Combined Modality Approach Research Articles

A5-02: Targeted therapy against VEGFR and/or EGFR signaling with AZD2171, vandetanib, and gefitinib as part of a combined modality approach for the treatment of non-small-cell lung cancer

A5-02: Targeted therapy against VEGFR and/or EGFR signaling with AZD2171, vandetanib, and gefitinib as part of a combined modality approach for the treatment of non-small-cell lung cancer

Role of Surgery in Ovarian Carcinoma

Surgery plays a critical role in the optimal management of all stages of ovarian carcinoma. In apparent early-stage ovarian cancer, a comprehensive surgical evaluation allows stratification of patients into low- and high-risk categories. Low-risk patients may be candidates for fertility-sparing surgery and can safely avoid chemotherapy and be observed. Treatment of patients with high-risk early- or advanced-stage ovarian cancer usually requires a combined modality approach. Although it is well known that epithelial ovarian cancer is moderately chemosensitive, what distinguishes it most from other metastatic solid tumors is that surgical cytoreduction of tumor volume is highly correlated with prolongation of patient survival. Procedures such as radical pelvic surgery, bowel resection, and aggressive upper abdominal surgery are commonly required to achieve optimal cytoreduction. Women who develop recurrent disease may be eligible for a secondary cytoreductive surgery or may require a surgical intervention to palliate disease-related symptoms. For women at high risk of ovarian cancer, prophylactic bilateral salpingo-oophorectomy significantly reduces the incidence of this disease. The purpose of this article is to provide a comprehensive review of the surgical management of ovarian carcinoma. The roles of primary, interval, and secondary cytoreductive surgeries; second-look procedures; and palliative surgery are reviewed. The indications for fertility-sparing and minimally invasive surgery as well as the current guidelines for prophylactic surgery in high-risk mutation carriers are also discussed.

Sequencing chemotherapy, radiotherapy and surgery in combined modality treatment of stage III nonsmall cell lung cancer

Combined modality treatment is nowadays the standard of care in stage III nonsmall cell lung cancer, but the overall survival is still poor. Therefore, the challenge for clinicians is to optimize the combination of the treatment modalities. The review will focus on bimodality and trimodality approaches in stage III nonsmall cell lung cancer. Although the role of surgical resection in combined modality treatment is unclear, surgery will be discussed as a potential part of the treatment approach. Concurrent chemoradiotherapy has proven to be more effective than chemotherapy followed by radiotherapy. Full-dose consolidation chemotherapy after concurrent chemoradiation showed an improvement of survival in some studies. Consolidation chemotherapy is, however, difficult to administer owing to its toxicity in these complex regimens. Both the Eastern Cooperative Oncology Group and the Radiation Therapy Oncology Group showed similar survival after surgery compared to sequential or concurrent chemoradiotherapy; however, pneumonectomies and residual malignant mediastinal disease after induction treatment had a negative impact on survival. Concurrent chemoradiotherapy in combination with full-dose chemotherapy should be the standard of care for nonsmall cell lung cancer stage IIIA/B. Surgery is still experimental, but seems to be promising for certain subgroups of patients. More research has to be done in optimizing radiotherapy schedules and chemotherapy schemes in order to minimize toxicity. Novel therapeutics have to be introduced in the combined modality approach of stage III nonsmall cell lung cancer.

Neoadjuvant chemotherapy (CT) and postoperative chemoradiation (PCRT) in locally advanced, resectable, gastric cancer (LAGC). Preliminary results of a pilot study

