Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy
Background and purpose
Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence.
Methods
Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5–3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0.
Results
Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p = 0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures.
Conclusions
ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.
Material and methods
Patient data
This IRB-approved retrospective study includes 27 patients with chest wall recurrence of breast cancer who received combined modality therapy with concurrent radiation, hyperthermia, and chemotherapy from February 1995 to June 2007 at the Duke University Medical Center. Four patients were treated from 1995 to 1998, and the remaining 23 from 2004 to 2007: competing protocols account for the small number of patients in this series and the gap in entry.
Patients were evaluated in a multidisciplinary setting by medical oncologists, surgeons, and radiation oncologists. All patients had unresectable disease. All patients had biopsy proven invasive cancer recurrence and had imaging to evaluate for distant meta-static disease with PET and or CT, or bone scan in patients that did not have a PET.
Treatment modalities
Radiation therapy
Radiation was delivered in 1.8–2 Gy fractions utilizing either photons or electrons, or a combination of both. In addition to treating the entire chest wall to a median dose of 45 Gy (range 34–50.4 Gy), areas that harbored malignant involvement, including enlarged locoregional lymph nodes, the flank(s), upper abdomen, back and arms were irradiated. Seven patients received a boost with smaller fields to residual gross disease to a median of 54 Gy (range 45–70 Gy). In patients who had not previously been irradiated (4 patients), or in those who had not had lymph node regions irradiated (16 patients), the supraclavicular fossa was included, and if the internal mammary lymph nodes could be included safely in partly wide tangents, they were treated as well (median dose of 40 Gy, range 34–54 Gy). Tissue equivalent bolus was used when appropriate. Patients were immobilized supine with their arms above their head. Radiotherapy was delivered once daily, on five consecutive days per week, holding only if patients required a toxicity related treatment break.
Hyperthermia
Patients were deemed appropriate hyperthermia candidates if they had superficial tumors, defined as no deeper than 3.0 cm from the skin surface. Hyperthermia was given using microwave spiral strip applicators, operating at 433 MHz and 915 MHz, and 1 MHz/3 MHz ultrasound applicators, depending on the tumor location and patient anatomy. Waterbolus was used between the hyperthermia applicators and the thoracic wall. The water temperature typically varied between 40 °C and 44 °C depending on patient tolerance.
If a patient had extensive disease that could not be encompassed by one hyperthermia applicator (maximum coverage 15 × 15 cm), the involved area was divided into adjacent hyperthermia fields, which were abutting, but not overlapping. The hyperthermia target volume was the gross disease on the chest wall, with a target temperature in tumor of 42–44 °C, as limited by patient tolerance. Maximally allowed temperatures in the adjacent normal tissue and tumor tissue were 43 °C and 50 °C, respectively.
The majority of patients had tumor temperatures measured on the surface due to the superficial nature of the recurrence. When feasible, thermometry catheters were placed in tumor tissue. A sterile, blind-ended interstitial catheter was placed in the tumor using computed tomography guidance as per Radiation Therapy Oncology Group (RTOG) guidelines; lidocaine HCl (1% solution buffered with 0.1 mEq sodium bicarbonate/mL lidocaine) was used for local anesthesia. Commercially available fiberoptic thermometers were used for temperature monitoring (Luxtron Corporation, Santa Clara, CA). These were moved in a stepwise fashion at 0.5-cm increments throughout the tumor volume using a mechanical device for automated temperature mapping. Thermometry probes were also placed on the skin and near scar lines within the HT field to monitor normal tissue and surface temperatures. Hyperthermia was administered twice weekly (1–2 h in length, separated by at least 48 h) 30 min prior to irradiation, for a median number of eight treatments (range 1–10). If patients experienced thermal injury related to hyperthermia administration, then it was held until it was deemed that the patient could receive further hyperthermia.
Chemotherapy
All patients received concurrent chemotherapy. The selection of which agent to be given was at the discretion of the administering medical oncologist. Capecitabine (1000 mg/m) was given orally twice daily (5 days per week) in 21 (78%) patients, paclitaxel IV (175 mg/m) once every 3 weeks in 4 (15%), and vinorelbine IV (25 mg/m) once weekly in 2 (7%) patients. No patient received chemotherapy while they were actually undergoing a hyperthermia procedure. Chemotherapy was held/dose reduced if their WBC counts were <2000/μL, or if hand/foot dysesthesias or oral ulcers occurred.
Follow-up
Patients under treatment were seen at least weekly during treatment, more frequently if required. At the completion of ThChRT, they were seen at 4–6 weeks in the radiation oncology department, and then on an alternating basis with medical oncology for as long as the patient remained alive and returned to our institution. Patients lost to follow-up were censored for local progression free survival (LPFS) at their last follow-up but were included in the acute toxicity analysis.
