Improvement In Local Control Rate Research Articles

In vitro evidence that combination treatment with anti-PD-1 and anti-CD47 immunotherapy may not be efficient in human soft tissue sarcoma.

e23560 Background: Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 70 histological subtypes of STSs, studies defining robust biomarkers of therapeutic value are lacking. Even with the improvements in local control rates, metastases and death occur in 50% of patients that are diagnosed with high-risk STSs. Across nearly all sarcoma types, macrophages dominate the immune landscape of STSs. While immune checkpoint inhibitors (ICIs) represent the major immunotherapeutic approach in malignancies with a high load of T cells, the anti-CD47 anti-cancer therapy mostly promotes macrophage-mediated phagocytosis. The efficacy of both therapies is critically dependent on the composition of the tumor microenvironment. Methods: In our study, we evaluated the potential additive effects of combining the anti-PD-1 immunotherapy and anti-CD47 immunotherapy ex vivo. The proportions of tumor cells and tumor-infiltrating lymphocytes were characterized ex vivo from resected tumors of 73 patients who underwent surgery for STS. The expression of CD47 on tumor cells was analyzed by immunohistochemistry. Cell suspensions were obtained from freshly resected tumors and the proportions of CD45+, CD45-, CD3+, CD4+, and CD8+ cells were measured by flow cytometry. The effect of the anti-PD-1 blockade, anti-CD47 blockade, and the combinatorial application of anti-PD-1 and anti-CD47 therapies on the immune cell activation in vitro was investigated by culturing of cell suspensions at a concentration 0.3x106/ul in the presence/absence of therapeutic monoclonal antibody (Nivolumab 2 ug/ml; anti-CD47 clone MIAP410 20ug/ml) and evaluated by a cytokine Luminex assay (Milliplex® MAP Human Cytokine Bead Panel (Sigma Aldrich) for TNFα, IFNγ, and IL-2 cytokines analysis). Results: The addition of anti-PD1 to CD3/CD28 stimulation drastically increased the production of all cytokines analyzed. This increase in pro-inflammatory cytokine secretion was even more pronounced after adding an anti-CD47 monoclonal antibody to the cell culture. However, a combinatorial application of anti-PD-1 and anti-CD47 agents in vitro was found to limit rather than potentiate the immune activation in the TME of human STS. On an individual level, the most profound response to anti-PD-1 was observed in high-grade leiomyosarcoma and the most profound response to anti-CD47 therapy was observed in an undifferentiated pleiomorphic sarcoma. Conclusions: Our data suggest that combinatorial strategies based on ICIs and anti-CD47 blockade may not provide the desired outcome in STSs. Both therapies, anti-PD-1, and anti-CD47 alone, could however bear a therapeutic potential in selected tumors after close evaluation of the CD47 and PD-1 expression status, as well as the extent of T cell/macrophage infiltration.

Magnetic Resonance Image Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: An Experience From a Tertiary Cancer Center in a Low and Middle Income Countries Setting

To determine the clinical impact of magnetic resonance image guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC) (stages II and III) in a tertiary care cancer hospital in a low and middle income countries setting. Ninety-four LACC patients enrolled in a prospective EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) protocol treated with external radiation therapy (45Gy in 25 fractions) with or without weekly cisplatin, followed by magnetic resonance IGABT (4 fractions of 7Gy), were analyzed in detail for dosimetric and clinical outcomes including late toxicities. The mean (± standard deviation) high-risk clinical target volume (HR-CTV) at the first session of brachytherapy and at the second session of brachytherapy for the current study cohort was 46.94±24.6cm3 and 42.7±22.5cm3, respectively, with mean minimum dose received by 90% volume (D90) of 88.3±4.4 equivalent 2-Gy fractionation (GyEQD2).At median follow-up (39months), the local control rate (LCR) and overall progression-free survival rate were 90.1%±3.4% and 72.1%±4.8%, respectively, with grade 3 bladder toxicity in 3% of patients and rectum toxicity in 9%. The LCR at 39months was significantly better in patients with stage IIB and IVA disease versus stage IIIB disease (100% vs 85%, P=.013). Local failures were limited to stage IIIB only and were associated with significantly larger HR-CTVs at brachytherapy (70±25.7cm3 vs 44.3±21.9cm3, P=.01) but not with HR-CTV D90 doses (which were similar for patients who had local failures vs those who did not: 86.3±3.9 α/β equal to 10 Gy (Gy10) vs 88.5±5 α/β equal to 10 Gy, P=.987). IGABT leads to a significant improvement in LCR and overall progression-free survival in LACC and should be considered for wider implementation in developing countries to improve outcomes.

