Phase I/II trial of intravenous Doxil® and whole abdomen hyperthermia in patients with refractory ovarian cancer

Objective: A phase I/II study of Doxil® combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects.

Patients and methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil® at a dose of 40?mg?m^?2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle.

Results: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60?min after either average vaginal and rectal temperatures of 40°C had been achieved or after 30?min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and six patients had been previously treated with Doxil®. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3–4 PPE toxicity. Doxil® systemic exposure was higher in those with grade 3–4 PPE compared to those with no PPE. None of the patients had grade 3–4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy.

Conclusions: Therapy with intravenous Doxil® and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.     

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer

IntroductionNeoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.MethodsWe conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m² IV weekly ×12 followed by doxorubicin 24 mg/m² IV weekly + cyclophosphamide 60 mg/m² PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade).ResultsSeventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER⁺ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue.ConclusionsNeoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.     

Surgery following neoadjuvant therapy in patients with HER2-positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study

Aim

To describe surgical outcomes in patients with HER2-positive locally advanced (LABC) or inflammatory breast cancer (IBC) participating in the NeOAdjuvant Herceptin (NOAH) study (ISRCTN86043495).

Patients and methods

A total of 235 patients with HER2-positive disease were randomized to neoadjuvant trastuzumab plus chemotherapy (doxorubicin plus paclitaxel, followed by paclitaxel, followed by cyclophosphamide, methotrexate and fluorouracil) or neoadjuvant chemotherapy alone. Of these patients, 228 received their allocated treatment (115 received trastuzumab plus chemotherapy and 113 received chemotherapy alone) and were potentially eligible for surgery. Mastectomy was required for all patients with IBC and was recommended for all patients with LABC. However, breast-conserving therapy could be considered for patients with peripheral neoplasms measuring ≤4 cm in diameter at diagnosis, with a favorable ratio of tumor to breast volume, or at the patient’s request if there had been a good response to treatment.

Results

As previously reported, the addition of trastuzumab to neoadjuvant chemotherapy improved the overall, complete and pathological complete response to therapy and significantly improved event-free survival (the primary endpoint of the study). Trastuzumab also enabled more patients to have breast conserving surgery (BCS) (23% versus 13% respectively) without an apparent detrimental effect on local disease control (no patient treated with trastuzumab plus chemotherapy had experienced a local recurrence after BCS at the time of analysis).

Conclusions

Although this was not an aim of the trial, neoadjuvant trastuzumab given concurrently with chemotherapy enabled 23% of patients with HER2-positive LABC/IBC to avoid mastectomy (including a small number of patients with IBC).     

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: A pilot study

Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used.

Purpose: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment.

Materials and methods: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging.

Results: The contrast agent in all tumours typically peaked in the first 1–4 min. The tumours’ WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002.

Conclusions: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.     

Second-line neoadjuvant vinorelbine and gemcitabine combination in locally advanced breast cancer showing no early response to TAC