Outcomes
The primary endpoints of this study were CR rates and duration of LPFS. Secondary endpoints included toxicity of ThChRT, incidence of distant metastases (DM), and overall survival (OS). Toxicity was graded using the modified NCI Common Terminology Criteria (CTC, version 4.0). A local progression was defined as any tumor recurrence within the heated/irradiated field. Distant metastases were determined by radiographic examinations with or without subsequent histopathologic confirmation. LPFS and OS were calculated from the last day of radiation therapy administration. Patients that were lost to follow-up were censored for the LPFS analysis. The Kaplan–Meier method was used to compute LPFS and OS [33]. Chi square and log-rank tests were utilized to compare endpoints based on response to therapy (i.e. CR versus PR). All measures were analyzed with statistical software (SAS, Cary, NC, USA), with a 2-sided alpha level <0.05 regarded as statistically significant.
Patients’ response to therapy was graded using the RECIST criteria, with confirmation at their first follow-up visit for the patients that returned for follow-up. A complete response (CR) was defined as disappearance of all measurable disease; a partial response (PR) was defined as a 30% decrease in measurable disease; stable disease (SD) was present when neither criteria for PR or PD were met; progressive disease (PD) was assigned when a 20% increase in disease extent was noted, and no CR, PR, or SD was achieved prior to growth [34].
Patient data
This IRB-approved retrospective study includes 27 patients with chest wall recurrence of breast cancer who received combined modality therapy with concurrent radiation, hyperthermia, and chemotherapy from February 1995 to June 2007 at the Duke University Medical Center. Four patients were treated from 1995 to 1998, and the remaining 23 from 2004 to 2007: competing protocols account for the small number of patients in this series and the gap in entry.
Patients were evaluated in a multidisciplinary setting by medical oncologists, surgeons, and radiation oncologists. All patients had unresectable disease. All patients had biopsy proven invasive cancer recurrence and had imaging to evaluate for distant meta-static disease with PET and or CT, or bone scan in patients that did not have a PET.
Treatment modalities
Radiation therapy
Radiation was delivered in 1.8–2 Gy fractions utilizing either photons or electrons, or a combination of both. In addition to treating the entire chest wall to a median dose of 45 Gy (range 34–50.4 Gy), areas that harbored malignant involvement, including enlarged locoregional lymph nodes, the flank(s), upper abdomen, back and arms were irradiated. Seven patients received a boost with smaller fields to residual gross disease to a median of 54 Gy (range 45–70 Gy). In patients who had not previously been irradiated (4 patients), or in those who had not had lymph node regions irradiated (16 patients), the supraclavicular fossa was included, and if the internal mammary lymph nodes could be included safely in partly wide tangents, they were treated as well (median dose of 40 Gy, range 34–54 Gy). Tissue equivalent bolus was used when appropriate. Patients were immobilized supine with their arms above their head. Radiotherapy was delivered once daily, on five consecutive days per week, holding only if patients required a toxicity related treatment break.
Hyperthermia
Patients were deemed appropriate hyperthermia candidates if they had superficial tumors, defined as no deeper than 3.0 cm from the skin surface. Hyperthermia was given using microwave spiral strip applicators, operating at 433 MHz and 915 MHz, and 1 MHz/3 MHz ultrasound applicators, depending on the tumor location and patient anatomy. Waterbolus was used between the hyperthermia applicators and the thoracic wall. The water temperature typically varied between 40 °C and 44 °C depending on patient tolerance.
If a patient had extensive disease that could not be encompassed by one hyperthermia applicator (maximum coverage 15 × 15 cm), the involved area was divided into adjacent hyperthermia fields, which were abutting, but not overlapping. The hyperthermia target volume was the gross disease on the chest wall, with a target temperature in tumor of 42–44 °C, as limited by patient tolerance. Maximally allowed temperatures in the adjacent normal tissue and tumor tissue were 43 °C and 50 °C, respectively.
The majority of patients had tumor temperatures measured on the surface due to the superficial nature of the recurrence. When feasible, thermometry catheters were placed in tumor tissue. A sterile, blind-ended interstitial catheter was placed in the tumor using computed tomography guidance as per Radiation Therapy Oncology Group (RTOG) guidelines; lidocaine HCl (1% solution buffered with 0.1 mEq sodium bicarbonate/mL lidocaine) was used for local anesthesia. Commercially available fiberoptic thermometers were used for temperature monitoring (Luxtron Corporation, Santa Clara, CA). These were moved in a stepwise fashion at 0.5-cm increments throughout the tumor volume using a mechanical device for automated temperature mapping. Thermometry probes were also placed on the skin and near scar lines within the HT field to monitor normal tissue and surface temperatures. Hyperthermia was administered twice weekly (1–2 h in length, separated by at least 48 h) 30 min prior to irradiation, for a median number of eight treatments (range 1–10). If patients experienced thermal injury related to hyperthermia administration, then it was held until it was deemed that the patient could receive further hyperthermia.
