Long-Term Results of Postoperative Hypofractionated Accelerated Breast and Lymph Node Radiotherapy (HypoAR) with Hypofractionated Boost.

We report long-term results (median follow-up 12 years) of hypofractionated accelerated radiotherapy (HypoAR) in patients treated with breast-conserving surgery. In total, 367 women were treated with HypoAR. Axillary and supraclavicular area (ASA) were treated in patients with involved nodes. In total, 290 patients (scheme A) received 3.5 Gy/day ×10 fractions (breast/ASA) followed by two 4 Gy fractions with electrons to the affected breast quadrant within 16 days. In total, 77 patients (Scheme B) received 2.7 Gy/day for 16 consecutive fractions (breast/ASA) within 22 days, while concurrently, the affected breast quadrant received an electron booster dose of 0.8 Gy for the first 13 fractions. Amifostine was offered to 252/367 patients. Early radiation toxicity was minimal. Regarding late toxicities, symptomatic breast edema was noted in 2.2%, asymptomatic breast fibrosis in 1.9%, and arm lymphedema in 3.7% of patients. Amifostine reduced early radiation dermatitis (p = 0.001). In total, 2.2% of patients developed contralateral breast and 1.6% other carcinomas. Locoregional recurrence (LR) occurred in 3.1% of patients (0% for in situ carcinomas). Positive margins after surgery, extracapsular node invasion, and HER2-enriched/triple-negative tumors were linked with significantly worse LR-free survival. The involvement of more than three nodes and luminal type other than A were independent prognostic variables of metastasis and death events. HypoAR delivering a biological dose of 50-52 Gy to the breast/ASA is a safe and effective therapy for patients treated with conservative surgery. The risk of carcinogenesis is low. Positive surgical margins, extracapsular node invasion, and HER2-enriched/triple-negative phenotypes appear as a cluster of features linked with a higher risk for locoregional relapse.

Is Locally Advanced Head-Neck Cancer One More Candidate for Accelerated Hypofractionation?

BACKGROUND/AIM: Hypofractionated accelerated radiotherapy (HypoAR) is widely applied for the treatment of early laryngeal cancer. Its role in locally advanced head-neck cancer (LA-HNC) is unexplored. PATIENTS AND METHODS: We present results of a prospective trial on 124 patients with LA-HNC, treated with radio-chemotherapy with three different HypoAR fractionations (3.5 Gy/day × 14-15 fractions, 2.7 Gy/day × 20-21 fractions, and 2.5 Gy/day × 21-22 fractions). RESULTS: Protraction of the overall treatment time due to oropharyngeal mucositis was enforced in 18/57 laryngeal, 6/19 nasopharyngeal, and 15/48 cancer patients with other tumors. Regarding late toxicities, laryngeal edema grade 3 was noted in 5/57 patients with laryngeal cancer, while severe dysphagia was noted in 4/124 and tracheoesophageal fistula formation in 1/124 patients. The complete response rates obtained were 73%, 84%, and 67% in patients with laryngeal, nasopharyngeal, and other tumors, respectively. The 3-year locoregional progression-free survival was 58%, 73%, and 55%, respectively. CONCLUSION: HypoAR chemoradiotherapy is feasible, with acceptable early and late radiotherapy toxicities, response rates and LPFS.

A pilot study on plasma levels of micro-RNAs involved in angiogenesis and vascular maturation in patients with breast cancer.

Micro-RNAs (miRNAs) have a complex role in carcinogenesis and tumour progression. Several miRNAs, such as miR-221, miR-27b and miR-132, have been implicated in the regulation of VEGF tumour angiogenic activity. In this pilot study, we assessed angiogenesis and DLL4+ vascular maturation index (VMI) in breast cancer tissues, in parallel with the plasma levels of the above-mentioned miRNAs. Significantly higher than control samples pre-operative levels were recorded in 10/11, 7/11 and 9/11 cases for the miR-221, miR-27b and miR-132, respectively. Seven days after surgery, a significant reduction of these miRNAs was noted in 6/11, 3/11 and 2/11 cases, respectively. High pre-operative levels of miR-27b were linked with node metastasis (p = 0.04). High pre-operative levels of miR-132 were linked with small tumours (p = 0.03) and her2 overexpression (p = 0.003). The DLL4+ VMI ranged from 26 to 69% (median 45%). Patients with poor DLL4+ VMI had significantly high pre-operative and post-operative levels of miR-221 (p = 0.01 and 0.02, respectively) and high post-operative levels of miR-132 (p = 0.02). It is concluded that angiogenesis-related miRs as detected in the plasma of patients may prove of a useful tool in the identification of patients with poor vascular maturation and high risk to develop metastasis. Whether such miRs may identify patients who would benefit from vascular normalization policies is a hypothesis that emerges from the current study.

Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis.

Delta-like ligand 4 (DLL4) is a ligand of the notch pathway. In tumor angiogenesis, DLL4 switches to vascular maturation by providing a negative feedback on VEGFR2 activity. We investigated the expression of DLL4 in the plasma and cancer tissues from breast cancer patients. Plasma samples were collected from 18 women with localized breast cancer, six women with benign breast disease and from six patients with widespread metastatic disease. DLL4 was assessed using ELISA and in cancer tissues using immunohistochemistry. Patients with metastatic breast cancer had significantly higher levels (median 6.7 ± 0.81 ng/ml) compared to patients with localized tumors (median 5.4 ± 0.70 ng/ml) (p = 0.005) and to patients with benign breast disease (median 4.3 ± 0.28) (p = 0.0003). High histology grade was significantly linked with higher plasma DLL4 levels (median 5.59 ± 0.62 vs. 5.12 ± 0.44 ng/ml; p = 0.01). Surgical removal of high-grade breast cancer resulted in significant reduction in DLL4 plasma levels (p = 0.003). DLL4 was expressed in tumor-associated vessels and in cancer cells. The ratio of DLL4+/CD31+ vascular density (VD) ranged from 23 to 88% (median 49 %). High DLL4 cancer cell expression and high DLL4+ VD were significantly linked with nodal involvement (p = 0.004 and 0.01, respectively). Linear regression analysis showed a significant association of DLL4 plasma levels with the percentage of DLL4+ cancer cells (p = 0.03, r = 0.50) and with DLL4+ VD (p = 0.0007, r = 0.60). It is concluded that DLL4 is overexpressed in breast cancer cells and breast cancer vasculature and is linked with nodal and distant metastasis. DLL4 plasma levels measurement can reliably estimate the total DLL4 breast cancer/vasculature activity.

Dose escalation of amifostine for radioprotection during pelvic accelerated radiotherapy.

OBJECTIVES: Experimental data suggest a dose-dependent efficacy of amifostine so that the low overall doses used in clinical trials may have masked the full potential of the drug. In this study, we report our experience with the role of escalated doses of amifostine in the protection of pelvic tissues. METHODS: A total of 354 patients with pelvic carcinomas recruited in prospective protocols applying hypofractionated and accelerated radiotherapy (HypoARC) supported with escalated daily doses of amifostine (0, 500, 750, 1000 mg subcutaneously) were analyzed. Conformal pelvic radiation delivered 14 daily fractions of 2.7 Gy within 18 days, whereas booster techniques increased the daily fraction to the target area to 3.4 Gy. RESULTS: Using a dose-individualization algorithm, 55.4% tolerated a daily amifostine dose of 1000 mg (level 3), 15.9% of 750 mg (level 2), and 17.5% of 500 mg (level 1), whereas intolerance induced amifostine interruption in 11.3% of the patients. Early grade 2/3 urinary frequency and dysuria grades 1 to 2 were significantly higher in level 0 patients (P = 0.04 and 0.01, respectively). The dose level (1 to 3) of amifostine did not influence the incidence of frequency/dysurea. Acute diarrhea and proctitis grade 2/3 were significantly lower only in level 3 (P < 0.0001 and 0.03, respectively). Dose level 3 was also linked to reduced incidence of late bladder and intestinal toxicities (P<0.05). Local control analysis showed no tumor protection effect of amifostine. CONCLUSIONS: Higher amifostine doses are tolerable by patients with pelvic malignancies and can better protect pelvic tissues against early and short-term late effects of radiotherapy.

Postmastectomy hypofractionated and accelerated radiation therapy with (and without) subcutaneous amifostine cytoprotection.