15078 Background: Curative surgery is achieved in fewer than 50% of patients (pts) in LAGC. PCRT has shown significant improvement in disease control and survival but a limited impact on metastatic disease. To improve this results, a combined modality approach, including IORT, was planned. Methods: Pts with resectable LAGC (stage T3–4 and/or N+) were eligible. EGDS, EUS, abdomen CT were used for staging. 3 cycles of ECF (Epirubicin 50mg/mq, q 3wks; Cisplatin 60mg/mq, q 3wks and 21-day c.i. 5-FU 200mg/mq/day) were planned before radical surgery. IORT (10–15 Gy) included the high risk area defined at surgery. Postop RT included gastric area, anastomosis, duodenal stump and draining lymph node stations. RT (41.4–45 Gy in 23–25 fractions) and concurrent c.i. 5-FU (200 mg/mq/day) were administered. An oral caloric intake >= 1500 Kcal was provided. Results: From June 2001 to December 2006, 22 pts (13 M and 9 F), median age 64 yrs (41–74), with uT3N1 (21pts) and uT2N1 (1pt), entered the study. Tumor location was proximal in 10, lower in 8 and middle in 4 pts, respectively. All pts underwent the planned neoadjuvant ECF with a median of 3 cycles (range 3–5). Toxicity was moderate (<= grade 3) without toxic deaths: nausea and vomiting in 3%, mucositis in 3%, hematological in 7%. Twenty/22 pts underwent surgery (in progress in 2 pts) and 15 (75%) had R0 resection. Tumor downstaging was reported in 9/20 (45%) pts (8 pT2, 1pT1). IORT with 12.5 Gy (10–15 Gy) was given to 12 pts and 12 pts had PCRT. Eight pts were excluded from PCRT for postop complications (2 pts), disease progression (3 pts) or pN3 (3 pts). All 12 pts completed RT with a median dose of 41.4 Gy (41.4–56Gy), but 3 (25%) required RT interruption and 5 pts (40%) also definitive 5-FU interruption (overall PCRT compliance of 60%). Major toxicity from PCRT consisted of G3 asthenia and anorexia, requiring parenteral nutrition. Conclusions: Neoadjuvant CT confirmed feasible in LAGC and resulted in a substantial downstaging with a favourable R0 resection rate. Combined modality approach with IORT and PCRT appears attractive, but limited compliance to PCRT was observed. A definitive evaluation and data on disease control and survival will be reported. No significant financial relationships to disclose.

Patterns of practice in radiation therapy for non-small cell lung cancer among members of American Society of Therapeutic Radiology and Oncology

7693 Purpose: To investigate the dominant pattern of current practice in radiation therapy (RT) for lung cancer among members of American Society of Therapeutic Radiology and Oncology (ASTRO). Methods: A 35-item survey was designed by a panel of 8 board certified radiation oncologists regarding RT for lung cancer. Surveys were sent through email to 3,800 radiation oncologist members on September 10, 2006, with the results collected online on December 10, 2006. Here we report results on radiation decisions for non-small cell lung cancer (NSCLC). Results: The response rate was 19% (n = 727). The respondents saw an average of 8 consults (ranged 1–25) monthly during the survey time (summing up to a total of >60,000 new cases yearly). For stage I peripherally located NSCLC, 33%, 10% and 20% of respondents reported conventional fractionated, hypofractioned and stereotactic RT, respectively. Another 25% of respondents would have offered stereotactic RT if this technique were available at their center. For stage I centrally located tumors, 78% of respondents did not agree with, but 10% selected, stereotactic RT. For stage II and III, 76% of respondents selected 60–70 Gy in 1.8–2 Gy with chemotherapy. With regard to the combined modality approach for stage II and III disease, 76–77% of respondents selected concurrent chemoRT followed by adjuvant chemotherapy, and 11–16% sequential followed by concurrent chemoRT for patients with good performance status. For stage IV NSCLC with remarkable local disease, the consideration of RT ranged from 0 Gy, 3 Gyx10, 3 Gyx15, 2.5 Gyx20, to 2 Gyx30 in 27%, 17%, 8%, 13%, and 21% of respondents, respectively. Conclusions: The dominant pattern of practice for stage II/III disease is concurrent chemoRT, consistent with results of phase III trials. The treatment decisions for stage I and IV disease are diverse, partially due to technology advancement and the lack of large phase III trials. No significant financial relationships to disclose.