Chemotherapy
All patients received concurrent chemotherapy. The selection of which agent to be given was at the discretion of the administering medical oncologist. Capecitabine (1000 mg/m) was given orally twice daily (5 days per week) in 21 (78%) patients, paclitaxel IV (175 mg/m) once every 3 weeks in 4 (15%), and vinorelbine IV (25 mg/m) once weekly in 2 (7%) patients. No patient received chemotherapy while they were actually undergoing a hyperthermia procedure. Chemotherapy was held/dose reduced if their WBC counts were <2000/μL, or if hand/foot dysesthesias or oral ulcers occurred.
Radiation therapy
Radiation was delivered in 1.8–2 Gy fractions utilizing either photons or electrons, or a combination of both. In addition to treating the entire chest wall to a median dose of 45 Gy (range 34–50.4 Gy), areas that harbored malignant involvement, including enlarged locoregional lymph nodes, the flank(s), upper abdomen, back and arms were irradiated. Seven patients received a boost with smaller fields to residual gross disease to a median of 54 Gy (range 45–70 Gy). In patients who had not previously been irradiated (4 patients), or in those who had not had lymph node regions irradiated (16 patients), the supraclavicular fossa was included, and if the internal mammary lymph nodes could be included safely in partly wide tangents, they were treated as well (median dose of 40 Gy, range 34–54 Gy). Tissue equivalent bolus was used when appropriate. Patients were immobilized supine with their arms above their head. Radiotherapy was delivered once daily, on five consecutive days per week, holding only if patients required a toxicity related treatment break.
Hyperthermia
Patients were deemed appropriate hyperthermia candidates if they had superficial tumors, defined as no deeper than 3.0 cm from the skin surface. Hyperthermia was given using microwave spiral strip applicators, operating at 433 MHz and 915 MHz, and 1 MHz/3 MHz ultrasound applicators, depending on the tumor location and patient anatomy. Waterbolus was used between the hyperthermia applicators and the thoracic wall. The water temperature typically varied between 40 °C and 44 °C depending on patient tolerance.
If a patient had extensive disease that could not be encompassed by one hyperthermia applicator (maximum coverage 15 × 15 cm), the involved area was divided into adjacent hyperthermia fields, which were abutting, but not overlapping. The hyperthermia target volume was the gross disease on the chest wall, with a target temperature in tumor of 42–44 °C, as limited by patient tolerance. Maximally allowed temperatures in the adjacent normal tissue and tumor tissue were 43 °C and 50 °C, respectively.
The majority of patients had tumor temperatures measured on the surface due to the superficial nature of the recurrence. When feasible, thermometry catheters were placed in tumor tissue. A sterile, blind-ended interstitial catheter was placed in the tumor using computed tomography guidance as per Radiation Therapy Oncology Group (RTOG) guidelines; lidocaine HCl (1% solution buffered with 0.1 mEq sodium bicarbonate/mL lidocaine) was used for local anesthesia. Commercially available fiberoptic thermometers were used for temperature monitoring (Luxtron Corporation, Santa Clara, CA). These were moved in a stepwise fashion at 0.5-cm increments throughout the tumor volume using a mechanical device for automated temperature mapping. Thermometry probes were also placed on the skin and near scar lines within the HT field to monitor normal tissue and surface temperatures. Hyperthermia was administered twice weekly (1–2 h in length, separated by at least 48 h) 30 min prior to irradiation, for a median number of eight treatments (range 1–10). If patients experienced thermal injury related to hyperthermia administration, then it was held until it was deemed that the patient could receive further hyperthermia.
Chemotherapy
All patients received concurrent chemotherapy. The selection of which agent to be given was at the discretion of the administering medical oncologist. Capecitabine (1000 mg/m) was given orally twice daily (5 days per week) in 21 (78%) patients, paclitaxel IV (175 mg/m) once every 3 weeks in 4 (15%), and vinorelbine IV (25 mg/m) once weekly in 2 (7%) patients. No patient received chemotherapy while they were actually undergoing a hyperthermia procedure. Chemotherapy was held/dose reduced if their WBC counts were <2000/μL, or if hand/foot dysesthesias or oral ulcers occurred.
Follow-up
Patients under treatment were seen at least weekly during treatment, more frequently if required. At the completion of ThChRT, they were seen at 4–6 weeks in the radiation oncology department, and then on an alternating basis with medical oncology for as long as the patient remained alive and returned to our institution. Patients lost to follow-up were censored for local progression free survival (LPFS) at their last follow-up but were included in the acute toxicity analysis.
Outcomes
The primary endpoints of this study were CR rates and duration of LPFS. Secondary endpoints included toxicity of ThChRT, incidence of distant metastases (DM), and overall survival (OS). Toxicity was graded using the modified NCI Common Terminology Criteria (CTC, version 4.0). A local progression was defined as any tumor recurrence within the heated/irradiated field. Distant metastases were determined by radiographic examinations with or without subsequent histopathologic confirmation. LPFS and OS were calculated from the last day of radiation therapy administration. Patients that were lost to follow-up were censored for the LPFS analysis. The Kaplan–Meier method was used to compute LPFS and OS [33]. Chi square and log-rank tests were utilized to compare endpoints based on response to therapy (i.e. CR versus PR). All measures were analyzed with statistical software (SAS, Cary, NC, USA), with a 2-sided alpha level <0.05 regarded as statistically significant.
