Hyperthermia and radiation therapy in the treatment of recurrent Merkel cell tumors

A high incidence of local recurrence, spread to regional lymph nodes, and distant metastases has been reported after surgical excision of Merkel cell tumors (MCT). The use of postoperative radiation therapy and/or chemotherapy is reviewed from the literature. Despite adjuvant treatment, local tumor recurrences frequently develop. Two patients are presented with metastatic MCT recurrent in previously irradiated sites who had excellent clinical responses and local control following retreatment with local hyperthermia in conjunction with low to moderate dose radiation therapy. These patients represent the first reported use of hyperthermia in the management of MCT. The encouraging local responses described suggest a potential role for the use of hyperthermia and concomitant radiation therapy in the treatment of recurrent MCT.     

热疗联合三维适形放疗治疗原发性肝癌 TACE 术后局部复发的临床研究

目的：探讨热疗联合三维适形放疗（3D—CRT）治疗原发性肝癌TACE后局部复发病例的疗效及不良反应。方法：40例接受TACE术后局部复发的原发性肝癌患者，随机分为实验组与对照组，实验组20例，行热疗联合三维适形放疗；对照组20例，仅采用三维适形放疗。结果：实验组与对照组近期有效率（CR＋PR）分别为85％、55％。不良反应发生上，实验组局部皮肤损伤显著。而在胃肠道反应、肝功能损害、骨髓毒性上与对照组无差异。结论：热疗联合三维适形放疗，能提高三维适形放疗治疗原发性肝癌TACE术后局部复发病例的近期疗效，且不良反应相似。     

Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection.

BACKGROUND AND PURPOSE: Evaluation of the efficacy of combined hyperthermia and radiotherapy (TRT) in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected locoregional, early recurrence with close margins or R1-resection. Main endpoint was local tumour control (LC); secondary endpoints were overall survival (OS), disease free survival (DFS) and acute toxicity. MATERIAL AND METHODS: Between 1997-2001, 50 patients were treated with TRT. Thirteen patients (group 1) received a post-operative TRT in a high-risk situation (free margin <1 cm or R1, N+), 37 patients (group 2) received TRT after close/R1 resection of a locoregional recurrence. Thirteen out of 37 patients in group 2 already had had two-to-seven recurrences prior to TRT. Median radiation dose was 60 Gy (range: 44-66.4 Gy), the additional local hyperthermia (>41 degrees C, 60 min) was given twice a week. Median follow-up for patients at risk was 28 months. All statistical tests were done using Statistica software. RESULTS: Actuarial OS for all patients at 3 years accounted for 89%, DFS for 68% and LC for 80%. Actuarial OS was 90% for group 1 and 89% for group 2, with four patients having died so far. DFS at 3 years was 64% in group 1 and 69% in group 2, actuarial 3 year LC was 75% and 81%, respectively. For patients with recurrent chest wall disease, there was no difference concerning local control between patients who underwent TRT with or without prior radiation. No prognostic factors could be detected due to the small number of patients investigated. The combined modality treatment was well tolerated. Grade IV toxicity, according to the Common Toxicity Criteria, did not occur. CONCLUSION: The results concerning local tumour control and overall survival in these high-risk patients are promising, especially for TRT for the treatment of local recurrences. A longer follow-up is needed to estimate late toxicity.     

The role of external beam radiation therapy after prostatectomy for prostate cancer

The role of radiation therapy as an adjuvant to prostatectomy is evaluated in 21 patients. Eleven were treated prior to clinical recurrence with 100% local control, no serious complications, and 86% long-term survival. Ten were treated after local recurrence with 80% local control, no serious complications, and 71% long-term survival. These data and the available literature indicate that the patient found to have capsular penetration, seminal vesicle involvement, or positive surgical margins at prostatectomy can be salvaged by postsurgical radiation therapy. When this is done after recovery from surgery, rather than waiting for clinical recurrence, a lower radiation dose can be used (6000 rad vs. 7000 rad), improved local control is obtained (94% vs. 79%), and fewer serious complications are observed.     