P3-13-08: Survival Analysis and Recurrence Patterns in Locally Advanced Breast Cancer Following Neoadjuvant Chemotherapy and Preoperative Concurrent Chemo Radiotherapy.

Abstract Introduction: Although not widely used, preoperative concurrent chemo radiotherapy (CCRth) following poor response to neo adjuvant chemotherapy (CT) has been recently associated with an improved prognosis in patients with locally advanced breast cancer (LABC) and high recurrence risk, showing acceptable toxicity profiles, acceptable post surgical complication rates and increases in both clinical and pathologic response rates and local control rates. The objective of this study was to assess disease free survival (DFS), overall survival (OS) and patterns of recurrence in a cohort of patients with LABC treated with pre operative CCRth following poor response to neo adjuvant CT. Methods: This longitudinal study included a total of 287 patients with LABC treated with pre operative CCRth following poor response to neo adjuvant CT between February 2000 and December 2002. Demographic, clinical/pathologic, therapeutic and follow up data were collected from patient charts to determine DFS, OS and recurrence patterns. Results: Stages IIB, IIIA and IIIB accounted for 22.3, 37.6 and 40% of the population, respectively. Clinical response rates compared to pathologic response rates following anthracyline based CT and CCRth were minimal or stable in 16% vs 62.4%, partial in 53 vs 76.3% and complete in 30 vs 23.3%. No significant treatment related toxicities were identified. Post surgical complications included flap ischemia in 16%, partial flap necrosis in 18%, both ischemia and partial flap necrosis in 13.2% and partial wound dehiscence in 7.7%. With an average follow up of 64.1 ± 37.2 months, (0-126.3 months), 36.9% of the population relapsed and 55.1% remained disease free. With regard to recurrence patterns, 22.6% presented loco regional relapse, 67.7% recurred at a distant site and 9.8% showed presented both. Median OS was 64.2 months (0-126 months). Five and ten year survival probability was shown to be 75% and 60%, respectively. Conclusions Despite improvements in local control rates and overall outcomes with current therapeutic regimens combining chemotherapy, surgery, and radiotherapy, 30 to 40% of patients with locally advanced breast cancer develop post treatment loco regional recurrence and 5 year overall survival remains low (50%). Multimodal treatment integrating pre operative CCRth is therefore a valid alternative in the LABC setting, showing promising results in regard to OS, DFS and recurrence rates. Prospective clinical studies to evaluate its use are warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-08.

Physics Contributions and Clinical Outcome With 3D-MRI–Based Pulsed-Dose-Rate Intracavitary Brachytherapy in Cervical Cancer Patients

To assess the physics contributions and clinical outcome with three-dimensional magnetic resonance imaging-guided pulsed-dose-rate (PDR) intracavitary brachytherapy in cervical cancer patients. The data from 45 patients with primary locally advanced cervical carcinoma were analyzed. The median tumor cervical volume was 64.0 cm(3) (range, 3-178). Of the 45 patients, 24 (53%) had histologic and/or radiologic pelvic involvement. After pelvic with or without para-aortic concomitant chemoradiotherapy, a PDR brachytherapy boost was delivered to a three-dimensional magnetic resonance imaging-based clinical target volume, taking into account the dose-volume constraints for critical organs and optimization of the target volume coverage. At a median follow-up of 26 months (range, 9-47), the 2-year overall survival and disease-free survival rate was 78% and 73%, respectively. At the last follow-up visit, the disease of all patients remained locally controlled. Adding external beam radiotherapy and PDR using the equivalent dose in 2-Gy fractions model, the median dose received by 100% and 90% of the target was 54.4 Gy(alpha/beta10) and 63.5 Gy(alpha/beta10) for the intermediate-risk clinical target volume and 61.6 Gy(alpha/beta10) and 74.9 Gy(alpha/beta10) for the high-risk clinical target volume, respectively. Of the 45 patients, 23 and 2 developed acute Grade 1-2 and Grade 3 complications, respectively; 21 patients presented with delayed Grade 1-2 complications. One other patient presented with Grade 3 vesicovaginal fistula. No Grade 4 or greater complications, whether acute or delayed, were observed. Magnetic resonance imaging-guided PDR brachytherapy with optimization integrating the limits of tolerance to critical organs allows for excellent local control rates. Moreover, the present results have confirmed that the ability to optimize dwell times can contribute to an improvement in local control rates with a low level of late side effects.