Patients’ response to therapy was graded using the RECIST criteria, with confirmation at their first follow-up visit for the patients that returned for follow-up. A complete response (CR) was defined as disappearance of all measurable disease; a partial response (PR) was defined as a 30% decrease in measurable disease; stable disease (SD) was present when neither criteria for PR or PD were met; progressive disease (PD) was assigned when a 20% increase in disease extent was noted, and no CR, PR, or SD was achieved prior to growth [34].
Results
Twenty-seven patients received ThChRT for chest wall recurrence of breast cancer, with a median follow-up of 6 months (range 0–70 months). Seven patients were lost to follow-up regarding local disease outcome, but did have follow-up regarding survival (all seven died of breast cancer). The median follow-up for the remaining 20 patients was 11 months (range 1–70 months). Median time from initial diagnosis to chest wall failure prompting study entry was 27 months (range 5–257 months). The median age was 51 (range 37–75); 96% were Caucasian. One-third of patients initially presented with stage IIIA disease, and 17 patients had nodal involvement at the time of original diagnosis. For full details of patient characteristics at initial diagnosis of breast cancer, see Table 1. At the time of their recurrence, 22 had chest wall disease only; 5 also had distant metastatic disease. The majority of patients had extensive burdens of disease, with diffuse superficial involvement of the entire chest wall. One patient had bilateral supraclavicular matted lymphadenopathy, with no disease on her chest wall and three patients had axillary and or supraclavicular failures in addition to chest wall disease. For individual characteristics of each patient, see Table 2. Twenty-six out of 27 patients completed the prescribed radiotherapy dose. The one patient that did not complete therapy developed rapidly progressive visceral metastatic disease.
Table 1
Patient characteristics at the time of initial diagnosis of breast cancer.
| Patient characteristic | Number of patients (%) |
|---|---|
| Age | Median 51 (range 37–75) |
| Histology | |
| Infiltrating ductal carcinoma | 22 (81%) |
| Infiltrating lobular carcinoma | 4 (15%) |
| Estrogen receptor | |
| Positive | 6 (22%) |
| Negative | 16 (59%) |
| Unknown | 5 (19%) |
| Progesterone receptor | |
| Positive | 7 (26%) |
| Negative | 14 (52%) |
| Unknown | 6 (22%) |
| Her2neu | |
| Not amplified | 5 (19%) |
| Amplified | 12 (44%) |
| Unknown | 10 (37%) |
| T stage | |
| T0 | 1 (4%) |
| T1 | 9 (33%) |
| T2 | 8 (30%) |
| T3 | 5 (19%) |
| T4 | 3 (11%) |
| Lymph nodal involvement | |
| N0 | 9 (33%) |
| N1 | 6 (22%) |
| N2 | 8 (30%) |
| N3 | 3 (11%) |
Table 2
Individual characteristics of patients’ chest wall/superficial recurrences and their response to thermochemoradiotherapy.
| Patient | Characteristics of chest wall recurrences | Response |
|---|---|---|
| 1 | 5 cm nodule surrounded by 9 × 6 cm nodular/erythematous area | CR |
| 2 | Multiple bilateral supraclavicular nodes | CR |
| 3 | Chest wall nodule and matted axillary LN’s resected with + margins/ECE; no gross disease | CR |
| 4 | Two nodules s/p resection with involvement of the capsule of her implant which was left intact; no gross disease | CR |
| 5 | 13 × 6 cm diffuse area of skin infiltration | PR |
| 6 | Diffuse erythema on >1/2 her chest wall | uCR |
| 7 | Diffuse raised erythematous rash over entire mastectomy scar | CR |
| 8 | 2 cm nodule in her intact right breast; 2 × 3 cm erythematous rash on her left chest wall | CR |
| 9 | 6 × 3 cm erythematous nodule | uPR |
| 10 | 7 × 7 cm erythematous rash on right chest wall; diffuse erythema on left neck/left chest wall | CR |
| 11 | Diffuse rash from scar superiorly to clavicle, with satellite smaller areas inferior and medial | CR |
| 12 | Diffuse nodules over entire left chest wall, with 3 cm left SCV matted LN’s and 4 cm conglomerate of matted left axillary LN’s | CR |
| 13 | Diffuse nodules throughout entire ipsilateral chest wall | CR |
| 14 | 15 × 30 cm erythematous rash on ipsilateral chest wall with extension to media upper arm and posteriorly onto her back; +ulceration in her axilla | CR |
| 15 | Erythematous rash on entire ipsilateral chest wall extending superiorly to clavicle | uPR |
| 16 | Diffuse erythema with multiple nodules | PR |
| 17 | Diffuse nodularity of entire chest wall | CR |
| 18 | Multiple nodules scattered throughout the chest wall, with synchronous axillary failure status post dissection | CR |
| 19 | 2 × 0.6 cm ulcerated lesion with 4 × 3 cm satellite nodule | uPR |
| 20 | Diffuse erythematous rash extending from her left mid-axillary line contiguously to her right posterior axillary line; 10–20 cm superior to inferior | PR |
| 21 | 6 × 6 × 4 cm sternal nodule with satellite 3 cm erythematous nodule in the tail of her left reconstructed breast | uPR |
| 22 | 4 cm left axillary LN, 2 cm sternal nodule, diffuse erythematous rash on right chest wall that extends posteriorly to back | PR |
| 23 | Multiple nodules on chest wall and upper inner arm, with erythema/induration extending throughout the ipsilateral chest wall | CR |
| 24 | Bilateral SCV LN’s with diffuse small erythematous nodules on the left chest wall, with erythema/induration in her right periareolar area | uPR |
| 25 | Diffuse erythematous nodules involving her right shoulder/SCV region/entire right chest wall, and her left and right upper abdominal quadrants | uCR |
| 26 | 3 cm ulcer with diffuse erythema over entire chestwall | CR |
| 27 | Diffuse involvement of her chest wall | CR |
CR = complete response; PR = partial response; LN = lymph nodes; ECE = extracapsular extension; uCR = unconfirmed CR; uPR = unconfirmed PR.