Interaction of hyperthermia and cis-diamminedichloroplatinum(II) alone or combined with radiation in a C3H mammary carcinoma in vivo

The interaction between hyperthermia and cis-diamminedichloroplatinum(II) (c-DDP) given in various schedules as an adjuvant to radiation treatment was investigated in a C3H mouse mammary carcinoma in vivo. Both hyperthermia (43.5 degrees C for 60 min) and c-DDP (6 mg/kg i.p.) caused a delay in tumor growth when given individually. When c-DDP was given 4 h prior to hyperthermia, the increase in tumor growth time corresponded to an additive effect, but when the interval was reduced to 15 min, the tumor growth delay was significantly greater than additive. The modifying effect of these schedules on radiation was studied using local tumor control (50% tumor control dose) as the endpoint. c-DDP alone did not result in any enhancement of tumor control, irrespective of whether it was given 15 min or 4 h after irradiation. In contrast, heat treatment at 43.5 degrees C for 60 min given 4 h after irradiation resulted in a significant reduction in the 50% tumor control dose, with an enhancement ratio of 1.8. From a clamped local tumor control assay, it was found that c-DDP selectively killed aerobic cells, whereas hyperthermia was primarily directed toward the hypoxic clonogenic cells in the tumors. Combining the two modalities (simultaneously) resulted in a significant additional increase in the killing of well-oxygenated clonogenic cells, but the destruction of hypoxic cells was not different from that obtained after heat alone.     

Phase I study of combined radiation, hyperthermia and intra-arterial carboplatin for local recurrence of cervical cancer.

BACKGROUND: Patients with cervical cancer who develop pelvic recurrence after primary surgery are usually treated with radiation-based therapy. However, their prognoses are dismal. We conducted a phase I study of combined radiation, hyperthermia and intra-arterial (IA) carboplatin for local recurrence of cervical cancer. PATIENTS AND METHODS: Patients with local recurrence of cervical cancer without extrapelvic recurrence were included in this study. Carboplatin was given as a 5-min IA infusion without hydration just before pelvic radiation every day. External pelvic irradiation (1.8 Gy/day for 28 days) was performed according to local standard schedules. After 20 Gy had been administered, hyperthermia was performed once a week with a radio frequency heating system for four cycles. RESULTS: Fifteen patients were entered through the four dose levels of carboplatin. The maximum tolerated dose was determined to be 25 mg/m(2 )and the dose-limiting toxicities were leukocytopenia, neutrocytopenia and diarrhea. Grade 3/4 leukocytopenia and diarrhea were observed in nine (60%) and three (20%) of 15 patients. Tumor responses included five complete responses and nine partial responses, and the overall response rate was 93.3% (14 of 15) (95% confidence interval 59.4% to 100%). Tumor reductions were observed only at 20 Gy in 10 cases of 14 responders (71.4%). CONCLUSION: The combination therapy of radiation, hyperthermia and IA carboplatin is safe and well-tolerated for locally recurrent cervical cancer.     

乳腺癌术后放射野内复发灶的加热放射治疗

分析 1 5例乳腺癌术后放射野内再复发灶加热 放疗的效果 ,治疗结束时获 73.3% ( 1 1 /1 5 )肿块完全退缩率 ,2 6 .7% ( 4 /1 5 )肿块部分退缩率 ,1 5例接受加热放疗的病人均没有发生明显副作用。结果揭示加热放射对放射野内复发灶的治疗是安全和有效的。但对于加热分割次数及加热和放射相结合治疗的最佳方案有待进一步研究。     

热疗加放疗治疗局部复发乳腺癌的疗效分析

目的评价热疗加放疗治疗局部复发乳腺癌的疗效.方法回顾性分析热疗加放疗治疗的85处病灶,其中39处病灶曾接受过放疗,未曾放疗的部位给予59.5±6.8 Gy(40～70 Gy)照射,曾放疗的病灶实施43.0±12.4 Gy(12～74.4 Gy)照射;热疗每周1次或1周2次,平均每例患者的热疗次数为4.5(2～9)次.结果治疗1个月后CR率为92.0%,过去未曾放疗的病灶CR率为47.1%(16/34),曾放疗过病灶的CR率为56.1%(23/41),虽然曾放疗组的剂量(43.0±12.4 Gy)明显低于未放疗组的剂量(59.5±6.8 Gy),但两组间CR率差异无显著性(P=0.40).治疗后4周时弥散/多发型病变较肿块/结节型病变的CR率高,而6个月后弥散/多发型的局部控制率却明显降低.结论局部热疗配合放疗可以提高复发乳腺癌的局部控制率,特别是对曾经接受过放疗的区域可以降低放疗的剂量.弥散/多发型肿块较肿块/结节型的病灶对治疗的反应较早,但是很容易在短时期内复发.     