Due to socioeconomic issues, locally advanced breast cancer (LABC) is still a common presentation of breast cancer in the third world. It was found that LABC patients showing a clinical response after two to four cycles of neoadjuvant chemotherapy have a higher probability of obtaining a pathological complete response at surgery than patients without an early response. In the present work, the short-term effects and toxicity of the neoadjuvant second-line vinorelbine and gemcitabine combination were evaluated in the treatment of LABC who did not show early response to anthracyclines and taxanes-containing regimen. The use of vinorelbine and gemcitabine was based on their use in metastatic breast cancer cases who had been treated before with anthracyclines and taxanes. This was a prospective phase II study accomplished at the Clinical Oncology and Nuclear Medicine Department of Mansoura University, Egypt. Seventy LABC patients not suitable for breast conservative surgery who failed to achieve early response to two cycles of a combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) were treated with a 3-weekly regimen of vinorelbine 30 mg/m² plus gemcitabine 1,200 mg/m² given on days 1 and 8 by intravenous infusion as a second-line neoadjuvant chemotherapy. Response was assessed after the second cycle. Stable and progressed patients were operated upon while responding cases received up to four cycles before the operation. Patient accrual was from June 20, 2007, to October 20, 2009. The objective response was evaluated clinically with breast sonography before every new cycle and before operation while the pathological response was determined postoperatively. The toxicity was evaluated according to the National Cancer Institute––Common Toxicity criteria version 3. The end points of this study were clinical response rate, pathological response rate, and treatment toxicity. Clinical response rate was achieved in 35 cases (50%) while pathological response rate was reported in 4 cases (5.7%). Breast conservative surgery (BCS) became possible in 31 cases (44%). The most common severe toxicities (grades 3 and 4) were neutropenia and thrombocytopenia in 25.7 and 22.8% of cases, respectively. Toxicities were reversible and did not cause death. It is possible to achieve objective clinical and pathological responses of LABC with potentially non-cross-resistant neoadjuvant second-line therapy, leading to BCS in a high proportion of patients. Thus, preoperative second-line chemotherapy appears to be justified when breast conservation is an important treatment goal.     

Prospective assessment of quality of life in ovarian cancer patients receiving whole abdomen hyperthermia and liposomal doxorubicin

Purpose: Prospective assessment of quality of life (QoL) in patients with refractory, residual or recurrent ovarian cancer receiving whole abdomen hyperthermia and intravenous liposomal doxorubicin chemotherapy.

Methods: Treatment consisted of six cycles of intravenous liposomal doxorubicin at 40?mg?m² followed by whole abdomen hyperthermia with each cycle delivered every 4 weeks. QoL assessment was performed at baseline, prior to each cycle of chemotherapy and every 3 months during follow-up using self-administered questionnaires. Global QoL was rated on a seven-point scale and specific domains of QoL, disease related symptoms and treatment related toxicity were rated on a four-point scale.

Results: Thirty-two patients were enrolled on the study and 129?QoL questionnaires were completed. Average age was 57.9 (range 45–76); nine patients had persistent and 23 recurrent disease. Ten patients completed six cycles of therapy. Three patients returned follow-up surveys. Subjects rated their overall QoL and health at baseline as above average with mean scores 5.10 (95% CI?=?4.62?5.58) and 4.66 (95% CI?=?4.23?5.08), respectively. No significant change in overall QoL was found between baseline and cycles 4–6 of therapy. Mean ratings of overall health and subject reported differences in QoL between cycles were not significantly changed during therapy. Limited follow-up data were available, but scores suggest possible improvement in QoL for patients completing all therapy. Subjects rated the greatest negative impact on QoL in areas of role functioning and social functioning, where the mean (SD) over all cycles was 2.00 (0.67) and 1.98 (0.70), respectively. For physical symptoms, fatigue and sleep disturbance had the most negative impact on QoL with means (SD) of 2.26 (0.62) and 1.91 (0.70). The moderate treatment related toxicity seen in this study did not significantly impact patients reported QoL.

Conclusions: Patients with unfavourable ovarian cancer responding to intravenous liposomal doxorubicin and whole abdomen hyperthermia maintained above average QoL during therapy. Limited data on patients completing protocol therapy demonstrated possible improvement in QoL.     

Short-course preoperative radiotherapy combined with chemotherapy,delayed surgery and local hyperthermia for rectal cancer: a phase II study

Purpose: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer.

Methods: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25?Gy in 5?Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000?mg/m² twice a day was given on days 1–14. Local hyperthermia, 41–45?°C for 60?min, was performed on days 3–5. Metronidazole 10?g/m² was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes.

Results: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%.

Conclusions: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.     