Previous therapy
These patients were heavily pre-treated, with 23 (85%) having received prior radiotherapy to a median dose of 60.4 Gy (range 50–67.9 Gy). Similarly high percentage of patients (89%) received prior systemic therapy. Twenty-two (81%) received prior chemotherapy, 9 (33%) received prior hormonal therapy, and 7 (26%) received both. Two patients underwent surgical resection of their chest wall recurrence but had positive margins and extranodal extension of disease.
Local progression free survival
Of the 27 patients treated, none progressed during therapy. Seven were not evaluated for remission status because they did not return for their 1 month follow-up. At the completion of their therapy, two had achieved a CR and five had a PR which were unable to be con-firmed. Of the 20 patients that we have a confirmed assessment of disease status 1 month post completion of therapy, 16 (80%) had a CR and 4 (20%) had a PR, for an overall response rate of 100%. Of these 20 patients, 4 (20%) patients developed a local progression within the irradiated/heated treatment field. One-year LPFS was 76%, with four patients having recurred/progressed locally (Fig. 1a).
Overall survival
Median overall survival for the entire cohort was 14.3 months (Fig. 1b). When analyzed by response to therapy, those patients who achieved a CR had a median OS of 23 months, while the partial responders survived a median of 5.4 months (p = 0.01) (Fig. 1c). Overall, 14 patients (52%) developed metastatic disease, most frequently to the lungs and liver.
Toxicity
Overall, there were 22 patients who experienced acute grade 1/ 2 toxicities. By far the most frequent was moist desquamation in 17 patients (63%), which was managed conservatively and did not require treatment interruption. Two patients developed clinically asymptomatic fat necrosis by physical examination, which was not pathologically confirmed, nor required therapy.
Thermal injury occurred in nine patients, two of which were small volume 3rd degree burns, both of which resolved. One of the patients developed a 3rd degree burn in a transverse rectus abdominis myocutaneous (TRAM) flap, and hyperthermia was discontinued only after four treatments. After 15 months, this area had healed without further intervention.
Chemotherapy was well tolerated and was administered as prescribed to 23 of 27 patients. There were no hematologic or other toxicities associated with paclitaxel or vinorelbine that required dose reduction or discontinuation. Capecitabine was held for 5 days in two patients secondary to palmar/plantar dysesthesias. It was dose reduced in one other for the same reason. Capecitabine was ultimately discontinued in one patient related to oral ulcers. There were no significant hematologic toxicities associated with its use.
Previous therapy
These patients were heavily pre-treated, with 23 (85%) having received prior radiotherapy to a median dose of 60.4 Gy (range 50–67.9 Gy). Similarly high percentage of patients (89%) received prior systemic therapy. Twenty-two (81%) received prior chemotherapy, 9 (33%) received prior hormonal therapy, and 7 (26%) received both. Two patients underwent surgical resection of their chest wall recurrence but had positive margins and extranodal extension of disease.
Local progression free survival
Of the 27 patients treated, none progressed during therapy. Seven were not evaluated for remission status because they did not return for their 1 month follow-up. At the completion of their therapy, two had achieved a CR and five had a PR which were unable to be con-firmed. Of the 20 patients that we have a confirmed assessment of disease status 1 month post completion of therapy, 16 (80%) had a CR and 4 (20%) had a PR, for an overall response rate of 100%. Of these 20 patients, 4 (20%) patients developed a local progression within the irradiated/heated treatment field. One-year LPFS was 76%, with four patients having recurred/progressed locally (Fig. 1a).
(a) Local progression-free survival for all patients (b) overall survival for all patients; (c) and for patients with CR versus PR.
