Pelagia G. Tsoutsou

Optimal timing for adjuvant radiation therapy in breast cancer A comprehensive review and perspectives

PURPOSE The optimal sequence of modalities involved in breast cancer treatment with respect to radiotherapy and the maximum acceptable interval between radiotherapy and surgery need to be determined. DESIGN This review attempts a critical reading of the literature. RESULTS A delay of radiotherapy more than 8-12 weeks after surgery adversely affects local recurrence. Radiotherapy should be administered within 7 months after surgery, when chemotherapy is administered first. Several chemotherapy regimens can be safely administered concurrently with radiotherapy. The concurrent use of tamoxifen with chemotherapy should be avoided, but not with radiotherapy. Data is insufficient with regard to concurrent use of aromatase inhibitors with radiotherapy. The use of trastuzumab concomitantly with radiotherapy may enhance toxicities but may also improve its efficacy. CONCLUSIONS Although the issue of radiotherapy delay and that of sequence with chemotherapy or tamoxifen are clarified, the sequence of radiotherapy with aromatase inhibitors and trastuzumab needs to be defined. Individual radiosensitivity may influence toxicity. New biologic markers have to be determined in the future for tailoring radiotherapy in breast cancer.

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.

Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a Phase II study.

PURPOSE Bevacizumab has established therapeutic activity in patients with metastatic colorectal cancer, and anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models. We assessed the feasibility and efficacy of preoperative radiochemotherapy combined with bevacizumab in patients with rectal cancer. METHODS AND MATERIALS Nineteen patients with radiologic T3 and/or N+ rectal carcinoma were treated with preoperative conformal hypofractionated accelerated radiotherapy (3.4 Gy in 10 consecutive fractions) supported with amifostine (500-1,000 mg daily), capecitabine (600 mg/m(2) twice daily, 5 days per week), and bevacizumab (5 mg/kg every 2 weeks for 2 cycles). Surgery followed 6 weeks after the end of radiotherapy. A cohort of 14 sequential patients treated with the same regimen without bevacizumab was available for comparison. RESULTS Grade 2 or 3 diarrhea was noted in 7 of 19 patients (36.8%), which was statistically worse than patients receiving the same regimen without bevacizumab (p = 0.01). A higher incidence of Grade 2 or 3 proctalgia was also noted (21.1%) (p = 0.03). Bladder and skin toxicity was negligible. All toxicities regressed completely within 2 weeks after the end of therapy. Pathologic complete and partial response was noted in 7 of 19 cases (36.8%) and 8 of 19 cases (42.1%). Within a median follow-up of 21 months, none of the patients has had late complications develop and only 1 of 18 evaluable cases (5.5%) has had locoregional relapse. CONCLUSIONS Bevacizumab can be safely combined with hypofractionated radiotherapy and capecitabine as a preoperative radiochemotherapy regimen for patients with rectal cancer. The high pathologic complete response rates urges the testing of bevacizumab in randomized studies.

Radiochemotherapy With Cetuximab, Cisplatin, and Amifostine for Locally Advanced Head and Neck Cancer: A Feasibility Study

PURPOSE Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with amifostine, was herein investigated. METHODS AND MATERIALS Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m(2)/week) and cetuximab (standard weekly regimen) therapy. The dose of amifostine was individualized according to tolerance. RESULTS A high daily amifostine dose (750-1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) was tolerated by 34.9% of patients. A high amifostine dose was linked to reduced RT delays (p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.). CONCLUSIONS In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash. A high daily dose of amifostine allows completion of therapy with minor delays.

Optimal Sequence of Implied Modalities in the Adjuvant Setting of Breast Cancer Treatment: An Update on Issues To Consider

The adjuvant setting of early breast cancer treatment is an evolving field where different modalities must be combined to improve outcomes; moreover, quality of life of breast cancer survivors emerges as a new important parameter to consider, thus implying a better understanding of toxicities of these modalities. We have conducted a review focusing on the latest literature of the past 3 years, trying to evaluate the existing data on the maximum acceptable delay of radiotherapy when given as sole adjuvant treatment after surgery and the optimal sequence of all these modalities with respect to each other. It becomes evident radiotherapy should be given as soon as possible and within a time frame of 6-20 weeks. Chemotherapy is given before radiotherapy and hormone therapy. However, radiotherapy should be started within 7 months after surgery in these cases. Hormone therapy with tamoxifen might be given safely concomitantly or sequentially with radiotherapy although solid data are still lacking. The concurrent administration of letrozole and radiotherapy seems to be safe, whereas data on trastuzumab can imply only that it is safe to use concurrently with radiotherapy. Randomized comparisons of hormone therapy and trastuzumab administration with radiotherapy need to be performed.

Hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection as short adjuvant regimen after breast-conserving surgery: interim report.

PURPOSE Short radiotherapy schedules might be more convenient for patients and overloaded radiotherapy departments, provided late toxicity is not increased. We evaluated the efficacy and toxicity of a hypofractionated and highly accelerated radiotherapy regimen supported with cytoprotection provided by amifostine in breast cancer patients treated with breast-conserving surgery. METHODS AND MATERIALS A total of 92 patients received 12 consecutive fractions of radiotherapy (3.5 Gy/fraction for 10 fractions) to the breast and/or axillary/supraclavicular area and 4 Gy/fraction for 2 fractions to the tumor bed). Amifostine at a dose of 1,000 mg/d was administered subcutaneously. The follow-up of patients was 30-60 months (median, 39). RESULTS Using a dose individualization algorithm, 77.1% of patients received 1,000 mg and 16.3% received 750 mg of amifostine daily. Of the 92 patients, 13% interrupted amifostine because of fever/rash symptoms. Acute Grade 2 breast toxicity developed in 6.5% of patients receiving 1,000 mg of amifostine compared with 46.6% of the rest of the patients (p < .0001). The incidence of Grade 2 late sequelae was less frequent in the high amifostine dose group (3.2% vs. 6.6%; p = NS). Grade 1 lung fibrosis was infrequent (3.3%). The in-field relapse rate was 3.3%, and an additional 2.2% of patients developed a relapse in the nonirradiated supraclavicular area. c-erbB-2 overexpression was linked to local control failure (p = .01). Distant metastasis appeared in 13% of patients, and this was marginally related to more advanced T/N stage (p = .06). CONCLUSION Within a minimal follow-up of 2.5 years after therapy, hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection has proved a well-tolerated and effective regimen. Longer follow-up is required to assess the long-term late sequelae.

Spirometric values in Gypsy (Roma) children

Values of spirometry indices vary among subjects of similar age, gender and somatometrics but of different ethnic origins. Low socioeconomic status in childhood is inversely related to lung growth. The aim of this investigation was to assess spirometry values in Gypsy children and compare them to reported values for Caucasians. Gypsy students attending primary schools in Central Greece were recruited. Spirometry indices were measured using a portable spirometer. Regression analysis was applied to construct prediction equations for forced vital capacity (FVC) and other spirometric indices (FEV(1), FEF(50), FEF(25), FEF(25-75)) based on standing height. Predicted spirometric values were compared to values for Caucasians from published studies. In 152 children (ages 5-14 years; 57 girls) lung function increased linearly with height: spirometry index=intercept+[slopexheight], (r(2)=0.68 for FVC and FEV(1) in girls; r(2)=0.78 for FVC and r(2)=0.74 for FEV(1) in boys). Excluding boys-but not girls-in puberty increased fit for FVC (r(2)=0.83) and FEV(1) (r(2)=0.79). Mean predicted values were 5-10% lower than values for Caucasians. In Gypsy children, FVC and expiratory flow function increase linearly with standing height and predicted values are lower than those for Caucasians of similar height.

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.

Role of interleukin-10 in idiopathic pulmonary fibrosis

To the Editors: We have read with great interest the article of Bergeron et al. 1, concerning the cytokine profile in tissues of patients with idiopathic pulmonary fibrosis (IPF). We strongly agree that finding out the roles of cytokines in IPF might be the key in understanding the pathogenesis of the disease, as well as inventing new therapy strategies for this foetal and unresolved disorder. We think that outlining the cytokine profile in the tissues of those patients is very important, even though, as the authors also mention, the number of patients included in their study (five) was unfortunately small. We conducted a study in the University Hospital in Thessaly (central Greece), involving 20 patients with IPF and …

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: A Biomarker for Use Beyond Prognosis?