Sequencing of trimodality therapy [cis-diamminedichloroplatinum(II)/hyperthermia/radiation] as determined by tumor growth delay and tumor cell survival in the FSaIIC fibrosarcoma

In order to improve local control of tumors over that achievable with local hyperthermia and radiation, we are testing the use of systemic cis-diamminedichloroplatinum(II) (CDDP) in conjunction with the other two modalities. In the FSaIIC fibrosarcoma, growth delay experiments indicated that the use of any two modalities resulted in at least additive effects on growth delay. When the trimodality treatment was tested, the sequence CDDP followed by hyperthermia followed by X-ray produced a growth delay of approximately 25 days which was superior to the growth delay produced by the sequences CDDP, X-ray, and hyperthermia (19 days) and X-ray, CDDP and hyperthermia (14 days). In excision experiments, also performed in the FSaIIC tumor system, we again observed clearly superior cytotoxicity in the sequence CDDP, hyperthermia, and X-rays over the other sequences tested. Our results indicate that scheduling CDDP just prior to heating and following the heat treatment with the radiation fractions results in the best tumor cell kill, probably because this sequence takes maximum advantage of the radiosensitizing properties of the combined heat-CDDP treatment. In addition, the strong cytotoxic interaction between CDDP and hyperthermia is also optimized by this scheduling. We believe these results have significant clinical implications.     

Treatment of superficial cancers by combination hyperthermia and radiation therapy.

Clinical studies are being carried out to evaluate whether radiation combined with hyperthermia evokes better tumor control than that achieved with radiation alone. Thus far, 54 patients with various superficial cancers have been treated with combination hyperthermia and radiation. The heating methods used have been temperature regulated water bath immersion and radiofrequency inductive heating. Hyperthermia alone has caused significant, though transitory, tumor regression in 10 out of 19 patients. Selective heating of tumor tissues has been achieved in 20 out of 24 lesions following radiofrequency inductive hyperthermia. The overall local tumor control rate after the combined therapy was 78 percent compared to 26 percent after radiation alone.     

Breast cancer: chest wall recurrences

Opinion statement Irradiation is indicated for patients undergoing mastectomy as surgical management for breast cancer treatment when clinical or pathologic tumor and nodal features predict risk of local/regional recurrence. Such features include: tumor size yy 5 cm, inadequate surgical margins; skin, facial, or skeletal muscle invasion; dermal lymphatic invasion; poorly differentiated tumor histology; four or more lymph nodes positive; gross extracapsular tumor nodal extension into soft tissues; and matted lymph nodes or enlarged lymph nodes > 2 cm. Patients who were treated with irradiation after mastectomy can develop local/regional recurrences despite such adjuvant therapy. General management for chest wall and nodal recurrences is structured on the extent and volume of local/ regional disease, the absence of distant metastases, the general health of the patient, and the extent of prior local/regional therapies, especially irradiation. Management of local/regional recurrence in the setting of no prior irradiation includes tumor debulking by systemic or surgical treatment followed by comprehensive chest wall and regional lymphatic irradiation. Doses are selected by tissue tolerances and volume of remaining disease. The management strategy for the patient with a history of irradiation parallels the nonirradiated patient with respect to systemic and surgical therapies to debulk the tumor to maximal response or no gross clinical disease. Radiation field design is determined by prior therapies. Doses to these fields are adjusted to normal tissue tolerance. Irradiation is given with a sensitizer such as hyperthermia or 5-fluorouracil chemotherapy. Use of radiation sensitizers can allow for a more meaningful biologic tumor effect when normal tissue tolerances prohibit delivery of standard tumor doses. Hyperthermia has been used effectively to promote complete tumor responses with use of irradiation in re-treatment cases.     

Hyperthermia: a potent enhancer of radiotherapy

Hyperthermia is generally regarded as an experimental treatment with no realistic future in clinical cancer therapy. This is totally wrong. Although the role of hyperthermia alone as a cancer treatment may be limited, there is extensive pre-clinical data showing that in combination with radiation it is one of the most effective radiation sensitisers known. Moreover, there are a number of large randomised clinical trials in a variety of tumour types that clearly show the potential of hyperthermia to significantly improve both local tumour control and survival after radiation therapy, without a significant increase in side-effects. Here we review the pre-clinical rationale for combining hyperthermia with radiation, and summarise the clinical data showing its efficacy.     