Phase I study of pegylated liposomal doxorubicin, paclitaxel, andcisplatin in?patients with advanced solid tumors

Background:The combination of doxorubicin, paclitaxel, andcisplatin has activity in gynecologic malignancies but requires colonystimulating factor (G-CSF) support. Moreover, there is concern aboutcardiotoxicity with doxorubicin/paclitaxel combinations. Pegylatedliposomal doxorubicin may result in less myelosuppression and cardiactoxicity than free doxorubicin. The purpose of this study was todetermine the maximal tolerated dose of pegylated liposomal doxorubicinwith fixed doses of paclitaxel and cisplatin without using G-CSF supportin advanced solid malignancies. Patients and methods:Twenty-three patients were enrolled; none of the patients hadreceived prior doxorubicin. Patients received paclitaxel (90mg/m² for dose level one, escalating to 135 mg/m²for all subsequent dose levels), with a fixed dose of cisplatin (60mg/m²), followed by escalating doses of pegylated liposomaldoxorubicin every 21 days. Results:A total of 73 cycleswas administered. Grade 4 neutropenia was seen after cycle one in two ofeight patients receiving 30 mg/m² of pegylated liposomaldoxorubicin and three of seven patients receiving 40 mg/m² ofpegylated liposomal doxorubicin when combined with 135 mg/m²of paclitaxel and 60 mg/m² of cisplatin. Two additionalpatients at the 40 mg/m² dose level developed grade 4neutropenia following cycles 2 and 5. The mean decline in leftventricular ejection fraction (LVEF) after 2 cycles was 5 percentagepoints (P= 0.012). Conclusion:The combinationof pegylated liposomal doxorubicin, paclitaxel and cisplatin is feasiblewithout G-CSF support.     

Neoadjuvant Combination Chemotherapy with Pegylated Liposomal Doxorubicin and Vinorelbine for Locally Advanced Breast Cancer

OBJECTIVE In China, vinorelbine plus an anthracycline is a common neoadjuvant regimen for locally-advanced breast cancer (LABC).Pegylated liposomal doxorubicin (PLD) is an alternate anthracycline formulation with a more favorable safety profile compared with conventional anthracyclines.METHODS In this open-label trial, 61 women with LABC received up to 6 cycles of PLD 30 mg/m2 on Day 1 and vinorelbine 25 mg/m2 on Days 1 and 8 every 21 days. Hormone receptor and/or HER2 status was not routinely available.RESULTS The overall clinical response rate (primary efficacy endpoint) was 80% (95% CI: 68%-89%). Two patients achieved a pathological complete response (3%), with 75% having their tumor down-staged, and 89% proceeding to tumor resection. The most frequent nonhematologic adverse events were stomatitis, fever,rash, and palmar-plantar erythrodysesthesia, with none considered serious. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 10% and 2% of patients, respectively.CONCLUSION PLD plus vinorelbine demonstrated comparable efficacy to conventional anthracyclines plus vinorelbine in the neoadjuvant treatment of LABC, but may offer safety advantages.     

A Phase II Trial of a Neoadjuvant Platinum Regimen for Locally Advanced Breast Cancer: Pathologic Response,Long-Term Follow-up,and Correlation With Biomarkers

PurposeThe purpose of this study is to determine the response, tolerability, and long-term outcome of a neoadjuvant platinum-containing regimen for locally advanced breast cancer (LABC) and to search for a correlation between pathologic complete response (pCR) and predefined biomarkers in this cohort.Patients and MethodsPatients with LABC received 8 cycles of either sequence A or B. Sequence A was doxorubicin 60 mg/m² and paclitaxel 175 mg/m² (AT) every 3 weeks × 4 followed by cisplatin (C) 60 mg/m² and paclitaxel 90 mg/m² (CT) every 2 weeks × 4. Sequence B was CT × 4 (with paclitaxel dose escalation) followed by AT × 4. In addition to estrogen receptor (ER) and HER2, immunohistochemistry for MDR-1, MRP-1, topoisomerase IIα (topo IIα), and p53 was performed.ResultsA total of 88 patients were evaluable for response and toxicity. Median follow-up was 97 months. The overall pCR rate was 21.5%. For subgroups ER+/HER2+, HER2+ and double negative (ER+/HER2+) disease, the pCR rates were 5.9%, 23.3%, and 35%, respectively (P = .006). Five-year overall survival for the entire cohort was 71.1%. Five-year overall survival was 88.1% (95% CI, 77.1%-99.1%) for the ER+/HER2+ group compared with 68.5% (95% CI, 51.3%-85.7%) and 49.5% (95% CI, 27.4%-71.6%) in the HER2+ and “double-negative” group, respectively (P = .0077). Overexpression of topo IIα was correlated with pCR (P < .001). There were no toxic deaths.ConclusionA platinum-containing neoadjuvant regimen was well tolerated and achieved a pCR comparable to other recent studies of multiagent chemotherapy. Further studies tailored for specific breast cancer subtypes are required.     

