Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs).

BACKGROUND: Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. METHODS: This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. RESULTS: Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. CONCLUSION: After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers.

BACKGROUND: Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. PATIENTS AND METHODS: Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0-1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m(2), and oxaliplatin at 75 mg/m(2) administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). RESULTS: A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4-10.5] and median survival 11.1 months (95% CI 8.2-15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3-4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%). CONCLUSION: The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Neoadjuvant therapy for organ preservation in head and neck cancer.

OBJECTIVES/HYPOTHESIS: We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies. METHODS: Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks. RESULTS: Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively. CONCLUSIONS: These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

NCCN Practice Guidelines for Cancer Pain.

The overall approach to pain management encompassed in these guidelines is comprehensive. It is based on objective pain assessments, utilizes both pharmacologic and nonpharmacologic interventions, and requires continual reevaluation of the patient. The NCCN Cancer Pain Practice Guidelines Panel believes that cancer pain can be well controlled in the vast majority of patients if the algorithms presented are systematically applied, carefully monitored, and tailored to the needs of the individual patient.

Chemotherapy in head and neck cancer. Overview of newer agents.

Several new chemotherapy agents show varying degrees of activity in head and neck cancer. The most extensively studied and most promising agents at this time are the taxanes, particularly paclitaxel. Its exact role in combination with other chemotherapeutic agents or with radiation is still being clarified in clinical testing, but it is certainly reasonable to use paclitaxel for palliation of metastatic or recurrent disease. Docetaxel is a more recently developed agent, and more information regarding its use in palliative therapy will be forthcoming as results from the international randomized trial become available. Gemcitabine has shown very modest activity when used as a single agent or in combination therapy, although further data from ongoing research have not yet been reported. It is an extraordinarily potent radiosensitizer in the head and neck, but unfortunately it appears to have a very narrow therapeutic ratio and should certainly not be used with radiation outside of a clinical trial with careful monitoring of toxicity. Topotecan does not appear to be a clinically useful single agent in treating head and neck cancer, and vinorelbine has shown minimal activity in the few clinical trials that have been conducted in head and neck cancer. Nedaplatin is a very new drug, and it is not possible to draw conclusions regarding its effectiveness until further evaluation has been completed. Continued investigation of new chemotherapeutic agents in head and neck cancer is needed.

Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy.

Malignant pheochromocytomas have exhibited partial responses to treatments with 131-I metaiodobenzylguanidine (MIBG) and with chemotherapy. The authors combined these two therapeutic methods to determine if beneficial effects from each would be additive. Patients with documented malignant pheochromocytomas were recruited with the intent of administering 131-I MIBG in three substantial amounts of radioactivity at 3-month intervals followed by a year of chemotherapy in which cyclophosphamide, dacarbazine, and vincristine were to be given in 21-day cycles. Six patients entered the protocol. After the 131-I MIBG treatments, three patients manifested declines in the presence of tumor (smaller tumor volume or abnormalities on bone and 131-I MIBG scans) and the function of tumor (decreased rate of normetanephrine excretion as the major index). Two patients completed at least 9 months of chemotherapy and showed further reductions in the presence and function of tumors and were classified as having partial responses. Progressive disease afflicted three of the other four subjects. Even though toxicity was minimal from 131-I MIBG, it was sufficient to force reduction in the dosages or duration of chemotherapy. A combination of 131-I MIBG treatments and chemotherapy produced additive effects in reducing malignant pheochromocytomas. Toxicity moderately curtailed the proposed chemotherapy protocol.

Concurrent chemoradiotherapy in head and neck cancer.

Historically, patients with unresectable head and neck cancer have been treated with definitive radiation therapy alone. In recent years, numerous trials have assessed the role of concurrent chemoradiation for these patients. Many of the larger, more recent trials are summarized here, with particular emphasis on the effect of combined therapy on survival and toxicity. Most of the trials have demonstrated modest benefit or a trend toward benefit in survival, progression-free survival, or local control in patients treated with concurrent chemoradiation. However, nearly every trial also showed increased toxicity with the more aggressive regimens. Two meta-analyses also show a small but significant improvement in survival and increased toxicity from a concurrent treatment approach. Therefore, patients should be well selected by their physicians to be able to tolerate the side effects of combined-modality therapy and must be well informed of the pros and cons of concurrent chemoradiation during the decision-making process.

Combined-modality treatment of esophageal cancer.

The use of chemotherapy and radiotherapy prior to surgery for patients with potentially resectable esophageal carcinoma has been investigated since the late 1970s, with trials yielding response rates approaching 50%. Although some of these trials suggested improved survival with preoperative chemoradiation plus surgery, as compared with historical controls treated with surgery or radiation alone, the question of survival benefit had to be addressed in prospective, randomized fashion. This review describes the experience with surgery or radiation alone vs preoperative chemoradiation in terms of long-term overall survival in the treatment of esophageal cancer.

Planned early neck dissection before radiation for persistent neck nodes after induction chemotherapy.