PURPOSE: Postmastectomy radiation therapy (PMRT) provides major local control and survival benefits. More aggressive radiation therapy schemes may, however, be necessary in specific subgroups, provided they are safely administered. We report the tolerance and efficacy of a highly accelerated and hypofractionated regimen (HypoARC). METHODS AND MATERIALS: One hundred twelve high-risk patients who had undergone mastectomy received 10 consecutive fractions of 3.5 Gy in 12 days (thoracic wall and axillary/supraclavicular areas). Two consecutive additional fractions of 4 Gy were given to the surgical scar area (electrons 8-10 MeV) and 1 3.5-Gy fraction to the axilla (in cases with extensive nodal involvement). A minimum follow-up of 24 months (median, 44 months) was allowed before analysis. Of 112 patients, 21 (18.7%) refused to receive amifostine, the remaining receiving tolerance-based individualized doses (500-1000 mg/day subcutaneously). RESULTS: By use of a dose individualization algorithm, 68.1%, 11%, and 18.7% of patients received 1000 mg, 750 mg, and 500 mg/day of amifostine. Patchy moist skin desquamation outside and inside the booster fields was noted in 14 of 112 (12.5%) and 26 of 112 (23.2%) patients, respectively. No case of acute pneumonitis was recorded. High amifostine dose offered a significant skin protection. Within a median follow-up time of 44 months, moderate subcutaneous edema outside and within the booster thoracic area was noted in 5 of 112 (4.4%) and 8 of 112 (7.1%) cases, respectively. Intense asymptomatic radiographic findings of in field lung fibrosis were noted in 4 of 112 (3.6%) patients. Amifostine showed a significant protection against lung and soft tissue fibrosis. A 97% projected 5-year local relapse free survival and 84% 5-year disease-specific survival were recorded. Lack of steroid receptor expression, simple human epidermal growth factor 2 positivity, or triple negative phenotype defined higher metastasis rates but had no effect on local control. CONCLUSIONS: PMRT with HypoARC showed an excellent early and short-term late toxicity profile, and amifostine further reduced early and late radiation sequelae. Encouraging local control rates are obtained in high-risk subgroups.

Postoperative pelvic hypofractionated accelerated radiotherapy with cytoprotection (HypoARC) for high-risk or recurrent prostate cancer.

AIM: We evaluated the feasibility and efficacy of postoperative hypofractionated and accelerated radiotherapy supported with amifostine cytoprotection (HypoARC) in patients with high-risk or recurrent prostate cancer. PATIENTS AND METHODS: Fourty-eight patients were recruited (median follow-up=41 months; range=12-84 months). Twenty-one received HypoARC after surgery and 27 at biochemical relapse. Radiotherapy was given with a 3D-conformal technique, delivering 2.7 Gy/day to the pelvis and 3.4 Gy to the peri-prostatic region for 14 fractions. A 15th fraction increased the total dose to the peri-prostatic area to 51 Gy (15×3.4 Gy) in 19 days. Amifostine was delivered before each radiotherapy fraction at an individualized (by tolerance) dose (0-1000 mg). RESULTS: Amifostine was delivered subcutaneously at 1000 mg in 35/48 (72.9%) patients, while lower doses were tolerated by the remaining patients. Twenty-six (54.2%) patients accomplished therapy without delays, while acute toxicities enforced 1 to 2 week delays in 11/48 patients (22.9%). Grade 2 proctitis was noted in 18.7%, while substantial bleeding occurred in 8.3% of patients. Grade 1 dysurea was noted in 27.1%, while diarrhea grade 2 appeared in 10.4% of patients. High amifostine dose was linked to a significant reduction of proctitis (p=0.04). No severe late toxicities were noted. Within a median of 41 months, 7/48 (14.6%) patients exhibited post-radiotherpy biochemical failure (in four due to metastasis). High-dose (1000 mg) amifostine defined a significantly better outcome (p=0.004), an effect sustained on multivariate analysis. CONCLUSION: Postoperative HypoARC is feasible with low-grade early and late toxicities, and emerges as a candidate for evaluation in randomized trials. The three-fold reduction of the overall treatment time renders HypoARC appealing for busy radiotherapy departments.

Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC).

INTRODUCTION: Radiotherapy (RT) for bladder cancer is as an effective alternative of cystectomy. Although rapid cancer clonogen repopulation contributes to radio-resistance, accelerated RT schemes based on ≤ 2 Gy fractions have failed to improve results. We suggest that accelerated hypofractionation (HypoARC) may be more effective, as it targets both tumors with increased clonogenic activity and tumors with low radio-sensitivity. PATIENTS AND METHODS: Eighty-two bladder cancer patients were treated with concomitant-boost conformal RT (14 × 2.7 Gy to the pelvis and 15 × 3.4 Gy to the bladder, within 19 days). Patients received a daily dose of 0/500/750/1,000 mg of amifostine using a dose-individualization algorithm (15.8%, 8.5%, 19.5%, and 56.1% of patients respectively). RESULTS: Early frequency grade 2-3, dysuria grade 1-2, diarrhea grade 2, and proctitis grade 2 appeared in 10.9%, 15.8%, 8.5%, and 13.4% of patients, respectively. The incidence of late sequelae was low (1.2% grade 2 frequency, 2.4% grade 2-3 dysuria, 2.4% grade 2-3 hematuria, 2.4% grade 2-3 incontinence). Patients receiving 1,000 mg of amifostine experienced significantly lower toxicities. The complete response rate, 3-year local control and disease specific survival rates were 86.6%, 56%, and 63%, respectively. CONCLUSIONS: HypoARC is linked with low early and late radiation toxicity, which is further reduced with the administration of high dose daily amifostine. The control and survival rates compare favorably with previously published data.