Modulation of Hypericin Photodynamic Therapy by Pretreatment with 12 Various Inhibitors of Arachidonic Acid Metabolism in Colon Adenocarcinoma HT‐29 Cells

One proposal to increase the efficiency of photodynamic therapy (PDT) is to accompany photosensitization with other treatment modalities, including modulation of arachidonic acid (AA) metabolism. The aim of this study was to evaluate the effectiveness of a combined modality approach employing 48 and 24 h pretreatment with various inhibitors of lipoxygenase (LOX; nordihydroguaiaretic acid, esculetin, AA-861, MK-886 and baicalein), cyclooxygenase (COX; diclofenac, flurbiprofen, ibuprofen, indomethacin, SC-560 and rofecoxib) and cytochrome P450-monooxygenase (proadifen) pathways, followed by hypericin-mediated PDT. Cytokinetic parameters like MTT assay, adherent and floating cell numbers, viability and cell cycle distribution analysis were examined 24 h after hypericin activation. Pretreatment of human colon cancer cells HT-29 prior to PDT with 5-LOX inhibitor MK-886 as well as 5, 12-LOX and 12-LOX inhibitors (esculetin and baicalein, respectively) resulted in significant and dose-dependent effects on all parameters tested. Pretreatment with diclofenac, flurbiprofen, ibuprofen and indomethacin, the nonspecific COX inhibitors, promoted hypericin-mediated PDT, but these effects were probably COX-independent. In contrast, application of SC-560 and rofecoxib, specific inhibitors of COX-1 and COX-2, respectively, attenuated PDT. Inhibition of P450 monooxygenase with proadifen implied also the significance of this metabolic pathway in cell survival and cell resistance to hypericin photocytotoxicity. In conclusion, our results testify that application of diverse inhibitors of AA metabolism may have different consequences on cellular response to hypericin-mediated PDT and that some of them could be considered for potentiation of PDT.

Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and results

Trimodality therapy seems to be the best treatment for malignant pleural mesothelioma (MPM). A large experience served to evaluate the efficacy of surgery followed by adjuvant chemo-radiotherapy. Trimodality therapy results have led us to test induction chemotherapy followed by EPP and adjuvant radiotherapy in stages I-III of MPM. The aim of our study was to evaluate the feasibility of this protocol and to estimate survival. From 2000 to 2003, 21 patients with MPM (14 males and 7 females, median age 59 years) were enrolled in the prospective study. Induction chemotherapy consisted of Carboplatin (AUC 5mg/mL/min on Day 1) and Gemcitabine (1000mg/m(2) on Days 1, 8, 15) for three to four cycles. EPP was performed 3-5 weeks after induction therapy, while post-operative RT was given 4-6 weeks after operation. Ten patients received three cycles of chemotherapy, 10 patients received four cycles and 1 patient had two cycles. Grades 3-4 haematological toxicity occurred in eight (38.1%) patients. Chemotherapy response rate was: complete 0%, partial 33.3% and stable disease 66.7%. Seventeen (80.9%) out of 21 patients underwent EPP with no intra or post-operative mortality with an overall major and minor morbidity rate at 52.4%. Median survival was 25.5 months, with an overall 1, 3 and 5-year survival rate of 71, 33 and 19%, respectively. In MPM, the combined modality approach using the Carboplatin/Gemcitabine combination as induction chemotherapy is feasible, with good results in terms of survival and morbidity. Our results are similar to those of other studies using a heavier modality treatment.

Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy.

There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003; Banu et al, 2005; Liang, 2005; Bria et al, 2006; Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51–0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32–1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI.

Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation

Purpose. To analyze the results of treatment and identify prognostic factors for primary squamous cell carcinoma (SCCA) of the vagina managed with radiotherapy at a single institution. Materials and methods. Seventy-eight patients were analyzed in this retrospective series. Mean characteristics: follow-up 89 months; age 65 years (range 33–99); tumor size 3.8 cm (0.3–10); treatment hemoglobin 12.4 g/dl (range 8.7–14.4); and tumor dose 72 Gy (range 6–127). In addition, 49% of our cohort had a prior hysterectomy. The FIGO stage distribution: I (42%); II (29%); III (17%); and IVA/B (11%). Sixty-two percent of patients were treated with a combination of external beam radiation (EBRT) and brachytherapy, 22% with EBRT alone and 13% with brachytherapy alone. Results. Kaplan–Meier (KM) 5-year pelvic control, distant metastasis free survival and disease specific survival probabilities: stage I, 83%, 100%, and 92%; stage II, 76%, 95%, and 68%; stage III, 62%, 65%, and 44%; and stage IV, 30%, 18%, and 13%. On multivariate analysis: stage; treatment hemoglobin; and prior hysterectomy were prognostic for DSS ( p < 0.05). The KM 5-year grade 3/4 (G3/4) complication free estimate of our cohort was 84%. G3/4 complications: tumor size and tumor dose were independently predictive ( p < 0.05). Conclusions. Radiotherapy as a single modality for early stage primary vaginal SCCA produces good results. Advanced stage disease necessitates a combined modality approach and/or new methods. Treatment Hg levels appear to be clinically significant and studies on correction of anemia during treatment are warranted.

Evidence-Based Recommendations for Local Therapy for Soft Tissue Sarcomas

There has been a gradual migration in the local treatment of soft tissue sarcomas from amputation and similar radical resectional approaches to more conservative, function-preserving surgery combined with radiotherapy. This progress has been made possible by small, single-institution, randomized trials that demonstrated the superiority of this more conservative, combined-modality approach. In the new millennium, attention has shifted to defining subsets of patients who might be adequately treated by surgery alone and defining the optimal sequence of surgery and radiation for patients who require both types of local therapy. There remains considerable discussion and debate surrounding the issue of pre- and postoperative chemotherapy for patients with localized soft tissue sarcomas. Adjuvant chemotherapy is a standard of care for adults who have the subtypes of soft tissue sarcomas that typically occur in pediatric patients (Ewing sarcoma, rhabdomyosarcoma), and just as clearly, adjuvant chemotherapy is not warranted in patients with low- and intermediate-risk disease (stages I and II). For patients with higher risk disease (stage III), the available randomized trials do not convincingly demonstrate a clinical benefit to adjuvant chemotherapy. As such, a complete accounting of potential risks and benefits is appropriate when discussing adjuvant chemotherapy with patients who have stage III disease.

Combining treatments for superior sulcus NSCLC

A combined-modality approach has been shown to improve survival in patients with superior-sulcus nonsmall-cell lung cancer (NSCLC; J Clin Oncol 2007; 25: 313–18). 110 patients (76 men and 34 women, aged 36–77 years) with superior sulcus NSCLC were treated with two cycles of cisplatin and etoposide concurrently with radiotherapy at 45 Gy. Six patients did not complete induction treatment, and a further nine were excluded because of disease progression. Of the 95 patients eligible for surgery, 88 underwent thoracotomy; two died postoperatively and 83 had complete resection. 49 patients received a further two cycles of chemotherapy, and six patients received one cycle. The median survival for all eligible patients was 33 months, and 94 months for those who had undergone complete resection. The researchers believe that local control and overall survival was substantially improved compared with previous studies of radiation and resection. Prudence Lam, Beth Israel Deaconess Medical Center, Boston, MA, USA, says: “these are encouraging results with the use of preoperative concurrent radiotherapy and cisplatin and etoposide, although it is still quite a toxic regimen. We have suggested that there is a need for early combined modality therapy. This study shows that this is benefi cial and that perhaps induction chemotherapy is not needed. I do think a multimodal approach is the most promising, although our fi rst priority must still be to decrease treatment toxicity. The most promising way to achieve this may be the use of novel, targeted, single agents in conjunction with radiation therapy”. Benedict Daly, Boston Medical Center, MA, USA, adds: “induction therapy for advanced potentially operable lung cancer has resulted in signifi cant increases in survival; however, the induction therapy in the current study uses lower radiation doses than more aggressive protocols that suggest even better results”.

