Require Multimodality Treatment Research Articles

Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience

BackgroundPatients with locally advanced or recurrent rectal cancer often require multimodality treatment. Intraoperative radiation therapy (IORT) is a focal approach which aims to improve local control.MethodsWe retrospectively reviewed 42 patients treated with IORT following definitive resection of a locally advanced or recurrent rectal cancer from 2000–2009. All patients were treated with the Intrabeam® Photon Radiosurgery System (PRS). A dose of 5 Gy was prescribed to a depth of 1 cm (surface dose range: 13.4-23.1, median: 14.4 Gy). Median survival times were calculated using Kaplan-Meier analysis.ResultsOf 42 patients, 32 had recurrent disease (76%) while 10 had locally advanced disease (24%). Eighteen patients (43%) had tumors fixed to the sidewall. Margins were positive in 19 patients (45%). Median follow-up after IORT was 22 months (range 0.2-101). Median survival time after IORT was 34 months. The 3-year overall survival rate was 49% (43% for recurrent and 65% for locally advanced patients). Local recurrence was evaluable in 34 patients, of whom 32% failed. The 1-year local recurrence rate was 16%. Distant metastasis was evaluable in 30 patients, of whom 60% failed. The 1-year distant metastasis rate was 32%. No intraoperative complications were attributed to IORT. Median duration of IORT was 35 minutes (range: 14–39). Median discharge time after surgery was 7 days (range: 2–59). Hydronephrosis after IORT occurred in 10 patients (24%), 7 of whom had documented concomitant disease recurrence.ConclusionsThe Intrabeam® PRS appears to be a safe technique for delivering IORT in rectal cancer patients. IORT with PRS marginally increased operative time, and did not appear to prolong hospitalization. Our rates of long-term toxicity, local recurrence, and survival rates compare favorably with published reports of IORT delivery with other methods.

Neoadjuvant Therapy of Pancreatic Cancer: The Emerging Paradigm?

Pancreatic cancer remains one of the deadliest cancers due to difficulty in early diagnosis and its high resistance to chemotherapy and radiation. It is now clear that even patients with potentially resectable disease require multimodality treatment including chemotherapy and/or radiation to improve resectability and reduce recurrence. Tremendous efforts are currently being invested in refining preoperative staging to identify optimal surgical candidates, and also in developing various neoadjuvant or adjuvant regimens to improve surgical outcome. Although at present no studies have been done to directly compare the benefit of neoadjuvant versus adjuvant approaches, accumulating evidence suggests that the neoadjuvant approach is probably beneficial for a subset of the patient population, particularly those with borderline resectable disease in which complete surgical resection is almost certainly unachievable. In this article, we review the literature and rationales of neoadjuvant chemotherapy and chemoradiation, as well as their potential limitations and caveats. We also review the pathological findings following neoadjuvant therapies, and potential surgical complications that may be associated with neoadjuvant therapies.

Advanced gastric cancer: is there enough evidence to call second-line therapy standard?

Gastric cancer and cancer of the gastro-oesophageal junction (GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates. The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment, surgery, and radiotherapy. During the past decade considerable improvements were achieved by advanced surgical techniques, tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics. In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens (+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment. Despite these improvements, the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%. These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined. Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival. Moreover two recently published phase-3 studies support the use of second-line chemotherapy. A South Korean study compared either, irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival. In this "Field of Vision" article, we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.

Basaloid squamous cell carcinoma of the head and neck: report of 18 cases

To evaluate the clinical course and pathological characteristics of basaloid head and neck squamous cell carcinoma. Retrospective study of 18 cases of basaloid head and neck squamous cell carcinoma. Epidemiological, clinical and histological data were analysed and the Kaplan-Meier test used to estimate survival rates. The majority of lesions were at an advanced stage. These lesions were primarily localised in the larynx, hypopharynx and oropharynx. Routine pre-therapeutic assessment of squamous cell carcinoma was performed. Pathological diagnosis was difficult, although immunostaining was extremely useful. Positive staining for KL1, MNF 116 and 34βE12 and negative immunostaining for chromogranin and synaptophysin were also important factors in obtaining a definitive diagnosis. In the majority of cases, treatment involved surgery and radiotherapy. The five-year survival rate was 5 per cent. Basaloid squamous cell carcinoma is an uncommon head and neck lesion, with a challenging histological diagnosis. These lesions must be carefully monitored due to their aggressive course, and require multimodality treatment.