The efficacy and hyperthermic release of doxorubicin from liposomal doxorubicin hydrochloride in rabbit VX2 tumours

Abstract

Purpose: To establish optimum conditions for anti-tumour therapy, we evaluated the efficacy of doxorubicin using liposomal doxorubicin and local hyperthermia to improve the anti-tumour efficacy over liposomal doxorubicin alone in rabbit VX2 tumours. Materials and methods: A VX2 tumour model was established in New Zealand white rabbits, which were randomly divided into five groups: 1) control, 2) free doxorubicin hydrochloride (Dox), 3) liposomal doxorubicin hydrochloride (L-Dox), 4) L-Dox plus 41?°C thermotherapy (L-Dox?+?41?°C TT); and 5) L-Dox plus 43?°C thermotherapy (L-Dox?+?43?°C TT). To achieve complete tumour remission, multiple high-dose administrations (5?mg/kg, once per week for a total of 3 weeks) were given. An ultrasound hyperthermia instrument was used to induce local hyperthermia and the systemic toxicity of Dox was evaluated by changes in weight, blood count and serum lactic dehydrogenase. The anti-tumour effect of Dox was evaluated by observing the gross tumour volume, weight and rabbit survival. Results: The white blood cell count following administration of Dox or L-Dox was lower than for control animals and those treated with L-Dox?+?41?°C TT. There was no difference between the groups with regard to the red blood cell count. Compared with the control and Dox groups, tumour proliferation was significantly inhibited following administration of L-Dox, L-Dox?+?41?°C TT and L-Dox?+?43?°C TT, as evidenced by the difference in tumour volume, weight and survival time. Differences in tumour proliferation were also found between the L-Dox and thermotherapy groups. Conclusion: Local hyperthermia combined with L-Dox can significantly improve anti-tumour efficacy and reduce systemic toxicity.     

Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial

Purpose: To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT.

Materials and methods: Data from a multicentre randomised clinical trial of concurrent CRT?+?HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT?+?HT group were available for the thermal analysis. Thus, 47 patients who received CRT?+?HT were included in the present study.

Results: Among the patients who received CRT?+?HT, a higher CEM43T90 (≥1?min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p?=?0.024) and multivariate (p?=?0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1?min) values tended to be better in comparison to patients with lower CEM43T90 (<1?min) value (p?=?0.071). A complete response tended to be associated with the CEM43T90 (p?=?0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p?=?0.036, p?=?0.036 and p?=?0.048).

Conclusions: Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT?+?HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.     

Neoadjuvant chemotherapy followed by radiotherapy and concurrent hyperthermia in patients with advanced-stage cervical cancer: A retrospective study

Objective: To evaluate the efficacy of neoadjuvant chemotherapy, followed by radiotherapy and concurrent hyperthermia (triple therapy) in patients with advanced-stage cervical cancer.

Methods: We selected 43 patients from our hyperthermia database, who were treated from 1996 to 2010 with triple therapy for large primary tumours (>6?cm) or para-aortic lymph node metastases. All patients received platinum-based chemotherapy followed by full-dose radiotherapy, brachytherapy and five hyperthermia treatments. The response was evaluated by gynaecological examination and a CT-scan. Time-to-event variables were estimated using the Kaplan Meier method and the Cox regression method.