Effective Neoadjuvant Therapy Prior to Metastasectomy

Effective Neoadjuvant Therapy Prior to Metastasectomy

Induction Chemoradiation and Surgical Resection for Superior Sulcus Non–Small-Cell Lung Carcinomas: Long-Term Results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160)

Traditional treatment for superior sulcus non-small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites. This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.

Radiation Therapy Can Still Be Used Safely in Combined Modality Approaches in Patients With Hodgkin's Lymphoma

In this issue of theJournalofClinicalOncology, Heidenreich et al 1 provide important information that further quantifies the cardiovascular risks associated with wide-field, high-dose radiation that was once used in the management of Hodgkin’s lymphoma. Their study suggests that Hodgkin’s lymphoma survivors who were treated with older radiation techniques are at high risk for heart disease and may therefore benefit from screening for cardiovascular disease. However, it is important to note that the results of this study may not be extrapolated to modern-day radiation treatments. Clinical trials have indicated that modern-day radiation therapy can be delivered safely and offers significant advantages in preventing disease recurrence. Therefore, these data should not influence decisions to use radiation treatment in the combined modality treatment of Hodgkin’s lymphoma. Unfortunately, it will take another generation of cured patients with Hodgkin’s lymphoma treated with these current radiation techniques before reports on radiation-induced cardiac toxicities become part of a historical background. The cardiovascular injury results presented in the Heidenreich et al 1 study needs to be understood in its appropriate historical context. The use of a radical approach of radiation therapy, which was pioneered in Stanford University in the 1960s by Henry Kaplan and Saul Rosenberg, offered patients with Hodgkin’s lymphoma the first hope for cure. 2 To compensate for the lack of systemic treatment, which became available in the early 1970s, radiation therapy utilized large fields that treated the entire lymphatic system to relatively high radiation dosages. Oftentimes, the entire heart was included in a component of the radiation fields, and much higher biologic doses were delivered compared with contemporary treatment. The cure rate of patients with Hodgkin’s lymphoma was further increased after the addition of chemotherapy combinations like MOPP (mechlorethamine, vincristine, procarbazine, and prednisone). 3 However, the toxicities from combining both modalities were significant. Many of the patients studied in the Heidenreich et al 1 report were treated in such a fashion. The realization of the high toxicity, including increased rates of cardiovascular injury and development of second malignancies, led to several randomized trials that shifted the practice of both medical and radiation oncologists. The toxic chemotherapy regimen, MOPP, was replaced by ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), which was found to be an equivalent, but less toxic, regimen. This was based on a study that compares six to eight cycles of MOPP with six to eight cycles of ABVD or to alternating ABVD and MOPP for 12 cylces. 4 Radiation oncologists also began a series of studies aimed at minimizing the toxicity of radiation therapy treatment. German Hodgkin’s Lymphoma Study Group (GHLSG) HD8 showed in a randomized trial that reducing the treatment volume from extended- to involved-field radiation therapy (IFRT), when combined with chemotherapy, is as effective as extended-field radiotherapy. 5 Furthermore, the long-term results of the European Organisation for Research and Treatment of Cancer (EORTC) H7 trial also showed that in combined-modality treatment (CMT), IFRT could safely replace subtotal nodal radiation for patients with clinical stage I and II Hodgkin’s lymphoma. 6

Adjuvant Therapy in Pancreatic Cancer

Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.