Adjuvant treatment of locally-advanced head and neck tumours

Every year about 40,000 new patients are diagnosed as having squamous cell carcinoma of the head and neck (HNSCC) and nearly 60% of this population present with locally-advanced, but non-metastatic, disease. For many years, radiation therapy (RT) alone has been the standard non-surgical treatment for locally-advanced disease. Nevertheless, even the most effective RT regimens (the once-daily, hyperfractionation, or accelerated fractionation) show an improvement in local control rates of 50%-70% and disease-free survival rates of 30%-40%. These modest results have stimulated the search for novel strategies combining RT and chemotherapy. Several chemotherapeutic agents have been tested in combination with RT and cisplatin appears to be the most powerful agent in the treatment of locally-advanced head and neck tumours; as has been demonstrated in a large meta-analysis and, recently, in two multi-centred randomised trials. Based on these results, concurrent chemo-radiotherapy may be considered the standard adjuvant treatment for locally-advanced head and neck tumours.

Pathogenesis and treatment of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC), an endemic tumor in southern China, has three unique etiologic factors, including genetic susceptibility, chemical carcinogens, and association with Epstein-Barr virus (EBV) infection. Recent identification of critical genetic changes in this cancer has allowed the description of a multistep model for the pathogenesis of NPC. NPC is highly radiosensitive and chemosensitive. Attempts have been made to improve treatment results by integrating radiotherapy with some form of chemotherapy. Here, we review the current evidence available on the various chemotherapy-radiotherapy sequencing approaches and seek to define the optimal integration of radiotherapy and chemotherapy. Despite consistently high response rates to platinum-based neoadjuvant chemotherapy, none of six randomized studies of neoadjuvant and/or adjuvant chemotherapy showed any improvement in overall survival, although two did demonstrate significant improvement in local control rates and progression-free survival. However, three randomized studies of concurrent cisplatin-radiotherapy one with, and two without, adjuvant chemotherapy demonstrated significant improvement in progression-free survival and two of these have demonstrated improvement in overall survival. Preliminary data on the use of neoadjuvant chemotherapy followed by concurrent chemoradiation have been highly encouraging. Concurrent cisplatin-radiation with or without adjuvant chemotherapy should be considered as standard practice for locoregionally advanced NPC. The addition of neoadjuvant chemotherapy warrants further investigation and appears to be the most likely approach to further improve treatment results.

Rationale for chemoradiotherapy

The rationale for combining chemotherapy (CT) and radiotherapy (RT) is based mainly on two ideas, one being spatial cooperation and the other the enhancement of radiation effects. Spatial cooperation is effective if CT is sufficiently active to eradicate subclinical metastases and if the primary local tumor is effectively treated by RT. In this regard, no interaction between RT and CT is required, but differing toxicities are needed so that both modalities can be used at effective dosages. To enhance RT by CT, five major mechanisms of CT-RT interactions are required. CT can enhance RT effects by: (1) direct enhancement of the initial radiation damage by incorporating drugs into DNA, (2) inhibiting cellular repair, (3) accumulating cells in a radiosensitive phase or eliminating radioresistant phase cells, (4) eliminating hypoxic cells, or (5) inhibiting the accelerated repopulation of tumor cells. However, virtually all chemotherapeutic agents enhance radiation damage to normal tissues as well. Consequently, therapeutic benefits are only achieved if the enhanced tumor response is greater than that for normal tissues. Due to the complex interaction between CT and RT, the sequence of CT and RT is important. Clinical results of induction CT followed by RT are disappointing, and improvements in local control rates of RT by induction CT have not been observed. On the other hand, clinical trials, including metaanalyses, have clearly shown that CT given concurrently with RT results in improved local control and survival. Although acute toxicities are inevitably increased in concurrent chemoradiotherapy (CRT), no significant increases in late toxicities were reported in most clinical trials. Thus, a therapeutic benefit was observed with the use of concurrent CRT.

Brachytherapy boost for breast cancer: what do we know? Where do we go?