Treatment of low-risk prostate cancer with radical hypofractionated accelerated radiotherapy with cytoprotection (HypoARC): an interim analysis of toxicity and efficacy.

AIM: Radiobiological analysis of clinical data suggests that prostate cancer has a low α/ß ratio, implying that large radiotherapy fractions may better control the disease. Acceleration of radiotherapy may be also of importance in a subset of tumors. In this study we assessed the feasibility and efficacy of a highly accelerated and hypofractionated scheme of radiotherapy (HypoARC), for the treatment of localized low risk prostate cancer. PATIENTS AND METHODS: Fifty-five patients with prostate cancer (T1-2 stage, Gleason score <7 and prostate specific antigen (PSA) <10 ng/ml) were treated with localized conformal 4-field radiotherapy to the prostate and seminal vesicles: 51 Gy were delivered (3.4 Gy/fraction, within 19 days). The biological dose to the prostate ranged from 67.9-91.7 Gy. Amifostine (0-1000 mg depending upon tolerance) was delivered daily for cytoprotection. The median follow-up of patients is 30 (6-69) months. RESULTS: Early toxicity was overall low, proctitis being the most frequent side-effect (23.6% grade II). High dose amifostine significantly protected against proctitis (p=0.005). Grade 2 frequency and dysurea occurred in 1.8% and 3.7% of cases, respectively. There was no late toxicity ≥grade 2. Amifostine significantly protected against chronic frequency (p=0.02). Within a median follow-up of 30 months, one patient (1.8%) experienced a biochemical relapse. CONCLUSION: HypoARC is feasible and safe for patients with low-risk prostate cancer and, considering also the high efficacy noted, a strong rationale is provided for the further evaluation of HypoARC in randomized trials.

Concurrent administration of liposomal doxorubicin improves the survival of patients with invasive bladder cancer undergoing hypofractionated accelerated radiotherapy (HypoARC).

Cisplatin-based radio-chemotherapy is an effective alternative to cystectomy. The position of cisplatin has been challenged by novel drugs, while altered radiotherapy fractionation is also tested against conventional radiotherapy (RT). This study focuses on liposomal doxorubicin (LDox) in combination with an aggressive radiotherapy scheme (HypoARC). Eighty-two bladder cancer patients were treated with hypofractionated/accelerated RT (14×2.7 Gy to the pelvis and 15×3.4 Gy to the bladder, within 19 days), supported with amifostine (0-1,000 mg sc.). Forty-one out of 82 patients received concurrently LDox (20 mg/m2 for 3 bi-weekly cycles). LDox was free of haematological toxicity, erythordysestesia grade 1 being the only side effect noted in 5/41 patients. Although the incidence of early toxicities did not increase with LDox, delays of radiotherapy were increased (P=0.16). Amifostine significantly protected patients against toxicities and delays. There were no severe late complications recorded. Complete response rate was similar in both groups (85.4 vs. 87.8%). The 3-year local relapse-free survival was better in patients receiving LDox, but at a non-statistical level (64 vs. 47%; P=0.59). The 3-year survival rate was significantly improved in T2-4 stage patients receiving LDox (72.1 vs. 58.7%; P=0.04). Multivariate analysis did not identify any independent prognostic variables of relapse or death events. LDox is a well-tolerated drug during pelvic radiotherapy. Although its efficacy in terms of bladder tumour control rates could not be substantiated due to the high efficacy of the HypoARC regimen applied, survival was improved suggesting either a spatial co-operation or a radio-sensitization of pelvic in-field subclinical disease.

Concurrent liposomal cisplatin (Lipoplatin), 5-fluorouracil and radiotherapy for the treatment of locally advanced gastric cancer: a phase I/II study.

PURPOSE: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin). METHODS AND MATERIALS: Lipoplatin was given at a dose of 120 mg/m(2)/week, 5-fluorouracil at 400mg/m(2)/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. RESULTS: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. CONCLUSIONS: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.