Value of PET-CT in Avoiding Multimodality Therapy in Operable Cervical Cancer

Posttreatment morbidity of multimodality therapy is substantially higher than either radical surgery or chemoradiation alone. Preoperative prediction of positive nodes limits optimal selection of the primary treatment modality. Computed tomography (CT) and magnetic resonance imaging have been tried for nodal assessment with modest results. Positron emission tomography (PET) combined with CT seems to be promising in this regard. This clinicopathologic study assesses the value of PET-CT in predicting nodal metastasis and avoiding multimodality therapy. Eighty patients with clinically operable cervical cancer underwent PET-CT during the preoperative evaluation followed by radical hysterectomy. Adjuvant chemoradiation was administered when indicated by histopathologic findings. The histopathologic finding of the pelvic nodes was correlated with the PET-CT findings for nodal metastasis. The chi2 test was used as the test of significance in the statistical analysis. Of 62 patients found PET-CT negative for nodal disease, 52 were true negative, whereas 10 were false negative on histopathologic examination. On the other hand, 14 of 18 patients found PET-CT positive for nodal disease were true positives. Specificity, sensitivity, positive predictive value, and negative predictive value of PET-CT in nodal assessment were found to be 92.8, 58.33, 77.7, and 83.8, respectively. Twenty-four patients (30%) with pelvic nodes positive for disease on histopathologic examination were administered adjuvant chemoradiation. Had we operated only on those patients who were PET-CT negative for nodal disease, 10 of 62 patients would have required adjuvant chemoradiation for positive nodes. Eighteen patients found PET-CT positive for nodal disease would be treated with primary chemoradiation. Inclusion of PET-CT in the decision-making process for primary surgery versus primary chemoradiation would allow 87.5% patients to receive a single modality of treatment (65%, only surgery; 22.5%, only chemoradiation) and the proportion of patients requiring multimodality treatment would reduce significantly from 30% to 12.5% (P < 0.01). Positron emission tomography combined with CT in the evaluation of operable cervical cancer can help in the optimal selection of patients for surgery such that multimodality treatment with its attendant increase in morbidity is avoided.

Temozolomide-induced inhibition of pituitary adenoma cells

Aggressive pituitary adenomas frequently require multimodality treatment including pituitary-suppressive medications, microsurgery, and radiation therapy or radiosurgery. The effectiveness of temozolomide in terms of growth suppression and decreased hormonal production is evaluated. Three pituitary adenoma cell lines--MMQ, GH3, and AtT20--were used. A dose escalation of temozolomide was performed for each cell line, and inhibition of cell proliferation was assessed using an MTT assay. Concentrations of temozolomide that produced statistically significant inhibition of cell proliferation for each cell type were identified. Extent of apoptosis for each selected temozolomide concentration was studied using TUNEL staining. The effect of temozolomide on prolactin secretion in MMQ and GH3 cells was also measured via ELISA. Significant inhibition of cell proliferation was noted for MMQ and GH3 cells at a concentration of 250 μM temozolomide. The AtT20 cells demonstrated statistically significant cell inhibition at a concentration of only 50 μM temozolomide (p < 0.05). Apoptosis significantly increased in all cell lines in as little as 24 hours of incubation at the respective temozolomide concentrations (p < 0.05). Prolactin secretion in the prolactin secreting MMQ and GH3 cell lines was inhibited by 250 μM temozolomide. Temozolomide inhibits cell proliferation and induces apoptotic cell death in aggressive pituitary adenoma cells. A reduction in hormonal secretion in prolactinoma cells was also afforded by temozolomide. Temozolomide may prove useful in the multimodality management of aggressive pituitary adenomas.