Since many years, Brachytherapy (BT) appears to play an important role in the treatment of many solid tumors. For breast cancer, BT is usually used as boost after postoperative external beam radiation therapy. In certain circumstances, BT can be used as sole radiation technique focalized on the tumor bed or more rarely, as second conservative treatment in case of local recurrence for woman refusing salvage mastectomy. Boost BT is most often applied via an interstitial technique while the dose rate can vary from low to high dose rate through pulse dose rate. All of those boost techniques were published and some of them compared the results obtained with BT and external beam electron therapy. The analysis of the published phase II and III trials was not able to show significant differences between the two boost techniques in term of local control as well as late skin side effects. However, we noted that the patients who received BT boost presented a higher risk of local recurrence compare to those treated with electron therapy, due to age, margin status or presence of extensive intraductal component. Only a phase III trial randomizing BT boost vs electron therapy boost could show a possible improvement of local control rate in the BT arm; however, this trial should enroll patients with a real high risk of local recurrence in order to take benefit from the dosimetric advantages of BT.

Soft tissue sarcomas.

Sarcomas are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm. They present most commonly as an asymptomatic mass originating in an extremity but can occur anywhere in the body, particularly the trunk, retroperitoneum, or the head and neck. Pretreatment radiologic imaging is critical for defining the local extent of a tumor, staging the disease, guiding biopsies, and aiding in diagnosis. Core-needle biopsy is the preferred biopsy technique for diagnosing soft tissue sarcomas. The American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcomas is based on histologic grade, the tumor size and depth, and the presence of distant or nodal metastases. Despite improvements in local control rates with wide local resections and radiation therapy, metastasis and death remain a significant problem in 50% of patients who present with high-risk soft tissue sarcomas. The most common site of metastasis is the lungs, and metastasis generally occurs within two to three years after the completion of therapy. Progress in the molecular characteristics of these tumors should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies.

Les traitements des cancers du nasopharynx : revue de la littérature

The conventional radiotherapy and the associated treatments improved the prognostic of nasopharyngeal cancer. A better selection of the patients who must have a more aggressive treatment also probably contributed to this improvement. Even if a relation could be found between the locoregional relapse rate and the distant relapse rate, these two events remain often independent. It results from it that the improvement of local control rate necessarily does not result in a better control of the disease. The patients with a locally advanced tumor, with or not an invasion of the base of the skull and/or neurological symptoms, must have an aggressive locally treatment. This probably includes the increase in dose delivered to the tumor via a more conformational radiotherapy, a brachytherapy, radiotherapy in stereotaxic conditions or other techniques. Dose within the tumor must be at least 70 Gy and the prophylactic nodal dose, at least 50 Gy. CT scan and MRI are essential for delineating the volumes of interest. The protocols of hyperfractionated radiotherapy did not give convincing results. Association with chemotherapy allowed, on the other hand, an improvement of the prognostic locally advanced cancers. Neoadjuvant or adjuvant chemotherapy was largely used to attempt to limit the risks of systemic dissemination, but an improvement of results was not clearly demonstrated. An improvement of the rates of survival and control of the disease, on the other hand, was observed in a certain number of studies with the chemoradiotherapy. In the event of locoregional relapse, an aggressive attitude can allow the control of the disease in the absence of systemic dissemination. Salvage treatments are, however, disappointing for when distant relapse occurs which suggests a difference in chemosensitivity between primary tumor and metastasis.

Combination of intraoperative radiation with resection of Cancer of the pancreas

The utility of intraoperative radiation therapy (IORT) as an adjuvant to the surgical resection of pancreatic cancer was studied. In 1976, as our first trial with this combined therapy, we applied IORT with 30 Gy of electron beam with 8 MeV to 15 patients to prevent local recurrence around the celiac axis and superior mesenteric artery after standard pancreatectomy. However, the combined therapy did not show an improvement in survival rate as compared to that of 19 patients with standard operation alone. Autopsies of three patients with the combined therapy did not show involved lymph nodes in the radiation field, but did show local recurrence around the aorta outside the radiation field. By comparison, we performed extended operation without IORT on nine patients, with almost complete dissection of the lymph nodes around the aorta, from the diaphragm to the level of the inferior mesenteric artery. This extended surgery did not improve survival time, and autopsy showed local recurrence in spite of the dissection of lymph nodes. Therefore, since 1984, we have performed IORT with a dose of 30 Gy, 9 MeV, and an extended radiation field from the diaphragm above to the inferior mesenteric artery below, following extended operation on 14 patients. The five-year cumulative survival rate of these cases was 33.3%. Four autopsies showed improvement of local control rate. No radiation-related complications were noticed postoperatively in patients who underwent extended IORT following pancreatectomy. We were encouraged to continue this approach for the cure of pancreatic cancer.

