HYPERTHERMIA

Jackson Farrow 22 September 2010

the medical benefit of making someone hot under the collar

HYPERTHERMIA – History

► Spontaneous remission following febrile episodes?

Coley 1893 - erysipelas

Westmark 1898 - hot baths

► 1st International Congress on Hyperthermic Oncology held in Washington in 1975

Initial Results less than expected

►Failed to show evidence of beneficial effect from Hyperthermia

Subsequent review found that inadequate equipment was to blame

Preclinical findings unreliable in predicting in vivo results

► Interest resurgence due to improved technology producing promising results in new studies

HYPERTHERMIA – Mechanisms of Action

►Tumor Selective Effects? NO intrinsic difference between hyperthermia

sensitivity of normal and tumor cells

►Molecular Effects Cell membrane, Cytoskeleton Intracellular Proteins Nucleic Acids

►“Heat Shock Response” (aka Thermotolerance) Protein synthesis helps prevent against

inappropriate interaction by denatured proteins

►Cell Cycle dependent effectiveness Greatest thermosensitivity during S & M phases

HYPERTHERMIA – Mechanisms of Action

►Augmentation of Blood Flow Increased flow at moderate temperatures

► 40 - 42° C

Decreased flow above 42° C

►Solid Tumor Architecture difference in cellular organization results in a

selective advantage in targeting cancer cells chaotic growth that outstrips blood supply

► regional hypoxemia, acidosis►increased sensitivity to diminished blood flow

HYPERTHERMIA - Methods

► Local External Intraluminal/Endocavitary Interstitial

► Regional Deep Tissue Regional Perfusion Continuous Hyperthermic Peritoneal Perfusion

► Whole Body Temperature limitation of 41.8-42 C

►Thermal Conduction (surface heating) heated water suits, heated blankets, hot wax baths

►Extracorporeal Induction►Radiant/Electromagnetic Induction

von Ardenne's systemic Cancer Multistep Therapy

►WBH, hyperglycemia and hyperoxemia

HYPERTHERMIA - Thermal Radiosensitization► Radiotherapy limitations

decreased efficacy in hypoxemic environments► Oxygen presence increases free radical formation

ineffective against cells during S phase

► Adjunctive Benefit of Hyperthermia Protein denaturation complements DNA damage from Radiotherapy

► Diminished ability to repair radiation-induced damage

Increase in Radiotherapy’s capability of causing damage► Increase in blood flow allows for increase in Oxygen radical formation

S phase cell kill

► Cytotoxicity enhancement: Super Additive & Complementary Effect Enhancement influenced by proximity of administration

► Greatest benefit noted when modalities are applied synchronously

► “probably the most potent radiosensitiser known to date” van der Zee J, 2002

HYPERTHERMIA – Proven Benefits► Majority of information involves trials examining Hyperthermia’s

potential benefit in treating small, superficially located tumors Head/Neck

► Advanced nodal metastasis, Cervical Nodes Valdagni et al. showed increased complete response rates (82 vs 37%; p < .015) and an

improvement in 5-year survival rates (53 vs 0%; p = .02) in patients who received 2-6 Hyperthermia treatments in addition to full dose radiation.

Melanoma► Cutaneous, subcutaneous and peripheral lymph node metastasis

Randomized Phase III trial showed significantly higher 2 yr local-regional control rate among tumors having received adjuvant hyperthermia (46 vs 28%; p = .008) without any increase in acute or late reactions.

Breast► Local, regional recurrences

Collaborative phase III involving MRC/ESHO/PMH demonstrated examined the addition of hyperthermia to treatment of primary or recurrent breast cancers. Hyperthermia when combined with radiotherapy showed an improvement in complete response rate (59 vs 41%), lower relapse rate among complete responders at 2 yrs (17 vs 28%) and no increase in side effects.

► Chest wall metastasis, Superficial Lesions Randomized trial by RTOG involving lesions less than 3 cm showed an improvement in complete

response rates for radiation plus hyperthermia (55 vs 33%; p < .62). Upon further analysis of all superficial lesions smaller than 3 cm a statistically significant improvement in probability of local control at 12 months was demonstrated (80 vs 15%; p < .02).

► Good local control rates have been documented for superficial metastases of multiple tumors including Hodgkin’s, Merkel cell tumors, adenoid cystic carcinomas and penile metastases from prostatic cancer

HYPERTHERMIA – Head/Neck Adjunct

Study Type Complete Response Rate p value

Radiotherapy Radiotherapy

+Hyperthermia

Arcangeli et al.(1985)

Nonrandomized 42 79 < .05

Valdagni et al.(1986)

Historical Controls

35 68 .034

Valdagni et al.(1988)

Prospectively Randomized

37 82 .015

HYPERTHERMIA – Head/Neck Adjunct

Study Fields Local Control Rate (%) Time Scale

Radiotherapy Radiotherapy+

Hyperthermia

Arcangeli et al.(1984)

81 14 58 24 month

Valdagni(1994)