Results: The mean age of the patients was 50.4 years (range 29–80). The median tumour size was 5.6?cm at diagnosis (range 2.6–8.2), positive lymph nodes were present in 90.7%. A total of 67% of the patients completed all six planned courses of chemotherapy. After completion of neoadjuvant chemotherapy, 83.7% of patients achieved a complete or partial response. At the end of treatment, the complete response rate was 81.4% (95%CI 69.2–93.5). Grade 2, 3 and 4 acute vascular toxicity occurred in 17 patients. The incidence of grade 3–4 haematological toxicity did not exceed 10% and no neutropenic fever occurred. For grade 1–2 renal toxicity, a switch to carboplatin was made (n?=?6). No acute grade 3–4 renal toxicity was observed. No treatment-related deaths were recorded. The median follow-up time was 29.8 months (range 4.1–124.8). Overall survival rate at 12 months was 79% (95%CI 57.4–92.3).

Conclusion: The triple therapy seems feasible and effective in the treatment of advanced-stage, high-risk cervical cancer. However, chemotherapy-induced vascular toxicity occurred frequently, which may warrant the use of prophylactic anticoagulants. We recommend a phase II trial for prospective confirmation for comparison with standard chemoradiation and the use of anticoagulants.     

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer

Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population.

Patients and methods: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21–35 days, followed immediately by chest wall MLHT for 1 hour at 40–42?°C. In the first trial 18 subjects received LTLD at 20, 30, or 40?mg/m²; in the second trial, 11 subjects received LTLD at 40 or 50?mg/m².

Results: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256?mg/m² of prior anthracyclines and a median dose of 61?Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50?mg/m², with seven subjects (24%) developing reversible grade 3–4 neutropenia and four (14%) reversible grade 3–4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30–66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses.

Conclusion: LTLD at 50?mg/m² and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.     

Enhanced drug delivery in rabbit VX2 tumours using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia

Purpose: The efficacy of anticancer drugs in solid tumours is impaired by their inability to reach all cancer cells in sufficient concentration to cause cytotoxicity. Hyperthermia-triggered release of drugs from thermosensitive liposomes can increase tumour drug concentration, but tumour-specific drug delivery requires precise temperature control, and effects on microregional distribution of anticancer drugs in tumours are unknown. Here we evaluate thermally triggered release of doxorubicin in a rabbit tumour model by comparing free versus thermosensitive liposomal doxorubicin administered systemically during magnetic resonance imaging (MRI)-controlled focused ultrasound hyperthermia.

Materials and methods: Twelve rabbits with a transplanted VX2 tumour in each thigh had a 10?mm diameter region in one tumour heated to 43°C using focused ultrasound with temperature control by MRI thermometry. Delivery of doxorubicin to tumours and normal tissues was quantified by fluorescence in tissue homogenates, and by fluorescence microscopy.

Results: Using thermosensitive liposomal doxorubicin (2.5?mg/kg), doxorubicin concentrations in heated tumours were 26.7 times higher than in unheated tumours (n?=?7, p?=?0.017, two-sided Wilcoxon signed-rank test). There was no significant enhancement with free doxorubicin in heated versus unheated tumours (n?=?3, p?=?0.5). With thermosensitive liposomes (8.3?mg/kg), fluorescence microscopy demonstrated increased doxorubicin fluorescence in heated versus unheated tumours, co-localised with nuclear staining throughout the tumour.

Conclusions: Localised image-guided delivery of high concentrations of doxorubicin to cancer cells was achieved non-invasively in implanted tumours with temperature-sensitive drug carriers and a preclinical MRI-controlled focused ultrasound hyperthermia system.     