Ectopic Recurrence of Skull Base Chordoma after Proton Therapy

Simple SummaryChordoma are very rare tumors of the spine and skull base. Due to close proximity of crucial organs, like the brain stem, complete removal can often not be achieved, and tumor tissue, either macroscopic or microscopic, remains in situ. Local recurrence up to 88% occurs in 10 years. Ectopic recurrence as an early sign of treatment failure is considered rare. We retrospectively reviewed five patients with ectopic recurrence as a first sign of treatment failure after treatment with surgery and proton therapy, and studied the applied treatment strategies and imaging follow-up. We found 18 ectopic recurrences in these five patients, of which 17 (94%) could be related to prior surgical tracts. Our theory is that these relapses occur due to microscopic tumor spill during surgery. These cells did not receive a therapeutic radiation dose. Advances in surgical possibilities and adjusted radiotherapy target volumes might improve local control and survival.AbstractBackground: Chordoma are rare tumors of the axial skeleton. The treatment gold standard is surgery, followed by particle radiotherapy. Total resection is usually not achievable in skull base chordoma (SBC) and high recurrence rates are reported. Ectopic recurrence as a first sign of treatment failure is considered rare. Favorable sites of these ectopic recurrences remain unknown. Methods: Five out of 16 SBC patients treated with proton therapy and surgical resection developed ectopic recurrence as a first sign of treatment failure were critically analyzed regarding prior surgery, radiotherapy, and recurrences at follow-up imaging. Results: Eighteen recurrences were defined in five patients. A total of 31 surgeries were performed for primary tumors and recurrences. Seventeen out of eighteen (94%) ectopic recurrences could be related to prior surgical tracts, outside the therapeutic radiation dose. Follow-up imaging showed that tumor recurrence was difficult to distinguish from radiation necrosis and anatomical changes due to surgery. Conclusions: In our cohort, we found uncommon ectopic recurrences in the surgical tract. Our theory is that these recurrences are due to microscopic tumor spill during surgery. These cells did not receive a therapeutic radiation dose. Advances in surgical possibilities and adjusted radiotherapy target volumes might improve local control and survival.     

Simultaneous radiotherapy and superficial hyperthermia for high-risk breast carcinoma: A randomised comparison of treatment sequelae in heated versus non-heated sectors of the chest wall hyperthermia

Purpose: In vitro data demonstrate that heat-induced radiosensitisation is maximised if hyperthermia and radiotherapy are given simultaneously, with the radiation fraction delivered midway through a hyperthermia session, rather than sequentially. The long-term normal tissue toxicity of full-dose simultaneous thermoradiotherapy is unknown.

Materials and methods: Patients with locally advanced breast cancer (T3, T4 or more than three involved nodes or local recurrence), no prior radiotherapy, received between four and eight sessions of simultaneous thermoradiotherapy. Hyperthermia always included the primary tumour site. In addition an electively heated sector (EHS) was included. The EHS was randomised to either medial or lateral to the tumour site, with the other side an irradiated but unheated control. As per our usual practice, patients received surgery and/or chemotherapy prior to radiotherapy. Radiation doses were 46–50?Gy followed by a boost of ≤16?Gy at 1.8–2?Gy per fraction. EHS and control sectors received the same dose.

Results: A total of 57 evaluable cases with average follow-up of 79 months experienced two local and two nodal recurrences. There was no significant difference in ≥grade 2 toxicity for heated versus control sectors (LR χ^2?=?0.78, p?=?0.38) with no relationship between number of hyperthermia sessions and toxicity (LR χ^2?=?2.90, p?=?0.09).

Conclusions: Simultaneous full-dose thermoradiotherapy for breast cancer is feasible and well tolerated, with no significant difference in late toxicity between electively heated and unheated control sectors. All patients had hyperthermia to the primary tumour site with excellent local control.     

链式CIK细胞免疫治疗联合适形调强放疗及微波热疗治疗局部晚期直肠癌临床研究

目的：比较链式CIK细胞免疫治疗联合适形调强放疗及微波热疗治疗局部晚期直肠癌临床疗效和安全性。方法选取90例局部晚期直肠癌患者进行前瞻性分析,分期均为Ⅲ～Ⅳ期,分为对照组和观察组,每组45例,对照组采用适形调强放疗（IMRT）联合微波热疗治疗,观察组在对照组基础上联合CIK细胞免疫治疗,比较两组患者临床疗效和不良反应发生情况。结果观察组患者2年生存率、2年局部控制率均高于对照组,2年局部复发率低于对照组,差异有统计学意义（P﹤0.01）;两组放射性直肠炎发生率无明显差异（P﹥0.05）;末次随访,观察组总有效率高于对照组,差异有统计学意义（P﹤0.05）。结论在局部晚期直肠癌的治疗中,链式CIK细胞免疫治疗联合适形调强放疗及微波热疗可有效提高治疗有效率和2年生存率,降低复发率,且不增加不良反应发生率,具有临床应用价值。     

