being re-treated.

 

 A second important trial was carried out by Jones et al., in which superficial heatable tumors were randomly allocated to RT alone or RT + HT. This trial is unique, in that the HT dose was prospectively prescribed and administered. One hundred eight patients were entered into the trial, approximately evenly divided between the two arms, with significant improvements in CR rate, as well as in duration of local control for the HT-treated patients, although no survival differences were seen.

 

 These two reports, as well as the numerous phase II trials in the literature for locally recurrent breast cancer, have led some to conclude HT should be a standard component of therapy for this clinical situation, particularly when local recurrence has developed following prior RT and consequently the dose of reirradiation is limited. Although there are no phase III trials comparing trimodality therapy for locally recurrent breast cancer, it is our usual practice to treat with a combination of superficial HT, RT, and CT, most often oral capecitabine. This combination is effective and quite well tolerated.

 

#. Head and Neck Carcinoma

 Three randomized trials investigating the efficacy of HT in head and neck carcinoma have been published over the last 20 years. The first, by Datta et al., radomized 65 patients to receive RT alone or RT + HT for stage I-IV head and neck carcinoma of various primary sites. Fifty-two of the 65 patients had stage III/IV disease. Although a benefit was seen for the addition of HT to RT, it was significant only in the stage III/IV patients, where the 2-year disease-free survivial was 25% in the RT/HT group, compared with 8% in the RT-alone group. No CT was used in this trial. The RT doses were approximately 65 Gy, and the heat was delivered via a diathermy machine.

 

 Valdagni et al. evaluated the treatment of cervical lymph nodes in patients with locally advanced head and neck cancer, randomizing 41 patients to treatment with either RT alone or RT + HT. Eighty-five percent of patients in the RT/HT arm achieved CR. Local control was 69% in the combined group at 5 years, and survival was 53%, compared with 24% and 0% in the RT-alone group. All difference were statistically significant. There was no enhancement of normal-tissue toxicity in the RT/HT group and no clear relationship between thermal dose received and outcome. Heat was delivered with an external microwave applicator.

 

 The third trial was an investigation of nasopharynx carcinoma by Hua et al. These investigators randomized 180 patients with advanced nasopharynx cancer to receive HT + RT or RT alone. HT treatment was carried out with an intracavitary microwave applicator. The CR rate was 95.6% in the RT/HT group, compared with 81% in the RT-alone group; local control was 91% versus 79%, and survival was 72.7% versus 63.1%, all differences statistically significant. The RT dose was 70 Gy in 2-Gy fractions. HT treatments were once weekly for 30 minutes following RT. All patients received concurrent cisplatin/5-FU CT as well.

 

#. Malignant Melanoma Trials

 Overgaard and colleagues randomized 129 melanoma superficial/skin lesions in 70 patients between RT alone and RT + HT. CR rate was 35% for those treated with RT alone, compared with 62% for those treated with the combination. Two-year local control rate was 46% in the RT/HT group, compared with 28% in the RT-alone group. All differences were statistically significant. Only 14% of the treatments in this study achieved the recommended thermal parameters of 43℃ for 60 minutes. The heating was carried out with microwave applicators. Nonetheless, the observed benefits were seen with no apparent relationship to thermal dose.

 

#. Glioblastoma Multiforme Trials

 At the University of California, San Francisco, Sneed and coworkers evaluated the use of interstitial HT combined with a brachytherapy boost for selected patients with glioblastoma multiforme. Eligible patients were those whose tumor was implantable with interstitial seeds following external beam RT to 59.4 Gy. Such patients were randomized to brachytherapy alone or the same plus interstitial HT. Of the 79 randomized patients, 69 were evalulable; 33 were randomized to RT alone and 36 to RT + HT. Time to treatment failure and 2-year overall survival were significantly prolonged in the HT arm, with 31% vs. 15% survivial for RT alone. CEM 43℃ T90 ranged from 0 to 771, with a median of 14.1. Adequate thermal dose was achieved for most patients, but there was no clear correlation between thermal dose and outcome.

 

#. Dutch Deep Hyperthermia Trials

 Among the more significant deep HT trials are those carried out by the Dutch group involving patients with cervical, rectal, and bladder cancer. In these trials, 258 patients with previously untreated, locally advanced pelvic carcinomas were randomized to receive RT alone or RT + HT. HT treatments were generally given once weekly for a total of five treatments. Generally, thermal goals were not achieved, and again there was no clear relationship between thermal dose and outcome. For the entire group of patients, the CR rates were 39% and 55%, respectively, for the RT-alone group or RT + HT(p >.001). The observed benefits, however, were largely confined to patients with cervical carcinoma. The CR rate for this group was 83% with RT + HT compared with 57% for RT alone; the overall survival at 3 years was 51% for the RT + HT group, compared with 27% for the RT-alone group. Local control was 61% at 3 years for the combined group versus 41% for the RT-alone patients.