Concurrent chemoradiation for locally advanced oropharyngeal cancer

Purpose The aim of this study was to assess the survival, pattern of failure, morbidity, and prognostic factors of concurrent chemoradiation for locally advanced oropharyngeal cancer. Materials and methods A retrospective survey of patients who underwent chemotherapy and radiation for locally advanced oropharyngeal carcinoma at the Veteran Affairs North Texas Health Care System, Dallas, Tex. Results Between December 1999 and September 2004, 48 patients with locally advanced oropharyngeal cancer underwent concurrent chemotherapy and radiation. At a median follow-up of 23 months, the 3- and 5-year survival for the whole group were, respectively, 52% and 41%. Seventeen patients (35%) developed recurrences. There were 12 (25%) locoregional failures (6 local failures alone and 6 local and regional failures). Distant metastases developed in 8 patients (5 alone, 3 associated with locoregional failures). Four patients (8%) developed second primaries. No difference was observed in survival between base of tongue and tonsillar carcinoma ( P = .32). The 5-year survival for T1-T2 and T3-T4 tumors was, respectively, 84% and 27% ( P = .01). No patient with T1-T2 tumors developed distant metastases ( P = .04). Forty-five patients (94%) developed toxicity grade 3 to 4 (40 mucositis and 26 hematological). The median weight loss was 18 lb (range, 0–47 lb). Eight patients (16%) developed aspiration pneumonia during and after treatment. Five patients (10%) died of aspiration (2 during and 3 post treatment). Four patients (8%) developed esophageal strictures requiring repeated dilatations post treatment. Two patients had radionecrosis (1 soft tissue and 1 bone) requiring hyperbaric oxygen. Eighteen patients (37%) had prolonged tube feedings (>3 months) after treatments because of severe dysphagia or aspiration. Conclusion Concurrent chemoradiation provided good locoregional control for locally advanced oropharyngeal carcinoma. Patients with small tumors (T1-T2) had excellent survival. The poor prognosis associated with large tumors may be due to the risk of developing distant metastases. Acute and late toxicities remained significant. Aspiration pneumonia and severe dysphagia were the most prevalent complications of the combined modality approach.

Phase II Trial of Sequential Chemotherapy Followed by Chemoradiation, Surgery, and Postoperative Chemotherapy for the Treatment of Stage IIIA/IIIB Non-Small-Cell Lung Cancer

BackgroundThe optimal treatment of locally advanced non–small-cell lung cancer remains a challenge. Although the benefit of combined chemoradiation has been established, the optimal chemotherapy regimen, timing of full-dose chemotherapy, and how best to combine chemotherapy with radiation to maximize systemic and radiosensitizing effects remain unclear. Patients and MethodsTwenty-nine patients with pathologically confirmed stage IIIA/IIIB non–small-cell lung cancer were included in a phase II trial of sequential carboplatin/paclitaxel followed by chemoradiation, surgery, and postoperative gemcitabine. Twenty-five patients (86%) completed the concurrent chemotherapy and radiation therapy phase and were eligible for surgery. At restaging, 7 patients (21%) showed disease progression. Seventeen patients (59%) went on to surgery. Few were able to tolerate full postoperative chemotherapy. ResultsThe 1-year overall survival rate was 61%, with a 2-year survival rate of 56%. Median overall survival was 25.2 months. Seven of the patients are alive and without recurrence at the time of this writing. Our median follow-up time was 22.2 months. Reversible grade 3/4 toxicities were fairly common, experienced in 45% of patients. ConclusionOur results with this combined modality approach are comparable with those of previous, similar studies. Postoperative chemotherapy after initial combined modality therapy is often not feasible, reinforcing the value of initial systemic therapy. Long-term results are still suboptimal and await studies adding targeted therapies to our usual chemotherapy/radiation approaches.

Prognostic Markers of Local Relapse in Rectal Cancer: Are We Any Further Forward?