Comparison of radiological and pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia (RHT) and study of response dependence on the applied thermal parameters in patients with soft tissue sarcomas (STS)

Purpose: To compare the radiological criteria RECIST, WHO, and tumor volume for evaluation of tumor response in patients with soft tissue sarcomas (STS) showing either good or poor pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia, and to examine the dependence of the findings on the applied thermal dose.

Materials and methods:19 patients with pathohistological complete response (no vital tumor cells, group 1) and 27 with pathohistological no response (<25% necrosis, group 2) were selected from our previous clinical trials. The change in tumor size before and after therapy was determined. Intratumoral temperature (T₉₀) and thermal dose (CEM 43°C T₉₀) were calculated for 13 patients.

Results: In the first group, 6 partial response (PR) and 13 stable disease (SD) according to RECIST, 7 PR and 12 SD according to WHO, 7 PR and 12 SD according to volumetric criteria were evaluated. In the second group, the results were 10 PR and 17 SD (RECIST), 9 PR and 18 SD (WHO), 8 PR and 19 SD (volume). The concordance of these criteria was 73.7% in group 1 and 74% in group 2. PR and SD were equally distributed in both groups (p > 0.421). Thermal parameters were not different between the groups (p > 0.327).

Conclusions: SD or PR in radiological response assessment does not correlate with the pathohistological response after neoadjuvant thermochemotherapy. RECIST, WHO and volumetric criteria for response evaluation in STS are in substantial agreement. For irregularly shaped lesions, volumetric criteria seem to be more appropriate.     

Hyperthermia classic commentary: ‘Arrhenius relationships from the molecule and cell to the clinic’ by William Dewey,Int. J. Hyperthermia, 10:457–483, 1994

Purpose: The management of head and neck cancer requires skilled integration of multiple modalities such as surgery, radiation, chemotherapy and hyperthermia. Chemoradiation can benefit from the addition of a proven modality such as hyperthermia in increasing survival, disease-free survival and quality of life without increasing the risk of complication.

The purpose of this retrospective study was to evaluate the feasibility and efficacy of hyperthermia with chemoradiation in advanced head and neck cancers.

Materials and methods: Between January 2004 and May 2008 40 patients with advanced head and neck cancers were allocated for hyperthermia with chemoradiotherapy. All patients underwent radiation on a telecobalt machine. A total dose of 70 Gy in 7 weeks with conventional fractionation was given with weekly chemotherapy of cisplatin 50 mg or paclitaxel 60 mg. Patients underwent hyperthermia on a radiofrequency machine at 8.2 MHz for 30 min at 41°–43°C with 10 min pre-cooling to 5°C.

Results: No patient had life-threatening complications. Only 38 out of 40 patients were eligible for assessment of immediate response as one patient died during treatment and the other did not complete treatment. Complete response was 76.23% (29 pts), and 23.68% (9 pts) had partial response. Overall survival by the Kaplan?Meir method was 75.69% at 1 year and 63.08% at 2 years.

No enhanced mucosal or thermal toxicities were documented as compared to our earlier experience with chemoradiation.

Conclusion: This retrospective analysis demonstrates the feasibility and efficacy of chemoradiation with hyperthermia in advanced head and neck cancer. The study is encouraging enough to start a randomised trial to compare chemoradiation with triple modality of treatment.     

A Phase II Neoadjuvant Trial of Sequential Nanoparticle Albumin-Bound Paclitaxel Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast Cancer

BackgroundNeoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer (LABC). Various regimens have explored the addition of newer agents to determine safety and efficacy. The aim of this phase II study was to incorporate albumin-bound paclitaxel with sequential anthracycline-based therapy.Patients and MethodsSixty-six women with LABC but without prior treatment and regardless of hormone receptor or HER2 status were enrolled. All patients were to receive albumin-bound paclitaxel weekly for 12 weeks followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Trastuzumab was allowed in HER2-positive (HER2⁺) patients. Primary endpoint was pathologic complete response (pCR; CR) in breast. Secondary endpoints included pCR in breast and nodes, clinical CR, 2-year progression-free survival, and overall survival.ResultsSixty-five patients received at least 1 dose of chemotherapy and were included in this analysis. Sixty-three patients completed 4 cycles of albumin-bound paclitaxel. Sixty-two patients received at least 1 dose of FEC, and 58 completed 4 cycles. Seventeen of 19 HER2⁺ women received trastuzumab. The pCR in breast was 29% (19 of 65). For the HER2⁺ subset, the pCR was 58% (11 of 19). Both albumin-bound paclitaxel and FEC were well tolerated. The most significant toxicities were grade 2/3 neuropathy (16%) with albumin-bound paclitaxel and grade 3/4 febrile neutropenia (7%) with FEC.ConclusionAlbumin-bound paclitaxel given over 12 weeks is well tolerated. Albumin-bound paclitaxel should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials.     

A phase II study of epirubicin, cisplatin and capecitabine as neoadjuvant chemotherapy in locally advanced or inflammatory breast cancer

AimTo assess the efficacy and safety of epirubicin, capecitabine and cisplatin (EXC) combination therapy in locally advanced breast cancer (LABC) and investigate the predictive value of selected biomarkers.MethodsNewly diagnosed LABC patients received four 3-weekly cycles of neoadjuvant EXC (epirubicin 60 mg/m² day 1; capecitabine 1000 mg/m² bid, days 1–14; cisplatin 60 mg/m²day 1) and two cycles of post-operative EXC.ResultsEight (17%) of 48 patients had inflammatory breast cancer. Overall response rate was 74% (95% CI: 59–86%), including complete responses in 13% (95% CI: 5–26%). Nine (22%; 95% CI: 11–38%) of 41 patients undergoing surgery achieved pathologic complete response (pCR), giving a pCR rate of 19% (95% CI: 9–33%) in the intent-to-treat population. Haematological toxicity was manageable. The most problematic toxicities were chemotherapy-induced nausea/vomiting and hypercoagulative disorders. None of the biomarkers investigated, including HER2, predicted response.ConclusionEXC showed high efficacy in LABC, with high clinical response and pCR rate. Nausea and vomiting were unexpectedly frequent, and more aggressive prophylaxis and management of these side effects is recommended in future studies of this combination.     

Preoperative weekly cisplatin,epirubicin, and paclitaxel (PET) improves prognosis in locally advanced breast cancer patients: an update of the Southern Italy Cooperative Oncology Group (SICOG) randomised trial 9908

BackgroundThe present article reports the updated survival outcome of the 200 patients enrolled in the Southern Italy Cooperative Oncology Group 9908 trial, which compared 12 weekly cycles of cisplatin–epirubicin–paclitaxel (PET) with 4 triweekly (once every 3 weeks) cycles of epirubicin–paclitaxel (ET) in patients with locally advanced breast cancer (LABC).MethodsThe effects of treatment, pathologically documented response (pathological response), pre- and post-treatment biomarkers on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) are analysed.ResultsAt a median follow-up of 74 (range 48–105 months) months, the 5-year RFS, DMFS, and OS were 64 % versus 53% (P = 0.11), 73% versus 55% (P = 0.04), and 82% versus 69% (P = 0.07) in PET and ET, respectively. At multivariate analysis, after adjusting treatment effect for pretreatment biomarkers, PET independently predicted better DMFS (P = 0.018) and OS (P = 0.03), whereas the impact on RFS was of borderline significance (0.057). PET treatment was significantly better than ET treatment only in high-grade or highly proliferating tumours. The better outcome in PET arm was the results of both the higher rate of patients with optimal pathological response and the lower rate of patients with biologically aggressive residual tumour.ConclusionsThe PET weekly regimen significantly improves both DMFS and OS in LABC patients, compared with the triweekly ET combination. The therapeutic advantage is limited to patients with highly aggressive tumours.