TO THE EDITOR: The report by Adams et al documents the important prognostic value of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), confirming previous observations by Loi et al in node-positive breast cancer (BC). These observations are in line with previous findings of spontaneous adaptive immune responses in other solid tumors and are timely, given the emergence of powerful approaches to mobilize and strengthen endogenous immunity against tumors. The implication to date is that TILs are evidence of immune recognition and attack and are directly responsible for the associated indolent course of disease. The important effect of TILs on the natural outcome of TNBC heralds new opportunities to personalize therapy. Important epidemiologic evidence of TILs being a potential predictive biomarker in BC has been gathered in human epidermal growth factor receptor 2 (HER2) –positive tumors, where a better response to anthracyclineonly chemotherapy was shown for TIL-rich tumors, and the benefit from trastuzumab was more pronounced in patients with preexisting TILs. We postulate that radiation therapy (RT) is an additional area of therapeutic opportunity exploiting antitumor immunity, where TILs can play an important biomarker role. Whether TIL-rich TNBC tumors exhibit different radiosensitivity properties is presently unknown. However, preexisting TILs independently predict tumor reduction and complete response to preoperative radiochemotherapy in other cancers, such as rectal cancer. RT has potent immunomodulatory effects, extensively studied by Adams et al, which can be quite sensitive to dose and schedule. Ablative hypofractionated RT was shown to generate strong CD8 T cell–dependent immunity, leading to increased local and distant control. Understanding in depth the effects of RT dose and schedule in the context of BC could result in better local control and eradication of micrometastases by mobilizing immunity. Bona fide immunomodulatory drugs will be an important part of the anticancer armamentarium, and the presence of TILs could be an important biomarker for the selection of patients. For example, in mouse models, the benefit of T-cell activation through checkpoint blockade combination is lost in tumors that have lost TILs. Accordingly, checkpoint blockade could be most beneficial in patients with TIL-rich TNBC tumors, a hypothesis that can be tested rapidly in the clinic. Two challenges remain: to standardize TILs as a biomarker for TNBC and to develop approaches to turn TIL-poor TNBC tumors into TIL-rich tumors. RT might be extremely efficient in driving a TIL response in tumors originally poorly infiltrated by TILs. For example, previous evidence in mice indicates that low-dose RT can reprogram the tumor microenvironment, with macrophage differentiation and vascular normalization that support enhanced T-cell infiltration. Dewan et al reported a significant interaction between RT and CTLA-4 blockade in a poorly immunogenic mouse model of breast cancer, but this interaction was observed only with hypofractionated RT. Optimaldose and -schedule RT approaches that synergize with antitumor immunity in tumors with pre-existing TILs or that can convert nonimmunogenic tumors to immunogenic tumors, eliciting a de novo T-cell infiltrate, must be thus discovered. The advent of high-precision RT technology (eg, intensity-modulated RT, stereotactic body RT) permitting precise irradiation of the tumor with maximum healthy tissue sparing has permitted testing different doses to maximize immune modulation of the tumor microenvironment. The relevance of pathologic complete response as a surrogate for survival after neoadjuvant RT and chemotherapy has been shown by Adams et al in a population of patients with BC who would today be defined as having TNBC or being HER2 positive. Pathologic response, along with quantification of TILs before and after RT, could be used as a surrogate end point in rapid window studies in the neoadjuvant setting, testing the interactions between different RT doses and schedules with TILs in TNBC and analyzing separately TIL-rich and TIL-poor tumors. After optimal doses have been identified, rational combinations can be developed using immunomodulatory high-precision stereotactic body RT with appropriate chemotherapy and pharmacologic interventions that enhance the function of antigen-presenting cells or T cells to identify optimal schemes for TNBC. The availability of tools to activate antigen-presenting cells (eg, CD40 or Toll-like receptor agonists), as well as T cells (eg, checkpoint blockade), today affords us numerous opportunities to develop well-tolerated and effective combinations for TIL-rich or TIL-poor TNBC, an area in great need for therapeutic innovation.