Rectal cancer is a major health problem affecting more than 100,000 patients in the United States and Europe each year. 1 Although it is a highly treatable and often curable disease when localized to the bowel, the prognosis for locally advanced disease varies, with local recurrence rates ranging from 4% to 40%; local recurrenceoftenisthecauseofseveremorbidityandpoormortalityin this disease. 2 Therefore, clinical approaches to prevent early recurrence are one of the major goals in the treatment of rectal cancer. The treatment for patients with clinically resectable, locally invasive rectal cancer has begun to evolve away from more radical surgical approaches such as abdominoperitoneal resection toward attempts at preservation of the anal sphincter and maintenance of anorectal function. 3 In the postoperative setting, there is clear evidence that adjuvant fluorouracil (FU) -based chemotherapy combined with radiotherapy significantly improves disease-free survival and overall survival in patients with rectal cancer. 4 More recently, several groups clearly have shown the benefit in reducing local recurrence rates and toxicity using neoadjuvant preoperative chemotherapy/radiotherapy combinations as opposed to adjuvant treatment. 5,6 Onesuchstudy,theGermanCAO/ARO/AIO-94rectalcancer group trial, randomly assigned 823 patients with T3/4 and/or node-positive rectal cancer to receive preoperative versus postoperative combined-modality therapy consisting of FU on weeks 1 and 5 and 50.4 Gy of concurrent radiation therapy. 4 There was a significant improvement in local recurrence rates (6% in the preoperative group v 13% in the postoperative group) as well as improvements in acute and long-term toxicity. Moreover, in the preoperative group, 39% of the patients initially requiring an abdominoperitoneal resection were able to undergo a sphinctersparing operation, whereas in the postoperatively treated group only 19% were eligible for a sphincter-sparing procedure. Although there was no difference in overall survival between the two groups, the preoperative combined-modality approach significantlyimprovedthechancesofsphincterpreservationandalsoled

Radioimmunotherapy of brain tumor

Despite years of intensive research, the prognosis of high-grade gliomas (HGG) remains poor, as these tumors are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies (MoAbs) in association with radioisotopes, in order to achieve better responses and prognosis. This article describes our experience in radioimmunotherapy (RIT) with MoAbs and tumor pre-targeting with the avidin-biotin system, either in systemic or locoregional administrations. This therapy offers the exciting prospect of increasing the specificity of tumor cell irradiation with radioisotopes. We suggest that RIT, both systemic and locoregional, should be used as part of a combined modality approach: in combination with surgery, radiotherapy and chemotherapy.

Modulation of integrin α5 in head and neck cancer cells by epidermal growth factor and its contribution to the malignant phenotype

15512 Background: The primary therapy for head and neck cancer consists of combination treatment with radiation and chemotherapy. While this combined modality approach is often curative, a significant fraction of patients have residual viable tumor cells after treatment that can result in progressive disease or relapse. We hypothesize that a significant contribution of cell survival results from interaction of cancer cells with the tumor microenvironment that includes soluble ligands of growth factor receptors and structural ligands of cell surface adhesion molecules. One of the growth factors with reported tumor survival effects is epidermal growth factor (EGF). We investigated the contribution of EGF to the relationship of 1483 head and neck cancer cells with their microenvironment. Methods: We treated 1483 head and neck cancer cells with variable concentrations of EGF from 0.1 to 20 nM and carried out western blots and flow cytometry to determine the expression of relevant integrins. Effects of interventions were evaluated by soft agar colony assays, proliferation and survival in tissue culture and adhesion to culture plates coated with integrin ligands. Results: Western blots demonstrated an EGF-induced increase in the expression of intgerin α5 but no change in the expression of integrins α2 or β1. The presence of dissolved fibronectin, a ligand of integrin α5β1, but not of collagen I, a ligand of integrin α2β1, provided a survival advantage to colonies in soft agar in EGF-treated cells. Experiments are determining whether this survival advantage translates to a shift in the dose-response curve to paclitaxel and ionizing radiation, on activation of caspases 3 and 8 and cleavage of poly (ADP- ribose) polymerase (PARP). These data are being correlated with EGF-induced modulation of adhesion to fibronectin, collagen and control plates. We have constructed adenoviral vectors expressing short hairpin RNA (shRNA) sequences to integrins α5 and α2 to confirm the role of integrin α5 expression in the EGF-induced modulation of survival. Conclusions: These data support a potential contribution to survival of head and neck cancer cells by modulation of integrins by EGF through interaction with their ligands in the microenvironment. No significant financial relationships to disclose.