 

 This trial was criticized for the apparent suboptimal outcome in the control group. In addition, the demonstration of the efficacy of CT combined with RT in cervix cancer in several recent phase III trials has resulted in a new standard therapy-namely HT and CT combined for locally advanced cervix carcinoma-and raised the question of whether the addition of HT to RT and CT would be beneficial. Nonetheless, the Dutch trial is an important demonstration of the worth of HT combined RT for deep-seated malignancies.

 

#. Phase III Trials of Hypertheria Plus Chemotherapy

 Kitamura et al. investigated the use of HT and CT for esophageal carcinoma compared with trimodality therpay(CT, RT, HT). Sixty-six patients were randomized. Intraluminal heating was delivered by a microwave applicator. Six HT treatments were delivered with a thermal goal of 42℃ to 44℃ at the tumor surface for 30 minutes. The treatment was given preoperatively and consisted of 30-Gy RT combined with either bleomycin or cisplatin. Subsequently, esophagectomy was performed. The pathologic CR rate was 25% for the trimodality group versus 6% in the CT/RT group. Three-years survival was 50.4% in the trimodality group and 24.2% in the CT/RT group, and the difference was statistically significant.

 

 Columbo et al. investigated the use of intravesical CT alone compared with the same plus HT for bladder carcinoma. Eighty-three patients were randomized to receive either mitomycin CT alone intravesically or the same plus HT. Each patient group, following complete transurethral resection of any bladder tumors, received eight weekly sessions of intravesical therapy, followed by a maintenance regimen of four monthly sessions. The duration of each treatment was 60 minutes. HT was delivered via an intravesical applicator. The temperature goal was a median temperature of 42℃ ± 2℃ for at least 40 minutes per session. The primary endpoint was recurrence-free survival, which was 35% at 2 years in the CT-alone patients and 80% in the CT + HT patients, a highly statistically significant result.

 

 A third very important trial investigating the use of CT and HT for soft tissue sarcomas was published by Issels et al. These investigators, in a multi-institutional European and North American study, randomized 241 patients with high-risk soft tissue sarcomas to receive neadjuvant CT alone(etoposide, ifosfamide, doxorubicin) or the same CT with deep HT. The primary endpoint was local progression-free survival. Treatment was given on days 1 and 4 of each CT cycle with a goal of achieving tumor temperatures of 42℃ for 60 minutes. Four cycles of CT were planned, followed by definitive surgical resection when possible and typically followed by postoperative RT as well. Neither the surgery nor the RT was randomized but was given to all suitable patients. At 4 years, local progression-free survival was 66% in the CT/HT group, compared with 55% in those receiving CT alone. This difference was highly statistically significant. Overall survival was comparable in the two groups as were distant metastatsis. Nonetheless, this study provides high-quality evidence for the chemosensitization apparently achieved by locoregional HT. The failure to achieve a survival benefit emphasizes the need for better systemic therapy in this disease.

 

#. Summary of Phase III Clinical Trials

 Results of the published phase III trials cited previously are intriguing and encouraging, despite significant problems in study design, with small numbers of patients in most trials and difficulties with HT administration, with failure to achieve thermal goals in many instances. The pattern of a beneficial effect from the addition of HT is striking and strongly suggests the worth of future trials and more widespread clinical application of HT.

 

#. Future Directions

> Technical Challenges

 The use of HT for the treatment of deep-seated tumors remains mostly experimental, with only one device, the BSD 2000, approved by the FDA for limited use in the United States. Deep heating often requires the use of invasive thermometry catheters; thus, particularly for deep heating, a team of skilled physicists, engineers, physicians, and nurses is required. Advances in noninvasive, MRI-based thermometry will assist greatly in helping to accurately determine and control thermal dose, but much work remains to be done in this area. The encouraging clinical data cited here for bladder tuors and soft tissue sarcomas will, it is hoped, stimulate further efforts along these lines. Small phase II investigations of other deep sites, such as locally advanced breast cancer, prostate, and rectal cancer, suggest a role for HT if technological advances proceed. Partnerships between academia and industry to facilitate equipment development are vitally necessary.

 

> Multimodality Therpay

 For the great majority of malignancies, single-modality therapy is a thing of the past. Successful treatment approaches often involve combinations of RT, CT, and surgery. HT must be considered in this context. The old model of investigating the combination of RT and HT without the use of CT is, for the most part, no longer applicable. Future trials addressing the value of HT need to ensure that best current treatment practice represents the control arm.

 The combination of HT and CT without RT is an exciting new area. Drug delivery to tumors remains a major challenge due to a number of physiologic barriers, as discussed earlier. HT offers much potential in this area. The clinical evidence from the sarcoma and bladder trials cited earlier is impressive, as is the phase II evidence from intraperitoneal CT and limb perfusion studies. In addition, HT may serve as a trigger for temperature-sensitive drug delivery systems such as liposomes, polymers, and hydrogels.

 Finally, a word about cost. Most new oncologic therapies are associated with significant cost profiles. Consider, for example, monoclonal antibodies, drugs that target angiogenesis, tyrosine kinase inhibitors, new RT technologies such as IMRT, proton beams, and the like. In this regard HT is relatively inexpensive. Given the results already achieved, further implementation and investigation seem clearly warranted.