Current Management of Epidermoid Carcinoma of the Anal Canal

Treatment with a combination of radiation therapy and chemotherapy currently allows about 80 per cent of patients with epidermoid carcinomas of the anal canal to retain anorectal function, with about a 70 per cent likelihood of cure at 5 years. In these programs, radical surgery is reserved for the management of residual cancer or of radiation- or chemotherapy-induced anorectal toxicity. Several different schedules of combined modality therapy are in use, but an important common element in most schedules appears to be the concurrent administration of radiation and 5-fluorouracil. The improvement in local control rates with combined radiation and chemotherapy, as compared to most series treated by either radical radiation or radical surgery, has not been matched by a marked improvement in survival rates, and the risk of distant metastases does not appear to have been altered by these combinations. The success of the combinations in improving local control has allowed the indications for local excision to be defined more narrowly, and should reduce the risks of local recurrence associated with conservative surgery.

Twice-a-day radiation therapy for cancer of the head and neck.

Experience with the twice-a-day (BID) radiation therapy program for carcinomas of the head and neck areas is presented. The program consists of 1.6 Gy per fraction, two fractions per day with 4 hours between fractions, for 12 days, 5 days a week. After 38.4 Gy, the patient is given a 2-week break for symptoms of acute mucositis to subside and then twice-a-day radiation therapy is resumed with similar fraction size, two fractions a day for an additional 8 days to bring the total dose to 64 Gy. In some instances the primary site was boosted to an additional BID day with a maximum of 67.2 Gy. The spinal cord dose was limited to 38.4 Gy. A subset of 321 patients with squamous cell carcinoma of the oral cavity (61 patients), oropharynx (74 patients), and larynx (186 patients) treated by this program is reported. Marked improvement in local control rate at 36 months was observed for advanced tumors (T3 and T4) and with nodal disease by BID radiation therapy program as compared to conventional once-a-day (QD) radiation therapy program. The improvement in local control for early lesions, T1 and T2 when treated with BID radiation therapy was not noted to reach a statistically significant level. However, the successful results are quite different when compared to QD radiation therapy program, with a trend suggesting that significant difference might exist if additional patients had been entered into the studies. Acute mucosal reactions are generally more severe than those produced by QD continuous radiation therapy, but the duration of symptoms is shorter. Late effects on the normal tissues, as observed during the 4-year follow-up period, show no undue subcutaneous or mucosal reactions nor an increase in chondronecrosis or osteoradionecrosis. With the dose limited to 38.4 Gy in 2.5 weeks to the spinal cord, no case of radiation myelitis has been encountered.

Proton beam therapy.

Conventional radiotherapy with high energy photons and electrons has been remarkably successful in treating many localized tumors. However, if tumors are large or are located very close to critical normal structures, it becomes very difficult to deliver a tumoricidal dose to the entire tumor volume without compromising the function of these adjacent organs. In such situations the local tumor control probability may be enhanced by improving the therapeutic ratio, defined as the ratio of the probability of tumor control to the probability of normal tissue injury. An increase in the therapeutic ratio may be' obtained by choosing a radiation modality that is more effective at killing tumor cells than normal cells or by employing a type of radiation that provides improved dose distribution relative to that achievable by conventional radiation modalities. Historically, great improvements in local control rates of deep-seated tumors were obtained through an increase in the energy of photon treatment beams. This occurred both at the time of the introduction of the 60 Cobalt teletherapy unit into radiation therapy, replacing X-ray machines with maximum energies of about 300 kVp, and with the introduction of high energy electron accelerators capable of producing bremsstrahlung beams with energies in the supervoltage range, i.e. above 2 MeV, such as Betatrons and linear accelerators (4). Since the introduc­ tion of high energy photon beams, physicists have continued to try to improve dose distributions through the use of sophisticated treatment plans, including multiportal and rotational techniques, beam modifiers such as compensating wedges, etc, and by the development of computer­ directed dynamic therapy techniques (8).