36 24 69 60 month

HYPERTHERMIA – Melanoma Adjunct

Study Type Complete Response Rate p value

Radiotherapy Radiotherapy+

Hyperthermia

Kim et al.(1982)

Nonrandomized, Matched Pair and Paired Lesions

42 79 < .05

Overgaard Matched Pair 20 73 < .05

Overgaard et al. Nonrandomized and Matched Pair

59 91 < .05

Gonzalez et al.(1986)

Nonrandomized Controls

50 83 –

Emani et al. (1988)

Nonrandomized Controls

24 59 .0003

HYPERTHERMIA – Melanoma Adjunct

Study Type Local Control Rate (%) Time Scale

Radiotherapy Radiotherapy+

Hyperthermia

Gonzalez et al.(1986)

24 17 83 < 36 mo

Overgaard(1987)

67 56 86 18 months

HYPERTHERMIA - Breast Adjunct

Study Type Complete Response Rate p value

Radiotherapy Radiotherapy+

Hyperthermia

Steves et al.(1986)

Matched Pair 31 45 < .05

Perez et al.(1989)

Randomized 33 55 .062

Van ser zee et al. (1988)

Nonrandomized Controls

27 82 –

RTOG Randomized 33% 55% < .62

HYPERTHERMIA - Breast AdjunctStudy Fields Local Control Rate (%) Time

ScaleRadiotherapy Radiotherapy

+Hyperthermia

RTOG 15 80 12 months

Perez et al.(1986)

70 31 61 6 months

Lindholm et al.(1987)

34 30 53 12 months

cont’d 34 30 45 24 months

TUMOR TREATMENT PATIENTS END POINT EFFECT w/ HT EFFECT w/o

Lymph nodes of Head/Neck Tumors

RT 41

CR rate 83% 41%

5-year local control 69% 24%

5-year survival 53% 0%

Melanoma RT 70

CR rate 62% 35%

2-year local control 46% 28%

Breast RT 306 CR rate 59% 41%

Glioblastoma multiforme Surgery, RT 68Median survival 85 weeks 76 weeks

2-year survival 31% 15%

Bladder, Cervix, Rectum RT 298CR rate 55% 39%

3-year survival 30% 24%

BladderRT, surgery 102 3-year survival 94% 67%

CT 52 pCR 66% 22%

CervixRT 40 CR 85% 50%

RT 64 CR 55% 31%

Various RT 92 Response 82% 63%

Lung CT 44 Response 68% 36%

Vulva/vagina CT 65 Response 59% 19%

Esophagus

RT, CT 66 CR 25% 6%

RT, CT, surgery 53 Palliation 70% 8%

RT 125 3-year survival 42% 24%

RectumRT, surgery 115 5-year survival 36% 7%

RT, surgery 122 pCR 23% 5%

van der Zee J. Heating the Patient: a promising approach?

Summary of randomized trials showing significantly better results following addition of Hyperthermia

HYPERTHERMIA - Thermal

Chemosensitization

► Adjunctive Benefit of Hyperthermia Increased blood flow allows for increased Drug concentrations Drug activity enhancement with increased temperature

►Nitrosureas, Cisplatin, Bleomycin, Doxorubicin► Resistance – Overcome or Induce?

Platinum-based compounds demonstrate increased efficacy when given in temperatures > 42° C

MDR induction► heat dependant inactivation of Topoisomerase II

► Molecular Effects Changes in fluid and electrolyte balance in addition to pH

changes alter the solubility and volume distribution of the chemotherapeutic agents

► LIMITED INFORMATION Increased Preclinical Data is needed to help direct Clinical Study

HYPERTHERMIA – Limitations ►Dosing

Difficult to produce reliable uniformity

►Different tissues absorb heat at different rates, have different levels of sensitivity

Nervous tissue (central > peripheral)

►Side effects electrolyte abnormalities decreased platelet count coagulation prolongation LFTs elevation (mild liver necrosis) CPK elevation (mild muscle necrosis) Increased CO (increased pulse rate)

►risk for arrhythmia, pulmonary edema, seizures

HYPERTHERMIA - References

►Further Research Needed

Randomized, Phase III trials

► WBH vs Local/Regional

► Proven Adjunct Benefit

Hyperthermic vs Normothermic

►Improvement in Temperature Distributions

Absolute Value

Homogeneity

HYPERTHERMIA - References

1) Luk KH, Hulse RM, Phillips TL. Hyperthermia in Cancer Therapy. West J Med 132: 179-185, Mar 1980

2) van der Zee J. Heating the patient: a promising approach? Annals Onc 13: 1173-1184, 2002

3) Hildebrandt B, Wust P, Ahlers O et al. The Cellular and Molecular Basis of Hyperthermia. Critical Reviews in Oncology/Hematology 43: 33-56, 2002.

4) Kapp DS, Hahn GM, Carlson RW. Principles of Hyperthermia. Cancer Medicine 6, 2000.