Abstract 215: CSE1L as a potential target to sensitize ovarian cancer cells to cisplatin

Abstract Human ovarian cancer is frequently (70% of cases) at advanced stage at presentation and requires multimodality treatment, consisting of cytoreductive surgery and chemotherapy based on platinum-drugs and taxanes. Patients are initially responsive to this treatment, but, in most cases, experience disease relapse because tumour cells acquire drug resistance. We demonstrated that the Hepatocyte Growth Factor (HGF) sensitizes to cisplatin (CDDP) and taxol an ovarian carcinoma cell line known to be resistant to platinum drugs: SK-OV-3, leading to an increased cancer cell death at very low drug doses both in vitro and in an animal model (Bardella et al., 2007; Rasola et al., 2004). This was an unexpected finding as HGF and its tyrosine kinase receptor, encoded by the MET oncogene, drives cell proliferation, survival and invasiveness during development and tumorigenesis. We also demonstrated that this effect is mediated by p38MAPK, which overwhelms the concomitant HGF activation of survival pathways, as the expression of a dominant negative form of p38MAPK abrogates the sensitization effect of HGF (Coltella et al., 2006). Using oligonucleotide microarrays, we studied the transcriptional responses of cell treated with CDDP in the presence or in the absence of HGF, and found that HGF pre-treatment modifies the transcriptional response to CDDP not only in SK-OV-3, but also in NIH-OVCAR-3, and TOV-21G ovarian cancer cells. The up- or down-modulation of the most differentially expressed genes found in common within these cell lines was reverted when the cells expressed a dominant negative form of p38MAPK, upholding once again the involvement of p38MAPK in this phenomenon. Among the top-ranked differentially expressed genes, which we identified, we focused functional studies on CSE1L/CAS. This gene is a nuclear transporter involved in both proliferation and apoptosis found to be amplified and over-expressed in ovarian cancer. Knocking down of CSE1L/CAS made ovarian cancer cells sensitized to low doses of cisplatin and triggered apoptosis while had no effect on other cancer and normal cell lines. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or to revert chemotherapy resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 215.

Poster 061: Recurrence of Minor Salivary Malignancies: An Analysis of the Mayo Clinic Experience

Minor salivary gland tumors account for approximately 15% of all salivary gland neoplasms. Approximately 50% of all minor salivary gland tumors are malignant. Treatment of these tumors has generally been associated with a favorable outcome. However, in many cases patients succumb to late regional and distant recurrence. Identification of patients at high risk for recurrence may help the surgeon appropriately tailor effective treatment. Using the Mayo Clinic Tumor Registry, patients who presented from 1993-2004 with minor salivary gland malignancies were identified. A retrospective chart review was performed to identify patient variables predictive of recurrence. Data was statistically analyzed using a univariate model to identify features predictive of tumor recurrence. One hundred and eleven patients with minor salivary gland malignancies were identified from the institution’s tumor registry. Of these, seventy-eight met inclusion criteria. Histologically, the population included mucoepidermoid carcinoma (41.5%), adenoid cystic carcinoma (34.5%), adenocarcinoma (17.5%), polymorphous low grade adenocarcinoma (3.5%), and acinic cell carcinoma (2.5%). Seventeen (21.8%) patients suffered a recurrence. The mean time to recurrence was 753 days and 87% of recurrence occurred within the first 3 years. Three tumors recurred locally, 8 regionally, and 6 distantly. Gender (p=0.1657), primary tumor location (p=0.3397) and grade (p=0.3958) were not associated with recurrence. Histologic subtype was suggestive of recurrence (p=0.0776). Advancing T stage (p=0.0003) and tumors requiring multimodality treatment (p<.0001) were statistically significant predictors of recurrence. The overall recurrence for this study population was 21.8%. While histologic subtype was suggestive of recurrence, extent of local disease and the need for postoperative adjuvant therapy were predictors of recurrence. Tumors amenable to surgical extirpation were the least recurrent. Therefore surgery is an essential component in the initial treatment of minor salivary gland malignancies and offers the most durable chance of cure in tumors amenable to resection.

Squamous cell carcinoma of the buccal mucosa: An aggressive cancer requiring multimodality treatment