Overall survival
Median overall survival for the entire cohort was 14.3 months (Fig. 1b). When analyzed by response to therapy, those patients who achieved a CR had a median OS of 23 months, while the partial responders survived a median of 5.4 months (p = 0.01) (Fig. 1c). Overall, 14 patients (52%) developed metastatic disease, most frequently to the lungs and liver.
Toxicity
Overall, there were 22 patients who experienced acute grade 1/ 2 toxicities. By far the most frequent was moist desquamation in 17 patients (63%), which was managed conservatively and did not require treatment interruption. Two patients developed clinically asymptomatic fat necrosis by physical examination, which was not pathologically confirmed, nor required therapy.
Thermal injury occurred in nine patients, two of which were small volume 3rd degree burns, both of which resolved. One of the patients developed a 3rd degree burn in a transverse rectus abdominis myocutaneous (TRAM) flap, and hyperthermia was discontinued only after four treatments. After 15 months, this area had healed without further intervention.
Chemotherapy was well tolerated and was administered as prescribed to 23 of 27 patients. There were no hematologic or other toxicities associated with paclitaxel or vinorelbine that required dose reduction or discontinuation. Capecitabine was held for 5 days in two patients secondary to palmar/plantar dysesthesias. It was dose reduced in one other for the same reason. Capecitabine was ultimately discontinued in one patient related to oral ulcers. There were no significant hematologic toxicities associated with its use.
Discussion
The utility of combined modality therapy with hyperthermia rests on several principles. Hyperthermia can be directly cytotoxic and is a known radiosensitizer [35], inhibiting potentially lethal and sublethal damage repair [36]. It is most effective in the S-phase of cell cycle, complementing the relative resistance of this phase to radiation injury [37]. It also alters tumor blood flow and may improve tumor oxygenation [38], which in turn may result in delivery of a higher concentration of chemotherapeutic agents as well as enhance the effect of radiotherapy by decreasing the amount of hypoxia. Hyperthermia may also act synergistically with the chemotherapeutic agents themselves to enhance cytotoxicity [39]. More than additive effects are seen with cell kill when hyperthermia is combined with alkylating agents, antibiotics and platinum drugs. When hyperthermia is used in conjunction with pyrimidine antagonists, with 5-fluorouracil being the most frequently studied, the effect is seemingly additive [39].
There has been considerable interest in combining hyperthermia with radiotherapy for superficial chest wall recurrences of breast cancer [19–27]. Multiple prospective [19,26] and retrospective [24] studies cite a statistically significant increase in the rate of CR when adding hyperthermia to radiotherapy versus radiotherapy alone, with CR rates typically in the range of 59–66% versus 41–42%, respectively. Complete response rates as high as 95% have been published with the addition of hyperthermia to radiation in a small single institution report [29].
The addition of hyperthermia to radiotherapy and chemotherapy in the setting of chest wall recurrence has been reported previously by two institutions [31,32]. The University of Lübeck treated 25 patients with epirubicin and ifosfamide and only administered one hyperthermia session per week. The radiotherapy also differed in that patients were treated with either conventional fractionation to a mean dose of 52.2 Gy, or hyperfractionated therapy to a mean of 43.3 Gy; the latter was used in patients with extensive disease burden, or those who experienced grade 3 skin toxicities from prior radiotherapy [32]. These investigators reported an overall response rate of 80%, with a CR rate of 44%.
The University of Athens enrolled 15 patients with chest wall recurrence who received concurrent hyperthermia (once every 4 weeks), liposomal doxorubicin and re-irradiation to a dose of 30.6 Gy [31]. The overall response rate was 100%; 80% PR and 20% CR. Only one patient (6.7%) developed moist desquamation.
Comparisons of retrospective series from different institutions are always problematic. Nonetheless, our overall response rate of 100% and CR rate of 80% appear to compare quite favorably to the reports from the above institutions. It remains unclear as to whether the addition of chemotherapy to hyperthermia and radiation improves results. As quoted above, CR rates in the range of 60% have been achieved with hyperthermia and radiation alone without chemotherapy. Because of the very extensive disease present in the great majority of our patients, we believe that the achieved CR rate of 80% represents an improvement over what might have been achieved with radiation and hyperthermia alone. Additional studies will clearly be necessary to demonstrate this, however.
The ThChRT reported herein obviously represents treatment intensification with the risk of worsened toxicity as well. The 63% reported rate of moist desquamation may seem high. However, moist desquamation was an expected consequence of treatment, given the extent of skin involvement of most of these patients and the use of bolus and electrons to maximize the tumor dose to the skin surface. The moist desquamation observed did heal with conservative measures. As far as thermal injury is concerned, only two patients sustained significant thermal injury with small volume 3rd degree burns, which also healed with conservative measures without surgical intervention. One of these patients had recurred in a prior TRAM flap reconstruction. These patients often have compromised skin sensation and thus are less able to report discomfort from hyperthermia. This places them at increased risk for thermal injury and makes them less than ideal candidates for thermal therapy.