Optimal management of advanced neck metastases as part of an organ preservation treatment approach for head and neck squamous carcinoma (HNSC) is unclear. Since 1989, our management paradigm for patients on organ preservation was modified to incorporate planned early neck dissection before radiation therapy for patients who did not achieve a complete response (CR) of neck nodes after induction chemotherapy (IC). The purpose of this study was to determine if planned early neck dissection is a safe and effective approach in the management of advanced nodal disease as part of organ preservation. Fifty-eight consecutive patients with advanced HNSC who were entered in organ preservation trials using induction chemotherapy and radiation with surgical salvage were studied. Median follow-up was 26 months. Of the 58 patients, 71% were stage IV. Patients were grouped by nodal response to chemotherapy and N class, and were analyzed with respect to patterns of recurrence, complications, and survival. Overall, the rate of CR of neck nodes was 49%. Fifty-one percent had less than a complete response of neck nodes after IC and required planned early neck dissection. There were no significant differences in patterns of recurrence, complications, interval time to start of radiation, recurrence, or survival rates between the CR and less than CR groups. These data suggest that planned early neck dissection for patients with less than CR in the neck after IC is not detrimental with respect to neck relapse or overall survival. We believe that planned early neck dissection can be safely incorporated into future organ preservation treatment protocols for patients with advanced head and neck carcinoma.

Chemotherapy followed by accelerated fractionated radiation for larynx preservation in patients with advanced laryngeal cancer.

PURPOSE: Larynx preservation in advanced, resectable laryngeal cancer may be achieved using induction chemotherapy (CT) followed in responding patients by definitive radiation (RT). To address potential accelerated repopulation of clonogenic tumor cells during the prolonged total treatment time, we studied the feasibility of accelerated fractionated RT after CT. METHODS: Patients with advanced laryngeal cancer received two cycles of cisplatin 100 mg/m2 and fluorouracil (5-Fu) 1,000 mg/m2/d for 5 days. Responding patients received a third cycle after which those who had complete response or tumor down-staging to T1 proceeded with accelerated RT: 70.4 Gy delivered over 5.5 weeks. Patients who achieved a lesser response to CT underwent total laryngectomy and postoperative RT. RESULTS: Thirty-three patients were accrued. Three died during the course of CT and two declined definitive treatment after CT. Twenty-one patients had a major response to CT, 20 of whom received accelerated RT. Median weight loss during RT was 11%. Late severe morbidity was observed in five patients (25%). All four patients who underwent salvage laryngectomy after accelerated RT experienced major postoperative complications. The locoregional failure rate was 25%. The larynx was preserved in 48% of the total study population and in 80% of the patients irradiated according to the study protocol. CONCLUSION: Accelerated RT after CT as delivered in this study may increase both acute and long-term morbidity rates compared with studies using standard RT after CT. It did not seem to improve local/regional tumor control or survival despite stringent patient selection criteria.

Extranodal non-Hodgkin's lymphoma of the head and neck: presentation in the facial bones.

1. The most common site of ENL is the head and neck, with Waldeyer's ring and specifically, the tonsil, standing as the most frequent area of involvement. Most patients have intermediate or high-grade histologies. 2. Patients present with identical signs and symptoms as squamous cell carcinoma of the head and neck, underscoring the importance of a thorough otolaryngological examination. 3. Biopsy samples should be submitted as fresh and permanent samples specifically labeled for lymphoma evaluation. 4. A thorough and timely staging work-up should be conducted once a positive biopsy diagnosis is obtained. 5. Treatment consists of radiation and/or chemotherapy. Prognosis depends on histology, stage, and site of lesion. Newer treatment strategies may lead to improved survival for patients with head and neck NHL.

Nonpharmacologic pain management in terminal care.

The elderly, terminally ill patient often experiences physical, emotional, and spiritual pain. While pharmacology remains the cornerstone of pain management, non-pharmacologic methods can serve as adjuncts for pain relief, and also serve to enhance the overall quality of the patient's life. Neurostimulation, such as TENS unit, acupuncture, and massage, are based on the gate theory of pain control. These treatments can be useful particularly in muscular pain. Methods aimed at altering the patient's behavior or mood, such as imagery and aromatherapy, can provide an atmosphere of relaxation and comfort. For those patients with localized, particularly difficult to manage areas of pain, specialized neurolytic or neurosurgical methods are available. It would behoove health care practitioners who deal with pain management in elderly, dying patients to add some of these non-pharmacologic methods to their armamentarium of therapies.

Single-agent paclitaxel and paclitaxel plus ifosfamide in the treatment of head and neck cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide both have activity when evaluated as single agents in patients with advanced squamous cell carcinoma of the head and neck. The Eastern Cooperative Oncology Group completed the first phase II trial of paclitaxel in this population, observing a 40% response rate. Confirmatory trials are in progress in the United States and Europe. The Eastern Cooperative Oncology Group is currently evaluating high-dose (200 mg/m2) and low-dose (135 mg/m2) paclitaxel in combination with cisplatin to assess dose-response effects, toxicity, and efficacy. In an effort to identify an alternate to the cisplatin/5-fluorouracil regimen, investigators at Johns Hopkins and the University of Michigan are evaluating the combination of paclitaxel/ifosfamide. The regimen is paclitaxel 170 mg/m2 followed by ifosfamide 5 g/m2 divided over 3 days with mesna. Granulocyte colony-stimulating factor is started 24 hours after completion of the ifosfamide infusion. To date, 13 patients with recurrent and metastatic squamous cell carcinoma of the head and neck have been enrolled in the study. Eight patients have had prior chemotherapy as part of initial curative treatment or for recurrent disease. The best response observed in II evaluable patients is five partial responses, five stable diseases, and one disease progression. On progression, patients who have not been treated with cisplatin/5-fluorouracil receive that combination as second-line therapy. The occurrence of severe, life-threatening toxicity, primarily myelosuppression, has caused this study to be terminated. However, the responses observed have prompted an evaluation of the reverse sequence (ifosfamide followed by paclitaxel), which is now accruing patients.