In our clinical practice, we have observed a high incidence of locoregional failure in squamous cell carcinoma (SCC) of the buccal mucosa. We analyze our treatment results of this cancer and compare these results with those in the literature. We intend to define the pattern and incidence of failure of buccal cancer and provide information for the design of a better multimodality treatment. During the period from 1983 through 2003, 121 previously untreated patients with M0 stage SCC of the buccal mucosa were treated with a curative intent at our hospital. Twenty-seven patients received surgery alone, 36 had radiotherapy alone, and 58 underwent surgery plus postoperative radiotherapy. The 5-year locoregional control, overall survival, and cause-specific survival rates for all patients were 36.3%, 34.3%, and 36.9%, respectively. The locoregional recurrence rate was 57% for all patients, with 80% occurring in the primary site alone. Patients with T1-2N0 disease who received surgery alone still had a high local recurrence incidence of 41%. For patients with locally advanced disease, surgery plus postoperative radiotherapy achieved better overall survival and locoregional control rates than surgery alone or radiotherapy alone. T classification was the only prognostic factor affecting locoregional control and survival in the surgery alone group, whereas N classification and skin invasion predicted a poorer survival for the surgery plus postoperative radiotherapy group. SCC of the buccal mucosa is an aggressive cancer with a high locoregional failure rate even in patients with T1-2N0 disease. Possible reasons include inadequate treatment and an intrinsically aggressive nature. Postoperative radiotherapy has resulted in a better locoregional control rate for patients with T3-4 or N+ disease and should also be considered for patients with T1-2N0 disease for whom adjuvant therapy after radical surgery currently is not recommended by most guidelines.

Ewing′s sarcoma with cutaneous metastasis - a rare entity: Report of three cases

Ewing's sarcoma (ES) is a small round cell tumor, usually arising from flat bones and diaphyseal region of long bones. It is commonly found in the first two decades of life. It is curable when diagnosed in the localized stage and requires multimodality treatment. ES is a chemosensitive tumor. It metastasizes commonly to lung, pleura and other bones. Less common sites of metastasis are lymph nodes, CNS and liver. Skin metastasis is extremely uncommon. It occurs in up to 9% of all patients with cancer. Growth pattern of cutaneous metastasis is unpredictable and may not reflect that of primary tumor. We hereby report three cases of Ewing's sarcoma that developed skin metastasis.

Management of paranasal sinus malignancy

Malignancies of the nasal cavity and paranasal sinuses represent a wide spectrum of histologies, tissues of origin, and anatomic primary sites. The inherent difficulty in generalizing treatment approaches is obvious, given the numerous variables associated with the broadly-based term, paranasal sinus malignancy (PNSCa). Nevertheless, the majority of epithelial and salivary malignancies of this region (ie, squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, sinonasal undifferentiated carcinoma, and esthesioneuroblastoma) require surgical intervention as part of any treatment regimen. Recent trends have broadened the indications for chemotherapeutic and radiotherapeutic options in the management of advanced PNSCa. Nonepithelial malignancies, including the wide variety of sarcomas arising in this region, most commonly require multimodality treatment including chemotherapy, radiation, and/or surgery for definitive treatment. Moreover, the proximity of the nasal cavity and paranasal sinuses to structures including the orbit, dura, brain, cranial nerves, and carotid arteries mandates careful radiologic and neurologic evaluations throughout the course of the disease. Surgical advances now permit complex tumor removal and reconstruction surrounding these structures resulting in functional and cosmetic improvements when compared to earlier techniques. However, additional clinical trials are necessary to systematically evaluate the locoregional control, organ-preservation strategies, and survival related to the variety of treatments currently available.

Comorbidity in bipolar disorder: a framework for rational treatment selection.

Bipolar disorders are heterogeneous disorders often requiring multimodality treatment. The expanding pharmacopeia for bipolar disorders invites the need for a treatment framework that both recognizes and anticipates the multidimensionality and comorbidity of the illness. No available neurotherapeutic agent is singularly efficacious for the complete mélange of bipolar symptomatology. An apparent paradox has emerged in the management of bipolar disorder; whilst results from rigorous controlled monotherapy trials suggest that a disparate assortment of neurotherapeutic agents are efficacious in distinct phases of bipolar disorder, the majority of tertiary-treated bipolar patients receive polypharmacotherapeutic regimens. The evidentiary base for polypharmacotherapy is sparse and has recently become an area of active research focus. In the interim, clinicians are encouraged to invoke an organizational schema for the treatment of bipolar disorder that considers the spectrum of effectiveness of putative and established mood stabilizers. This schema should be further informed by the treatment data for comorbid and accessory conditions. The authors propose a schema to provide the impetus for further work in the area.