Conclusions
Patients experiencing chest wall recurrence of breast cancer that are surgically unresectable, following prior mastectomy and post mastectomy radiotherapy may still experience long-term LPFS when treated with ThChRT with an acceptable treatment related toxicity. The use of hyperthermia and chemotherapy allows for reduced doses of radiation in these heavily pre-treated patients. The exact role of the various components of this trimodality program is uncertain and further studies are warranted.
Abstract
Background and purpose
Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence.
Methods
Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5–3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0.
Results
Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p = 0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures.
Conclusions
ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.
Local recurrence rates of breast cancer after mastectomy alone have been reported as high as 45% for those with T3/T4 or node positive disease [1]. This high rate of failure can be reduced to 2–15% with the addition of postmastectomy radiation therapy (PMRT) and usually chemotherapy as well [2–10], with a corresponding improvement in overall survival [3,4,7]. Treatment for patients that recur in the setting of previous mastectomy and PMRT is quite problematic.
Options for additional therapy may include surgery, chemotherapy, or re-irradiation with or without sensitization (i.e. concurrent chemotherapy or hyperthermia). The utility of further surgery in achieving local control and long-term survival has been reported in several small retrospective series, but the majority of patients are not resectable [11–16]. In the setting of prior radiation therapy, chest wall re-irradiation alone results in complete responses (CR) and long-term local control in relatively few patients [17,18].
Based on the poor results obtained with re-irradiation alone, some investigators advocate combining hyperthermia and radiation in patients that have been previously irradiated, which is supported by randomized and non-randomized studies [19–30]. With its radiosensitizing properties, hyperthermia presumably lowers the radiation dose needed to achieve durable local control, which in turn has potential implications for decreased long-term toxicities in patients with a prior history of radiotherapy. The addition of concurrent chemotherapy to hyperthermia and radiation therapy, constituting thermochemoradiotherapy (ThChRT)), has been evaluated in phase I/II trials by several researchers and found to be well-tolerated, with moderate success [31,32].
Our hypothesis was that the radiosensitizing properties of both chemotherapy and hyperthermia would presumably allow for reduced doses of radiation with equivalent efficacy—an important consideration in patients who received prior radiation—and result in prolonged LPFS and long-term palliation, with limited toxicity.
Footnotes
Conflicts of interest statement
E.L. Jones, M.D., Ph.D., on speaker’s bureau and consultant, BSD Medical; M.W. Dewhirst is a paid consultant and Chair of the Scientific Advisory Board of Celsion, Inc., and is recipient of research contracts from Varian Corporation and GlaxoSmithKline, Inc., M.W.D. and V.J. are recipients of grants from the National Institutes of Health; all other authors had none.
Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy is an approved Duke University Protocol, #00003793.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the United States Government.
For CDR Edward F. Miles—I am a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
References
- 1. Lee MC, Jagsi RPostmastectomy radiation therapy: indications and controversies. Surg Clin North Am. 2007;87:511–26. xi.[PubMed][Google Scholar]
- 2. Buchanan CL, Dorn PL, Fey J, et al Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg. 2006;203:469–74.[PubMed][Google Scholar]
- 3. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997;337:949–55.[PubMed]
- 4. Overgaard M, Jensen MB, Overgaard J, et al Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999;353:1641–8.[PubMed][Google Scholar]
- 5. Ragaz J, Olivotto IA, Spinelli JJ, et al Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst. 2005;97:116–26.[PubMed][Google Scholar]
- 6. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists’ Collaborative Group. N Engl J Med. 1995;333:1444–55.[PubMed]
- 7. Clarke M, Collins R, Darby S, et al Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087–106.[PubMed][Google Scholar]
- 8. Killander F, Anderson H, Ryden S, et al Radiotherapy and tamoxifen after mastectomy in postmenopausal women—20 year follow-up of the South Sweden Breast Cancer Group randomised trial SSBCG II:I. Eur J Cancer. 2007;43:2100–8.[PubMed][Google Scholar]
- 9. Nielsen HM, Overgaard M, Grau C, et al Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c randomized studies. J Clin Oncol. 2006;24:2268–75.[PubMed][Google Scholar]
- 10. Katz A, Strom EA, Buchholz TA, et al Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation. J Clin Oncol. 2000;18:2817–27.[PubMed][Google Scholar]