Two or six hyperthermia treatments as an adjunct to radiation therapy yield similar tumor responses: results of a randomized trial

From March 1984 to February 1988, 70 patients with 179 separate treatment fields containing superficially located (less than 3 cm from surface) recurrent or metastatic malignancies were stratified based on tumor size, histology, and prior radiation therapy and enrolled in prospective randomized trials comparing two versus six hyperthermia treatments as an adjunct to standardized courses of radiation therapy. A total of 165 fields completed the combined hyperthermia-radiation therapy protocols and were evaluable for response. No statistically significant differences were observed between the two treatment arms with respect to tumor location; histology; initial tumor volume; patient age and pretreatment performance status; extent of prior radiation therapy, chemotherapy, hormonal therapy, or immunotherapy; or concurrent radiation therapy. The means for all fields of the averaged minimum, maximum, and average measured intratumoral temperatures were 40.2 degrees C, 44.8 degrees C, 42.5 degrees C, respectively, and did not differ significantly between the fields randomized to two or six hyperthermia treatments. The treatment was well tolerated with an acceptable level of complications. At 3 weeks after completion of therapy, complete disappearance of all measurable tumor was noted in 52% of the fields, greater than or equal to 50% tumor reduction was noted in 7% of the fields, less than 50% tumor reduction was noted in 21% of the fields, and continuing regression (monotonic regression to less than 50% of initial volume) was noted in 20% of the fields. No significant differences were noted in tumor responses at 3 weeks for fields randomized to two versus six hyperthermia treatments (p = 0.89). Cox regression analyses were performed to identify pretreatment or treatment parameters that correlated with duration of local control. Tumor histology, concurrent radiation doses, and tumor volume all correlated with duration of local control. The mean of the minimum intratumoral temperatures (less than 41 degrees C vs. greater than or equal to 41 degrees C) was of borderline prognostic significance in the univariate analysis, and added to the power of the best three covariate model. Neither the actual number of hyperthermia treatments administered nor the hyperthermia protocol group (two versus six treatments) correlated with duration of local control. The development of thermotolerance is postulated to be, at least in part, responsible for limiting the effectiveness of multiple closely spaced hyperthermia treatments.     

Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion

Purpose : Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. Materials and methods : Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70Gy was administered to both groups. Hyperthermia was performed for 45-60min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. Results : For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. Conclusions : Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.     

Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion.

PURPOSE: Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. MATERIALS AND METHODS: Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70 Gy was administered to both groups. Hyperthermia was performed for 45-60 min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. RESULTS: For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M(0) patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M(0) patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. CONCLUSIONS: Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.     

Reply: ‘Thermal dose’: Comments on papers presented at the NAHG workshop

In 1986, 25 patients with stage II and III carcinoma of the cervix were treated by a combination of radiation and local hyperthermia using an endotract intravaginal applicator. Another 25 patients were treated with radiation alone. Both groups were followed up for a minimum period of 18 months. The acute and long-term toxicity of local hyperthermia was closely monitored. Our study shows that whereas local hyperthermia adds significantly to the local control achieved with radiation alone, it is not in any way associated with any significant short-or long-term toxicity, and does not enhance the radiation reactions.     

Radiation therapy for early breast cancer

In women with early-stage breast cancer treated with surgery alone, microscopic residual disease may not be eliminated and can eventually cause life-threatening metastatic recurrence. Radiation therapy has been widely recommended for local control after breast-conserving surgery (BCS) and after a complete mastectomy in women at high risk of recurrence. However, even with widespread support for these recommendations within the medical community, they are not always heeded. Because local recurrence, when detected early, can often be treated with additional surgery alone, some physicians and patients still elect to avoid radiation therapy. It was felt, based upon individual trial data, that radiation therapy did not affect overall survival, but just decreased local relapse. The meta-analysis, published in the December 17/2005 Lancet, analysed individual data from 42,000 women, collected during 78 different randomised trials conducted since 1985. The availability of extensive 15-year survival data allowed the investigators to quantify the relationship between successful local control and long-term survivorship. Moreover, individual trials all show a benefit in local control and some trends toward survival advantages. The pooled meta-analysis of breast conservative surgery with or without radiation therapy Vinh Hung (2004) demonstrates a significant impact on local relapse and a small but significant impact on survival. It is considered that after BCS and in certain cases after mastectomy, radiation therapy is the standard treatment for improved local control and long-term survival.