Otolaryngologic manifestations of PHACE syndrome

Two case reports of PHACE syndrome (posterior fossa malformations (P), hemangiomas (H), arterial anomalies (A), coarctation of the aorta and cardiac defects (C), and eye abnormalities (E)) are presented. Clinical characteristics consisted of cutaneous and airway hemangiomas, aortic coarctation, and left superior vena cava in one child and cutaneous and airway hemangiomas, sternal clefting, and supraumbilical raphe in the other child. Treatment modalities included systemic and intralesional steroids for cutaneous and airway hemangiomas, submucosal resection and laryngotracheal reconstruction for airway hemangiomas, repair of aortic coarctation, and laser treatment of cutaneous hemangiomas. PHACE syndrome poses a significant potential for airway compromise from hemangiomas, which may require multimodality treatment.

Axillary lymph node status, but not tumor size, predicts locoregional recurrence and overall survival after mastectomy for breast cancer.

To assess the significance of axillary lymph node status and tumor size for predicting locoregional recurrence (LRR) and overall survival after mastectomy for breast cancer and to discuss the utility of postmastectomy radiation therapy. Patients with locally advanced breast cancer require multimodality treatment combining chemotherapy (and/or hormonal therapy), surgery, and radiation. Randomized trials have demonstrated that postmastectomy radiation reduces LRR, but no overall survival benefit has been established. Criteria for accrual to the Alabama Breast Cancer Project (1975-1978) were female gender and T2-3 breast cancer with M0 status. Patients underwent a radical or a modified radical mastectomy. Node-positive patients received adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy or adjuvant melphalan. Patients were evaluated for LRR and overall survival based on the number of positive axillary lymph nodes and (in N0 patients) pathologic tumor size. Significance was determined using chi-square analysis. Survival curves were generated using the Kaplan-Meier method and were compared by log-rank analysis. After median follow-up of 15 years, neither type of surgery nor chemotherapy was shown to affect locoregional disease-free or overall survival. LRR rates were higher and overall survival rates were lower in patients with nodal involvement, while tumor size was not shown to significantly affect these rates. Patients with axillary lymph node metastases may benefit from postmastectomy radiation, but the use of postmastectomy radiation in N0 patients is not supported when it is based on tumor size alone.

Function and responsibility of an interdisciplinary tumor center. Need for a "cancer center" for multimodal therapy concepts

Cancer will be the leading cause of death in industrialized countries within the next few years. A successful treatment represents a great challenge within the next years and requires multimodality treatment approaches. An multidisciplinary tumour center is essential for coordination and communication between different departments and institutions and is important to maintain standards in diagnostic and therapeutic procedures. Two years ago, a cancer center was founded in Marburg. The central facility of its work is a twice weekly tumour conference, where patients requiring multimodality treatment approaches are presented and treatment procedures are fixed and documented. Furthermore, guidelines for diagnosis and treatment of the various cancer diseases will be established and the transfer of clinical and experimental research to the actual patient treatment is intended. A total of 407 patients were discussed within the first year. Leading cancer entities were lung cancer, colorectal cancer and tumours of the upper GI-tract. The tumour conference has improved the communication between all involved disciplines. The process of standardisation of diagnostic and therapeutic procedures is ongoing. The next step will be the documentation of the further follow up of all patients discussed in the tumour conference. In the communication between all disciplines involved in cancer patient care, success, be it a survival benefit or an improvement in quality of life, is most likely. All the described tasks are best organized within a cancer center.

Primary tumors of the mediastinum

Diagnostic and therapeutic approaches to mediastinal tumors have changed over the past three decades. We reviewed our recent experience with these tumors and assessed the role of a multidisciplinary treatment approach. A retrospective review of 124 patients with primary mediastinal tumors over a 25-year period. Median age was 35 years. Symptoms were present in 86 of 124 (69%) patients. One hundred and eleven of 124 (90%) tumors were malignant. Distant metastases were present at diagnosis in 14 of 124 (11%) patients. The most common tumor was thymoma (38/124, 31%), followed by germ-cell tumor (29/124, 23%), lymphoma (24/124, 19%), and neurogenic tumors (15/124, 12%). Seventy-four of 124 (60%) patients underwent resection, 88 (71%) received chemotherapy, and 97 (78%) received radiation therapy. Tumor recurrence occurred in 52% (47/91) of patients who initially had a complete resection or response to treatment. Median time to recurrence was 10 months. Overall median survival was 44 months. Metastatic disease at presentation (P = 0.02) and tumor recurrence (P = 0.00001) were the only significant independent predictors of survival on multivariate analysis. Malignant primary mediastinal tumors often require multimodality treatment. Despite improvements in survival with multimodality treatment, death from recurrent disease remains a problem.