- 11. Beck TM, Hart NE, Woodard DA, et al Local or regionally recurrent carcinoma of the breast: results of therapy in 121 patients. J Clin Oncol. 1983;1:400–5.[PubMed][Google Scholar]
- 12. Chagpar A, Meric-Bernstam F, Hunt KK, et al Chest wall recurrence after mastectomy does not always portend a dismal outcome. Ann Surg Oncol. 2003;10:628–34.[PubMed][Google Scholar]
- 13. Dahlstrom KK, Andersson AP, Andersen M, et al Wide local excision of recurrent breast cancer in the thoracic wall. Cancer. 1993;72:774–7.[PubMed][Google Scholar]
- 14. Veronesi G, Scanagatta P, Goldhirsch A, et al Results of chest wall resection for recurrent or locally advanced breast malignancies. Breast. 2007;16:297–302.[PubMed][Google Scholar]
- 15. Kolodziejski LS, Wysocki WM, Komorowski ALFull-thickness chest wall resection for recurrence of breast malignancy. Breast J. 2005;11:273–7.[PubMed][Google Scholar]
- 16. Pameijer CR, Smith D, McCahill LE, et al Full-thickness chest wall resection for recurrent breast carcinoma: an institutional review and meta-analysis. Am Surg. 2005;71:711–5.[PubMed][Google Scholar]
- 17. Harms W, Krempien R, Grehn C, et al Reirradiation of chest wall local recurrences from breast cancer. Zentralbl Gynakol. 2004;126:19–23.[PubMed][Google Scholar]
- 18. Harms W, Krempien R, Hensley FW, et al Results of chest wall reirradiation using pulsed-dose-rate (PDR) brachytherapy molds for breast cancer local recurrences. Int J Radiat Oncol Biol Phys. 2001;49:205–10.[PubMed][Google Scholar]
- 19. Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35:731–44.[PubMed]
- 20. Hehr T, Lamprecht U, Glocker S, et al Thermoradiotherapy for locally recurrent breast cancer with skin involvement. Int J Hyperthermia. 2001;17:291–301.[PubMed][Google Scholar]
- 21. Welz S, Hehr T, Lamprecht U, et al Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection. Int J Hyperthermia. 2005;21:159–67.[PubMed][Google Scholar]
- 22. Dragovic J, Seydel HG, Sandhu T, et al Local superficial hyperthermia in combination with low-dose radiation therapy for palliation of locally recurrent breast carcinoma. J Clin Oncol. 1989;7:30–5.[PubMed][Google Scholar]
- 23. Li G, Mitsumori M, Ogura M, et al Local hyperthermia combined with external irradiation for regional recurrent breast carcinoma. Int J Clin Oncol. 2004;9:179–83.[PubMed][Google Scholar]
- 24. Phromratanapongse P, Steeves RA, Severson SB, et al Hyperthermia and irradiation for locally recurrent previously irradiated breast cancer. Strahlenther Onkol. 1991;167:93–7.[PubMed][Google Scholar]
- 25. van der Zee J, van der Holt B, Rietveld PJ, et al Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation. Br J Cancer. 1999;79:483–90.[Google Scholar]
- 26. Jones EL, Oleson JR, Prosnitz LR, et al Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol. 2005;23:3079–85.[PubMed][Google Scholar]
- 27. Wahl AO, Rademaker A, Kiel KD, et al Multi-institutional review of repeat irradiation of chest wall and breast for recurrent breast cancer. Int J Radiat Oncol Biol Phys. 2008;70:477–84.[PubMed][Google Scholar]
- 28. Gonzalez Gonzalez D, van Dijk JD, Blank LEChestwall recurrences of breast cancer: results of combined treatment with radiation and hyperthermia. Radiother Oncol. 1988;12:95–103.[PubMed][Google Scholar]
- 29. Engin K, Tupchong L, Waterman FM, et al Multiple field hyperthermia combined with radiotherapy in advanced carcinoma of the breast. Int J Hyperthermia. 1994;10:587–603.[PubMed][Google Scholar]
- 30. Myerson RJ, Straube WL, Moros EG, et al Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment. Int J Hyperthermia. 1999;15:251–66.[PubMed][Google Scholar]
- 31. Kouloulias VE, Dardoufas CE, Kouvaris JR, et al Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clin Cancer Res. 2002;8:374–82.[PubMed][Google Scholar]
- 32. Feyerabend T, Wiedemann GJ, Jager B, et al Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease. Int J Radiat Oncol Biol Phys. 2001;49:1317–25.[PubMed][Google Scholar]
- 33. Dinse GE, Lagakos SWNonparametric estimation of lifetime and disease onset distributions from incomplete observations. Biometrics. 1982;38:921–32.[PubMed][Google Scholar]
- 34. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.[PubMed]
- 35. Kampinga HH, Dikomey EHyperthermic radiosensitization: mode of action and clinical relevance. Int J Radiat Biol. 2001;77:399–408.[PubMed][Google Scholar]
- 36. Raaphorst GP, Ng CE, Yang DPThermal radiosensitization and repair inhibition in human melanoma cells: a comparison of survival and DNA double strand breaks. Int J Hyperthermia. 1999;15:17–27.[PubMed][Google Scholar]
- 37. Westra A, Dewey WCVariation in sensitivity to heat shock during the cell-cycle of Chinese hamster cells in vitro. Int J Radiat Biol Relat Stud Phys Chem Med. 1971;19:467–77.[PubMed][Google Scholar]
- 38. Dewhirst MWConcepts of oxygen transport at the microcirculatory level. Semin Radiat Oncol. 1998;8:143–50.[PubMed][Google Scholar]
- 39. Kampinga HHCell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. Int J Hyperthermia. 2006;22:191–6.[PubMed][Google Scholar]